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[ { "id": "15825391__text", "type": "abstract", "text": [ "Molecular basis for the selective toxicity of amphotericin B for yeast and filipin for animal cells. Among the polyene antibiotics, many, like filipin, cannot be used clinically because they are toxic; amphotericin B, however, is useful in therapy of human fungal infections because it is less toxic. Both the toxicity of filipin and the therapeutic value of amphotericin B can be rationalized at the cellular and molecular level by the following observations: (i) these polyene antibiotics showed differential effects on cells; filipin was more potent in lysing human red blood cells, whereas amphotericin B was more potent in inhibiting yeast cell growth; and (ii) the effects of filipin were more efficiently inhibited by added cholesterol, the major membrane sterol in human cells, whereas the effects of amphotericin B were more efficiently inhibited by ergosterol, the major membrane sterol in yeast. The simplest inference is that the toxicity and effectiveness of polyenes are determined by their relative avidities for the predominant sterol in cell membranes." ], "offsets": [ [ 0, 1069 ] ] } ]

[ { "id": "15825391_T1", "type": "DRUG", "text": [ "amphotericin B" ], "offsets": [ [ 46, 60 ] ], "normalized": [] }, { "id": "15825391_T2", "type": "DRUG_N", "text": [ "filipin" ], "offsets": [ [ 75, 82 ] ], "normalized": [] }, { "id": "15825391_T3", "type": "GROUP", "text": [ "polyene antibiotics" ], "offsets": [ [ 111, 130 ] ], "normalized": [] }, { "id": "15825391_T4", "type": "DRUG_N", "text": [ "filipin" ], "offsets": [ [ 143, 150 ] ], "normalized": [] }, { "id": "15825391_T5", "type": "DRUG", "text": [ "amphotericin B" ], "offsets": [ [ 202, 216 ] ], "normalized": [] }, { "id": "15825391_T6", "type": "DRUG_N", "text": [ "filipin" ], "offsets": [ [ 322, 329 ] ], "normalized": [] }, { "id": "15825391_T7", "type": "DRUG", "text": [ "amphotericin B" ], "offsets": [ [ 359, 373 ] ], "normalized": [] }, { "id": "15825391_T8", "type": "GROUP", "text": [ "polyene antibiotics" ], "offsets": [ [ 471, 490 ] ], "normalized": [] }, { "id": "15825391_T9", "type": "DRUG_N", "text": [ "filipin" ], "offsets": [ [ 529, 536 ] ], "normalized": [] }, { "id": "15825391_T10", "type": "DRUG", "text": [ "amphotericin B" ], "offsets": [ [ 594, 608 ] ], "normalized": [] }, { "id": "15825391_T11", "type": "DRUG_N", "text": [ "filipin" ], "offsets": [ [ 682, 689 ] ], "normalized": [] }, { "id": "15825391_T12", "type": "DRUG", "text": [ "amphotericin B" ], "offsets": [ [ 809, 823 ] ], "normalized": [] } ]

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[ { "id": "1089817__text", "type": "abstract", "text": [ "Ascorbic acid and the common cold. Evaluation of its efficacy and toxicity. We reviewed the clinical data relating to the efficacy and safety of pharmacologic doses of ascorbic acid in the prevention and treatment of the common cold. Although one study tentatively supports the hypothesis that such doses of ascorbic acid may be efficacious, a second study by the same group did not confirm the significant findings, and no clear, reproducible pattern of efficacy has emerged from the review of all the evidence. Similarly, there is currently little adequate evidence on either the presence or the absence of serious adverse reactions to such doses of ascorbic acid, although many such reactions have been hypothesized. The unrestricted use of ascorbic acid for these purposes cannot be advocated on the basis of the evidence currently available." ], "offsets": [ [ 0, 846 ] ] } ]

[ { "id": "1089817_T1", "type": "DRUG", "text": [ "Ascorbic acid" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "1089817_T2", "type": "DRUG", "text": [ "ascorbic acid" ], "offsets": [ [ 168, 181 ] ], "normalized": [] }, { "id": "1089817_T3", "type": "DRUG", "text": [ "ascorbic acid" ], "offsets": [ [ 308, 321 ] ], "normalized": [] }, { "id": "1089817_T4", "type": "DRUG", "text": [ "ascorbic acid" ], "offsets": [ [ 652, 665 ] ], "normalized": [] }, { "id": "1089817_T5", "type": "DRUG", "text": [ "ascorbic acid" ], "offsets": [ [ 744, 757 ] ], "normalized": [] } ]

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[ { "id": "7654327__text", "type": "abstract", "text": [ "Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. 1,25-Dihydroxycholecalciferol D3 (1,25(OH)2D3), the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have shown that MCF-7 cells treated with 100 nM 1,25(OH)2D3 exhibit characteristic apoptotic morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, nuclear matrix protein reorganization) within 48 h. In the experiments reported here, we examined the interactions between 1,25(OH)2D3 and the antiestrogen 4-hydroxytamoxifen (TAM), which also induces apoptosis in MCF-7 cells. Our data suggest that TAM significantly potentiates the reduction in cell number induced by 1,25(OH)2D3 alone. Combined treatment with 1,25(OH)2D3 and TAM enhances the degree of apoptosis assessed using morphological markers that identify chromatin and nuclear matrix protein condensation. We have selected a subclone of MCF-7 cells resistant to 1,25(OH)2D3 (MCF-7D3Res). These cells express the vitamin D receptor and exhibit doubling times comparable to the parental MCF-7 cells, even when grown in 100 mM 1,25(OH)2D3. Treatment of both parental and resistant MCF-7 cells with TAM induces apoptosis and clusterin. These data emphasize that apoptosis can be induced in MCF-7 cells either by activation of vitamin-D-mediated signalling or disruption of estrogen-dependent signalling." ], "offsets": [ [ 0, 1427 ] ] } ]

[ { "id": "7654327_T1", "type": "GROUP", "text": [ "vitamin D" ], "offsets": [ [ 61, 70 ] ], "normalized": [] }, { "id": "7654327_T2", "type": "GROUP", "text": [ "antiestrogens" ], "offsets": [ [ 75, 88 ] ], "normalized": [] }, { "id": "7654327_T3", "type": "DRUG", "text": [ "25-Dihydroxycholecalciferol D3" ], "offsets": [ [ 92, 122 ] ], "normalized": [] }, { "id": "7654327_T4", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 124, 135 ] ], "normalized": [] }, { "id": "7654327_T5", "type": "GROUP", "text": [ "vitamin D" ], "offsets": [ [ 163, 172 ] ], "normalized": [] }, { "id": "7654327_T6", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 303, 314 ] ], "normalized": [] }, { "id": "7654327_T7", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 540, 551 ] ], "normalized": [] }, { "id": "7654327_T8", "type": "GROUP", "text": [ "antiestrogen" ], "offsets": [ [ 560, 572 ] ], "normalized": [] }, { "id": "7654327_T9", "type": "DRUG_N", "text": [ "4-hydroxytamoxifen" ], "offsets": [ [ 573, 591 ] ], "normalized": [] }, { "id": "7654327_T10", "type": "DRUG_N", "text": [ "TAM" ], "offsets": [ [ 593, 596 ] ], "normalized": [] }, { "id": "7654327_T11", "type": "DRUG_N", "text": [ "TAM" ], "offsets": [ [ 666, 669 ] ], "normalized": [] }, { "id": "7654327_T12", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 736, 747 ] ], "normalized": [] }, { "id": "7654327_T13", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 779, 790 ] ], "normalized": [] }, { "id": "7654327_T14", "type": "DRUG_N", "text": [ "TAM" ], "offsets": [ [ 795, 798 ] ], "normalized": [] }, { "id": "7654327_T15", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 990, 1001 ] ], "normalized": [] }, { "id": "7654327_T16", "type": "DRUG", "text": [ "1,25(OH)2D3" ], "offsets": [ [ 1152, 1163 ] ], "normalized": [] }, { "id": "7654327_T17", "type": "DRUG_N", "text": [ "TAM" ], "offsets": [ [ 1223, 1226 ] ], "normalized": [] }, { "id": "7654327_T18", "type": "GROUP", "text": [ "vitamin-D" ], "offsets": [ [ 1350, 1359 ] ], "normalized": [] }, { "id": "7654327_T19", "type": "GROUP", "text": [ "estrogen" ], "offsets": [ [ 1397, 1405 ] ], "normalized": [] } ]

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[ { "id": "7654327_R1", "type": "EFFECT", "arg1_id": "7654327_T11", "arg2_id": "7654327_T12", "normalized": [] }, { "id": "7654327_R2", "type": "EFFECT", "arg1_id": "7654327_T13", "arg2_id": "7654327_T14", "normalized": [] } ]

[ { "id": "2981680__text", "type": "abstract", "text": [ "Intestinal absorption of arsenate in the chick. The intestinal absorption of arsenate(As(V)) has been investigated in the chick by means of the in situ ligated duodenal loop technique. By this procedure, it was observed that arsenate is rapidly and essentially completely absorbed (80-95%) from the lumen at As(V) concentrations up to 5 mM, declining to about 50% absorption at 50 mM. Transfer from the intestinal lumen to the mucosal cells at low As(V) concentration (0.1 mM) is rapid, while transfer from the mucosal cells to the body occurs more slowly. At stable As(V) concentrations greater than 1 mM, fractional mucosal cell accumulation of As(V) remains constant, while fractional transfer to the body declines. However, total mucosal accumulation of As(V) and that transferred to the body increase in a linear logarithmic fashion from 0.05 to 5 mm As(V). The results indicate that As(V) readily penetrates both the mucosal and serosal surfaces of the epithelial membrane. Furthermore, arsenate and phosphate do not appear to share a common transport pathway in the duodenum and no evidence was obtained for any interaction between the two at this level. Vitamin D3 administration to rachitic chicks was effective in significantly elevating duodenal arsenate absorption, acting primarily to enhance serosal transport." ], "offsets": [ [ 0, 1324 ] ] } ]

[ { "id": "2981680_T1", "type": "DRUG_N", "text": [ "arsenate" ], "offsets": [ [ 25, 33 ] ], "normalized": [] }, { "id": "2981680_T2", "type": "DRUG_N", "text": [ "arsenate" ], "offsets": [ [ 77, 85 ] ], "normalized": [] }, { "id": "2981680_T3", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 86, 91 ] ], "normalized": [] }, { "id": "2981680_T4", "type": "DRUG_N", "text": [ "arsenate" ], "offsets": [ [ 225, 233 ] ], "normalized": [] }, { "id": "2981680_T5", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 308, 313 ] ], "normalized": [] }, { "id": "2981680_T6", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 448, 453 ] ], "normalized": [] }, { "id": "2981680_T7", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 567, 572 ] ], "normalized": [] }, { "id": "2981680_T8", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 647, 652 ] ], "normalized": [] }, { "id": "2981680_T9", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 758, 763 ] ], "normalized": [] }, { "id": "2981680_T10", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 856, 861 ] ], "normalized": [] }, { "id": "2981680_T11", "type": "DRUG_N", "text": [ "As(V)" ], "offsets": [ [ 889, 894 ] ], "normalized": [] }, { "id": "2981680_T12", "type": "DRUG_N", "text": [ "arsenate" ], "offsets": [ [ 993, 1001 ] ], "normalized": [] }, { "id": "2981680_T13", "type": "DRUG", "text": [ "phosphate" ], "offsets": [ [ 1006, 1015 ] ], "normalized": [] }, { "id": "2981680_T14", "type": "DRUG", "text": [ "Vitamin D3" ], "offsets": [ [ 1162, 1172 ] ], "normalized": [] }, { "id": "2981680_T15", "type": "DRUG_N", "text": [ "arsenate" ], "offsets": [ [ 1257, 1265 ] ], "normalized": [] } ]

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[ { "id": "2981680_R1", "type": "MECHANISM", "arg1_id": "2981680_T14", "arg2_id": "2981680_T15", "normalized": [] } ]

[ { "id": "3969689__text", "type": "abstract", "text": [ "Increased hepatotoxicity of acetaminophen by concomitant administration of caffeine in the rat. Since caffeine is frequently co-administered with acetaminophen, it is of clinical interest to study the effect of caffeine on the hepatotoxicity of acetaminophen. In male Sprague-Dawley rats fasted for 18 h, concomitant administration of caffeine (0.1 g/kg, i.p.) as judged by increased serum enzyme activities and increased incidence of hepatic necrosis. Careful observations on hepatotoxicity are suggested when acetaminophen is prescribed with caffeine." ], "offsets": [ [ 0, 553 ] ] } ]

[ { "id": "3969689_T1", "type": "DRUG", "text": [ "acetaminophen" ], "offsets": [ [ 28, 41 ] ], "normalized": [] }, { "id": "3969689_T2", "type": "DRUG", "text": [ "caffeine" ], "offsets": [ [ 75, 83 ] ], "normalized": [] }, { "id": "3969689_T3", "type": "DRUG", "text": [ "caffeine" ], "offsets": [ [ 102, 110 ] ], "normalized": [] }, { "id": "3969689_T4", "type": "DRUG", "text": [ "acetaminophen" ], "offsets": [ [ 146, 159 ] ], "normalized": [] }, { "id": "3969689_T5", "type": "DRUG", "text": [ "caffeine" ], "offsets": [ [ 211, 219 ] ], "normalized": [] }, { "id": "3969689_T6", "type": "DRUG", "text": [ "acetaminophen" ], "offsets": [ [ 245, 258 ] ], "normalized": [] }, { "id": "3969689_T7", "type": "DRUG", "text": [ "caffeine" ], "offsets": [ [ 335, 343 ] ], "normalized": [] }, { "id": "3969689_T8", "type": "DRUG", "text": [ "acetaminophen" ], "offsets": [ [ 511, 524 ] ], "normalized": [] }, { "id": "3969689_T9", "type": "DRUG", "text": [ "caffeine" ], "offsets": [ [ 544, 552 ] ], "normalized": [] } ]

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[ { "id": "3969689_R1", "type": "EFFECT", "arg1_id": "3969689_T1", "arg2_id": "3969689_T2", "normalized": [] }, { "id": "3969689_R2", "type": "EFFECT", "arg1_id": "3969689_T8", "arg2_id": "3969689_T9", "normalized": [] } ]

[ { "id": "11158747__text", "type": "abstract", "text": [ "Pharmacokinetic Interaction between amprenavir and rifabutin or rifampin in healthy males. The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC(ss)) of rifabutin by 2.93-fold and the AUC(ss) of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC(ss) of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT." ], "offsets": [ [ 0, 1910 ] ] } ]

[ { "id": "11158747_T1", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 36, 46 ] ], "normalized": [] }, { "id": "11158747_T2", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 51, 60 ] ], "normalized": [] }, { "id": "11158747_T3", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 64, 72 ] ], "normalized": [] }, { "id": "11158747_T4", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 183, 193 ] ], "normalized": [] }, { "id": "11158747_T5", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 208, 217 ] ], "normalized": [] }, { "id": "11158747_T6", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 221, 229 ] ], "normalized": [] }, { "id": "11158747_T7", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 410, 420 ] ], "normalized": [] }, { "id": "11158747_T8", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 511, 520 ] ], "normalized": [] }, { "id": "11158747_T9", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 560, 568 ] ], "normalized": [] }, { "id": "11158747_T10", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 628, 638 ] ], "normalized": [] }, { "id": "11158747_T11", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 644, 653 ] ], "normalized": [] }, { "id": "11158747_T12", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 689, 699 ] ], "normalized": [] }, { "id": "11158747_T13", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 705, 713 ] ], "normalized": [] }, { "id": "11158747_T14", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 777, 787 ] ], "normalized": [] }, { "id": "11158747_T15", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 789, 798 ] ], "normalized": [] }, { "id": "11158747_T16", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 804, 812 ] ], "normalized": [] }, { "id": "11158747_T17", "type": "DRUG_N", "text": [ "25-O-desacetyl metabolites" ], "offsets": [ [ 823, 849 ] ], "normalized": [] }, { "id": "11158747_T18", "type": "DRUG", "text": [ "Rifabutin" ], "offsets": [ [ 908, 917 ] ], "normalized": [] }, { "id": "11158747_T19", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "11158747_T20", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 978, 988 ] ], "normalized": [] }, { "id": "11158747_T21", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 1067, 1076 ] ], "normalized": [] }, { "id": "11158747_T22", "type": "DRUG_N", "text": [ "25-O-desacetylrifabutin" ], "offsets": [ [ 1109, 1132 ] ], "normalized": [] }, { "id": "11158747_T23", "type": "DRUG", "text": [ "Rifampin" ], "offsets": [ [ 1147, 1155 ] ], "normalized": [] }, { "id": "11158747_T24", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 1195, 1205 ] ], "normalized": [] }, { "id": "11158747_T25", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 1218, 1228 ] ], "normalized": [] }, { "id": "11158747_T26", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 1246, 1254 ] ], "normalized": [] }, { "id": "11158747_T27", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 1273, 1283 ] ], "normalized": [] }, { "id": "11158747_T28", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 1369, 1378 ] ], "normalized": [] }, { "id": "11158747_T29", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 1383, 1391 ] ], "normalized": [] }, { "id": "11158747_T30", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 1443, 1453 ] ], "normalized": [] }, { "id": "11158747_T31", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 1459, 1467 ] ], "normalized": [] }, { "id": "11158747_T32", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 1488, 1498 ] ], "normalized": [] }, { "id": "11158747_T33", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 1504, 1513 ] ], "normalized": [] }, { "id": "11158747_T34", "type": "DRUG", "text": [ "Rifampin" ], "offsets": [ [ 1579, 1587 ] ], "normalized": [] }, { "id": "11158747_T35", "type": "DRUG", "text": [ "amprenavir" ], "offsets": [ [ 1634, 1644 ] ], "normalized": [] }, { "id": "11158747_T36", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 1687, 1697 ] ], "normalized": [] }, { "id": "11158747_T37", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 1735, 1744 ] ], "normalized": [] }, { "id": "11158747_T38", "type": "DRUG_N", "text": [ "25-O-desacetylrifabutin" ], "offsets": [ [ 1749, 1772 ] ], "normalized": [] }, { "id": "11158747_T39", "type": "DRUG", "text": [ "Amprenavir" ], "offsets": [ [ 1815, 1825 ] ], "normalized": [] }, { "id": "11158747_T40", "type": "DRUG", "text": [ "rifampin" ], "offsets": [ [ 1850, 1858 ] ], "normalized": [] }, { "id": "11158747_T41", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 1863, 1872 ] ], "normalized": [] } ]

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[ { "id": "11158747_R1", "type": "MECHANISM", "arg1_id": "11158747_T20", "arg2_id": "11158747_T21", "normalized": [] }, { "id": "11158747_R2", "type": "MECHANISM", "arg1_id": "11158747_T20", "arg2_id": "11158747_T22", "normalized": [] }, { "id": "11158747_R3", "type": "MECHANISM", "arg1_id": "11158747_T23", "arg2_id": "11158747_T24", "normalized": [] }, { "id": "11158747_R4", "type": "EFFECT", "arg1_id": "11158747_T32", "arg2_id": "11158747_T33", "normalized": [] }, { "id": "11158747_R5", "type": "MECHANISM", "arg1_id": "11158747_T34", "arg2_id": "11158747_T35", "normalized": [] }, { "id": "11158747_R6", "type": "MECHANISM", "arg1_id": "11158747_T36", "arg2_id": "11158747_T37", "normalized": [] }, { "id": "11158747_R7", "type": "MECHANISM", "arg1_id": "11158747_T36", "arg2_id": "11158747_T38", "normalized": [] } ]

[ { "id": "15830476__text", "type": "abstract", "text": [ "Effect of probenecid on the apparent volume of distribution and elimination of cloxacillin. According to Gibaldi et al. (1968, 1970), the higher serum concentrations of penicillins and cephaloridine reached after administration of probenecid are due not only to slower renal elimination but also to an altered distribution in the body. To determine whether probenecid has a direct effect on the distribution of cloxacillin, the elimination and distribution of cloxacillin was studied in six patients, five lacking kidney function and one with a partially impaired renal function, in the presence or absence of probenecid. No significant difference was found between the mean values of the volume of distribution of cloxacillin with and without probenecid (13.0 and 12.6 liters, respectively). Thus, the hypothesis of Gibaldi et al. could not be confirmed for cloxacillin in patients lacking kidney function. In spite of the absence of kidney function, the value of the elimination rate constant was significantly decreased in the presence of probenecid (from 0.326 to 0.263/h). This might be explained by a blockade by probenecid of the elimination of cloxacillin by the liver." ], "offsets": [ [ 0, 1177 ] ] } ]

[ { "id": "15830476_T1", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 10, 20 ] ], "normalized": [] }, { "id": "15830476_T2", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 79, 90 ] ], "normalized": [] }, { "id": "15830476_T3", "type": "GROUP", "text": [ "penicillins" ], "offsets": [ [ 169, 180 ] ], "normalized": [] }, { "id": "15830476_T4", "type": "DRUG", "text": [ "cephaloridine" ], "offsets": [ [ 185, 198 ] ], "normalized": [] }, { "id": "15830476_T5", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 231, 241 ] ], "normalized": [] }, { "id": "15830476_T6", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 357, 367 ] ], "normalized": [] }, { "id": "15830476_T7", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 411, 422 ] ], "normalized": [] }, { "id": "15830476_T8", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 460, 471 ] ], "normalized": [] }, { "id": "15830476_T9", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 610, 620 ] ], "normalized": [] }, { "id": "15830476_T10", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 715, 726 ] ], "normalized": [] }, { "id": "15830476_T11", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 744, 754 ] ], "normalized": [] }, { "id": "15830476_T12", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 859, 870 ] ], "normalized": [] }, { "id": "15830476_T13", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 1042, 1052 ] ], "normalized": [] }, { "id": "15830476_T14", "type": "DRUG", "text": [ "probenecid" ], "offsets": [ [ 1119, 1129 ] ], "normalized": [] }, { "id": "15830476_T15", "type": "DRUG", "text": [ "cloxacillin" ], "offsets": [ [ 1152, 1163 ] ], "normalized": [] } ]

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[ { "id": "15830476_R1", "type": "MECHANISM", "arg1_id": "15830476_T3", "arg2_id": "15830476_T5", "normalized": [] }, { "id": "15830476_R2", "type": "MECHANISM", "arg1_id": "15830476_T4", "arg2_id": "15830476_T5", "normalized": [] }, { "id": "15830476_R3", "type": "MECHANISM", "arg1_id": "15830476_T14", "arg2_id": "15830476_T15", "normalized": [] } ]

[ { "id": "11271411__text", "type": "abstract", "text": [ "Acute hydrocortisone administration does not affect subjective responses to d-amphetamine in humans. RATIONALE: Stress and glucocorticoids facilitate and reinstate psychostimulant self-administration in rodents. However, the effects of stress and glucocorticoids on the subjective and behavioral effects of psychostimulants have not been well studied in humans. OBJECTIVES: To examine the effects of acute hydrocortisone pretreatment on the subjective and behavioral effects of d-amphetamine. METHODS: Hydrocortisone (100 mg) and d-amphetamine (20 mg) were administered orally to 16 healthy male and female volunteers in a four-session, placebo-controlled, within-subject, crossover design. To prevent stomach irritation, subjects received rantidine hydrochloride before each experimental session. Dependent measures included self-reported mood and subjective effects (Addiction Research Center inventory, the profile of mood states, and a series of visual analogue scales), vital signs, salivary cortisol, and psychomotor performance. RESULTS: Hydrocortisone elevated salivary cortisol levels, produced modest dysphoria, and reduced subjects' reports of wanting more drug. However, hydrocortisone pretreatment did not affect any of the physiological, behavioral, or subjective effects of d-amphetamine. CONCLUSIONS: In contrast to the effects of glucocorticoids in rodent studies, these results indicate that an acute increase in cortisol does not enhance the psychostimulant effects of d-amphetamine in humans." ], "offsets": [ [ 0, 1512 ] ] } ]

[ { "id": "11271411_T1", "type": "DRUG", "text": [ "hydrocortisone" ], "offsets": [ [ 6, 20 ] ], "normalized": [] }, { "id": "11271411_T2", "type": "DRUG", "text": [ "d-amphetamine" ], "offsets": [ [ 76, 89 ] ], "normalized": [] }, { "id": "11271411_T3", "type": "GROUP", "text": [ "glucocorticoids" ], "offsets": [ [ 123, 138 ] ], "normalized": [] }, { "id": "11271411_T4", "type": "GROUP", "text": [ "glucocorticoids" ], "offsets": [ [ 247, 262 ] ], "normalized": [] }, { "id": "11271411_T5", "type": "GROUP", "text": [ "psychostimulants" ], "offsets": [ [ 307, 323 ] ], "normalized": [] }, { "id": "11271411_T6", "type": "DRUG", "text": [ "hydrocortisone" ], "offsets": [ [ 406, 420 ] ], "normalized": [] }, { "id": "11271411_T7", "type": "DRUG", "text": [ "d-amphetamine" ], "offsets": [ [ 478, 491 ] ], "normalized": [] }, { "id": "11271411_T8", "type": "DRUG", "text": [ "Hydrocortisone" ], "offsets": [ [ 502, 516 ] ], "normalized": [] }, { "id": "11271411_T9", "type": "DRUG", "text": [ "d-amphetamine" ], "offsets": [ [ 530, 543 ] ], "normalized": [] }, { "id": "11271411_T10", "type": "DRUG", "text": [ "rantidine hydrochloride" ], "offsets": [ [ 740, 763 ] ], "normalized": [] }, { "id": "11271411_T11", "type": "DRUG", "text": [ "Hydrocortisone" ], "offsets": [ [ 1045, 1059 ] ], "normalized": [] }, { "id": "11271411_T12", "type": "DRUG", "text": [ "hydrocortisone" ], "offsets": [ [ 1183, 1197 ] ], "normalized": [] }, { "id": "11271411_T13", "type": "DRUG", "text": [ "d-amphetamine" ], "offsets": [ [ 1289, 1302 ] ], "normalized": [] }, { "id": "11271411_T14", "type": "GROUP", "text": [ "glucocorticoids" ], "offsets": [ [ 1347, 1362 ] ], "normalized": [] }, { "id": "11271411_T15", "type": "DRUG", "text": [ "d-amphetamine" ], "offsets": [ [ 1488, 1501 ] ], "normalized": [] } ]

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[ { "id": "11217868__text", "type": "abstract", "text": [ "The emerging roles of non-nucleoside reverse transcriptase inhibitors in antiretroviral therapy. The availability of potent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for antiretroviral therapy and concerns regarding protease inhibitor (PI)-related metabolic disturbances have led to significant shifts in treatment practices in HIV infection. NNRTI-based regimens may have several advantages over PI-based therapy for initial or prolonged therapy, including more convenient administration regimens, lower tablet volume, fewer drug interactions, and central nervous system penetration. No data from prospective clinical trials currently exist comparing the 3 approved agents (efavirenz, nevirapine or delavirdine). Both efavirenz and nevirapine have been compared to triple therapy with the PI indinavir over 48 weeks as initial therapy, with similar responses being observed with nevirapine regimens and superiority observed with efavirenz. A smaller 24-week study has suggested nevirapine may be superior to the PI nelfinavir. Limited comparative data in patients with high viral loads treated with nevirapine- or delavirdine-based regimens currently exist. However, cohort data and selected patient data from clinical trials suggest comparable activity to PI-based regimens in these patients. The superiority of efavirenz over indinavir-based regimens has been observed in comparative data in a subset of patients with high viral loads. In treatment-experienced patients, available uncontrolled data suggest these agents contribute to regimen efficacy in NNRTI-na ve, treatment-experienced patients. Efavirenz has demonstrated superiority over nelfinavir in nucleoside-experienced patients, although combining these 2 agents may represent the best approach in these circumstances. The tolerability of NNRTIs appears generally good with few individuals discontinuing in clinical studies as a result of adverse drug events. The majority of adverse events with NNRTIs occur within the first month, and are predictable and manageable without therapy interruption." ], "offsets": [ [ 0, 2090 ] ] } ]

[ { "id": "11217868_T1", "type": "GROUP", "text": [ "non-nucleoside reverse transcriptase inhibitors" ], "offsets": [ [ 22, 69 ] ], "normalized": [] }, { "id": "11217868_T2", "type": "GROUP", "text": [ "antiretroviral" ], "offsets": [ [ 73, 87 ] ], "normalized": [] }, { "id": "11217868_T3", "type": "GROUP", "text": [ "non-nucleoside reverse transcriptase inhibitor" ], "offsets": [ [ 124, 170 ] ], "normalized": [] }, { "id": "11217868_T4", "type": "GROUP", "text": [ "NNRTI" ], "offsets": [ [ 172, 177 ] ], "normalized": [] }, { "id": "11217868_T5", "type": "GROUP", "text": [ "antiretroviral" ], "offsets": [ [ 198, 212 ] ], "normalized": [] }, { "id": "11217868_T6", "type": "GROUP", "text": [ "protease inhibitor" ], "offsets": [ [ 244, 262 ] ], "normalized": [] }, { "id": "11217868_T7", "type": "GROUP", "text": [ "PI" ], "offsets": [ [ 264, 266 ] ], "normalized": [] }, { "id": "11217868_T8", "type": "GROUP", "text": [ "NNRTI" ], "offsets": [ [ 371, 376 ] ], "normalized": [] }, { "id": "11217868_T9", "type": "GROUP", "text": [ "PI" ], "offsets": [ [ 425, 427 ] ], "normalized": [] }, { "id": "11217868_T10", "type": "DRUG", "text": [ "efavirenz" ], "offsets": [ [ 703, 712 ] ], "normalized": [] }, { "id": "11217868_T11", "type": "DRUG", "text": [ "nevirapine" ], "offsets": [ [ 714, 724 ] ], "normalized": [] }, { "id": "11217868_T12", "type": "DRUG", "text": [ "delavirdine" ], "offsets": [ [ 728, 739 ] ], "normalized": [] }, { "id": "11217868_T13", "type": "DRUG", "text": [ "efavirenz" ], "offsets": [ [ 747, 756 ] ], "normalized": [] }, { "id": "11217868_T14", "type": "DRUG", "text": [ "nevirapine" ], "offsets": [ [ 761, 771 ] ], "normalized": [] }, { "id": "11217868_T15", "type": "GROUP", "text": [ "PI" ], "offsets": [ [ 818, 820 ] ], "normalized": [] }, { "id": "11217868_T16", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 821, 830 ] ], "normalized": [] }, { "id": "11217868_T17", "type": "DRUG", "text": [ "nevirapine" ], "offsets": [ [ 908, 918 ] ], "normalized": [] }, { "id": "11217868_T18", "type": "DRUG", "text": [ "efavirenz" ], "offsets": [ [ 958, 967 ] ], "normalized": [] }, { "id": "11217868_T19", "type": "DRUG", "text": [ "nevirapine" ], "offsets": [ [ 1007, 1017 ] ], "normalized": [] }, { "id": "11217868_T20", "type": "GROUP", "text": [ "PI" ], "offsets": [ [ 1041, 1043 ] ], "normalized": [] }, { "id": "11217868_T21", "type": "DRUG", "text": [ "nelfinavir" ], "offsets": [ [ 1044, 1054 ] ], "normalized": [] }, { "id": "11217868_T22", "type": "DRUG", "text": [ "nevirapine" ], "offsets": [ [ 1128, 1138 ] ], "normalized": [] }, { "id": "11217868_T23", "type": "DRUG", "text": [ "delavirdine" ], "offsets": [ [ 1143, 1154 ] ], "normalized": [] }, { "id": "11217868_T24", "type": "GROUP", "text": [ "PI" ], "offsets": [ [ 1286, 1288 ] ], "normalized": [] }, { "id": "11217868_T25", "type": "DRUG", "text": [ "efavirenz" ], "offsets": [ [ 1342, 1351 ] ], "normalized": [] }, { "id": "11217868_T26", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 1357, 1366 ] ], "normalized": [] }, { "id": "11217868_T27", "type": "GROUP", "text": [ "NNRTI" ], "offsets": [ [ 1585, 1590 ] ], "normalized": [] }, { "id": "11217868_T28", "type": "DRUG", "text": [ "Efavirenz" ], "offsets": [ [ 1631, 1640 ] ], "normalized": [] }, { "id": "11217868_T29", "type": "DRUG", "text": [ "nelfinavir" ], "offsets": [ [ 1675, 1685 ] ], "normalized": [] }, { "id": "11217868_T30", "type": "GROUP", "text": [ "NNRTIs" ], "offsets": [ [ 1832, 1838 ] ], "normalized": [] }, { "id": "11217868_T31", "type": "GROUP", "text": [ "NNRTIs" ], "offsets": [ [ 1989, 1995 ] ], "normalized": [] } ]

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[ { "id": "1115721__text", "type": "abstract", "text": [ "Drug interactions: How to identify them. Interactions between theraputic agents have been recognized as increasingly important causes of drug at their usual recommended dose may, under certain conditions, produce toxicity of life-endangering proportions. While the recognition of drug toxicity resulting from interactions is of importance to all physciains, it is especially so for the clinician responsible for the welfare of those in the aerospace environment. This paper attempts to provide a basis for the understanding and identifications of important drug interactions. Guidelines are provided to assist the clinician in his logical approach to the identification of drug interactions when serious drug toxicity is encountered in a pateint. Only with knowledge of the interaction can the therapeutic regimen be altered so as to provide therapeutic levels of necessary drugs while avoiding toxicity." ], "offsets": [ [ 0, 904 ] ] } ]

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[ { "id": "11137320__text", "type": "abstract", "text": [ "Cypermethrin-induced oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol. Considering that the involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides, this study was designed to investigate the possibility of oxidative stress induction by cypermethrin, a Type II pyrethroid. Either single (170 mg/kg) or repeated (75 mg/kg per day for 5 days) oral administration of cypermethrin was found to produce significant oxidative stress in cerebral and hepatic tissues of rats, as was evident by the elevation of the level of thiobarbituric acid reactive substances (TBARS) in both tissues, either 4 or 24 h after treatment. Much higher changes were observed in liver, increasing from a level of 60% at 4 h up to nearly 4 times the control at 24 h for single dose. Reduced levels (up to 20%) of total glutathione (total GSH), and elevation of conjugated dienes ( approximately 60% in liver by single dose at 4 h) also indicated the presence of an oxidative insult. Glutathione-S-transferase (GST) activity, however, did not differ from control values for any dose or at any time point in cerebral and hepatic tissues. Pretreatment of rats with allopurinol (100 mg/kg, ip) or Vitamin E (100 mg/kg per day, ig, for 3 days and a dose of 40 mg/kg on the 4th day) provided significant protection against the elevation of TBARS levels in cerebral and hepatic tissues, induced by single high dose of oral cypermethrin administration within 4 h. Thus, the results suggest that cypermethrin exposure of rats results in free radical-mediated tissue damage, as indicated by elevated cerebral and hepatic lipid peroxidation, which was prevented by allopurinol and Vitamin E." ], "offsets": [ [ 0, 1731 ] ] } ]

[ { "id": "11137320_T1", "type": "DRUG", "text": [ "Cypermethrin" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "11137320_T2", "type": "DRUG", "text": [ "vitamin E" ], "offsets": [ [ 77, 86 ] ], "normalized": [] }, { "id": "11137320_T3", "type": "DRUG", "text": [ "allopurinol" ], "offsets": [ [ 90, 101 ] ], "normalized": [] }, { "id": "11137320_T4", "type": "DRUG", "text": [ "cypermethrin" ], "offsets": [ [ 316, 328 ] ], "normalized": [] }, { "id": "11137320_T5", "type": "DRUG_N", "text": [ "Type II pyrethroid" ], "offsets": [ [ 332, 350 ] ], "normalized": [] }, { "id": "11137320_T6", "type": "DRUG", "text": [ "cypermethrin" ], "offsets": [ [ 443, 455 ] ], "normalized": [] }, { "id": "11137320_T7", "type": "DRUG", "text": [ "allopurinol" ], "offsets": [ [ 1213, 1224 ] ], "normalized": [] }, { "id": "11137320_T8", "type": "DRUG", "text": [ "Vitamin E" ], "offsets": [ [ 1244, 1253 ] ], "normalized": [] }, { "id": "11137320_T9", "type": "DRUG", "text": [ "cypermethrin" ], "offsets": [ [ 1467, 1479 ] ], "normalized": [] }, { "id": "11137320_T10", "type": "DRUG", "text": [ "cypermethrin" ], "offsets": [ [ 1538, 1550 ] ], "normalized": [] }, { "id": "11137320_T11", "type": "DRUG", "text": [ "allopurinol" ], "offsets": [ [ 1705, 1716 ] ], "normalized": [] }, { "id": "11137320_T12", "type": "DRUG", "text": [ "Vitamin E" ], "offsets": [ [ 1721, 1730 ] ], "normalized": [] } ]

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[ { "id": "11137320_R1", "type": "EFFECT", "arg1_id": "11137320_T1", "arg2_id": "11137320_T2", "normalized": [] }, { "id": "11137320_R2", "type": "EFFECT", "arg1_id": "11137320_T1", "arg2_id": "11137320_T3", "normalized": [] }, { "id": "11137320_R3", "type": "EFFECT", "arg1_id": "11137320_T7", "arg2_id": "11137320_T9", "normalized": [] }, { "id": "11137320_R4", "type": "EFFECT", "arg1_id": "11137320_T8", "arg2_id": "11137320_T9", "normalized": [] }, { "id": "11137320_R5", "type": "EFFECT", "arg1_id": "11137320_T10", "arg2_id": "11137320_T11", "normalized": [] }, { "id": "11137320_R6", "type": "EFFECT", "arg1_id": "11137320_T10", "arg2_id": "11137320_T12", "normalized": [] } ]

[ { "id": "3918122__text", "type": "abstract", "text": [ "Selective survival in pentazocine and tripelennamine of Pseudomonas aeruginosa serotype O11 from drug addicts. The growth of Pseudomonas aeruginosa, particularly serotype O11, in pentazocine and tripelennamine was evaluated as a possible explanation for the association of deep-seated infection with this organism and abuse of these drugs. The mean reduction of growth caused by the drugs was 1,000-fold greater for 49 Pseudomonas strains from normal subjects than for 32 strains from drug addicts (4.2 vs. 1.3 logs of reduction at 2 hr, P less than .0005). A common phenotypic subset of the serotype O11 strains from drug addicts was especially resistant to the inhibitory effects. Twelve strains of Staphylococcus aureus (a frequent cause of infection in heroin, but not in pentazocine and tripelennamine, addicts) were completely inhibited by the drug combination. Dose-response curves (derived from the results of using the tablets as well as pure powders) showed that tripelennamine was responsible for the inhibitory activity, which was partially antagonized by pentazocine. We conclude that an ability of some P. aeruginosa serotype O11 strains, but not S. aureus, to survive in pentazocine and tripelennamine may explain in part a shift from S. aureus to P. aeruginosa as common pathogens of drug addicts in areas where abuse of this combination of drugs has increased." ], "offsets": [ [ 0, 1377 ] ] } ]

[ { "id": "3918122_T1", "type": "DRUG", "text": [ "pentazocine" ], "offsets": [ [ 22, 33 ] ], "normalized": [] }, { "id": "3918122_T2", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 38, 52 ] ], "normalized": [] }, { "id": "3918122_T3", "type": "DRUG", "text": [ "pentazocine" ], "offsets": [ [ 179, 190 ] ], "normalized": [] }, { "id": "3918122_T4", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 195, 209 ] ], "normalized": [] }, { "id": "3918122_T5", "type": "DRUG_N", "text": [ "heroin" ], "offsets": [ [ 757, 763 ] ], "normalized": [] }, { "id": "3918122_T6", "type": "DRUG", "text": [ "pentazocine" ], "offsets": [ [ 776, 787 ] ], "normalized": [] }, { "id": "3918122_T7", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 792, 806 ] ], "normalized": [] }, { "id": "3918122_T8", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 973, 987 ] ], "normalized": [] }, { "id": "3918122_T9", "type": "DRUG", "text": [ "pentazocine" ], "offsets": [ [ 1068, 1079 ] ], "normalized": [] }, { "id": "3918122_T10", "type": "DRUG", "text": [ "pentazocine" ], "offsets": [ [ 1186, 1197 ] ], "normalized": [] }, { "id": "3918122_T11", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 1202, 1216 ] ], "normalized": [] } ]

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[ { "id": "3918122_R1", "type": "EFFECT", "arg1_id": "3918122_T6", "arg2_id": "3918122_T7", "normalized": [] }, { "id": "3918122_R2", "type": "EFFECT", "arg1_id": "3918122_T8", "arg2_id": "3918122_T9", "normalized": [] } ]

[ { "id": "6545985__text", "type": "abstract", "text": [ "Interaction on the antinociceptive effect between neurotensin and enkephalins or tuftsin. The aim of this paper was to study the interaction between neurotensin and both enkephalins or its synthetic analogue D-Ala2-metenkephalinamide, or tuftsin, on the antinonciceptive effect of these peptides in mice after intracisternal injection. Antinociception was measured by the hot-plate method. It was shown that neurotensin antagonized evidently the antinociceptive effect of enkephalins and their analogue. On the contrary, neurotensin and tuftsin were agonists in induction of analgesia. It is concluded that neurotensin modulates in an opposite way the function of the enkephalinergic neurons and the central action of tuftsin." ], "offsets": [ [ 0, 726 ] ] } ]

[ { "id": "6545985_T1", "type": "DRUG_N", "text": [ "neurotensin" ], "offsets": [ [ 50, 61 ] ], "normalized": [] }, { "id": "6545985_T2", "type": "DRUG_N", "text": [ "enkephalins" ], "offsets": [ [ 66, 77 ] ], "normalized": [] }, { "id": "6545985_T3", "type": "DRUG_N", "text": [ "tuftsin" ], "offsets": [ [ 81, 88 ] ], "normalized": [] }, { "id": "6545985_T4", "type": "DRUG_N", "text": [ "neurotensin" ], "offsets": [ [ 149, 160 ] ], "normalized": [] }, { "id": "6545985_T5", "type": "DRUG_N", "text": [ "enkephalins" ], "offsets": [ [ 170, 181 ] ], "normalized": [] }, { "id": "6545985_T6", "type": "DRUG_N", "text": [ "D-Ala2-metenkephalinamide" ], "offsets": [ [ 208, 233 ] ], "normalized": [] }, { "id": "6545985_T7", "type": "DRUG_N", "text": [ "tuftsin" ], "offsets": [ [ 238, 245 ] ], "normalized": [] }, { "id": "6545985_T8", "type": "DRUG_N", "text": [ "neurotensin" ], "offsets": [ [ 408, 419 ] ], "normalized": [] }, { "id": "6545985_T9", "type": "DRUG_N", "text": [ "enkephalins" ], "offsets": [ [ 472, 483 ] ], "normalized": [] }, { "id": "6545985_T10", "type": "DRUG_N", "text": [ "neurotensin" ], "offsets": [ [ 521, 532 ] ], "normalized": [] }, { "id": "6545985_T11", "type": "DRUG_N", "text": [ "tuftsin" ], "offsets": [ [ 537, 544 ] ], "normalized": [] }, { "id": "6545985_T12", "type": "DRUG_N", "text": [ "neurotensin" ], "offsets": [ [ 607, 618 ] ], "normalized": [] }, { "id": "6545985_T13", "type": "DRUG_N", "text": [ "tuftsin" ], "offsets": [ [ 718, 725 ] ], "normalized": [] } ]

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[ { "id": "6545985_R1", "type": "EFFECT", "arg1_id": "6545985_T1", "arg2_id": "6545985_T2", "normalized": [] }, { "id": "6545985_R2", "type": "EFFECT", "arg1_id": "6545985_T1", "arg2_id": "6545985_T3", "normalized": [] }, { "id": "6545985_R3", "type": "EFFECT", "arg1_id": "6545985_T8", "arg2_id": "6545985_T9", "normalized": [] }, { "id": "6545985_R4", "type": "EFFECT", "arg1_id": "6545985_T10", "arg2_id": "6545985_T11", "normalized": [] }, { "id": "6545985_R5", "type": "EFFECT", "arg1_id": "6545985_T12", "arg2_id": "6545985_T13", "normalized": [] } ]

[ { "id": "7635041__text", "type": "abstract", "text": [ "Immunosuppressive drugs and their complications. Drugs that suppress the immune system are widely used. They are part of the treatment of patients with organ transplants, malignancy, and increasingly those with conditions such as psoriasis, rheumatoid arthritis, and liver and bowel disease in which inflammation is an aetiological factor. Because of the broadening indications for immunosuppressive drugs, and the prolonged survival in conditions for which they are being used, many patients on immunosuppression are now cared for in the community or seen in non-specialist hospitals, usually in close collaboration with a specialist. This article looks at five commonly used immunosuppressive drugs in turn (corticosteroids, cyclosporin, azathioprine, methotrexate, cyclophosphamide), discussing the main, non-infection, unwanted effects, ways to avoid them and what to do if problems arise. The management of infection is dealt with as a separate section." ], "offsets": [ [ 0, 958 ] ] } ]

[ { "id": "7635041_T1", "type": "GROUP", "text": [ "Immunosuppressive drugs" ], "offsets": [ [ 0, 23 ] ], "normalized": [] }, { "id": "7635041_T2", "type": "GROUP", "text": [ "immunosuppressive drugs" ], "offsets": [ [ 382, 405 ] ], "normalized": [] }, { "id": "7635041_T3", "type": "GROUP", "text": [ "immunosuppressive drugs" ], "offsets": [ [ 677, 700 ] ], "normalized": [] }, { "id": "7635041_T4", "type": "GROUP", "text": [ "corticosteroids" ], "offsets": [ [ 710, 725 ] ], "normalized": [] }, { "id": "7635041_T5", "type": "DRUG", "text": [ "cyclosporin" ], "offsets": [ [ 727, 738 ] ], "normalized": [] }, { "id": "7635041_T6", "type": "DRUG", "text": [ "azathioprine" ], "offsets": [ [ 740, 752 ] ], "normalized": [] }, { "id": "7635041_T7", "type": "DRUG", "text": [ "methotrexate" ], "offsets": [ [ 754, 766 ] ], "normalized": [] }, { "id": "7635041_T8", "type": "DRUG", "text": [ "cyclophosphamide" ], "offsets": [ [ 768, 784 ] ], "normalized": [] } ]

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[ { "id": "15825399__text", "type": "abstract", "text": [ "Studies on the mechanism of action of miconazole: effect of miconazole on respiration and cell permeability of Candida albicans. The antifungal drug, miconazole nitrate, inhibits the growth of several species of Candida. Candida albicans, one of the pathogenic species, was totally inhibited at a concentration of approximately 10 mug/ml. Endogenous respiration was unaffected by the drug at a concentration as high as 100 mug/ml, whereas exogenous respiration was markedly sensitive and inhibited to an extent of 85%. The permeability of the cell membrane was changed as evidenced by the leakage of 260-nm absorbing materials, amino acids, proteins, and inorganic cations. The results we present clearly show that the drug alters the cellular permeability, and thus the exogenous respiration becomes sensitive to the drug." ], "offsets": [ [ 0, 823 ] ] } ]

[ { "id": "15825399_T1", "type": "DRUG", "text": [ "miconazole" ], "offsets": [ [ 38, 48 ] ], "normalized": [] }, { "id": "15825399_T2", "type": "DRUG", "text": [ "miconazole" ], "offsets": [ [ 60, 70 ] ], "normalized": [] }, { "id": "15825399_T3", "type": "GROUP", "text": [ "antifungal drug" ], "offsets": [ [ 133, 148 ] ], "normalized": [] }, { "id": "15825399_T4", "type": "DRUG", "text": [ "miconazole nitrate" ], "offsets": [ [ 150, 168 ] ], "normalized": [] } ]

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[ { "id": "11210678__text", "type": "abstract", "text": [ "Effect of diazepam and midazolam on the antinociceptive effect of morphine, metamizol and indomethacin in mice. The influence of midazolam and diazepam on antinociceptive effect of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg) was investigated in a mouse model using the tail-flick and hot-plate tests. All drugs were injected intraperitoneally. Benzodiazepines were administered to mice 30 min before applying the analgesic drugs. Measurement of nociception was performed within 2 h after benzodiazepine administration. Diazepam at doses of 0.25 mg/kg and 2.5 mg/kg injected with morphine was found to decrease the antinociceptive effect of morphine. Similarly, diazepam decreased the antinociceptive effect of metamizol (only in the tail-flick test) and indomethacin. Midazolam used at doses of 1.25 mg/kg and 2.5 mg/kg decreased the antinociceptive effect of morphine, metamizol (only in the tail-flick test) and indomethacin." ], "offsets": [ [ 0, 954 ] ] } ]

[ { "id": "11210678_T1", "type": "DRUG", "text": [ "diazepam" ], "offsets": [ [ 10, 18 ] ], "normalized": [] }, { "id": "11210678_T2", "type": "DRUG", "text": [ "midazolam" ], "offsets": [ [ 23, 32 ] ], "normalized": [] }, { "id": "11210678_T3", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 66, 74 ] ], "normalized": [] }, { "id": "11210678_T4", "type": "DRUG", "text": [ "metamizol" ], "offsets": [ [ 76, 85 ] ], "normalized": [] }, { "id": "11210678_T5", "type": "DRUG", "text": [ "indomethacin" ], "offsets": [ [ 90, 102 ] ], "normalized": [] }, { "id": "11210678_T6", "type": "DRUG", "text": [ "midazolam" ], "offsets": [ [ 129, 138 ] ], "normalized": [] }, { "id": "11210678_T7", "type": "DRUG", "text": [ "diazepam" ], "offsets": [ [ 143, 151 ] ], "normalized": [] }, { "id": "11210678_T8", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 181, 189 ] ], "normalized": [] }, { "id": "11210678_T9", "type": "DRUG", "text": [ "metamizol" ], "offsets": [ [ 202, 211 ] ], "normalized": [] }, { "id": "11210678_T10", "type": "DRUG", "text": [ "indomethacin" ], "offsets": [ [ 228, 240 ] ], "normalized": [] }, { "id": "11210678_T11", "type": "GROUP", "text": [ "Benzodiazepines" ], "offsets": [ [ 371, 386 ] ], "normalized": [] }, { "id": "11210678_T12", "type": "GROUP", "text": [ "analgesic drugs" ], "offsets": [ [ 440, 455 ] ], "normalized": [] }, { "id": "11210678_T13", "type": "GROUP", "text": [ "benzodiazepine" ], "offsets": [ [ 515, 529 ] ], "normalized": [] }, { "id": "11210678_T14", "type": "DRUG", "text": [ "Diazepam" ], "offsets": [ [ 546, 554 ] ], "normalized": [] }, { "id": "11210678_T15", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 606, 614 ] ], "normalized": [] }, { "id": "11210678_T16", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 667, 675 ] ], "normalized": [] }, { "id": "11210678_T17", "type": "DRUG", "text": [ "diazepam" ], "offsets": [ [ 688, 696 ] ], "normalized": [] }, { "id": "11210678_T18", "type": "DRUG", "text": [ "metamizol" ], "offsets": [ [ 737, 746 ] ], "normalized": [] }, { "id": "11210678_T19", "type": "DRUG", "text": [ "indomethacin" ], "offsets": [ [ 781, 793 ] ], "normalized": [] }, { "id": "11210678_T20", "type": "DRUG", "text": [ "Midazolam" ], "offsets": [ [ 795, 804 ] ], "normalized": [] }, { "id": "11210678_T21", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 887, 895 ] ], "normalized": [] }, { "id": "11210678_T22", "type": "DRUG", "text": [ "metamizol" ], "offsets": [ [ 897, 906 ] ], "normalized": [] }, { "id": "11210678_T23", "type": "DRUG", "text": [ "indomethacin" ], "offsets": [ [ 941, 953 ] ], "normalized": [] } ]

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[ { "id": "11210678_R1", "type": "EFFECT", "arg1_id": "11210678_T14", "arg2_id": "11210678_T15", "normalized": [] }, { "id": "11210678_R2", "type": "EFFECT", "arg1_id": "11210678_T17", "arg2_id": "11210678_T18", "normalized": [] }, { "id": "11210678_R3", "type": "EFFECT", "arg1_id": "11210678_T17", "arg2_id": "11210678_T19", "normalized": [] }, { "id": "11210678_R4", "type": "EFFECT", "arg1_id": "11210678_T20", "arg2_id": "11210678_T21", "normalized": [] }, { "id": "11210678_R5", "type": "EFFECT", "arg1_id": "11210678_T20", "arg2_id": "11210678_T22", "normalized": [] }, { "id": "11210678_R6", "type": "EFFECT", "arg1_id": "11210678_T20", "arg2_id": "11210678_T23", "normalized": [] } ]

[ { "id": "11121884__text", "type": "abstract", "text": [ "Interference of biocytin with opioid-evoked hyperpolarization and membrane properties of rat spinal substantia gelatinosa neurons. In our laboratory, preliminary whole-cell, tight seal recordings of rat spinal substantia gelatinosa neurons including biocytin in the patch pipette yielded a significantly smaller proportion of neurons hyperpolarized by selective opioid agonists compared with recordings without biocytin. Therefore, we investigated the effects of biocytin inclusion on opioid responses and other membrane properties during whole-cell, tight seal recordings of these neurons. The percentage of neurons hyperpolarized by mu-, delta(1)-, and kappa-selective opioids was significantly reduced when 1% but not < or =0.2% biocytin was included in the recording pipette, compared with neurons recorded without biocytin. However, a significantly higher proportion of neurons fired spontaneous action potentials with either 0.05-0.2 or 1% biocytin compared to no biocytin. Resting membrane potential, input impedance and the proportion of neurons displaying transient outward rectification were each significantly altered for neurons recorded with 1% but not 0.05-0.2% biocytin. These effects may be due to a relatively specific blockade of diverse potassium channel types. Because efficient labeling can be achieved with 0.1% biocytin with whole-cell recording, higher concentrations are contraindicated." ], "offsets": [ [ 0, 1412 ] ] } ]

[ { "id": "11121884_T1", "type": "GROUP", "text": [ "opioid" ], "offsets": [ [ 30, 36 ] ], "normalized": [] }, { "id": "11121884_T2", "type": "GROUP", "text": [ "selective opioid agonists" ], "offsets": [ [ 352, 377 ] ], "normalized": [] }, { "id": "11121884_T3", "type": "GROUP", "text": [ "opioid" ], "offsets": [ [ 485, 491 ] ], "normalized": [] }, { "id": "11121884_T4", "type": "GROUP", "text": [ "mu-", "selective opioids" ], "offsets": [ [ 635, 638 ], [ 661, 678 ] ], "normalized": [] }, { "id": "11121884_T5", "type": "GROUP", "text": [ "delta(1)-", "selective opioids" ], "offsets": [ [ 640, 649 ], [ 661, 678 ] ], "normalized": [] }, { "id": "11121884_T6", "type": "GROUP", "text": [ "kappa-selective opioids" ], "offsets": [ [ 655, 678 ] ], "normalized": [] } ]

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[ { "id": "11178969__text", "type": "abstract", "text": [ "Green tea polyphenols as potent enhancers of glucocorticoid-induced mouse mammary tumor virus gene expression. The effect of natural and synthetic galloyl esters on glucocorticoid-induced gene expression was evaluated by using rat fibroblast 3Y1 cells stably transfected with a luciferase reporter gene under the transcriptional regulation of the mouse mammary tumor virus promoter. The glucocorticoid-induced gene transcription was strongly suppressed by synthetic alkyl esters; n-dodecyl gallate showed the most potent inhibition (66% inhibition at 10 microM), which was far more potent than that of crude tannic acid. n-Octyl and n-cetyl gallate also showed good inhibition, while gallic acid itself was not so active, suggesting that the presence of hydrophobic side chain is important for the suppressive effect. On the other hand, surprisingly, green tea gallocatechins, (-)-epigallocatechin-3-O-gallate and theasinensin A, potently enhanced the promoter activity (182 and 247% activity at 1 microM, respectively). The regulation of the level of the glucocorticoid-induced gene expression by the antioxidative gallates is of great interest from a therapeutic point of view." ], "offsets": [ [ 0, 1179 ] ] } ]

[ { "id": "11178969_T1", "type": "DRUG", "text": [ "Green tea polyphenols" ], "offsets": [ [ 0, 21 ] ], "normalized": [] }, { "id": "11178969_T2", "type": "DRUG", "text": [ "enhancers" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "11178969_T3", "type": "DRUG", "text": [ "promoter" ], "offsets": [ [ 373, 381 ] ], "normalized": [] }, { "id": "11178969_T4", "type": "DRUG", "text": [ "n-dodecyl gallate" ], "offsets": [ [ 480, 497 ] ], "normalized": [] }, { "id": "11178969_T5", "type": "DRUG", "text": [ "tannic acid" ], "offsets": [ [ 608, 619 ] ], "normalized": [] }, { "id": "11178969_T6", "type": "DRUG", "text": [ "green tea gallocatechins" ], "offsets": [ [ 851, 875 ] ], "normalized": [] } ]

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[ { "id": "11064383__text", "type": "abstract", "text": [ "Note: dissolution of aerosol particles of budesonide in Survanta, a model lung surfactant. The effect of a pulmonary surfactant extract from bovine lung, Survanta, on the dissolution rate of aerosol particles of budesonide was determined. Aerosol particles of budesonide were generated from an ethanol solution, dried, and collected by a cascade impactor for characterization or by a liquid impinger for dissolution experiments. Powder x-ray diffraction, differential scanning calorimetry, differential thermal analysis, and scanning electron microscopy were used to characterize the aerosol particles and starting material. No change in phase was detected, although the aerosol particles appeared to contain residual solvent. The dissolution rate of the aerosol particles in saline was low and variable. Survanta increased the extent of dissolution of budesonide in proportion to the added concentration, which was also verified by equilibrium solubilization studies. Survanta also increased rate of dissolution, in a manner similar to sodium dodecyl sulfate. Analysis of the concentration of budesonide following ultracentrifugation indicated that there is rapid equilibration of budesonide between the Survanta and aqueous phase. These results show that lung surfactant has the potential of enhancing the rate and extent of dissolution of drugs administered to the lung." ], "offsets": [ [ 0, 1373 ] ] } ]

[ { "id": "11064383_T1", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 42, 52 ] ], "normalized": [] }, { "id": "11064383_T2", "type": "BRAND", "text": [ "Survanta" ], "offsets": [ [ 56, 64 ] ], "normalized": [] }, { "id": "11064383_T3", "type": "GROUP", "text": [ "lung surfactant" ], "offsets": [ [ 74, 89 ] ], "normalized": [] }, { "id": "11064383_T4", "type": "GROUP", "text": [ "pulmonary surfactant" ], "offsets": [ [ 107, 127 ] ], "normalized": [] }, { "id": "11064383_T5", "type": "BRAND", "text": [ "Survanta" ], "offsets": [ [ 154, 162 ] ], "normalized": [] }, { "id": "11064383_T6", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 212, 222 ] ], "normalized": [] }, { "id": "11064383_T7", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 260, 270 ] ], "normalized": [] }, { "id": "11064383_T8", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 294, 301 ] ], "normalized": [] }, { "id": "11064383_T9", "type": "GROUP", "text": [ "solvent" ], "offsets": [ [ 718, 725 ] ], "normalized": [] }, { "id": "11064383_T10", "type": "BRAND", "text": [ "Survanta" ], "offsets": [ [ 805, 813 ] ], "normalized": [] }, { "id": "11064383_T11", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 853, 863 ] ], "normalized": [] }, { "id": "11064383_T12", "type": "BRAND", "text": [ "Survanta" ], "offsets": [ [ 969, 977 ] ], "normalized": [] }, { "id": "11064383_T13", "type": "DRUG_N", "text": [ "sodium dodecyl sulfate" ], "offsets": [ [ 1037, 1059 ] ], "normalized": [] }, { "id": "11064383_T14", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 1094, 1104 ] ], "normalized": [] }, { "id": "11064383_T15", "type": "DRUG", "text": [ "budesonide" ], "offsets": [ [ 1182, 1192 ] ], "normalized": [] }, { "id": "11064383_T16", "type": "BRAND", "text": [ "Survanta" ], "offsets": [ [ 1205, 1213 ] ], "normalized": [] }, { "id": "11064383_T17", "type": "GROUP", "text": [ "lung surfactant" ], "offsets": [ [ 1257, 1272 ] ], "normalized": [] } ]

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[ { "id": "11206187__text", "type": "abstract", "text": [ "Vancomycin resistance reversal in enterococci by flavonoids. The development of clinical vancomycin-resistant strains of enterococci (VRE) is a major cause for concern. Here we show that a combination of galangin or 3,7-dihydroxyflavone with vancomycin may be used to sensitize resistant strains of Enterococcus faecalis and Enterococcus faecium to the level of vancomycin-sensitive strains. Minimum inhibitory concentrations (MICs) and viable counts were determined in Iso-sensitest broth using a microtitre method. MICs of vancomycin against 67% of resistant clinical isolates and a type strain of enterococci were lowered from > 250 microg mL(-1) to 1 4 microg mL(-1) in the presence of galangin (12.5 microg mL(-1)) or 3,7-dihydroxyflavone (6.25 microg mL(-1)). Viable counts for type culture E. faecalis ATCC 51299 showed the flavonoids alone significantly lowered numbers of colony forming units (CFUs). CFUs were maintained at low levels (10(3) CFU mL(-1)) for 24 h by vancomycin/flavone combinations. This combinational action in reversing vancomycin resistance of enterococci highlights novel drug targets and has importance in the design of new therapeutic regimes against resistant pathogens." ], "offsets": [ [ 0, 1203 ] ] } ]

[ { "id": "11206187_T1", "type": "DRUG", "text": [ "galangin" ], "offsets": [ [ 204, 212 ] ], "normalized": [] }, { "id": "11206187_T2", "type": "DRUG", "text": [ "vancomycin" ], "offsets": [ [ 242, 252 ] ], "normalized": [] }, { "id": "11206187_T3", "type": "DRUG", "text": [ "vancomycin" ], "offsets": [ [ 525, 535 ] ], "normalized": [] }, { "id": "11206187_T4", "type": "DRUG", "text": [ "galangin" ], "offsets": [ [ 690, 698 ] ], "normalized": [] }, { "id": "11206187_T5", "type": "DRUG", "text": [ "vancomycin" ], "offsets": [ [ 976, 986 ] ], "normalized": [] } ]

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[ { "id": "10978746__text", "type": "abstract", "text": [ "Differential regulation of tyrosine phosphorylation in tumor cells by contortrostatin, a homodimeric disintegrin, and monomeric disintegrins echistatin and flavoridin. The homodimeric disintegrin contortrostatin was compared directly to the monomeric disintegrins echistatin and flavoridin for the ability to affect protein tyrosine phosphorylation in tumor cells. It was observed that contortrostatin had a dramatic effect on the tyrosine phosphorylation status of several proteins in T24 human bladder cancer cells, including robust induction of phosphorylation of proteins in the range of 120-140 kDa. Echistatin alone had no effect on tyrosine phosphorylation in T24 cells, but dose-dependently inhibits the effects of contortrostatin when both are added simultaneously. Among the proteins that undergo tyrosine phosphorylation in response to contortrostatin treatment is CAS, a 130 kDa adapter protein involved in integrin signaling. Flavoridin alone was found to have no effect on CAS, but can completely block contortrostatin-induced phosphorylation of this protein in MDA-MB-435 cells. These observations strongly suggest that the homodimeric structure of contortrostatin functionally distinguishes it from other monomeric members of the disintegrin family." ], "offsets": [ [ 0, 1265 ] ] } ]

[ { "id": "10978746_T1", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 70, 85 ] ], "normalized": [] }, { "id": "10978746_T2", "type": "DRUG_N", "text": [ "echistatin" ], "offsets": [ [ 141, 151 ] ], "normalized": [] }, { "id": "10978746_T3", "type": "DRUG_N", "text": [ "flavoridin" ], "offsets": [ [ 156, 166 ] ], "normalized": [] }, { "id": "10978746_T4", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 196, 211 ] ], "normalized": [] }, { "id": "10978746_T5", "type": "DRUG_N", "text": [ "echistatin" ], "offsets": [ [ 264, 274 ] ], "normalized": [] }, { "id": "10978746_T6", "type": "DRUG_N", "text": [ "flavoridin" ], "offsets": [ [ 279, 289 ] ], "normalized": [] }, { "id": "10978746_T7", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 386, 401 ] ], "normalized": [] }, { "id": "10978746_T8", "type": "DRUG_N", "text": [ "Echistatin" ], "offsets": [ [ 605, 615 ] ], "normalized": [] }, { "id": "10978746_T9", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 723, 738 ] ], "normalized": [] }, { "id": "10978746_T10", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 847, 862 ] ], "normalized": [] }, { "id": "10978746_T11", "type": "DRUG_N", "text": [ "Flavoridin" ], "offsets": [ [ 939, 949 ] ], "normalized": [] }, { "id": "10978746_T12", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 1017, 1032 ] ], "normalized": [] }, { "id": "10978746_T13", "type": "DRUG_N", "text": [ "contortrostatin" ], "offsets": [ [ 1164, 1179 ] ], "normalized": [] } ]

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[ { "id": "10978746_R1", "type": "EFFECT", "arg1_id": "10978746_T8", "arg2_id": "10978746_T9", "normalized": [] }, { "id": "10978746_R2", "type": "EFFECT", "arg1_id": "10978746_T11", "arg2_id": "10978746_T12", "normalized": [] } ]

[ { "id": "10978751__text", "type": "abstract", "text": [ "Modification of surface histidine residues abolishes the cytotoxic activity of Clostridium difficile toxin A. Clostridium difficile toxin A displays both cytotoxic and enterotoxic activities. It has recently been demonstrated that toxin A exerts its cytotoxic effect by the glucosylation of the small GTP-binding proteins of the Rho family. Diethyl pyrocarbonate, at pH 7.0, was used to chemically modify exposed histidine residues on toxin A. Modification of toxin A with diethyl pyrocarbonate abolished both its cytotoxic activity and the ability of the toxin to bind Zn-Sepharose gel. Treatment of toxin A with [(14)C]-diethyl pyrocarbonate revealed concentration dependent labelling of histidine residues on the toxin molecules. The effects of diethyl pyrocarbonate could be reversed by hydroxylamine treatment. These data suggest the modified histidine residues on toxin A are critical to its cytotoxic activity. Histidine modification had no effect on the glucosyl transferase enzyme activity of toxin A. However, modification abolished the 'cold' binding of toxin to bovine thyroglobulin in an ELISA and reduced ligand binding activity in a rabbit erythrocyte haemagglutination assay. The data suggest that the histidine residues may be crucial to the receptor-binding activity of toxin A. Exposed histidines on toxin A are available for zinc chelation, and these have been exploited in the development of a novel purification protocol for toxin A using zinc-chelating chromatography." ], "offsets": [ [ 0, 1491 ] ] } ]

[ { "id": "10978751_T1", "type": "DRUG_N", "text": [ "Clostridium difficile toxin A" ], "offsets": [ [ 79, 108 ] ], "normalized": [] }, { "id": "10978751_T2", "type": "DRUG_N", "text": [ "Clostridium difficile toxin A" ], "offsets": [ [ 110, 139 ] ], "normalized": [] }, { "id": "10978751_T3", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 231, 238 ] ], "normalized": [] }, { "id": "10978751_T4", "type": "DRUG_N", "text": [ "Diethyl pyrocarbonate" ], "offsets": [ [ 341, 362 ] ], "normalized": [] }, { "id": "10978751_T5", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 435, 442 ] ], "normalized": [] }, { "id": "10978751_T6", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 460, 467 ] ], "normalized": [] }, { "id": "10978751_T7", "type": "DRUG_N", "text": [ "diethyl pyrocarbonate" ], "offsets": [ [ 473, 494 ] ], "normalized": [] }, { "id": "10978751_T8", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 601, 608 ] ], "normalized": [] }, { "id": "10978751_T9", "type": "DRUG_N", "text": [ "diethyl pyrocarbonate" ], "offsets": [ [ 622, 643 ] ], "normalized": [] }, { "id": "10978751_T10", "type": "DRUG_N", "text": [ "diethyl pyrocarbonate" ], "offsets": [ [ 748, 769 ] ], "normalized": [] }, { "id": "10978751_T11", "type": "DRUG_N", "text": [ "hydroxylamine" ], "offsets": [ [ 791, 804 ] ], "normalized": [] }, { "id": "10978751_T12", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 870, 877 ] ], "normalized": [] }, { "id": "10978751_T13", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 1002, 1009 ] ], "normalized": [] }, { "id": "10978751_T14", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 1288, 1295 ] ], "normalized": [] }, { "id": "10978751_T15", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 1319, 1326 ] ], "normalized": [] }, { "id": "10978751_T16", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 1345, 1349 ] ], "normalized": [] }, { "id": "10978751_T17", "type": "DRUG_N", "text": [ "toxin A" ], "offsets": [ [ 1447, 1454 ] ], "normalized": [] }, { "id": "10978751_T18", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 1461, 1465 ] ], "normalized": [] } ]

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[ { "id": "11137351__text", "type": "abstract", "text": [ "Effect of ginsenosides on voltage-dependent Ca(2+) channel subtypes in bovine chromaffin cells. In previous reports we have shown that ginsenosides inhibit high threshold voltage-dependent Ca(2+) channels in neuronal cells. However, these studies did not show whether ginsenosides-induced inhibition of Ca(2+) currents discriminates among the various Ca(2+) channel subtypes, although it is known that there are at least five different Ca(2+) channel subtypes in neuronal cells. In this study we investigated the effect of ginsenosides on high threshold voltage-dependent Ca(2+) channel subtypes using their selective Ca(2+) channel blockers nimodipine (L-type), omega-conotoxin GVIA (N-type), or omega-agatoxin IVA (P-type) in bovine chromaffin cells. We could observe that ginsenosides inhibited high threshold voltage-dependent Ca(2+) currents in a dose-dependent manner. The IC(50) was about 120 microgram/ml. Nimodipine had no effect on ginsenosides response. These data suggest that ginsenosides are negatively coupled to three types of calcium channels in bovine chromaffin cell, including an omega-conotoxin GVIA-sensitive (N-type) channel, an omega-agatoxin IVA-sensitive (P-type) channel and nimodipine/omega-conotoxin GVIA/omega-agatoxin VIA-resistant (presumptive Q-type) channel. Thus, the selective regulation of voltage-dependent Ca(2+) subtypes by ginsenosides in bovine chromaffin cell could be the cellular basis of antistress effects induced by ginseng." ], "offsets": [ [ 0, 1472 ] ] } ]

[ { "id": "11137351_T1", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 10, 22 ] ], "normalized": [] }, { "id": "11137351_T2", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 135, 147 ] ], "normalized": [] }, { "id": "11137351_T3", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 268, 280 ] ], "normalized": [] }, { "id": "11137351_T4", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 523, 535 ] ], "normalized": [] }, { "id": "11137351_T5", "type": "GROUP", "text": [ "selective Ca(2+) channel blockers" ], "offsets": [ [ 608, 641 ] ], "normalized": [] }, { "id": "11137351_T6", "type": "DRUG", "text": [ "nimodipine" ], "offsets": [ [ 642, 652 ] ], "normalized": [] }, { "id": "11137351_T7", "type": "DRUG_N", "text": [ "omega-conotoxin GVIA" ], "offsets": [ [ 663, 683 ] ], "normalized": [] }, { "id": "11137351_T8", "type": "DRUG_N", "text": [ "omega-agatoxin IVA" ], "offsets": [ [ 697, 715 ] ], "normalized": [] }, { "id": "11137351_T9", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 775, 787 ] ], "normalized": [] }, { "id": "11137351_T10", "type": "DRUG", "text": [ "Nimodipine" ], "offsets": [ [ 914, 924 ] ], "normalized": [] }, { "id": "11137351_T11", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 942, 954 ] ], "normalized": [] }, { "id": "11137351_T12", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 989, 1001 ] ], "normalized": [] }, { "id": "11137351_T13", "type": "DRUG_N", "text": [ "omega-conotoxin GVIA" ], "offsets": [ [ 1100, 1120 ] ], "normalized": [] }, { "id": "11137351_T14", "type": "DRUG_N", "text": [ "omega-agatoxin IVA" ], "offsets": [ [ 1152, 1170 ] ], "normalized": [] }, { "id": "11137351_T15", "type": "DRUG", "text": [ "nimodipine" ], "offsets": [ [ 1202, 1212 ] ], "normalized": [] }, { "id": "11137351_T16", "type": "DRUG_N", "text": [ "omega-conotoxin GVIA" ], "offsets": [ [ 1213, 1233 ] ], "normalized": [] }, { "id": "11137351_T17", "type": "DRUG_N", "text": [ "omega-agatoxin VIA" ], "offsets": [ [ 1234, 1252 ] ], "normalized": [] }, { "id": "11137351_T18", "type": "DRUG_N", "text": [ "ginsenosides" ], "offsets": [ [ 1364, 1376 ] ], "normalized": [] }, { "id": "11137351_T19", "type": "DRUG", "text": [ "ginseng" ], "offsets": [ [ 1464, 1471 ] ], "normalized": [] } ]

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[ { "id": "11115418__text", "type": "abstract", "text": [ "The mechanism of resveratrol-induced vasorelaxation differs in the mesenteric resistance arteries of lean and obese rats. Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P<0.001) endothelial dysfunction, as indicated by a decrease (>20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5-35 micromol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of >95% at a concentration of 35 micromol/l. However, L-NAME (100 and 300 micromol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration-responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO." ], "offsets": [ [ 0, 1674 ] ] } ]

[ { "id": "11115418_T1", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 17, 28 ] ], "normalized": [] }, { "id": "11115418_T2", "type": "DRUG_N", "text": [ "Resveratrol" ], "offsets": [ [ 122, 133 ] ], "normalized": [] }, { "id": "11115418_T3", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 226, 237 ] ], "normalized": [] }, { "id": "11115418_T4", "type": "DRUG_N", "text": [ "Resveratrol" ], "offsets": [ [ 537, 548 ] ], "normalized": [] }, { "id": "11115418_T5", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 653, 666 ] ], "normalized": [] }, { "id": "11115418_T6", "type": "DRUG", "text": [ "KCl" ], "offsets": [ [ 685, 688 ] ], "normalized": [] }, { "id": "11115418_T7", "type": "DRUG_N", "text": [ "L-NAME" ], "offsets": [ [ 888, 894 ] ], "normalized": [] }, { "id": "11115418_T8", "type": "DRUG_N", "text": [ "reseveratrol" ], "offsets": [ [ 949, 961 ] ], "normalized": [] }, { "id": "11115418_T9", "type": "DRUG", "text": [ "Indomethacin" ], "offsets": [ [ 1051, 1063 ] ], "normalized": [] }, { "id": "11115418_T10", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 1097, 1108 ] ], "normalized": [] }, { "id": "11115418_T11", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 1172, 1185 ] ], "normalized": [] }, { "id": "11115418_T12", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 1247, 1258 ] ], "normalized": [] }, { "id": "11115418_T13", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 1413, 1424 ] ], "normalized": [] }, { "id": "11115418_T14", "type": "DRUG_N", "text": [ "resveratrol" ], "offsets": [ [ 1549, 1560 ] ], "normalized": [] } ]

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[ { "id": "11206417__text", "type": "abstract", "text": [ "Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans. AIMS/HYPOTHESIS: There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy. METHODS: We carried out two different 3-way crossover studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/ 1, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively. RESULTS: Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions. CONCLUSIONS/INTERPRETATION: Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed." ], "offsets": [ [ 0, 1599 ] ] } ]

[ { "id": "11206417_T1", "type": "DRUG", "text": [ "Glucose" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "11206417_T2", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 12, 19 ] ], "normalized": [] }, { "id": "11206417_T3", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 131, 138 ] ], "normalized": [] }, { "id": "11206417_T4", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 143, 150 ] ], "normalized": [] }, { "id": "11206417_T5", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 275, 282 ] ], "normalized": [] }, { "id": "11206417_T6", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 577, 584 ] ], "normalized": [] }, { "id": "11206417_T7", "type": "DRUG", "text": [ "somatostatin" ], "offsets": [ [ 719, 731 ] ], "normalized": [] }, { "id": "11206417_T8", "type": "DRUG", "text": [ "Insulin" ], "offsets": [ [ 981, 988 ] ], "normalized": [] }, { "id": "11206417_T9", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1182, 1189 ] ], "normalized": [] }, { "id": "11206417_T10", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 1194, 1201 ] ], "normalized": [] }, { "id": "11206417_T11", "type": "DRUG", "text": [ "somatostatin" ], "offsets": [ [ 1221, 1233 ] ], "normalized": [] }, { "id": "11206417_T12", "type": "DRUG", "text": [ "Glucose" ], "offsets": [ [ 1314, 1321 ] ], "normalized": [] }, { "id": "11206417_T13", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 1326, 1333 ] ], "normalized": [] } ]

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[ { "id": "11166779__text", "type": "abstract", "text": [ "Effects of etofibrate upon the metabolism of chylomicron-like emulsions in patients with coronary artery disease. Slow chylomicron intravascular catabolism has been associated with coronary artery disease and screening for drugs that can speed-up this process can be important. In this study, the effects of etofibrate upon chylomicron metabolism was tested by determination of the plasma kinetics of a chylomicron-like emulsion model in 12 patients with coronary artery disease, aged 59+/-11 years, (total cholesterol: 240+/-41 mg/dl; triglycerides: 188+/-42 mg/dl) submitted to a randomized, crossover, double-blind, placebo-controlled study with administration of 1 g per day etofibrate or placebo for 1-month. A 1-month washout period was inserted between the treatment periods. Patients were intravenously injected a chylomicron-like emulsion doubly labeled with 14C-cholesteryl oleate and 3H-triolein at baseline and after treatments. After etofibrate treatment, there was decrease of total cholesterol and triglyceride plasma levels and a trend to increase high-density lipoprotein cholesterol plasma levels. Etofibrate elicited 62% enhancement of post-heparin lipolytic activity and 100% increase of 3H-triglyceride fractional clearance rate compared with placebo treatment. 14C-cholesterol ester fractional clearance rate was 260% greater after etofibrate than after placebo. Therefore, a potent effect of etofibrate on both chylomicron lipolysis and remnant removal was achieved, indicating that this drug can be used to improve this metabolism in future prospective studies." ], "offsets": [ [ 0, 1585 ] ] } ]

[ { "id": "11166779_T1", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 11, 21 ] ], "normalized": [] }, { "id": "11166779_T2", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 308, 318 ] ], "normalized": [] }, { "id": "11166779_T3", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 679, 689 ] ], "normalized": [] }, { "id": "11166779_T4", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "11166779_T5", "type": "DRUG", "text": [ "Etofibrate" ], "offsets": [ [ 1116, 1126 ] ], "normalized": [] }, { "id": "11166779_T6", "type": "DRUG", "text": [ "heparin" ], "offsets": [ [ 1160, 1167 ] ], "normalized": [] }, { "id": "11166779_T7", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 1354, 1364 ] ], "normalized": [] }, { "id": "11166779_T8", "type": "DRUG", "text": [ "etofibrate" ], "offsets": [ [ 1415, 1425 ] ], "normalized": [] } ]

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[ { "id": "11166779_R1", "type": "EFFECT", "arg1_id": "11166779_T5", "arg2_id": "11166779_T6", "normalized": [] } ]

[ { "id": "1167797__text", "type": "abstract", "text": [ "Interaction between oxytocin and antidiuretic hormone and its effect on the milk secretion by alveoli of the mammary gland of lactating rats. Interaction between exogenous and endogenous oxytocin and vasopressin was found to affect the mechanism of milk ejection by the alveoli of the mammary gland in lactating rats. Inhibition and stimulation of the effect of oxytocin on milk ejection by vasopressin was demonstrated. On the basis of the principles observed the concentrations fo these hormones were investigated in the plasma of dogs deprived of water for 3 days and then allowed to drink." ], "offsets": [ [ 0, 593 ] ] } ]

[ { "id": "1167797_T1", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 20, 28 ] ], "normalized": [] }, { "id": "1167797_T2", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 187, 195 ] ], "normalized": [] }, { "id": "1167797_T3", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 362, 370 ] ], "normalized": [] } ]

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[ { "id": "11206048__text", "type": "abstract", "text": [ "Phenytoin intoxication induced by fluvoxamine. A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine." ], "offsets": [ [ 0, 703 ] ] } ]

[ { "id": "11206048_T1", "type": "DRUG", "text": [ "fluvoxamine" ], "offsets": [ [ 34, 45 ] ], "normalized": [] }, { "id": "11206048_T2", "type": "DRUG", "text": [ "fluvoxamine" ], "offsets": [ [ 108, 119 ] ], "normalized": [] }, { "id": "11206048_T3", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 190, 199 ] ], "normalized": [] }, { "id": "11206048_T4", "type": "DRUG", "text": [ "fluvoxamine" ], "offsets": [ [ 256, 267 ] ], "normalized": [] }, { "id": "11206048_T5", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 317, 326 ] ], "normalized": [] }, { "id": "11206048_T6", "type": "DRUG", "text": [ "drugs" ], "offsets": [ [ 337, 342 ] ], "normalized": [] }, { "id": "11206048_T7", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 367, 376 ] ], "normalized": [] }, { "id": "11206048_T8", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 437, 446 ] ], "normalized": [] }, { "id": "11206048_T9", "type": "DRUG", "text": [ "CYP2C9" ], "offsets": [ [ 479, 485 ] ], "normalized": [] }, { "id": "11206048_T10", "type": "DRUG", "text": [ "CYP2C9" ], "offsets": [ [ 589, 595 ] ], "normalized": [] }, { "id": "11206048_T11", "type": "DRUG", "text": [ "CYP2C9" ], "offsets": [ [ 672, 678 ] ], "normalized": [] }, { "id": "11206048_T12", "type": "DRUG", "text": [ "fluvoxamine" ], "offsets": [ [ 691, 702 ] ], "normalized": [] } ]

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[ { "id": "11180038__text", "type": "abstract", "text": [ "Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. OBJECTIVE: Our objective was to characterize the steady-state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation. METHOD: This study was a multicenter randomized double-blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone. Blood sampling for the pharmacokinetics of everolimus and cyclosporine was performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, and 12. Everolimus dose-proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure-response relationships between area under the blood concentration-time curve (AUC) and changes in platelets, leukocytes, and lipids were explored with the median-effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed in the context of ANOVA. RESULTS: Everolimus steady state was reached on or before day 7, with a median 3-fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady-state maximum concentration and AUC were dose proportional over the full dose range when assessed on day 1, as well as for the full duration of the study at steady state. There was evidence for longitudinal stability in AUC of everolimus during the course of the study. The interindividual pharmacokinetic variability for AUC was 85.4% and intraindividual, interoccasion variability was 40.8%. Age (range, 17-69 years), weight (range, 49-106 kg), and sex (65 men and 36 women) were not significant contributors to variability. There was an increasing incidence of transient thrombocytopenia (or =100 x 10(9)/L) with increasing everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study regardless of the co-administered everolimus dose level (P = .13, .82, and .76, respectively). CONCLUSIONS: Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. For a 4-fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics." ], "offsets": [ [ 0, 2551 ] ] } ]

[ { "id": "11180038_T1", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 27, 37 ] ], "normalized": [] }, { "id": "11180038_T2", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 182, 194 ] ], "normalized": [] }, { "id": "11180038_T3", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 278, 288 ] ], "normalized": [] }, { "id": "11180038_T4", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 293, 305 ] ], "normalized": [] }, { "id": "11180038_T5", "type": "DRUG", "text": [ "ciclosporin" ], "offsets": [ [ 312, 323 ] ], "normalized": [] }, { "id": "11180038_T6", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 556, 566 ] ], "normalized": [] }, { "id": "11180038_T7", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 626, 638 ] ], "normalized": [] }, { "id": "11180038_T8", "type": "DRUG", "text": [ "prednisone" ], "offsets": [ [ 643, 653 ] ], "normalized": [] }, { "id": "11180038_T9", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 698, 708 ] ], "normalized": [] }, { "id": "11180038_T10", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 713, 725 ] ], "normalized": [] }, { "id": "11180038_T11", "type": "DRUG", "text": [ "Everolimus" ], "offsets": [ [ 809, 819 ] ], "normalized": [] }, { "id": "11180038_T12", "type": "DRUG", "text": [ "Everolimus" ], "offsets": [ [ 933, 943 ] ], "normalized": [] }, { "id": "11180038_T13", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 1154, 1166 ] ], "normalized": [] }, { "id": "11180038_T14", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 1218, 1228 ] ], "normalized": [] }, { "id": "11180038_T15", "type": "DRUG", "text": [ "Everolimus" ], "offsets": [ [ 1286, 1296 ] ], "normalized": [] }, { "id": "11180038_T16", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 1687, 1697 ] ], "normalized": [] }, { "id": "11180038_T17", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 2087, 2097 ] ], "normalized": [] }, { "id": "11180038_T18", "type": "DRUG", "text": [ "Cyclosporine" ], "offsets": [ [ 2113, 2125 ] ], "normalized": [] }, { "id": "11180038_T19", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 2265, 2275 ] ], "normalized": [] }, { "id": "11180038_T20", "type": "DRUG", "text": [ "Everolimus" ], "offsets": [ [ 2339, 2349 ] ], "normalized": [] }, { "id": "11180038_T21", "type": "DRUG", "text": [ "everolimus" ], "offsets": [ [ 2456, 2466 ] ], "normalized": [] }, { "id": "11180038_T22", "type": "DRUG", "text": [ "cyclosporine" ], "offsets": [ [ 2511, 2523 ] ], "normalized": [] } ]

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[ { "id": "6545279__text", "type": "abstract", "text": [ "Excretion of thioethers in urine after exposure to electrophilic chemicals. Electrophilic agents--a class of chemicals that includes most genotoxic compounds--can be inactivated by reaction with glutathione or other SH-bearing molecules. The conjugates so formed often appear in the urine as mercapturic acids or other thioether products. This paper critically reviews the suitability of the urinary thioether assay as a method for the detection of exposure to electrophilic agents or their precursors. In practice, the greatest value of the thioether assay appears to lie in its signal function. This is demonstrated for cigarette smokers and industrial workers involved in chemical waste incineration. Whenever increased thioether excretion is observed, it is likely to be due to exposure to one or more suspect compounds. However, when the thioether concentration ranges within the limits of the normal value, one must not conclude that there is no, or negligible, exposure. More specific applications of the assay of thio compounds in urine allow development of selective methods that may be useful for biological monitoring." ], "offsets": [ [ 0, 1129 ] ] } ]

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[ { "id": "6443625__text", "type": "abstract", "text": [ "Changes in urinary homocysteine following synthetic steroidal estrogen and progestogen administration to rats. The present work involved the administration of both ethynyl estradiol and levonorgestrel to groups of rats, followed by determination of the homocysteine excretion rate in urine. The results indicate that a statistically significant difference exists between the excreted levels of homocysteine in the urine of both control and levonorgestrel-treated rats and the levels shown by rats treated with ethynyl estradiol. The implications of these results are discussed, especially with respect to observations which indicate that homocysteine may be a precipitating factor in the development of thrombosis. Also included in this paper is a study which confirms the identity of the HPLC peak as being homocysteine by forming a radioactive derivative of this particular sulphydryl-containing amino acid, and then analysing the resulting mixture by TLC." ], "offsets": [ [ 0, 958 ] ] } ]

[ { "id": "6443625_T1", "type": "GROUP", "text": [ "synthetic steroidal estrogen" ], "offsets": [ [ 42, 70 ] ], "normalized": [] }, { "id": "6443625_T2", "type": "GROUP", "text": [ "synthetic steroidal", "progestogen" ], "offsets": [ [ 42, 61 ], [ 75, 86 ] ], "normalized": [] }, { "id": "6443625_T3", "type": "DRUG", "text": [ "ethynyl estradiol" ], "offsets": [ [ 164, 181 ] ], "normalized": [] }, { "id": "6443625_T4", "type": "DRUG", "text": [ "levonorgestrel" ], "offsets": [ [ 186, 200 ] ], "normalized": [] }, { "id": "6443625_T5", "type": "DRUG", "text": [ "levonorgestrel" ], "offsets": [ [ 440, 454 ] ], "normalized": [] }, { "id": "6443625_T6", "type": "DRUG", "text": [ "ethynyl estradiol" ], "offsets": [ [ 510, 527 ] ], "normalized": [] } ]

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[ { "id": "3871245__text", "type": "abstract", "text": [ "Neurochemical and functional consequences following 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and methamphetamine. The neurochemical and functional consequences following MPTP administration to the rat were evaluated and compared to similar effects following methamphetamine administration. It was observed that MPTP induced long lasting depletions of striatal dopamine concentrations and this neurotoxic effect could be prevented by pargyline pretreatment. The MPTP-induced neuronal damage produced a tolerance to the disruptive effects of amphetamine and a supersensitivity to the disruptive effects of apomorphine in rats responding in a schedule controlled paradigm. Methamphetamine, like MPTP, produced depletions of striatal dopamine but these actions were potentiated by pargyline pretreatment. These observations are discussed in reference to possible deleterious effects following the administration of pargyline to patients with Parkinson's Disease." ], "offsets": [ [ 0, 969 ] ] } ]

[ { "id": "3871245_T1", "type": "DRUG_N", "text": [ "1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine" ], "offsets": [ [ 52, 96 ] ], "normalized": [] }, { "id": "3871245_T2", "type": "DRUG_N", "text": [ "MPTP" ], "offsets": [ [ 98, 102 ] ], "normalized": [] }, { "id": "3871245_T3", "type": "DRUG", "text": [ "methamphetamine" ], "offsets": [ [ 108, 123 ] ], "normalized": [] }, { "id": "3871245_T4", "type": "DRUG_N", "text": [ "MPTP" ], "offsets": [ [ 181, 185 ] ], "normalized": [] }, { "id": "3871245_T5", "type": "DRUG", "text": [ "methamphetamine" ], "offsets": [ [ 269, 284 ] ], "normalized": [] }, { "id": "3871245_T6", "type": "DRUG_N", "text": [ "MPTP" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "3871245_T7", "type": "DRUG", "text": [ "pargyline" ], "offsets": [ [ 444, 453 ] ], "normalized": [] }, { "id": "3871245_T8", "type": "DRUG", "text": [ "MPTP" ], "offsets": [ [ 472, 476 ] ], "normalized": [] }, { "id": "3871245_T9", "type": "DRUG", "text": [ "amphetamine" ], "offsets": [ [ 551, 562 ] ], "normalized": [] }, { "id": "3871245_T10", "type": "DRUG", "text": [ "apomorphine" ], "offsets": [ [ 615, 626 ] ], "normalized": [] }, { "id": "3871245_T11", "type": "DRUG", "text": [ "Methamphetamine" ], "offsets": [ [ 681, 696 ] ], "normalized": [] }, { "id": "3871245_T12", "type": "DRUG_N", "text": [ "MPTP" ], "offsets": [ [ 703, 707 ] ], "normalized": [] }, { "id": "3871245_T13", "type": "DRUG", "text": [ "pargyline" ], "offsets": [ [ 788, 797 ] ], "normalized": [] }, { "id": "3871245_T14", "type": "DRUG", "text": [ "pargyline" ], "offsets": [ [ 922, 931 ] ], "normalized": [] } ]

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[ { "id": "3871245_R1", "type": "EFFECT", "arg1_id": "3871245_T6", "arg2_id": "3871245_T7", "normalized": [] }, { "id": "3871245_R2", "type": "EFFECT", "arg1_id": "3871245_T8", "arg2_id": "3871245_T9", "normalized": [] }, { "id": "3871245_R3", "type": "EFFECT", "arg1_id": "3871245_T8", "arg2_id": "3871245_T10", "normalized": [] }, { "id": "3871245_R4", "type": "EFFECT", "arg1_id": "3871245_T11", "arg2_id": "3871245_T13", "normalized": [] } ]

[ { "id": "1113260__text", "type": "abstract", "text": [ "In vitro interaction of prostaglandin F2alpha and oxytocin in placental vessels. The interaction of prostaglandin F2alpha and synthetic oxytocin on placental vessels was studied in vitro. Resistance was measured near the placental margin after spontaneous term delivery. In seven experiments reactions to norepinephrine and oxytocin were PGF2alpha. PGF2alpha produced significantly increased vasoconstriction after a single administration of oxytocin. In eight experiments the perfusion medium contained oxytocin. There was no change after a single dose of PGF2alpha. The reaction after norepinephrine remained the same in both groups of experiments. There is thus an enhancement effect There is thus an enhancement effect of PGF2alpha upon the reaction of placental vessels to oxytocin in vitro." ], "offsets": [ [ 0, 796 ] ] } ]

[ { "id": "1113260_T1", "type": "DRUG", "text": [ "prostaglandin F2alpha" ], "offsets": [ [ 24, 45 ] ], "normalized": [] }, { "id": "1113260_T2", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 50, 58 ] ], "normalized": [] }, { "id": "1113260_T3", "type": "DRUG", "text": [ "prostaglandin F2alpha" ], "offsets": [ [ 100, 121 ] ], "normalized": [] }, { "id": "1113260_T4", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 136, 144 ] ], "normalized": [] }, { "id": "1113260_T5", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 305, 319 ] ], "normalized": [] }, { "id": "1113260_T6", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 324, 332 ] ], "normalized": [] }, { "id": "1113260_T7", "type": "DRUG", "text": [ "PGF2alpha" ], "offsets": [ [ 338, 347 ] ], "normalized": [] }, { "id": "1113260_T8", "type": "DRUG", "text": [ "PGF2alpha" ], "offsets": [ [ 349, 358 ] ], "normalized": [] }, { "id": "1113260_T9", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 442, 450 ] ], "normalized": [] }, { "id": "1113260_T10", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 504, 512 ] ], "normalized": [] }, { "id": "1113260_T11", "type": "DRUG", "text": [ "PGF2alpha" ], "offsets": [ [ 557, 566 ] ], "normalized": [] }, { "id": "1113260_T12", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 587, 601 ] ], "normalized": [] }, { "id": "1113260_T13", "type": "DRUG", "text": [ "PGF2alpha" ], "offsets": [ [ 726, 735 ] ], "normalized": [] }, { "id": "1113260_T14", "type": "DRUG", "text": [ "oxytocin" ], "offsets": [ [ 778, 786 ] ], "normalized": [] } ]

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[ { "id": "1113260_R1", "type": "INT", "arg1_id": "1113260_T1", "arg2_id": "1113260_T2", "normalized": [] }, { "id": "1113260_R2", "type": "EFFECT", "arg1_id": "1113260_T8", "arg2_id": "1113260_T9", "normalized": [] }, { "id": "1113260_R3", "type": "EFFECT", "arg1_id": "1113260_T13", "arg2_id": "1113260_T14", "normalized": [] } ]

[ { "id": "11155575__text", "type": "abstract", "text": [ "Systemic antibiotic agents. Understanding the breadth of systemic antimicrobial agents available for use by the dermatologist and their associated side-effect profiles and drug interactions allows the clinician to offer patients optimal care in the management of cutaneous infectious disease." ], "offsets": [ [ 0, 292 ] ] } ]

[ { "id": "11155575_T1", "type": "GROUP", "text": [ "antibiotic agents" ], "offsets": [ [ 9, 26 ] ], "normalized": [] }, { "id": "11155575_T2", "type": "GROUP", "text": [ "antimicrobial agents" ], "offsets": [ [ 66, 86 ] ], "normalized": [] } ]

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[ { "id": "11125022__text", "type": "abstract", "text": [ "Increased stability of nucleophosmin/B23 in anti-apoptotic effect of ras during serum deprivation. We obtained evidence that increased stability of nucleophosmin/B23 is involved in antiapoptotic effect of ras during serum deprivation. Nucleophosmin/B23 in serum-deprived (0% serum) NIH-3T3 cells was found to be highly unstable with a half-life less than 4 h. In contrast, nucleophosmin/B23 in serum-deprived ras-transformed (RAS-3T3) cells was as stable as that in serum-supplemented NIH-3T3 or RAS-3T3 cells. Treatment of RAS-3T3 cells with nucleophosmin/B23 antisense oligomer significantly potentiated the apoptosis induced by serum deprivation. Much less caspase-3 activity was noted in the lysate derived from serum-deprived RAS-3T3 cells compared with that in the lysate of serum-deprived NIH-3T3 cells. Cell permeable caspase-3 inhibitor added in the medium blocked the decrease of nucleophosmin/B23 and apoptosis induced by serum deprivation in NIH-3T3 cells. The inhibitor, on the other hand, promoted significant decrease of nucleolin/C23 in NIH-3T3 cells during serum deprivation. Unlike nucleolin/C23, down-regulation of nucleophosmin/B23 was thus not proliferation-dependent but caspase-3- and apoptosis-dependent. Our results indicate important relationships among ras, nucleophosmin/B23, activation of caspase-3, and induction of apoptosis." ], "offsets": [ [ 0, 1356 ] ] } ]

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[ { "id": "2982252__text", "type": "abstract", "text": [ "Influence of calcium-channel blockers on platelet function and arachidonic acid metabolism. Available data indicate that platelet function and arachidonic acid metabolism are important factors in hemostasis and regulation of vascular tone. Plasma membrane and intracellular mobilization of calcium ions are intimately related to platelet activation and release of platelet contents. Release of arachidonic acid from membrane phospholipids as well as subsequent synthesis and release of vasoconstrictor thromboxane A2 are also regulated by movement of calcium ions. Adenosine 3':5'-cyclic phosphate in turn controls levels of free calcium ions in platelets and regulates calcium-dependent reactions. Slow-channel calcium blockers, such as verapamil, diltiazem and nifedipine, inhibit platelet activation in vitro, and decrease platelet adhesion intravascularly. These agents have also been shown to decrease platelet nucleotide release and thromboxane A2 generation. Some preliminary data suggest that calcium blockers also increase generation of vasodilator and platelet antiaggregant prostacyclin, which could contribute to decrease in platelet function. These effects of calcium blockers on platelet function and arachidonic acid metabolism could contribute in part to their efficacy in patients with ischemic heart disease." ], "offsets": [ [ 0, 1326 ] ] } ]

[ { "id": "2982252_T1", "type": "GROUP", "text": [ "calcium-channel blockers" ], "offsets": [ [ 13, 37 ] ], "normalized": [] }, { "id": "2982252_T2", "type": "GROUP", "text": [ "Slow-channel calcium blockers" ], "offsets": [ [ 699, 728 ] ], "normalized": [] }, { "id": "2982252_T3", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 738, 747 ] ], "normalized": [] }, { "id": "2982252_T4", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 749, 758 ] ], "normalized": [] }, { "id": "2982252_T5", "type": "DRUG", "text": [ "nifedipine" ], "offsets": [ [ 763, 773 ] ], "normalized": [] }, { "id": "2982252_T6", "type": "GROUP", "text": [ "calcium blockers" ], "offsets": [ [ 1001, 1017 ] ], "normalized": [] }, { "id": "2982252_T7", "type": "GROUP", "text": [ "calcium blockers" ], "offsets": [ [ 1173, 1189 ] ], "normalized": [] } ]

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[ { "id": "7780789__text", "type": "abstract", "text": [ "[Hippocampus as interaction sites between cerebral memory systems]\nMost of the current theories assume that there are multiple forms of memory that are supported by separate brain systems and have different characteristics. Animals studies on the various dual-memory theories have been carried out mainly on the basis of hippocampal system function. Specifically, they have focused on aspects of learning and memory that are impaired (vs. spared) by lesions of the hippocampal formation. However, there are several instances in the animal literature showing that hippocampal lesions actually produced enhanced learning and memory function. Moreover, the acquisition of tasks that are facilitated by hippocampal lesions (or dysfunction) is nevertheless associated, in intact subjects, with specific neurobiological alterations in the hippocampus. This problem has been analysed using two different tasks in mice: a bar-press conditioning and a spatial discrimination task. Results showed that, depending on the task considered, the same pharmacological treatment produced either a facilitation or an impairment of acquisition. Moreover, each task induced significant alterations in hippocampal adenylate cyclase activity but in opposite directions. Together with previous findings, these results suggest that the hippocampus is involved in both the so-called \"hippocampal-dependent\" \"hippocampal-independent\" forms of memory. It is postulated that some of the observed training-induced neurobiological alterations might reflect the interaction between two (or more) competing memory systems at the hippocampal level. Thus, in addition to its proposed specific information processing functions (i.e., relational), the hippocampus would play a role in addressing information to the brain memory system that, in a given situation, has the best adaptive value.(ABSTRACT TRUNCATED AT 250 WORDS)" ], "offsets": [ [ 0, 1888 ] ] } ]

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[ { "id": "11160777__text", "type": "abstract", "text": [ "New oral therapies for type 2 diabetes mellitus: The glitazones or insulin sensitizers. Type 2 diabetes mellitus is a growing problem not only in the United States but also across the world. There is now strong evidence that intensive control of blood glucose can significantly reduce and retard the microvascular complications of retinopathy, nephropathy, and neuropathy. Ultimately however, up to 80% of type 2 diabetics die from macrovascular cardiovascular disease. This increased incidence of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is strong evidence that insulin resistance is involved in the development of not only hyperglycemia, but also dyslipidemia, hypertension, hypercoagulation, vasculopathy, and ultimately atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed the insulin resistance or cardiovascular dysmetabolic syndrome. The thiazolidinediones (rosiglitazone and pioglitazone), a new class of oral antidiabetic agents, are \"insulin sensitizers\" and exert direct effects on the mechanisms of insulin resistance. These effects not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the cardiovascular dysmetabolic syndrome. Long-term studies are needed to determine whether the insulin-sensitizing effects of the glitazones can prevent or delay premature atherosclerotic cardiovascular disease, morbidity, and death." ], "offsets": [ [ 0, 1588 ] ] } ]

[ { "id": "11160777_T1", "type": "GROUP", "text": [ "glitazones" ], "offsets": [ [ 53, 63 ] ], "normalized": [] }, { "id": "11160777_T2", "type": "GROUP", "text": [ "thiazolidinediones" ], "offsets": [ [ 994, 1012 ] ], "normalized": [] }, { "id": "11160777_T3", "type": "DRUG", "text": [ "rosiglitazone" ], "offsets": [ [ 1014, 1027 ] ], "normalized": [] }, { "id": "11160777_T4", "type": "DRUG", "text": [ "pioglitazone" ], "offsets": [ [ 1032, 1044 ] ], "normalized": [] }, { "id": "11160777_T5", "type": "GROUP", "text": [ "antidiabetic agents" ], "offsets": [ [ 1067, 1086 ] ], "normalized": [] }, { "id": "11160777_T6", "type": "GROUP", "text": [ "glitazones" ], "offsets": [ [ 1485, 1495 ] ], "normalized": [] } ]

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[ { "id": "7794883__text", "type": "abstract", "text": [ "Interaction between glycine and glutamate in the development of spontaneous motility in chick embryos. In this study we investigated whether also glycine fulfils the function as co-activator in glutamatergic activation of NMDA receptors in the neuronal apparatus of spontaneous motility in chick embryos. The successive application of glycine (5 or 10 mg/kg egg weight (e.w.) and glutamate (15 mg/kg e.w.) The successive application of glycine (5 or 10 mg/kg egg weight (e.w.) and glutamate (15 mg/kg e.w.) in a 10 min interval significantly increased the activation of spontaneous motility of 17-day-old chick embryos in comparison with the effect of glutamate alone. This effect did not depend on the order of application of the drugs. In 13-day-old embryos, glycine was ineffective in both doses. It is concluded from these results that the modulatory effect of glycine is evidently a later developmental acquisition (after day 15 of incubation) in the embryogenesis of NMDA-ergic activation of spontaneous motility in chick embryos similarly as glycinergic inhibition." ], "offsets": [ [ 0, 1072 ] ] } ]

[ { "id": "7794883_T1", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 20, 27 ] ], "normalized": [] }, { "id": "7794883_T2", "type": "DRUG", "text": [ "glutamate" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "7794883_T3", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 146, 153 ] ], "normalized": [] }, { "id": "7794883_T4", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 335, 342 ] ], "normalized": [] }, { "id": "7794883_T5", "type": "DRUG", "text": [ "glutamate" ], "offsets": [ [ 380, 389 ] ], "normalized": [] }, { "id": "7794883_T6", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 436, 443 ] ], "normalized": [] }, { "id": "7794883_T7", "type": "DRUG", "text": [ "glutamate" ], "offsets": [ [ 481, 490 ] ], "normalized": [] }, { "id": "7794883_T8", "type": "DRUG", "text": [ "glutamate" ], "offsets": [ [ 652, 661 ] ], "normalized": [] }, { "id": "7794883_T9", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 761, 768 ] ], "normalized": [] }, { "id": "7794883_T10", "type": "DRUG", "text": [ "glycine" ], "offsets": [ [ 865, 872 ] ], "normalized": [] } ]

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[ { "id": "7794883_R1", "type": "EFFECT", "arg1_id": "7794883_T1", "arg2_id": "7794883_T2", "normalized": [] }, { "id": "7794883_R2", "type": "EFFECT", "arg1_id": "7794883_T6", "arg2_id": "7794883_T7", "normalized": [] } ]

[ { "id": "11213561__text", "type": "abstract", "text": [ "[Drug treatment of erection disorders in patients with cardiovascular disease]\nErectile dysfunction is a frequent condition in cardiovascular patients. Since the arrival of oral erection-supporting medication, patients want to know how safe sexual activity is in cardiovascular disease in general and during use of erection-supporting medication in particular. Sexual intercourse with a steady partner causes no more cardiovascular risk than normal daily activities such as ironing, 2 kilometers of walking without climbing, paperhanging, playing golf or gardening. The relative risk of myocardial infarction during sexual activity is not significantly higher than for healthy persons. The incidence of cardiovascular morbidity and mortality is not higher among users of sildenafil. Sildenafil is contraindicated in patients using long-acting nitrates or who may need to use short-acting nitrates, because the combination may cause a sharp fall of the blood pressure. No interactions have been observed with beta-receptor blockers, calcium antagonists, thiazide and loop diuretics and ACE inhibitors. Before prescribing a symptomatic (pharmaceutical) treatment for patients with an erection disorder, attention should be given tot the sexological, psychological and medical backgrounds of the disorder. Secondary prevention of atherosclerotic risk factors is also important: regulation of blood pressure and blood sugar level, hyperlipidaemia and obesity, as well as a change of lifestyle (giving up smoking, adapting of diet and more physical exertion). Patients with a very low cardiac capacity should be advised to refrain from treatment of the erection disorder." ], "offsets": [ [ 0, 1666 ] ] } ]

[ { "id": "11213561_T1", "type": "GROUP", "text": [ "erection-supporting medication" ], "offsets": [ [ 178, 208 ] ], "normalized": [] }, { "id": "11213561_T2", "type": "GROUP", "text": [ "erection-supporting medication" ], "offsets": [ [ 315, 345 ] ], "normalized": [] }, { "id": "11213561_T3", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 771, 781 ] ], "normalized": [] }, { "id": "11213561_T4", "type": "DRUG", "text": [ "Sildenafil" ], "offsets": [ [ 783, 793 ] ], "normalized": [] }, { "id": "11213561_T5", "type": "GROUP", "text": [ "long-acting nitrates" ], "offsets": [ [ 831, 851 ] ], "normalized": [] }, { "id": "11213561_T6", "type": "GROUP", "text": [ "short-acting nitrates" ], "offsets": [ [ 875, 896 ] ], "normalized": [] }, { "id": "11213561_T7", "type": "GROUP", "text": [ "beta-receptor blockers" ], "offsets": [ [ 1008, 1030 ] ], "normalized": [] }, { "id": "11213561_T8", "type": "GROUP", "text": [ "calcium antagonists" ], "offsets": [ [ 1032, 1051 ] ], "normalized": [] }, { "id": "11213561_T9", "type": "GROUP", "text": [ "thiazide", "diuretics" ], "offsets": [ [ 1053, 1061 ], [ 1071, 1080 ] ], "normalized": [] }, { "id": "11213561_T10", "type": "GROUP", "text": [ "loop diuretics" ], "offsets": [ [ 1066, 1080 ] ], "normalized": [] }, { "id": "11213561_T11", "type": "GROUP", "text": [ "ACE inhibitors" ], "offsets": [ [ 1085, 1099 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11213561_R1", "type": "ADVISE", "arg1_id": "11213561_T4", "arg2_id": "11213561_T5", "normalized": [] }, { "id": "11213561_R2", "type": "ADVISE", "arg1_id": "11213561_T4", "arg2_id": "11213561_T6", "normalized": [] } ]

[ { "id": "11125235__text", "type": "abstract", "text": [ "Suppression by verapamil of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in wistar rats. BACKGROUND: The effects of combined administration of bombesin and verapamil hydrochloride (verapamil), a calcium channel blocker, on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male Wistar rats. METHODS: From the beginning of the experiment, rats were given 10 weekly subcutaneous injections of AOM (7.4 mg/kg body weight) and subcutaneous injections of bombesin (40 microg/kg body weight) every other day, and from week 16, intraperitoneal injections of verapamil (10 or 20 mg/kg body weight) every other day until the end fo the experiment in week 45. RESULTS: Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum. Although verapamil administered at either dose had little or no effect on the enhancement of intestinal carcinogenesis by bombesin or on the location, histologic type, depth of involvement, labeling index, apoptotic index or tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. Verapamil also significantly decreased the incidence of lymphatic invasion of adenocarcinomas, which was enhanced by bombesin. CONCLUSION: These findings indicate that verapamil inhibits cancer metastasis through actions that do not affect the growth of intestinal cancers." ], "offsets": [ [ 0, 1534 ] ] } ]

[ { "id": "11125235_T1", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 15, 24 ] ], "normalized": [] }, { "id": "11125235_T2", "type": "DRUG_N", "text": [ "bombesin" ], "offsets": [ [ 28, 36 ] ], "normalized": [] }, { "id": "11125235_T3", "type": "DRUG_N", "text": [ "azoxymethane" ], "offsets": [ [ 109, 121 ] ], "normalized": [] }, { "id": "11125235_T4", "type": "DRUG_N", "text": [ "bombesin" ], "offsets": [ [ 192, 200 ] ], "normalized": [] }, { "id": "11125235_T5", "type": "DRUG", "text": [ "verapamil hydrochloride" ], "offsets": [ [ 205, 228 ] ], "normalized": [] }, { "id": "11125235_T6", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 230, 239 ] ], "normalized": [] }, { "id": "11125235_T7", "type": "GROUP", "text": [ "calcium channel blocker" ], "offsets": [ [ 244, 267 ] ], "normalized": [] }, { "id": "11125235_T8", "type": "DRUG_N", "text": [ "azoxymethane" ], "offsets": [ [ 352, 364 ] ], "normalized": [] }, { "id": "11125235_T9", "type": "DRUG_N", "text": [ "AOM" ], "offsets": [ [ 366, 369 ] ], "normalized": [] }, { "id": "11125235_T10", "type": "DRUG_N", "text": [ "AOM" ], "offsets": [ [ 555, 558 ] ], "normalized": [] }, { "id": "11125235_T11", "type": "DRUG_N", "text": [ "bombesin" ], "offsets": [ [ 614, 622 ] ], "normalized": [] }, { "id": "11125235_T12", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 715, 724 ] ], "normalized": [] }, { "id": "11125235_T13", "type": "DRUG_N", "text": [ "Bombesin" ], "offsets": [ [ 823, 831 ] ], "normalized": [] }, { "id": "11125235_T14", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 941, 950 ] ], "normalized": [] }, { "id": "11125235_T15", "type": "DRUG_N", "text": [ "bombesin" ], "offsets": [ [ 1054, 1062 ] ], "normalized": [] }, { "id": "11125235_T16", "type": "DRUG", "text": [ "Verapamil" ], "offsets": [ [ 1261, 1270 ] ], "normalized": [] }, { "id": "11125235_T17", "type": "DRUG_N", "text": [ "bombesin" ], "offsets": [ [ 1378, 1386 ] ], "normalized": [] }, { "id": "11125235_T18", "type": "DRUG", "text": [ "verapamil" ], "offsets": [ [ 1429, 1438 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11125235_R1", "type": "EFFECT", "arg1_id": "11125235_T1", "arg2_id": "11125235_T2", "normalized": [] }, { "id": "11125235_R2", "type": "EFFECT", "arg1_id": "11125235_T16", "arg2_id": "11125235_T17", "normalized": [] } ]

[ { "id": "46730__text", "type": "abstract", "text": [ "Repeated oral administration of coumaphos in sheep: interactions of coumaphos with bishydroxycoumarin, trichlorfon, and phenobarbital sodium. Interactions between treatments with coumaphos, bishydroxycoumarin (an anticoagulant), trichlorfon (an organophosphorous compound), and phenobarbital sodium (an inducer of microsomal enzymes) were investigated in sheep. A daily dose of 2 mg of coumaphos/kg of body weight for 6 days did not affect the plasma enzymes or the antiprothrombinemic effect of bishydroxy-coumarin in wethers. The treatment of ewes with an intravenous (IV) injection of trichlorfon, insufficient to produce significant inhibition of erythrocyte acetylcholinesterase (AChE) activity, appeared to produce additive effects with those produced by subsequent treatment with 4 mg of coumaphos/kg/day. In ewes given 40 mg of phenobarbital sodium/kg for 5 days intraperitoneally (IP), the anticholinesterase effect of 4 mg of coumaphos/kg was significantly reduced and signs of toxicity were not present. Treatment with daily doses of 2 mg of coumaphos/kg for 6 days did not modify the anticholinesterase effect of a 2nd series of treatments given 6 weeks later." ], "offsets": [ [ 0, 1172 ] ] } ]

[ { "id": "46730_T1", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "46730_T2", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 68, 77 ] ], "normalized": [] }, { "id": "46730_T3", "type": "DRUG", "text": [ "bishydroxycoumarin" ], "offsets": [ [ 83, 101 ] ], "normalized": [] }, { "id": "46730_T4", "type": "DRUG_N", "text": [ "trichlorfon" ], "offsets": [ [ 103, 114 ] ], "normalized": [] }, { "id": "46730_T5", "type": "DRUG", "text": [ "phenobarbital sodium" ], "offsets": [ [ 120, 140 ] ], "normalized": [] }, { "id": "46730_T6", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 179, 188 ] ], "normalized": [] }, { "id": "46730_T7", "type": "DRUG", "text": [ "bishydroxycoumarin" ], "offsets": [ [ 190, 208 ] ], "normalized": [] }, { "id": "46730_T8", "type": "GROUP", "text": [ "anticoagulant" ], "offsets": [ [ 213, 226 ] ], "normalized": [] }, { "id": "46730_T9", "type": "DRUG_N", "text": [ "trichlorfon" ], "offsets": [ [ 229, 240 ] ], "normalized": [] }, { "id": "46730_T10", "type": "GROUP", "text": [ "organophosphorous compound" ], "offsets": [ [ 245, 271 ] ], "normalized": [] }, { "id": "46730_T11", "type": "DRUG", "text": [ "phenobarbital sodium" ], "offsets": [ [ 278, 298 ] ], "normalized": [] }, { "id": "46730_T12", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 386, 395 ] ], "normalized": [] }, { "id": "46730_T13", "type": "DRUG", "text": [ "bishydroxy-coumarin" ], "offsets": [ [ 496, 515 ] ], "normalized": [] }, { "id": "46730_T14", "type": "DRUG_N", "text": [ "trichlorfon" ], "offsets": [ [ 588, 599 ] ], "normalized": [] }, { "id": "46730_T15", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 795, 804 ] ], "normalized": [] }, { "id": "46730_T16", "type": "DRUG", "text": [ "phenobarbital sodium" ], "offsets": [ [ 836, 856 ] ], "normalized": [] }, { "id": "46730_T17", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 936, 945 ] ], "normalized": [] }, { "id": "46730_T18", "type": "DRUG_N", "text": [ "coumaphos" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] } ]

[]

[]

[ { "id": "46730_R1", "type": "EFFECT", "arg1_id": "46730_T14", "arg2_id": "46730_T15", "normalized": [] }, { "id": "46730_R2", "type": "EFFECT", "arg1_id": "46730_T16", "arg2_id": "46730_T17", "normalized": [] } ]

[ { "id": "11114408__text", "type": "abstract", "text": [ "Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats. Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP." ], "offsets": [ [ 0, 1481 ] ] } ]

[ { "id": "11114408_T1", "type": "DRUG", "text": [ "clozapine" ], "offsets": [ [ 16, 25 ] ], "normalized": [] }, { "id": "11114408_T2", "type": "DRUG_N", "text": [ "phencyclidine" ], "offsets": [ [ 30, 43 ] ], "normalized": [] }, { "id": "11114408_T3", "type": "DRUG_N", "text": [ "Phencyclidine" ], "offsets": [ [ 111, 124 ] ], "normalized": [] }, { "id": "11114408_T4", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 126, 129 ] ], "normalized": [] }, { "id": "11114408_T5", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 345, 348 ] ], "normalized": [] }, { "id": "11114408_T6", "type": "GROUP", "text": [ "atypical antipsychotic" ], "offsets": [ [ 405, 427 ] ], "normalized": [] }, { "id": "11114408_T7", "type": "DRUG", "text": [ "clozapine" ], "offsets": [ [ 428, 437 ] ], "normalized": [] }, { "id": "11114408_T8", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 487, 490 ] ], "normalized": [] }, { "id": "11114408_T9", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 614, 617 ] ], "normalized": [] }, { "id": "11114408_T10", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 701, 704 ] ], "normalized": [] }, { "id": "11114408_T11", "type": "DRUG", "text": [ "clozapine" ], "offsets": [ [ 883, 892 ] ], "normalized": [] }, { "id": "11114408_T12", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 935, 938 ] ], "normalized": [] }, { "id": "11114408_T13", "type": "DRUG", "text": [ "clozapine" ], "offsets": [ [ 1078, 1087 ] ], "normalized": [] }, { "id": "11114408_T14", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1144, 1147 ] ], "normalized": [] }, { "id": "11114408_T15", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1217, 1220 ] ], "normalized": [] }, { "id": "11114408_T16", "type": "GROUP", "text": [ "antipsychotics" ], "offsets": [ [ 1355, 1369 ] ], "normalized": [] }, { "id": "11114408_T17", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1477, 1480 ] ], "normalized": [] } ]

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[ { "id": "11180036__text", "type": "abstract", "text": [ "Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs." ], "offsets": [ [ 0, 2027 ] ] } ]

[ { "id": "11180036_T1", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 57, 66 ] ], "normalized": [] }, { "id": "11180036_T2", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 71, 80 ] ], "normalized": [] }, { "id": "11180036_T3", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 164, 173 ] ], "normalized": [] }, { "id": "11180036_T4", "type": "GROUP", "text": [ "macrolide immunosuppressant" ], "offsets": [ [ 177, 204 ] ], "normalized": [] }, { "id": "11180036_T5", "type": "GROUP", "text": [ "calcium channel blocker" ], "offsets": [ [ 236, 259 ] ], "normalized": [] }, { "id": "11180036_T6", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 260, 269 ] ], "normalized": [] }, { "id": "11180036_T7", "type": "GROUP", "text": [ "immunosuppressive drugs" ], "offsets": [ [ 388, 411 ] ], "normalized": [] }, { "id": "11180036_T8", "type": "GROUP", "text": [ "calcium antagonists" ], "offsets": [ [ 460, 479 ] ], "normalized": [] }, { "id": "11180036_T9", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 657, 666 ] ], "normalized": [] }, { "id": "11180036_T10", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 697, 706 ] ], "normalized": [] }, { "id": "11180036_T11", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 874, 883 ] ], "normalized": [] }, { "id": "11180036_T12", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1061, 1070 ] ], "normalized": [] }, { "id": "11180036_T13", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1131, 1140 ] ], "normalized": [] }, { "id": "11180036_T14", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1236, 1245 ] ], "normalized": [] }, { "id": "11180036_T15", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1293, 1302 ] ], "normalized": [] }, { "id": "11180036_T16", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1318, 1327 ] ], "normalized": [] }, { "id": "11180036_T17", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1416, 1425 ] ], "normalized": [] }, { "id": "11180036_T18", "type": "DRUG_N", "text": [ "desacetyldiltiazem" ], "offsets": [ [ 1427, 1445 ] ], "normalized": [] }, { "id": "11180036_T19", "type": "DRUG_N", "text": [ "desmethyldiltiazem" ], "offsets": [ [ 1451, 1469 ] ], "normalized": [] }, { "id": "11180036_T20", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1511, 1520 ] ], "normalized": [] }, { "id": "11180036_T21", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1560, 1569 ] ], "normalized": [] }, { "id": "11180036_T22", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1687, 1696 ] ], "normalized": [] }, { "id": "11180036_T23", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1730, 1739 ] ], "normalized": [] }, { "id": "11180036_T24", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1807, 1816 ] ], "normalized": [] }, { "id": "11180036_T25", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1890, 1899 ] ], "normalized": [] }, { "id": "11180036_T26", "type": "DRUG", "text": [ "diltiazem" ], "offsets": [ [ 1900, 1909 ] ], "normalized": [] }, { "id": "11180036_T27", "type": "DRUG", "text": [ "sirolimus" ], "offsets": [ [ 1935, 1944 ] ], "normalized": [] } ]

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[ { "id": "11180036_R1", "type": "MECHANISM", "arg1_id": "11180036_T1", "arg2_id": "11180036_T2", "normalized": [] }, { "id": "11180036_R2", "type": "MECHANISM", "arg1_id": "11180036_T11", "arg2_id": "11180036_T12", "normalized": [] }, { "id": "11180036_R3", "type": "MECHANISM", "arg1_id": "11180036_T15", "arg2_id": "11180036_T16", "normalized": [] }, { "id": "11180036_R4", "type": "MECHANISM", "arg1_id": "11180036_T22", "arg2_id": "11180036_T23", "normalized": [] }, { "id": "11180036_R5", "type": "ADVISE", "arg1_id": "11180036_T25", "arg2_id": "11180036_T26", "normalized": [] } ]

[ { "id": "11144988__text", "type": "abstract", "text": [ "Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers. The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin." ], "offsets": [ [ 0, 1756 ] ] } ]

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[ { "id": "1116650__text", "type": "abstract", "text": [ "Responses to arginine of the perfused pancreas of the genetically diabetic Chinese hamster. Nonketotic, genetically diabetic Cinese hamsters show subnormal pancreatic insulin release and impaired suppression of glucagon in response to glucose. To study the pancreatic effects of other agents, dynamic insulin and glucagon release was measured from the in vitro perfused pancreases of normal and diabetic Chinese hamsters in response to various combinations of arginine (20mM), glucose (100 or 150 mg. per 100 ml.), and theophylline (10 mM). Theophylline alone caused identical insulin and glucagon release in diabetics and normals. Glucose, alone and in the presence of theophylline, caused subnormal insulin release and less suppression of glucagon release in the diabectics than in the normals. Arginine, in the presence of glucose and theophylline, caused excessive glucagon release but nearly normal insulin release in the diabetics. Arginine, in the absence of glucose or theophylline, caused excessive glucagon release in the diabetics and undetectable insulin release in either diabetics or normals. Pancreatic content after perfusion did not correlate with release during perfusion. Infusion of arginine alone markedly decreased the amount of extractable pancreatic insulin and glucagon. These results indicate that the pancreatic alpha cell of the diabetic Chinese hamster responds excessively to arginine, as is seen in the human diabetic. This defect is not related to acute insulin release or the presence of glucose. Further, these results confirm that the diabetic Chinese hamster's alpha and beta cells respond normally to theophylline, but are relatively insensitive to glucose." ], "offsets": [ [ 0, 1694 ] ] } ]

[ { "id": "1116650_T1", "type": "DRUG", "text": [ "arginine" ], "offsets": [ [ 13, 21 ] ], "normalized": [] }, { "id": "1116650_T2", "type": "DRUG", "text": [ "arginine" ], "offsets": [ [ 460, 468 ] ], "normalized": [] }, { "id": "1116650_T3", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 477, 484 ] ], "normalized": [] }, { "id": "1116650_T4", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 519, 531 ] ], "normalized": [] }, { "id": "1116650_T5", "type": "DRUG", "text": [ "Theophylline" ], "offsets": [ [ 541, 553 ] ], "normalized": [] }, { "id": "1116650_T6", "type": "DRUG", "text": [ "Glucose" ], "offsets": [ [ 632, 639 ] ], "normalized": [] }, { "id": "1116650_T7", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 670, 682 ] ], "normalized": [] }, { "id": "1116650_T8", "type": "DRUG", "text": [ "Arginine" ], "offsets": [ [ 797, 805 ] ], "normalized": [] }, { "id": "1116650_T9", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 826, 833 ] ], "normalized": [] }, { "id": "1116650_T10", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 838, 850 ] ], "normalized": [] }, { "id": "1116650_T11", "type": "DRUG", "text": [ "Arginine" ], "offsets": [ [ 938, 946 ] ], "normalized": [] }, { "id": "1116650_T12", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 966, 973 ] ], "normalized": [] }, { "id": "1116650_T13", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 977, 989 ] ], "normalized": [] }, { "id": "1116650_T14", "type": "DRUG", "text": [ "arginine" ], "offsets": [ [ 1203, 1211 ] ], "normalized": [] }, { "id": "1116650_T15", "type": "DRUG", "text": [ "arginine" ], "offsets": [ [ 1406, 1414 ] ], "normalized": [] }, { "id": "1116650_T16", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1521, 1528 ] ], "normalized": [] }, { "id": "1116650_T17", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 1638, 1650 ] ], "normalized": [] }, { "id": "1116650_T18", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1686, 1693 ] ], "normalized": [] } ]

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[ { "id": "11151029__text", "type": "abstract", "text": [ "Acute effect of different antidepressants on glycemia in diabetic and non-diabetic rats. Diabetic patients have a 20% higher risk of depression than the general population. Treatment with antidepressant drugs can directly interfere with blood glucose levels or may interact with hypoglycemic agents. The treatment of depression in diabetic patients must take into account variations of glycemic levels at different times and a comparison of the available antidepressant agents is important. In the present study we evaluated the interference of antidepressants with blood glucose levels of diabetic and non-diabetic rats. In a first experiment, male adult Wistar rats were fasted for 12 h. Imipramine (5 mg/kg), moclobemide (30 mg/kg), clonazepam (0.25 mg/kg), fluoxetine (20 mg/kg) sertraline (30 mg/kg) or vehicle was administered. After 30 min, fasting glycemia was measured. An oral glucose overload of 1 ml of a 50% glucose solution was given to rats and blood glucose was determined after 30, 60 and 90 min. Imipramine and clonazepam did not change fasting or overload glycemia. Fluoxetine and moclobemide increased blood glucose at different times after the glucose overload. Sertraline neutralized the increase of glycemia induced by oral glucose overload. In the second experiment, non-diabetic and streptozotocin-induced diabetic rats were fasted, and the same procedures were followed for estimation of glucose tolerance 30 min after glucose overload. Again, sertraline neutralized the increase in glycemia after glucose overload both in diabetic and non-diabetic rats. These data raise the question of whether sertraline is the best choice for prolonged use for diabetic individuals, because of its antihyperglycemic effects. Clonazepam would be useful in cases with potential risk of hypoglycemia." ], "offsets": [ [ 0, 1810 ] ] } ]

[ { "id": "11151029_T1", "type": "GROUP", "text": [ "antidepressants" ], "offsets": [ [ 26, 41 ] ], "normalized": [] }, { "id": "11151029_T2", "type": "GROUP", "text": [ "antidepressant drugs" ], "offsets": [ [ 188, 208 ] ], "normalized": [] }, { "id": "11151029_T3", "type": "GROUP", "text": [ "hypoglycemic agents" ], "offsets": [ [ 279, 298 ] ], "normalized": [] }, { "id": "11151029_T4", "type": "GROUP", "text": [ "antidepressant agents" ], "offsets": [ [ 455, 476 ] ], "normalized": [] }, { "id": "11151029_T5", "type": "GROUP", "text": [ "antidepressants" ], "offsets": [ [ 545, 560 ] ], "normalized": [] }, { "id": "11151029_T6", "type": "DRUG", "text": [ "Imipramine" ], "offsets": [ [ 690, 700 ] ], "normalized": [] }, { "id": "11151029_T7", "type": "DRUG", "text": [ "moclobemide" ], "offsets": [ [ 712, 723 ] ], "normalized": [] }, { "id": "11151029_T8", "type": "DRUG", "text": [ "clonazepam" ], "offsets": [ [ 736, 746 ] ], "normalized": [] }, { "id": "11151029_T9", "type": "DRUG", "text": [ "fluoxetine" ], "offsets": [ [ 761, 771 ] ], "normalized": [] }, { "id": "11151029_T10", "type": "DRUG", "text": [ "sertraline" ], "offsets": [ [ 783, 793 ] ], "normalized": [] }, { "id": "11151029_T11", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 887, 894 ] ], "normalized": [] }, { "id": "11151029_T12", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 921, 928 ] ], "normalized": [] }, { "id": "11151029_T13", "type": "DRUG", "text": [ "Imipramine" ], "offsets": [ [ 1014, 1024 ] ], "normalized": [] }, { "id": "11151029_T14", "type": "DRUG", "text": [ "clonazepam" ], "offsets": [ [ 1029, 1039 ] ], "normalized": [] }, { "id": "11151029_T15", "type": "DRUG", "text": [ "Fluoxetine" ], "offsets": [ [ 1085, 1095 ] ], "normalized": [] }, { "id": "11151029_T16", "type": "DRUG", "text": [ "moclobemide" ], "offsets": [ [ 1100, 1111 ] ], "normalized": [] }, { "id": "11151029_T17", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1128, 1135 ] ], "normalized": [] }, { "id": "11151029_T18", "type": "DRUG", "text": [ "Sertraline" ], "offsets": [ [ 1183, 1193 ] ], "normalized": [] }, { "id": "11151029_T19", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1247, 1254 ] ], "normalized": [] }, { "id": "11151029_T20", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1414, 1421 ] ], "normalized": [] }, { "id": "11151029_T21", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1445, 1452 ] ], "normalized": [] }, { "id": "11151029_T22", "type": "DRUG", "text": [ "sertraline" ], "offsets": [ [ 1470, 1480 ] ], "normalized": [] }, { "id": "11151029_T23", "type": "DRUG", "text": [ "glucose" ], "offsets": [ [ 1524, 1531 ] ], "normalized": [] }, { "id": "11151029_T24", "type": "DRUG", "text": [ "sertraline" ], "offsets": [ [ 1622, 1632 ] ], "normalized": [] }, { "id": "11151029_T25", "type": "DRUG", "text": [ "Clonazepam" ], "offsets": [ [ 1738, 1748 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11151029_R1", "type": "INT", "arg1_id": "11151029_T2", "arg2_id": "11151029_T3", "normalized": [] } ]

[ { "id": "11085328__text", "type": "abstract", "text": [ "The effects of DCG-IV and L-CCG-1 upon phencyclidine (PCP)-induced locomotion and behavioral changes in mice. The behavioral changes of mice induced by acute and repeated i.p. injection of phencyclidine (PCP) were observed by measuring locomotor activity and stereotyped behavior. Then, the effects of metabotropic glutamate receptor (mGluR) agonists, DCG-IV and L-CCG-1, on the above behavioral changes induced by PCP were found. The effects of DCG-IV were very strong and completely depressed the PCP-induced hyperlocomotion. The effects of L-CCG-1 were not so strong. Repeated injection of PCP for 20 days into mice induced lower locomotor activity than that in acutely injected mice. These behavioral changes may be related with the negative symptoms of schizophrenia. In order to examine some molecular mechanisms of PCP-induced behavioral changes, Northern blot analysis of total RNA from prefrontal cortical tissues of mice treated with PCP, DCG-IV, and L-CCG-1 was carried out." ], "offsets": [ [ 0, 985 ] ] } ]

[ { "id": "11085328_T1", "type": "DRUG_N", "text": [ "DCG-IV" ], "offsets": [ [ 15, 21 ] ], "normalized": [] }, { "id": "11085328_T2", "type": "DRUG_N", "text": [ "L-CCG-1" ], "offsets": [ [ 26, 33 ] ], "normalized": [] }, { "id": "11085328_T3", "type": "DRUG_N", "text": [ "phencyclidine" ], "offsets": [ [ 39, 52 ] ], "normalized": [] }, { "id": "11085328_T4", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 54, 57 ] ], "normalized": [] }, { "id": "11085328_T5", "type": "DRUG_N", "text": [ "phencyclidine" ], "offsets": [ [ 189, 202 ] ], "normalized": [] }, { "id": "11085328_T6", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 204, 207 ] ], "normalized": [] }, { "id": "11085328_T7", "type": "DRUG_N", "text": [ "DCG-IV" ], "offsets": [ [ 352, 358 ] ], "normalized": [] }, { "id": "11085328_T8", "type": "DRUG_N", "text": [ "L-CCG-1" ], "offsets": [ [ 363, 370 ] ], "normalized": [] }, { "id": "11085328_T9", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 415, 418 ] ], "normalized": [] }, { "id": "11085328_T10", "type": "DRUG_N", "text": [ "DCG-IV" ], "offsets": [ [ 446, 452 ] ], "normalized": [] }, { "id": "11085328_T11", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 499, 502 ] ], "normalized": [] }, { "id": "11085328_T12", "type": "DRUG_N", "text": [ "L-CCG-1" ], "offsets": [ [ 543, 550 ] ], "normalized": [] }, { "id": "11085328_T13", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 593, 596 ] ], "normalized": [] }, { "id": "11085328_T14", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 822, 825 ] ], "normalized": [] }, { "id": "11085328_T15", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "11085328_T16", "type": "DRUG_N", "text": [ "DCG-IV" ], "offsets": [ [ 949, 955 ] ], "normalized": [] }, { "id": "11085328_T17", "type": "DRUG_N", "text": [ "L-CCG-1" ], "offsets": [ [ 961, 968 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11085328_R1", "type": "EFFECT", "arg1_id": "11085328_T10", "arg2_id": "11085328_T11", "normalized": [] } ]

[ { "id": "2857499__text", "type": "abstract", "text": [ "[Quantitative approach to treatment with incisive neuroleptics by therapeutic monitoring]; The problems encountered during the longterm treatment of psychotic patients with neuroleptics are illustrated by six typical case reports. A group of patients who had had a new acute episode despite seemingly adequate treatment were selected. In these six cases it was demonstrated that the neuroleptics dosage was inappropriate, being either too high or too low as judged from the plasma concentrations. Ways of improving the adequacy of the treatment of psychotic patients with neuroleptics are discussed." ], "offsets": [ [ 0, 599 ] ] } ]

[ { "id": "2857499_T1", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 50, 62 ] ], "normalized": [] }, { "id": "2857499_T2", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 173, 185 ] ], "normalized": [] }, { "id": "2857499_T3", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 383, 395 ] ], "normalized": [] }, { "id": "2857499_T4", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 572, 584 ] ], "normalized": [] } ]

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[ { "id": "3966974__text", "type": "abstract", "text": [ "Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU. Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and \"early\" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the \"early\" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation." ], "offsets": [ [ 0, 1646 ] ] } ]

[ { "id": "3966974_T1", "type": "DRUG_N", "text": [ "Misonidazole" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "3966974_T2", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 80, 84 ] ], "normalized": [] }, { "id": "3966974_T3", "type": "GROUP", "text": [ "nitrosourea" ], "offsets": [ [ 98, 109 ] ], "normalized": [] }, { "id": "3966974_T4", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 110, 114 ] ], "normalized": [] }, { "id": "3966974_T5", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 270, 274 ] ], "normalized": [] }, { "id": "3966974_T6", "type": "DRUG_N", "text": [ "misonidazole" ], "offsets": [ [ 332, 344 ] ], "normalized": [] }, { "id": "3966974_T7", "type": "GROUP", "text": [ "nitrosoureas" ], "offsets": [ [ 425, 437 ] ], "normalized": [] }, { "id": "3966974_T8", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 666, 670 ] ], "normalized": [] }, { "id": "3966974_T9", "type": "DRUG_N", "text": [ "Misonidazole" ], "offsets": [ [ 785, 797 ] ], "normalized": [] }, { "id": "3966974_T10", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "3966974_T11", "type": "DRUG_N", "text": [ "Misonidazole" ], "offsets": [ [ 957, 969 ] ], "normalized": [] }, { "id": "3966974_T12", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 999, 1003 ] ], "normalized": [] }, { "id": "3966974_T13", "type": "GROUP", "text": [ "nitrosourea" ], "offsets": [ [ 1050, 1061 ] ], "normalized": [] }, { "id": "3966974_T14", "type": "DRUG_N", "text": [ "Misonidazole" ], "offsets": [ [ 1129, 1141 ] ], "normalized": [] }, { "id": "3966974_T15", "type": "GROUP", "text": [ "nitrosourea" ], "offsets": [ [ 1167, 1178 ] ], "normalized": [] }, { "id": "3966974_T16", "type": "GROUP", "text": [ "nitrosourea" ], "offsets": [ [ 1304, 1315 ] ], "normalized": [] }, { "id": "3966974_T17", "type": "DRUG", "text": [ "CCNU" ], "offsets": [ [ 1513, 1517 ] ], "normalized": [] }, { "id": "3966974_T18", "type": "DRUG_N", "text": [ "misonidazole" ], "offsets": [ [ 1534, 1546 ] ], "normalized": [] } ]

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[ { "id": "3966974_R1", "type": "EFFECT", "arg1_id": "3966974_T1", "arg2_id": "3966974_T2", "normalized": [] }, { "id": "3966974_R2", "type": "EFFECT", "arg1_id": "3966974_T9", "arg2_id": "3966974_T10", "normalized": [] }, { "id": "3966974_R3", "type": "MECHANISM", "arg1_id": "3966974_T11", "arg2_id": "3966974_T12", "normalized": [] }, { "id": "3966974_R4", "type": "MECHANISM", "arg1_id": "3966974_T17", "arg2_id": "3966974_T18", "normalized": [] } ]

[ { "id": "7744123__text", "type": "abstract", "text": [ "Pharmacokinetic profile of etodolac in special populations. The pharmacokinetics of etodolac in healthy normal volunteers has been extensively studied and is well described. Etodolac is characterised by a high oral bioavailability, low clearance, a small volume of distribution, and a 7-hour half-life. It is essentially completely metabolised, therefore little is excreted unchanged. Etodolac is highly protein bound. To investigate the effect of disease states or concomitant drug administration on a patient's response to etodolac, additional pharmacokinetic studies were carried out in special populations. Since etodolac has a well-defined pharmacokinetic-pharmacodynamic relationship, measurement of pharmacokinetic parameters is clinically relevant. Data from studies to date show that disease states, underlying conditions, and concomitantly administered highly protein-bound drugs have essentially no effect on etodolac pharmacokinetics. Therefore, etodolac can generally be given without the need for dosage modifications in special populations such as uncompromised elderly patients, those with moderate renal impairment, and patients with stable hepatic disease." ], "offsets": [ [ 0, 1174 ] ] } ]

[ { "id": "7744123_T1", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 27, 35 ] ], "normalized": [] }, { "id": "7744123_T2", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 84, 92 ] ], "normalized": [] }, { "id": "7744123_T3", "type": "DRUG", "text": [ "Etodolac" ], "offsets": [ [ 174, 182 ] ], "normalized": [] }, { "id": "7744123_T4", "type": "DRUG", "text": [ "Etodolac" ], "offsets": [ [ 385, 393 ] ], "normalized": [] }, { "id": "7744123_T5", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 525, 533 ] ], "normalized": [] }, { "id": "7744123_T6", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 617, 625 ] ], "normalized": [] }, { "id": "7744123_T7", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 920, 928 ] ], "normalized": [] }, { "id": "7744123_T8", "type": "DRUG", "text": [ "etodolac" ], "offsets": [ [ 958, 966 ] ], "normalized": [] } ]

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[ { "id": "11210403__text", "type": "abstract", "text": [ "Lack of interaction between levofloxacin and oxycodone: pharmacokinetics and drug disposition. Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone, 5 mg p.o. Q4H, and levofloxacin, 500 mg p.o. 1 hour after starting the oxycodone or levofloxacin 500 mg p.o. alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p > 0.05) in AUC (48.59 +/- 8.52 vs. 49.9 +/- 9.93), Cmax (7.73 +/- 2.6 vs. 6.6 +/- 2.0), and tmax (1.1 +/- 0.6 vs. 1.6 +/- 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax." ], "offsets": [ [ 0, 1255 ] ] } ]

[ { "id": "11210403_T1", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 28, 40 ] ], "normalized": [] }, { "id": "11210403_T2", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 45, 54 ] ], "normalized": [] }, { "id": "11210403_T3", "type": "DRUG", "text": [ "trovafloxacin" ], "offsets": [ [ 185, 198 ] ], "normalized": [] }, { "id": "11210403_T4", "type": "DRUG", "text": [ "ciprofloxacin" ], "offsets": [ [ 203, 216 ] ], "normalized": [] }, { "id": "11210403_T5", "type": "GROUP", "text": [ "opiate" ], "offsets": [ [ 269, 275 ] ], "normalized": [] }, { "id": "11210403_T6", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 284, 292 ] ], "normalized": [] }, { "id": "11210403_T7", "type": "DRUG", "text": [ "trovafloxacin" ], "offsets": [ [ 361, 374 ] ], "normalized": [] }, { "id": "11210403_T8", "type": "DRUG", "text": [ "ciprofloxacin" ], "offsets": [ [ 379, 392 ] ], "normalized": [] }, { "id": "11210403_T9", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 519, 528 ] ], "normalized": [] }, { "id": "11210403_T10", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 533, 545 ] ], "normalized": [] }, { "id": "11210403_T11", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 641, 650 ] ], "normalized": [] }, { "id": "11210403_T12", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 671, 683 ] ], "normalized": [] }, { "id": "11210403_T13", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 723, 732 ] ], "normalized": [] }, { "id": "11210403_T14", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 736, 748 ] ], "normalized": [] }, { "id": "11210403_T15", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 1061, 1073 ] ], "normalized": [] }, { "id": "11210403_T16", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 1081, 1093 ] ], "normalized": [] }, { "id": "11210403_T17", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 1094, 1103 ] ], "normalized": [] }, { "id": "11210403_T18", "type": "DRUG", "text": [ "oxycodone" ], "offsets": [ [ 1141, 1150 ] ], "normalized": [] }, { "id": "11210403_T19", "type": "DRUG", "text": [ "levofloxacin" ], "offsets": [ [ 1155, 1167 ] ], "normalized": [] } ]

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[ { "id": "11210403_R1", "type": "MECHANISM", "arg1_id": "11210403_T3", "arg2_id": "11210403_T5", "normalized": [] }, { "id": "11210403_R2", "type": "MECHANISM", "arg1_id": "11210403_T3", "arg2_id": "11210403_T6", "normalized": [] }, { "id": "11210403_R3", "type": "MECHANISM", "arg1_id": "11210403_T4", "arg2_id": "11210403_T5", "normalized": [] }, { "id": "11210403_R4", "type": "MECHANISM", "arg1_id": "11210403_T4", "arg2_id": "11210403_T6", "normalized": [] } ]

[ { "id": "7496198__text", "type": "abstract", "text": [ "[2 epidemics of arsenical encephalopathy in the treatment of trypanosomiasis, Uganda, 1992-1993] Since 1988, the french non-governmental organisation M decins Sans Fronti res is running a control program of human african trypanosomiasis in the district of Moyo, North-Uganda. Between 1988 and 1993, more than 7,000 patients were diagnosed and treated. Since 1988, it has been noted that incidence of melarsoprol reaction had increased systematically between June and October of each year, indicating strong seasonal variation. In 1992 and 1993, two outbreaks of arsenical reactive encephalopathy (ARE) occurred in the sleeping sickness center of Adjumani. The incidence of ARE suddenly exceeded 10% of the patients treated by melarsoprol during August 1992 and September 1993. The onset of 80% of those \"epidemic\" cases, occurred between the 5th and the 11th day of treatment. Two retrospective studies were conducted in 1992 (75 cases) and in 1993 (51 cases). Among the risk factors studied, two appear to increase the risk of ARE: the prescription of thiabendazole to treat strongyloidiasis during the melarsoprol cure and the bad general clinical conditions of patients. These observations suggest that exogenous co-factors could be involved in the occurrence of ARE. Recommendations were to avoid administration of diffusible anti-helminthic treatment during the cure, and to improve the general conditions of patients before the cure of melarsoprol." ], "offsets": [ [ 0, 1456 ] ] } ]

[ { "id": "7496198_T1", "type": "DRUG", "text": [ "melarsoprol" ], "offsets": [ [ 402, 413 ] ], "normalized": [] }, { "id": "7496198_T2", "type": "DRUG", "text": [ "melarsoprol" ], "offsets": [ [ 728, 739 ] ], "normalized": [] }, { "id": "7496198_T3", "type": "DRUG", "text": [ "thiabendazole" ], "offsets": [ [ 1055, 1068 ] ], "normalized": [] }, { "id": "7496198_T4", "type": "DRUG", "text": [ "melarsoprol" ], "offsets": [ [ 1106, 1117 ] ], "normalized": [] }, { "id": "7496198_T5", "type": "GROUP", "text": [ "anti-helminthic" ], "offsets": [ [ 1332, 1347 ] ], "normalized": [] }, { "id": "7496198_T6", "type": "DRUG", "text": [ "melarsoprol" ], "offsets": [ [ 1444, 1455 ] ], "normalized": [] } ]

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[]

[ { "id": "7496198_R1", "type": "EFFECT", "arg1_id": "7496198_T3", "arg2_id": "7496198_T4", "normalized": [] } ]

[ { "id": "11152855__text", "type": "abstract", "text": [ "Effect of dofetillide on the pharmacokinetics of digoxin. The effect of dofetilide on the steady-state pharmacokinetics of digoxin was evaluated in a randomized, double-blind study. Five days of dofetilide treatment did not significantly affect steady-state pharmacokinetic variables of digoxin compared with placebo; therefore, the use of dofetilide does not necessitate an adjustment in digoxin dose to maintain therapeutic digoxin levels." ], "offsets": [ [ 0, 441 ] ] } ]

[ { "id": "11152855_T1", "type": "DRUG", "text": [ "dofetillide" ], "offsets": [ [ 10, 21 ] ], "normalized": [] }, { "id": "11152855_T2", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 49, 56 ] ], "normalized": [] }, { "id": "11152855_T3", "type": "DRUG", "text": [ "dofetilide" ], "offsets": [ [ 72, 82 ] ], "normalized": [] }, { "id": "11152855_T4", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 123, 130 ] ], "normalized": [] }, { "id": "11152855_T5", "type": "DRUG", "text": [ "dofetilide" ], "offsets": [ [ 195, 205 ] ], "normalized": [] }, { "id": "11152855_T6", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 287, 294 ] ], "normalized": [] }, { "id": "11152855_T7", "type": "DRUG", "text": [ "dofetilide" ], "offsets": [ [ 340, 350 ] ], "normalized": [] }, { "id": "11152855_T8", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 389, 396 ] ], "normalized": [] } ]

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[ { "id": "2857099__text", "type": "abstract", "text": [ "[The GABA-ergic system and brain edema] It has been shown in rats with experimental toxic and traumatic edemas that picrotoxin (1 mg/kg) removes the antiedematous action of diazepam, phenazepam, phenibut and amizyl and reduces the action of phentolamine. When the dose of picrotoxin is minimized to 0.5 mg/kg such an effect is not observed. Prolonged daily administration of picrotoxin in a dose of 1 mg/kg results in the development of brain edema. It is recommended that GABA-positive drugs be included into a complex of treatment measures for edema." ], "offsets": [ [ 0, 552 ] ] } ]

[ { "id": "2857099_T1", "type": "DRUG_N", "text": [ "picrotoxin" ], "offsets": [ [ 116, 126 ] ], "normalized": [] }, { "id": "2857099_T2", "type": "DRUG", "text": [ "diazepam" ], "offsets": [ [ 173, 181 ] ], "normalized": [] }, { "id": "2857099_T3", "type": "DRUG_N", "text": [ "phenazepam" ], "offsets": [ [ 183, 193 ] ], "normalized": [] }, { "id": "2857099_T4", "type": "DRUG_N", "text": [ "phenibut" ], "offsets": [ [ 195, 203 ] ], "normalized": [] }, { "id": "2857099_T5", "type": "DRUG_N", "text": [ "amizyl" ], "offsets": [ [ 208, 214 ] ], "normalized": [] }, { "id": "2857099_T6", "type": "DRUG", "text": [ "phentolamine" ], "offsets": [ [ 241, 253 ] ], "normalized": [] }, { "id": "2857099_T7", "type": "DRUG_N", "text": [ "picrotoxin" ], "offsets": [ [ 272, 282 ] ], "normalized": [] }, { "id": "2857099_T8", "type": "DRUG_N", "text": [ "picrotoxin" ], "offsets": [ [ 375, 385 ] ], "normalized": [] } ]

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[]

[ { "id": "2857099_R1", "type": "EFFECT", "arg1_id": "2857099_T1", "arg2_id": "2857099_T2", "normalized": [] }, { "id": "2857099_R2", "type": "EFFECT", "arg1_id": "2857099_T1", "arg2_id": "2857099_T3", "normalized": [] }, { "id": "2857099_R3", "type": "EFFECT", "arg1_id": "2857099_T1", "arg2_id": "2857099_T4", "normalized": [] }, { "id": "2857099_R4", "type": "EFFECT", "arg1_id": "2857099_T1", "arg2_id": "2857099_T5", "normalized": [] }, { "id": "2857099_R5", "type": "EFFECT", "arg1_id": "2857099_T1", "arg2_id": "2857099_T6", "normalized": [] } ]

[ { "id": "11172561__text", "type": "abstract", "text": [ "Pharmacology and pharmacotherapy of cardiovascular drugs in patients with chronic renal disease. Cardiovascular disease is a common comorbidity and a major cause of mortality in patients with chronic renal disease. Drug regimens in patients with cardiovascular disease are frequently complex and can be significantly affected by alterations in renal function. In addition, several cardiovascular drugs directly affect renal function and the management of patients with renal disease. This article reviews the impact of renal disease on the pharmacokinetics of cardiovascular drugs and identifies clinically important interactions between these and other drugs commonly used in the management of chronic renal disease. Several classes of cardiovascular drugs are also discussed in relationship to their differential effects on the management and progression of renal disease." ], "offsets": [ [ 0, 874 ] ] } ]

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[ { "id": "11137650__text", "type": "abstract", "text": [ "In vitro activity of KRM-1648, either singly or in combination with ofloxacin, against Mycobacterium ulcerans. The antimicrobial effect of a benzoxazinorifamycin, KRM-1648, either alone or in combination with ofloxacin, was evaluated in vitro against two type strains and six clinical isolates of Mycobacterium ulcerans. Growth of M. ulcerans was measured by plate counts and the BACTEC radiometric method. The minimal inhibitory concentration as well as minimal bactericidal concentration of KRM-1648 against M. ulcerans was between 0.012 and 0.025 mg/l, while corresponding values for rifampicin and rifabutin were in the range of 0.1-0.8 mg/l and 0.1-0.4 mg/l respectively. When combined with ofloxacin, KRM-1648 exhibited strong synergistic activity while only additive effects were observed with the combination of rifampicin (or rifabutin) and ofloxacin. These results suggest that KRM-1648 has a great potential in the treatment of M. ulcerans infection." ], "offsets": [ [ 0, 961 ] ] } ]

[ { "id": "11137650_T1", "type": "DRUG_N", "text": [ "KRM-1648" ], "offsets": [ [ 21, 29 ] ], "normalized": [] }, { "id": "11137650_T2", "type": "DRUG", "text": [ "ofloxacin" ], "offsets": [ [ 68, 77 ] ], "normalized": [] }, { "id": "11137650_T3", "type": "DRUG_N", "text": [ "benzoxazinorifamycin" ], "offsets": [ [ 141, 161 ] ], "normalized": [] }, { "id": "11137650_T4", "type": "DRUG_N", "text": [ "KRM-1648" ], "offsets": [ [ 163, 171 ] ], "normalized": [] }, { "id": "11137650_T5", "type": "DRUG", "text": [ "ofloxacin" ], "offsets": [ [ 209, 218 ] ], "normalized": [] }, { "id": "11137650_T6", "type": "DRUG_N", "text": [ "KRM-1648" ], "offsets": [ [ 493, 501 ] ], "normalized": [] }, { "id": "11137650_T7", "type": "DRUG", "text": [ "rifampicin" ], "offsets": [ [ 587, 597 ] ], "normalized": [] }, { "id": "11137650_T8", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 602, 611 ] ], "normalized": [] }, { "id": "11137650_T9", "type": "DRUG", "text": [ "ofloxacin" ], "offsets": [ [ 696, 705 ] ], "normalized": [] }, { "id": "11137650_T10", "type": "DRUG_N", "text": [ "KRM-1648" ], "offsets": [ [ 707, 715 ] ], "normalized": [] }, { "id": "11137650_T11", "type": "DRUG", "text": [ "rifampicin" ], "offsets": [ [ 820, 830 ] ], "normalized": [] }, { "id": "11137650_T12", "type": "DRUG", "text": [ "rifabutin" ], "offsets": [ [ 835, 844 ] ], "normalized": [] }, { "id": "11137650_T13", "type": "DRUG", "text": [ "ofloxacin" ], "offsets": [ [ 850, 859 ] ], "normalized": [] }, { "id": "11137650_T14", "type": "DRUG_N", "text": [ "KRM-1648" ], "offsets": [ [ 888, 896 ] ], "normalized": [] } ]

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[ { "id": "11137650_R1", "type": "EFFECT", "arg1_id": "11137650_T9", "arg2_id": "11137650_T10", "normalized": [] }, { "id": "11137650_R2", "type": "EFFECT", "arg1_id": "11137650_T11", "arg2_id": "11137650_T13", "normalized": [] }, { "id": "11137650_R3", "type": "EFFECT", "arg1_id": "11137650_T12", "arg2_id": "11137650_T13", "normalized": [] } ]

[ { "id": "11197768__text", "type": "abstract", "text": [ "Toxicity of cadmium and zinc to miracidia of Schistosoma mansoni. The specific objectives of this study were to elucidate metal toxicity to hatching, survival and avoidance behaviour of Schistosoma mansoni miracidia. The toxicity of cadmium, zinc, and cadmium/zinc mixtures at concentrations ranging from 10000 to 10 microg/l was investigated. Metal mixture toxicity investigation was undertaken with equal concentrations of the metals. The hatching of miracidia from eggs was inhibited by concentrations of 1000-10000 microg/l of single metals. Metal mixtures had no effect on egg hatching. Survival of miracidia was reduced by increasing metal concentration except at concentrations of 10 microg/l for single metal toxicity where survival was increased above the control. Miracidia demonstrated a rapid avoidance behaviour when briefly exposed to heavy metals. The mechanisms of metal toxicity to miracidia are briefly discussed." ], "offsets": [ [ 0, 931 ] ] } ]

[ { "id": "11197768_T1", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "11197768_T2", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 242, 246 ] ], "normalized": [] }, { "id": "11197768_T3", "type": "DRUG", "text": [ "egg" ], "offsets": [ [ 578, 581 ] ], "normalized": [] } ]

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[ { "id": "3155550__text", "type": "abstract", "text": [ "Differential actions of intrathecal naloxone on blocking the tail-flick inhibition induced by intraventricular beta-endorphin and morphine in rats. In the present study, it is proposed that the opioids applied to supraspinal brain sites produced their analgesic effects by the activation of different descending pain inhibitory systems. The blockade of the spinal endorphinergic system by intrathecal naloxone on the production of tail-flick inhibition induced by intraventricular beta-endorphin and morphine was then studied. Intraventricular injection of beta-endorphin and morphine produced an inhibition of the tail-flick response to the heat stimulus in rats. Intrathecal injection of naloxone at doses of 0.4 to 40 micrograms caused a dose-related blockade of the inhibition of the tail-flick response induced by intraventricular injection of beta-endorphin, and a high dose of naloxone (40 micrograms) completely blocked the tail-flick inhibition induced by intraventricular beta-endorphin (16 micrograms). On the other hand, intrathecal naloxone (12-120 micrograms) had only a very weak effect on the tail-flick inhibition induced by intraventricular morphine (40 micrograms). Intraventricular injection of naloxone at doses of 1.2 to 12 micrograms equally antagonized in a dose-dependent manner the tail-flick inhibition induced by intraventricular beta-endorphin and morphine. The results indicate that a spinal naloxone-sensitive endorphinergic system is involved in the production of beta-endorphin but not morphine-induced tail-flick inhibition, and suggest that intraventricular beta-endorphin and morphine elicit their pharmacological actions via the activation of different descending pain inhibitory systems; descending epsilon and mu systems for beta-endorphin and morphine, respectively, are proposed." ], "offsets": [ [ 0, 1820 ] ] } ]

[ { "id": "3155550_T1", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 36, 44 ] ], "normalized": [] }, { "id": "3155550_T2", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 111, 125 ] ], "normalized": [] }, { "id": "3155550_T3", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 130, 138 ] ], "normalized": [] }, { "id": "3155550_T4", "type": "GROUP", "text": [ "opioids" ], "offsets": [ [ 194, 201 ] ], "normalized": [] }, { "id": "3155550_T5", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 401, 409 ] ], "normalized": [] }, { "id": "3155550_T6", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 481, 495 ] ], "normalized": [] }, { "id": "3155550_T7", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 500, 508 ] ], "normalized": [] }, { "id": "3155550_T8", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 557, 571 ] ], "normalized": [] }, { "id": "3155550_T9", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 576, 584 ] ], "normalized": [] }, { "id": "3155550_T10", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 690, 698 ] ], "normalized": [] }, { "id": "3155550_T11", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 849, 863 ] ], "normalized": [] }, { "id": "3155550_T12", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 884, 892 ] ], "normalized": [] }, { "id": "3155550_T13", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 982, 996 ] ], "normalized": [] }, { "id": "3155550_T14", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1045, 1053 ] ], "normalized": [] }, { "id": "3155550_T15", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1159, 1167 ] ], "normalized": [] }, { "id": "3155550_T16", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1215, 1223 ] ], "normalized": [] }, { "id": "3155550_T17", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 1358, 1372 ] ], "normalized": [] }, { "id": "3155550_T18", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1377, 1385 ] ], "normalized": [] }, { "id": "3155550_T19", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1422, 1430 ] ], "normalized": [] }, { "id": "3155550_T20", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 1496, 1510 ] ], "normalized": [] }, { "id": "3155550_T21", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1519, 1527 ] ], "normalized": [] }, { "id": "3155550_T22", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 1593, 1607 ] ], "normalized": [] }, { "id": "3155550_T23", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1612, 1620 ] ], "normalized": [] }, { "id": "3155550_T24", "type": "DRUG_N", "text": [ "beta-endorphin" ], "offsets": [ [ 1764, 1778 ] ], "normalized": [] }, { "id": "3155550_T25", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1783, 1791 ] ], "normalized": [] } ]

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[]

[ { "id": "3155550_R1", "type": "EFFECT", "arg1_id": "3155550_T10", "arg2_id": "3155550_T11", "normalized": [] }, { "id": "3155550_R2", "type": "EFFECT", "arg1_id": "3155550_T12", "arg2_id": "3155550_T13", "normalized": [] }, { "id": "3155550_R3", "type": "EFFECT", "arg1_id": "3155550_T14", "arg2_id": "3155550_T15", "normalized": [] }, { "id": "3155550_R4", "type": "EFFECT", "arg1_id": "3155550_T16", "arg2_id": "3155550_T17", "normalized": [] }, { "id": "3155550_R5", "type": "EFFECT", "arg1_id": "3155550_T16", "arg2_id": "3155550_T18", "normalized": [] } ]

[ { "id": "2857198__text", "type": "abstract", "text": [ "Dual effect of ouabain on the palytoxin-induced contraction and norepinephrine release in the guinea-pig vas deferens. Palytoxin (PTX), C129H223N3O54, isolated from marine coelenterates of Palythoa tuberculosa, caused a first rapid contraction followed by the slow phasic contraction of guinea-pig vas deferens. In the presence of ouabain (10(-5) M), PTX (10(-8) M) failed to cause the first contraction; however, the second contraction was potentiated. In the presence of phentolamine (10(-6) M), the second contraction was inhibited selectively. When ouabain was applied to the muscle in the presence of phentolamine, both first and second contractile responses to PTX were abolished. When the muscle was exposed to the potassium-depleted solution, the first contractile response to PTX was rather potentiated. PTX caused the release of norepinephrine from the muscle. Exposure of the muscle to ouabain (10(-5) M) markedly increased the PTX-induced release. It is indicated that the first and second contractile responses to PTX have entirely different properties. The second response is due to a release of norepinephrine from nerves and was potentiated by ouabain through the increase in the norepinephrine release, whereas the first response was not due to the norepinephrine release but presumably to a direct action on smooth muscle cell and was inhibited by ouabain. The mechanism of the action of PTX was discussed in the relation with Na,K-ATPase." ], "offsets": [ [ 0, 1457 ] ] } ]

[ { "id": "2857198_T1", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 15, 22 ] ], "normalized": [] }, { "id": "2857198_T2", "type": "DRUG_N", "text": [ "palytoxin" ], "offsets": [ [ 30, 39 ] ], "normalized": [] }, { "id": "2857198_T3", "type": "DRUG_N", "text": [ "Palytoxin" ], "offsets": [ [ 119, 128 ] ], "normalized": [] }, { "id": "2857198_T4", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 130, 133 ] ], "normalized": [] }, { "id": "2857198_T5", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 331, 338 ] ], "normalized": [] }, { "id": "2857198_T6", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 351, 354 ] ], "normalized": [] }, { "id": "2857198_T7", "type": "DRUG", "text": [ "phentolamine" ], "offsets": [ [ 473, 485 ] ], "normalized": [] }, { "id": "2857198_T8", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 553, 560 ] ], "normalized": [] }, { "id": "2857198_T9", "type": "DRUG", "text": [ "phentolamine" ], "offsets": [ [ 606, 618 ] ], "normalized": [] }, { "id": "2857198_T10", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 667, 670 ] ], "normalized": [] }, { "id": "2857198_T11", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 785, 788 ] ], "normalized": [] }, { "id": "2857198_T12", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 813, 816 ] ], "normalized": [] }, { "id": "2857198_T13", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 897, 904 ] ], "normalized": [] }, { "id": "2857198_T14", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 939, 942 ] ], "normalized": [] }, { "id": "2857198_T15", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 1027, 1030 ] ], "normalized": [] }, { "id": "2857198_T16", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 1160, 1167 ] ], "normalized": [] }, { "id": "2857198_T17", "type": "DRUG", "text": [ "ouabain" ], "offsets": [ [ 1366, 1373 ] ], "normalized": [] }, { "id": "2857198_T18", "type": "DRUG_N", "text": [ "PTX" ], "offsets": [ [ 1406, 1409 ] ], "normalized": [] } ]

[]

[]

[ { "id": "2857198_R1", "type": "EFFECT", "arg1_id": "2857198_T5", "arg2_id": "2857198_T6", "normalized": [] }, { "id": "2857198_R2", "type": "EFFECT", "arg1_id": "2857198_T8", "arg2_id": "2857198_T9", "normalized": [] }, { "id": "2857198_R3", "type": "EFFECT", "arg1_id": "2857198_T13", "arg2_id": "2857198_T14", "normalized": [] } ]

[ { "id": "7599505__text", "type": "abstract", "text": [ "Interactions of cobalt and iron in absorption and retention. The effects of supplementary oral cobalt and iron, as well as the interaction between both at the absorption site, fecal and urinary excretion as well as the retention of these trace elements were determined by using four diets containing either 9 or 63 micrograms/kg of Co and 48 or 446 mg/kg of Fe over a period of 19 days in a total of 24 rats. Retention was calculated by the balance technique and by the comparative slaughter technique. After one day, fecal as well as urinary excretion of both elements had already responded to the dietary treatments, with constant values being reached after approximately three days. Cobalt excretion was enhanced by supplementary cobalt; fecal excretion, too, was increased by supplementary iron; whereas urinary excretion was decreased in both cases. Additional iron significantly inhibited the absorption of cobalt in both dietary cobalt treatments. The lower rate of absorption in the groups receiving 446 mg Fe instead of 48 mg of Fe per kg diet resulted in a decreased renal excretion of cobalt. Consequently, the effect of iron on the retention of cobalt was lower than on absorption. This suggests that interactions between the two elements only take place at the site of absorption. Because of the low dietary cobalt concentration as compared to the iron contents of the diets, no effect of cobalt on iron absorption and excretion occurred. Differences in iron balance were only observed between both dietary concentrations, showing a higher absolute but a lower relative absorption as well as retention in the groups fed further Fe.(ABSTRACT TRUNCATED AT 250 WORDS)" ], "offsets": [ [ 0, 1677 ] ] } ]

[ { "id": "7599505_T1", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 16, 22 ] ], "normalized": [] }, { "id": "7599505_T2", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "7599505_T3", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 95, 101 ] ], "normalized": [] }, { "id": "7599505_T4", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "7599505_T5", "type": "DRUG", "text": [ "Co" ], "offsets": [ [ 332, 334 ] ], "normalized": [] }, { "id": "7599505_T6", "type": "DRUG", "text": [ "Fe" ], "offsets": [ [ 358, 360 ] ], "normalized": [] }, { "id": "7599505_T7", "type": "DRUG", "text": [ "Cobalt" ], "offsets": [ [ 686, 692 ] ], "normalized": [] }, { "id": "7599505_T8", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 733, 739 ] ], "normalized": [] }, { "id": "7599505_T9", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 794, 798 ] ], "normalized": [] }, { "id": "7599505_T10", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "7599505_T11", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 913, 919 ] ], "normalized": [] }, { "id": "7599505_T12", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 936, 942 ] ], "normalized": [] }, { "id": "7599505_T13", "type": "DRUG", "text": [ "Fe" ], "offsets": [ [ 1015, 1017 ] ], "normalized": [] }, { "id": "7599505_T14", "type": "DRUG", "text": [ "Fe" ], "offsets": [ [ 1038, 1040 ] ], "normalized": [] }, { "id": "7599505_T15", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 1096, 1102 ] ], "normalized": [] }, { "id": "7599505_T16", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 1132, 1136 ] ], "normalized": [] }, { "id": "7599505_T17", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 1157, 1163 ] ], "normalized": [] }, { "id": "7599505_T18", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 1321, 1327 ] ], "normalized": [] }, { "id": "7599505_T19", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 1361, 1365 ] ], "normalized": [] }, { "id": "7599505_T20", "type": "DRUG", "text": [ "cobalt" ], "offsets": [ [ 1402, 1408 ] ], "normalized": [] }, { "id": "7599505_T21", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 1412, 1416 ] ], "normalized": [] }, { "id": "7599505_T22", "type": "DRUG", "text": [ "iron" ], "offsets": [ [ 1467, 1471 ] ], "normalized": [] }, { "id": "7599505_T23", "type": "DRUG", "text": [ "Fe" ], "offsets": [ [ 1641, 1643 ] ], "normalized": [] } ]

[]

[]

[ { "id": "7599505_R1", "type": "MECHANISM", "arg1_id": "7599505_T1", "arg2_id": "7599505_T2", "normalized": [] }, { "id": "7599505_R2", "type": "MECHANISM", "arg1_id": "7599505_T10", "arg2_id": "7599505_T11", "normalized": [] }, { "id": "7599505_R3", "type": "MECHANISM", "arg1_id": "7599505_T10", "arg2_id": "7599505_T12", "normalized": [] }, { "id": "7599505_R4", "type": "MECHANISM", "arg1_id": "7599505_T13", "arg2_id": "7599505_T15", "normalized": [] }, { "id": "7599505_R5", "type": "MECHANISM", "arg1_id": "7599505_T16", "arg2_id": "7599505_T17", "normalized": [] } ]

[ { "id": "11085333__text", "type": "abstract", "text": [ "Behavioral responses to repeated cocaine exposure in mice selectively bred for differential sensitivity to pentobarbital. Mice from the 20th generation of three lines divergently selected for response to pentobarbital-induced sedation times [long-sedation time (LST), short sedation time (SST), and randomly bred control (RBC)] were used to study cocaine-induced behavioral sensitization. These lines showed variable degrees of locomotor activities in response to cocaine. At a low cocaine dose and long withdrawal period (10 mg/kg, twice a day for 5 days followed by a 14-day withdrawal), the LST mice showed tolerance development. In response to cocaine, the locomotor activities of the SST were not significantly different from the RBC group. At a higher dose and a shorter withdrawal period (20 mg/kg, daily for 7 days followed by a 3-day withdrawal), the SST mice showed behavioral sensitization similar to the RBC mice, but the LST mice did not develop sensitization. The different responses in locomotor activity induced by cocaine suggest that genetic factors may play a role in determining the magnitude of response to this drug. Dopamine (DA) levels did not differ significantly in either striatum (STR) or nucleus accumbens (NAC) for the cocaine-treated animals to their corresponding saline-treated controls. The affinity (Kd) of D2 in the NAC decreased significantly, without changes in density (Bmax), in the cocaine-treated SST and RBC mice. On the other hand, the density of D2 binding sites in the SST and the RBC mice in the STR was significantly increased in cocaine-treated groups without change in Kd. The LST mice did not show any changes in the Kd and Bmax in either the STR or the NAC. Taken together, these findings suggest that the changes in the Kd of D2 in the NAC and the Bmax of D2 in the STR may contribute to the differences in locomotor responses to cocaine exposure in these mouse lines." ], "offsets": [ [ 0, 1921 ] ] } ]

[ { "id": "11085333_T1", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 33, 40 ] ], "normalized": [] }, { "id": "11085333_T2", "type": "DRUG", "text": [ "pentobarbital" ], "offsets": [ [ 107, 120 ] ], "normalized": [] }, { "id": "11085333_T3", "type": "DRUG", "text": [ "pentobarbital" ], "offsets": [ [ 204, 217 ] ], "normalized": [] }, { "id": "11085333_T4", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 347, 354 ] ], "normalized": [] }, { "id": "11085333_T5", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 464, 471 ] ], "normalized": [] }, { "id": "11085333_T6", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 482, 489 ] ], "normalized": [] }, { "id": "11085333_T7", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 648, 655 ] ], "normalized": [] }, { "id": "11085333_T8", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1031, 1038 ] ], "normalized": [] }, { "id": "11085333_T9", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1249, 1256 ] ], "normalized": [] }, { "id": "11085333_T10", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1423, 1430 ] ], "normalized": [] }, { "id": "11085333_T11", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1578, 1585 ] ], "normalized": [] }, { "id": "11085333_T12", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1883, 1890 ] ], "normalized": [] } ]

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[ { "id": "3968644__text", "type": "abstract", "text": [ "Stereoselective behavioral effects of N-allylnormetazocine in pigeons and squirrel monkeys. The behavioral effects of the stereoisomers of N-allylnormetazocine (NANM) were compared with those of phencyclidine (PCP) in pigeons and squirrel monkeys responding under a multiple fixed-interval fixed-ratio (FI FR) schedule of food presentation. Intermediate doses of (+)-NANM or PCP produced transient increases in FI responding in monkeys and sustained increases in FI responding in pigeons; higher doses decreased FI and FR responding in both species. In contrast to its enantiomer, (-)-NANM failed to increase FI responding significantly in either species; at high doses, (-)-NANM decreased FI and FR responding. In monkeys, (-)-NANM was about 10 times more potent than (+)-NANM in decreasing responding, whereas in pigeons (-)-NANM was about equipotent with (+)-NANM. In both species, (-)-NANM, but not (+)-NANM, antagonized the rate-decreasing effects of morphine on FI and FR responding. In monkeys, the effects of (-)-NANM, but not (+)-NANM or PCP, were antagonized by naloxone; the doses of naloxone required to antagonize the effects of (-)-NANM were more than 100 times higher than those required to antagonize the effects of morphine. In pigeons, naloxone did not systematically alter the effects of (-)-NANM, (+)-NANM or PCP. Haloperidol reduced or eliminated the increases in FI responding produced by intermediate doses of either (+)-NANM or PCP in pigeons, but did not antagonize the decreases in FI or FR responding produced by high doses of PCP or either stereoisomer of NANM. The results demonstrate a high degree of stereoselectivity in the behavioral effects of NANM. The levorotatory isomer had opioid-antagonist and non-opioid agonist effects in pigeons and mixed opioid agonist-antagonist effects in monkeys. The dextrorotatory isomer, on the other hand, had effects similar to those of PCP in both species." ], "offsets": [ [ 0, 1926 ] ] } ]

[ { "id": "3968644_T1", "type": "DRUG_N", "text": [ "N-allylnormetazocine" ], "offsets": [ [ 38, 58 ] ], "normalized": [] }, { "id": "3968644_T2", "type": "DRUG_N", "text": [ "N-allylnormetazocine" ], "offsets": [ [ 139, 159 ] ], "normalized": [] }, { "id": "3968644_T3", "type": "DRUG_N", "text": [ "NANM" ], "offsets": [ [ 161, 165 ] ], "normalized": [] }, { "id": "3968644_T4", "type": "DRUG_N", "text": [ "phencyclidine" ], "offsets": [ [ 195, 208 ] ], "normalized": [] }, { "id": "3968644_T5", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 210, 213 ] ], "normalized": [] }, { "id": "3968644_T6", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 363, 371 ] ], "normalized": [] }, { "id": "3968644_T7", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 375, 378 ] ], "normalized": [] }, { "id": "3968644_T8", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 581, 589 ] ], "normalized": [] }, { "id": "3968644_T9", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 671, 679 ] ], "normalized": [] }, { "id": "3968644_T10", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 724, 732 ] ], "normalized": [] }, { "id": "3968644_T11", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 769, 777 ] ], "normalized": [] }, { "id": "3968644_T12", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 823, 831 ] ], "normalized": [] }, { "id": "3968644_T13", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 858, 866 ] ], "normalized": [] }, { "id": "3968644_T14", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 885, 893 ] ], "normalized": [] }, { "id": "3968644_T15", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 903, 911 ] ], "normalized": [] }, { "id": "3968644_T16", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 956, 964 ] ], "normalized": [] }, { "id": "3968644_T17", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 1017, 1025 ] ], "normalized": [] }, { "id": "3968644_T18", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 1035, 1043 ] ], "normalized": [] }, { "id": "3968644_T19", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1047, 1050 ] ], "normalized": [] }, { "id": "3968644_T20", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1072, 1080 ] ], "normalized": [] }, { "id": "3968644_T21", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1095, 1103 ] ], "normalized": [] }, { "id": "3968644_T22", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 1142, 1150 ] ], "normalized": [] }, { "id": "3968644_T23", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1232, 1240 ] ], "normalized": [] }, { "id": "3968644_T24", "type": "DRUG", "text": [ "naloxone" ], "offsets": [ [ 1254, 1262 ] ], "normalized": [] }, { "id": "3968644_T25", "type": "DRUG_N", "text": [ "(-)-NANM" ], "offsets": [ [ 1307, 1315 ] ], "normalized": [] }, { "id": "3968644_T26", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 1317, 1325 ] ], "normalized": [] }, { "id": "3968644_T27", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1329, 1332 ] ], "normalized": [] }, { "id": "3968644_T28", "type": "DRUG", "text": [ "Haloperidol" ], "offsets": [ [ 1334, 1345 ] ], "normalized": [] }, { "id": "3968644_T29", "type": "DRUG_N", "text": [ "(+)-NANM" ], "offsets": [ [ 1440, 1448 ] ], "normalized": [] }, { "id": "3968644_T30", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1452, 1455 ] ], "normalized": [] }, { "id": "3968644_T31", "type": "DRUG_N", "text": [ "NANM" ], "offsets": [ [ 1584, 1588 ] ], "normalized": [] }, { "id": "3968644_T32", "type": "DRUG_N", "text": [ "NANM" ], "offsets": [ [ 1678, 1682 ] ], "normalized": [] }, { "id": "3968644_T33", "type": "DRUG_N", "text": [ "PCP" ], "offsets": [ [ 1906, 1909 ] ], "normalized": [] } ]

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[ { "id": "3968644_R1", "type": "EFFECT", "arg1_id": "3968644_T14", "arg2_id": "3968644_T16", "normalized": [] }, { "id": "3968644_R2", "type": "EFFECT", "arg1_id": "3968644_T17", "arg2_id": "3968644_T20", "normalized": [] }, { "id": "3968644_R3", "type": "EFFECT", "arg1_id": "3968644_T21", "arg2_id": "3968644_T22", "normalized": [] }, { "id": "3968644_R4", "type": "EFFECT", "arg1_id": "3968644_T21", "arg2_id": "3968644_T23", "normalized": [] }, { "id": "3968644_R5", "type": "EFFECT", "arg1_id": "3968644_T28", "arg2_id": "3968644_T29", "normalized": [] }, { "id": "3968644_R6", "type": "EFFECT", "arg1_id": "3968644_T28", "arg2_id": "3968644_T30", "normalized": [] } ]

[ { "id": "11199955__text", "type": "abstract", "text": [ "The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. Quetiapine fumarate ('Seroquel') is a newly introduced atypical antipsychotic with demonstrated efficacy in the treatment of positive and negative symptoms of schizophrenia. It is extensively metabolized, predominantly by cytochrome P450 3A4. Therefore, concurrent administration of drugs that induce or inhibit this enzyme may affect quetiapine pharmacokinetics. This study demonstrated that the potent cytochrome P450 enzyme-inducer phenytoin did indeed have a marked effect on the metabolism of quetiapine, resulting in a 5-fold increase in clearance when administered concomitantly to patients with DSM-IV-diagnosed schizophrenia, schizoaffective disorder, or bipolar disorder. These results indicate that dosage adjustment of quetiapine may be necessary when the two drugs are given concurrently and that caution may be required when administering other drugs that inhibit or induce cytochromes, particularly P450 3A4." ], "offsets": [ [ 0, 1027 ] ] } ]

[ { "id": "11199955_T1", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 27, 36 ] ], "normalized": [] }, { "id": "11199955_T2", "type": "DRUG", "text": [ "quetiapine" ], "offsets": [ [ 92, 102 ] ], "normalized": [] }, { "id": "11199955_T3", "type": "DRUG", "text": [ "Quetiapine fumarate" ], "offsets": [ [ 104, 123 ] ], "normalized": [] }, { "id": "11199955_T4", "type": "BRAND", "text": [ "Seroquel" ], "offsets": [ [ 126, 134 ] ], "normalized": [] }, { "id": "11199955_T5", "type": "GROUP", "text": [ "atypical antipsychotic" ], "offsets": [ [ 159, 181 ] ], "normalized": [] }, { "id": "11199955_T6", "type": "DRUG", "text": [ "quetiapine" ], "offsets": [ [ 439, 449 ] ], "normalized": [] }, { "id": "11199955_T7", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 539, 548 ] ], "normalized": [] }, { "id": "11199955_T8", "type": "DRUG", "text": [ "quetiapine" ], "offsets": [ [ 602, 612 ] ], "normalized": [] }, { "id": "11199955_T9", "type": "DRUG", "text": [ "quetiapine" ], "offsets": [ [ 835, 845 ] ], "normalized": [] } ]

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[ { "id": "11199955_R1", "type": "MECHANISM", "arg1_id": "11199955_T7", "arg2_id": "11199955_T8", "normalized": [] } ]

[ { "id": "7756960__text", "type": "abstract", "text": [ "[The effect of sandimmune on the activity of mixed-function mono-oxidases in the liver microsomes] The effects of the immunodepressant--the drug sandimmune--on hepatic microsomal monooxygenase activities were studied. The agent was found to produce some inhibiting activity against hepatic microsomal 7-ethoxycoumarine deethylase in male Wistar rats in vitro and in vivo experiments. When given in a dose of 50 mg/kg, sandimmune produced no statistically significant effect on the duration of hexanal-induced sleep in mice. The findings suggest that the agent has slight effects on the tested activities." ], "offsets": [ [ 0, 604 ] ] } ]

[ { "id": "7756960_T1", "type": "BRAND", "text": [ "sandimmune" ], "offsets": [ [ 15, 25 ] ], "normalized": [] }, { "id": "7756960_T2", "type": "GROUP", "text": [ "immunodepressant" ], "offsets": [ [ 118, 134 ] ], "normalized": [] }, { "id": "7756960_T3", "type": "BRAND", "text": [ "sandimmune" ], "offsets": [ [ 145, 155 ] ], "normalized": [] }, { "id": "7756960_T4", "type": "BRAND", "text": [ "sandimmune" ], "offsets": [ [ 418, 428 ] ], "normalized": [] } ]

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[ { "id": "4469683__text", "type": "abstract", "text": [ "Interferon induction: tool for establishing interactions among homopolyribonucleotides. Hitherto unrecognized interactions between homopolyribonucleotides and complexes thereof are suggested by interferon induction data obtained in a highly sensitive assay system of primary rabbit kidney cell cultures superinduced by metabolic inhibitors." ], "offsets": [ [ 0, 340 ] ] } ]

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[ { "id": "1115367__text", "type": "abstract", "text": [ "Interaction of ketamine and halothane in rats. The interaction of intramuscularly injected ketamine and its N-demethylated metabolite (metabolite I) with halothane was evaluated in rats. Five, 10, 20, or 50 mg/kg of ketamine alone or 20, 50, or 100 mg/kg of metabolite I alone produced less than 10 minutes of hypnosis. However, halothane anesthetic requirement (i.e., MAC) was depressed in a dose-dependent fashion as much as 56% 1-2 hours and as much as 14% 5-6 hours after injection of ketamine, 50 mg/kg, im. The reduction in MAC was correlated with brain levels of ketamine or metabolite I, suggesting a ketamine:metabolite I potency ration of 3:1. The half-life of ketamine in plasma and brain was longer in the presence of halothane than when ketamine was given alone. It is concluded that ketamine is not a short-acting drug and that concomitant use with halothane would be expected to prolong further the duration of its action on the central nervous system." ], "offsets": [ [ 0, 967 ] ] } ]

[ { "id": "1115367_T1", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 15, 23 ] ], "normalized": [] }, { "id": "1115367_T2", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 28, 37 ] ], "normalized": [] }, { "id": "1115367_T3", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 91, 99 ] ], "normalized": [] }, { "id": "1115367_T4", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 154, 163 ] ], "normalized": [] }, { "id": "1115367_T5", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 216, 224 ] ], "normalized": [] }, { "id": "1115367_T6", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 329, 338 ] ], "normalized": [] }, { "id": "1115367_T7", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 489, 497 ] ], "normalized": [] }, { "id": "1115367_T8", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 570, 578 ] ], "normalized": [] }, { "id": "1115367_T9", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 609, 617 ] ], "normalized": [] }, { "id": "1115367_T10", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 671, 679 ] ], "normalized": [] }, { "id": "1115367_T11", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 730, 739 ] ], "normalized": [] }, { "id": "1115367_T12", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 750, 758 ] ], "normalized": [] }, { "id": "1115367_T13", "type": "DRUG", "text": [ "ketamine" ], "offsets": [ [ 797, 805 ] ], "normalized": [] }, { "id": "1115367_T14", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 863, 872 ] ], "normalized": [] } ]

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[ { "id": "1115367_R1", "type": "INT", "arg1_id": "1115367_T1", "arg2_id": "1115367_T2", "normalized": [] }, { "id": "1115367_R2", "type": "MECHANISM", "arg1_id": "1115367_T6", "arg2_id": "1115367_T7", "normalized": [] }, { "id": "1115367_R3", "type": "MECHANISM", "arg1_id": "1115367_T10", "arg2_id": "1115367_T11", "normalized": [] }, { "id": "1115367_R4", "type": "EFFECT", "arg1_id": "1115367_T13", "arg2_id": "1115367_T14", "normalized": [] } ]

[ { "id": "10959916__text", "type": "abstract", "text": [ "Optimal designs for the individual and joint exposure general logistic regression models. Interest in administering compounds in combination lies both in enhancing efficacious effects and in limiting adverse effects. Although much statistical work has focused on developing mathematical functions to model the joint dose-response curves, relatively little work exists in regard to designing experiments for assessing joint action. A variety of parametric dose-response models based on either the normal or logistic probability distribution have been proposed in the literature. These models are typically nonlinear in the parameters, and as such, a nonlinear weighted least squares approach can be employed for the purpose of designing experiments. The approach is applicable across a wide variety of settings commonly associated with joint action data, including continuous and discrete responses, alternative error structures, and nonzero background response. Further, designs can be expressed in terms of proportionate responses associated with the individual compounds rather than dose levels, thereby providing for results that are applicable across compounds. As a precursor to this effort, optimal and minimal experimental designs for the case in which a single compound is administered have also been developed. Although the proposed methodology for deriving experimental designs can be applied to any nonlinear regression model, primary focus is given to the additive and nonadditive independent joint action (IJA) models for individual and combined exposures proposed by Barton, Braunberg, and Friedman (1)." ], "offsets": [ [ 0, 1617 ] ] } ]

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[ { "id": "11213358__text", "type": "abstract", "text": [ "Influence of estradiol and progesterone on the sensitivity of rat thoracic aorta to noradrenaline. The aim of this study was to investigate the effects of low and high doses of estradiol, and of progesterone on the response to noradrenaline in rat thoracic aorta. Two weeks after bilateral ovariectomy, female rats received a s.c. injection of vehicle (corn oil, 0.1 mL/day), estradiol (10 microg/kg/day or 4 mg/kg/day) and/or progesterone (20 mg/kg/day), for eight days. On the ninth day, the rats were sacrificed and aortic rings, with or without endothelium, were used to generate concentration-response curves to noradrenaline. Aortic rings with intact endothelium from the high-dose (4 mg/kg/day) estradiol group were supersensitive to noradrenaline compared to the vehicle or low-dose (10 microg/kg/day) estradiol groups (pD2 values = 7.86+/-0.09, 7.30+/-0.11 and 7.35+/-0.04, respectively). Endothelium-intact aortic rings from high-estradiol rats were supersensitive to noradrenaline when compared to vehicle-, progesterone- and progesterone + high-estradiol-treated rats (pD2 values = 7.77+/-0.12, 7.21+/-0.13, 6.93+/-0.04 and 7.22+/-0.18, respectively). There were no significant differences among the pD2 values for noradrenaline in aortic rings without endothelium. Both of these effects were endothelium-dependent." ], "offsets": [ [ 0, 1327 ] ] } ]

[ { "id": "11213358_T1", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 13, 22 ] ], "normalized": [] }, { "id": "11213358_T2", "type": "DRUG", "text": [ "progesterone" ], "offsets": [ [ 27, 39 ] ], "normalized": [] }, { "id": "11213358_T3", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 84, 97 ] ], "normalized": [] }, { "id": "11213358_T4", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 177, 186 ] ], "normalized": [] }, { "id": "11213358_T5", "type": "DRUG", "text": [ "progesterone" ], "offsets": [ [ 195, 207 ] ], "normalized": [] }, { "id": "11213358_T6", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 227, 240 ] ], "normalized": [] }, { "id": "11213358_T7", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 376, 385 ] ], "normalized": [] }, { "id": "11213358_T8", "type": "DRUG", "text": [ "progesterone" ], "offsets": [ [ 427, 439 ] ], "normalized": [] }, { "id": "11213358_T9", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 617, 630 ] ], "normalized": [] }, { "id": "11213358_T10", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 702, 711 ] ], "normalized": [] }, { "id": "11213358_T11", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 741, 754 ] ], "normalized": [] }, { "id": "11213358_T12", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 940, 949 ] ], "normalized": [] }, { "id": "11213358_T13", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 978, 991 ] ], "normalized": [] }, { "id": "11213358_T14", "type": "DRUG", "text": [ "progesterone" ], "offsets": [ [ 1019, 1031 ] ], "normalized": [] }, { "id": "11213358_T15", "type": "DRUG", "text": [ "progesterone" ], "offsets": [ [ 1037, 1049 ] ], "normalized": [] }, { "id": "11213358_T16", "type": "DRUG", "text": [ "estradiol" ], "offsets": [ [ 1057, 1066 ] ], "normalized": [] }, { "id": "11213358_T17", "type": "DRUG", "text": [ "noradrenaline" ], "offsets": [ [ 1227, 1240 ] ], "normalized": [] } ]

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[ { "id": "11213358_R1", "type": "EFFECT", "arg1_id": "11213358_T10", "arg2_id": "11213358_T11", "normalized": [] }, { "id": "11213358_R2", "type": "EFFECT", "arg1_id": "11213358_T12", "arg2_id": "11213358_T13", "normalized": [] } ]

[ { "id": "11121387__text", "type": "abstract", "text": [ "A proposed mechanism for the potentiation of cAMP-mediated acid secretion by carbachol. Acid secretion in isolated rabbit gastric glands was monitored by the accumulation of [(14)C]aminopyrine. Stimulation of the glands with carbachol synergistically augmented the response to dibutyryl cAMP. The augmentation persisted even after carbachol was washed out and was resistant to chelated extracellular Ca(2+) and to inhibitors of either protein kinase C or calmodulin kinase II. Cytochalasin D at 10 microM preferentially blocked the secretory effect of carbachol and its synergism with cAMP, whereas it had no effect on histamine- or cAMP-stimulated acid secretion within 15 min. Cytochalasin D inhibited the carbachol-stimulated intracellular Ca(2+) concentration ([Ca(2+)](i)) increase due to release from the Ca(2+) store. Treatment of the glands with cytochalasin D redistributed type 3 inositol 1,4,5-trisphosphate receptor (the major subtype in the parietal cell) from the fraction containing membranes of large size to the microsomal fraction, suggesting a dissociation of the store from the plasma membrane. These findings suggest that intracellular Ca(2+) release by cholinergic stimulation is critical for determining synergism with cAMP in parietal cell activation and that functional coupling between the Ca(2+) store and the receptor is maintained by actin microfilaments." ], "offsets": [ [ 0, 1384 ] ] } ]

[ { "id": "11121387_T1", "type": "DRUG", "text": [ "carbachol" ], "offsets": [ [ 77, 86 ] ], "normalized": [] }, { "id": "11121387_T2", "type": "DRUG", "text": [ "aminopyrine" ], "offsets": [ [ 181, 192 ] ], "normalized": [] }, { "id": "11121387_T3", "type": "DRUG", "text": [ "carbachol" ], "offsets": [ [ 225, 234 ] ], "normalized": [] }, { "id": "11121387_T4", "type": "DRUG", "text": [ "carbachol" ], "offsets": [ [ 331, 340 ] ], "normalized": [] }, { "id": "11121387_T5", "type": "DRUG_N", "text": [ "Cytochalasin D" ], "offsets": [ [ 477, 491 ] ], "normalized": [] }, { "id": "11121387_T6", "type": "DRUG", "text": [ "carbachol" ], "offsets": [ [ 552, 561 ] ], "normalized": [] }, { "id": "11121387_T7", "type": "DRUG_N", "text": [ "Cytochalasin D" ], "offsets": [ [ 679, 693 ] ], "normalized": [] }, { "id": "11121387_T8", "type": "DRUG", "text": [ "carbachol" ], "offsets": [ [ 708, 717 ] ], "normalized": [] }, { "id": "11121387_T9", "type": "DRUG_N", "text": [ "cytochalasin D" ], "offsets": [ [ 854, 868 ] ], "normalized": [] } ]

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[ { "id": "11121387_R1", "type": "EFFECT", "arg1_id": "11121387_T5", "arg2_id": "11121387_T6", "normalized": [] }, { "id": "11121387_R2", "type": "EFFECT", "arg1_id": "11121387_T7", "arg2_id": "11121387_T8", "normalized": [] } ]

[ { "id": "6536282__text", "type": "abstract", "text": [ "Altered responsiveness to alcohol after exposure to organic lead. Ethyl alcohol is known to effect the functional integrity of the limbic system, particularly the hippocampus, and to alter behaviors which are thought to be mediated through limbic function. Organometals also compromise the limbic system and result in deficits in learning and memory. Since both alcohol and organoleads are present in the environment and seem to influence limbic integration, the interaction of these two compounds was assessed in the present experiment. Thirty male rats of the Fischer-344 strain were divided into three equal groups and were given injections of trimethyl lead (TML) (8.0 or 17.0 mg/kg/ml SC) or the saline vehicle. Fourteen days later, all animals were challenged with a single hypnotic dose of ethanol (3.5 g/kg IP). The 20% v/v solution of alcohol was prepared in water from a stock solution of 95% ethanol. The latency to loss of the righting reflex and duration of sleep time were recorded while the rats were kept in sound-attenuating chambers. The rats treated with the highest dose of TML manifested significantly longer latencies to lose the righting reflex and shorter durations of sleep than did controls. These results suggest that exposure to environmental lead may alter the biological and behavioral responsiveness of an animal to alcohol." ], "offsets": [ [ 0, 1355 ] ] } ]

[ { "id": "6536282_T1", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 26, 33 ] ], "normalized": [] }, { "id": "6536282_T2", "type": "DRUG", "text": [ "Ethyl alcohol" ], "offsets": [ [ 66, 79 ] ], "normalized": [] }, { "id": "6536282_T3", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 362, 369 ] ], "normalized": [] }, { "id": "6536282_T4", "type": "DRUG_N", "text": [ "trimethyl lead" ], "offsets": [ [ 647, 661 ] ], "normalized": [] }, { "id": "6536282_T5", "type": "DRUG_N", "text": [ "TML" ], "offsets": [ [ 663, 666 ] ], "normalized": [] }, { "id": "6536282_T6", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 797, 804 ] ], "normalized": [] }, { "id": "6536282_T7", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 844, 851 ] ], "normalized": [] }, { "id": "6536282_T8", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 903, 910 ] ], "normalized": [] }, { "id": "6536282_T9", "type": "DRUG_N", "text": [ "TML" ], "offsets": [ [ 1094, 1097 ] ], "normalized": [] }, { "id": "6536282_T10", "type": "DRUG_N", "text": [ "lead" ], "offsets": [ [ 1271, 1275 ] ], "normalized": [] }, { "id": "6536282_T11", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 1347, 1354 ] ], "normalized": [] } ]

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[ { "id": "6536282_R1", "type": "EFFECT", "arg1_id": "6536282_T10", "arg2_id": "6536282_T11", "normalized": [] } ]

[ { "id": "11218973__text", "type": "abstract", "text": [ "[Pharmacologic interactions in chronic treatments: corrective measures for its prevention in a basic area of rural health]\nOBJECTIVES: To identify the pharmacological interactions of clinical relevance (PICR) in the medication authorization cards (MAC) of the chronically ill and to establish strategies to minimise their appearance. DESIGN: Cross-sectional descriptive study. SETTING: Rural primary care centre. PATIENTS: Random sample of 626 MAC out of a total of 1306. MEASUREMENTS AND MAIN RESULTS: In December 1998, the following was gathered for every MAC with more than one drug treatment: age, sex, number of drugs, intrinsic value, drugs prescribed, daily dose and pharmacological interactions (PI), classified (using the scale of Hansten 1996) into light and clinically relevant. Statistical analysis: Mantel-Haenszel (alpha = 0.05). Patients' mean age was 69.1 (95% CI, +/- 1.2). Mean number of drugs per MAC was 4 (95% CI, +/- 0.2). 341 PI affecting 197 patients (31.5%, 95% CI, +/- 3.6) were identified. 24.9% (95% CI, +/- 4.5) were PICR, detected in 11.7% (95% CI, +/- 2.5) of the MAC. The existence of PI was related to the number of drugs prescribed to each patient (p < 0.01). There were 26 PI with drugs of low intrinsic value (7.6%; 95% CI, +/- 2.8). 74.1% (95% CI, +/- 9.3) of the total PICR could be avoided by simple recommendations; and the remaining 25.9% (95% CI, +/- 9.3) by monitoring and follow-up of patients. CONCLUSIONS: It is important to identify the medications most commonly involved in the PICR so as to establish corrective measures to minimise the risks arising from multiple medication. Four educational messages advise on over 60% of the PICR detected." ], "offsets": [ [ 0, 1692 ] ] } ]

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[ { "id": "8640374__text", "type": "abstract", "text": [ "Administration of lithium prophylaxis. Successful prophylaxis of manic-depressive disorder requires more than the prescription of lithium carbonate. The administrative arrangements in an area of Scotland were accompanied by a 300% increase in the frequency of admissions for mania, whereas in an area of the West Midlands, a large decrease was achieved." ], "offsets": [ [ 0, 353 ] ] } ]

[ { "id": "8640374_T1", "type": "DRUG", "text": [ "lithium" ], "offsets": [ [ 18, 25 ] ], "normalized": [] }, { "id": "8640374_T2", "type": "DRUG", "text": [ "lithium carbonate" ], "offsets": [ [ 130, 147 ] ], "normalized": [] } ]

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[ { "id": "7653281__text", "type": "abstract", "text": [ "Interaction of the constituents of alcoholic beverages in the promotion of liver damage. Little has been studied of the adverse effects of the exposure of the liver to the interaction of ethanol with its congeners and acetaldehyde, coexisting in the contents of alcoholic beverages. Twenty four male Wistar rats were divided into four groups. Two groups (SH/DA; SH/FA) were submitted to daily treatment with synthetic hydroalcoholic solutions containing ethanol, methanol, higher alcohols and acetaldehyde in the same proportions as those found in most common distilled and fermented alcoholic beverages; the third group (SH/EA) was treated with a hydroalcoholic solution of ethanol; the fourth group served as control and received an equivalent volume of an isocaloric solution of dextrose. All the animals were killed at the end of the 9th week of the experiment. The ratio between the liver weight and body weight was found to be lower in the treated animals than in the control group. The histology of the liver was altered in the three groups which were submitted to treatment with the hydroalcoholic solutions, with quantitative and qualitative differences between the groups. These results suggest that the hepatoxicity of ethanol in alcoholic beverages is enhanced by interaction with its congeners and acetaldehyde; they also suggest that alcoholic beverages are not equivalent in their potential to cause liver damage." ], "offsets": [ [ 0, 1428 ] ] } ]

[ { "id": "7653281_T1", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 187, 194 ] ], "normalized": [] }, { "id": "7653281_T2", "type": "DRUG_N", "text": [ "acetaldehyde" ], "offsets": [ [ 218, 230 ] ], "normalized": [] }, { "id": "7653281_T3", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 454, 461 ] ], "normalized": [] }, { "id": "7653281_T4", "type": "DRUG_N", "text": [ "methanol" ], "offsets": [ [ 463, 471 ] ], "normalized": [] }, { "id": "7653281_T5", "type": "DRUG_N", "text": [ "alcohols" ], "offsets": [ [ 480, 488 ] ], "normalized": [] }, { "id": "7653281_T6", "type": "DRUG_N", "text": [ "acetaldehyde" ], "offsets": [ [ 493, 505 ] ], "normalized": [] }, { "id": "7653281_T7", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 675, 682 ] ], "normalized": [] }, { "id": "7653281_T8", "type": "DRUG", "text": [ "dextrose" ], "offsets": [ [ 782, 790 ] ], "normalized": [] }, { "id": "7653281_T9", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 1230, 1237 ] ], "normalized": [] }, { "id": "7653281_T10", "type": "DRUG_N", "text": [ "acetaldehyde" ], "offsets": [ [ 1311, 1323 ] ], "normalized": [] } ]

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[ { "id": "7653281_R1", "type": "EFFECT", "arg1_id": "7653281_T9", "arg2_id": "7653281_T10", "normalized": [] } ]

[ { "id": "7786695__text", "type": "abstract", "text": [ "Magnesium and therapeutics. Two different types of therapy with magnesium are used: physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and pharmacological magnesium therapy which may induce toxicity since it creates iatrogenic magnesium overload. Primary and secondary magnesium deficiencies constitute the sole indication of physiological oral magnesium therapy. It is therefore necessary to be well acquainted with the clinical and paraclinical pattern of magnesium deficit and to discriminate between magnesium deficiency due to an insufficient magnesium intake which only requires oral physiological supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires more or less specific regulation of its causal dysregulation. Physiological oral magnesium load constitutes the best tool for diagnosis of magnesium deficiency and the first step of its treatment. Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet or with magnesium salts, with practically only one contra-indication: overt renal failure. Specific and aspecific treatments of magnesium depletion are tricky using for example magnesium sparing diuretics, pharmacological doses of vitamin B6, physiological doses of vitamin D and of selenium. In order to use the pharmacological properties of induced therapeutic hypermagnesaemia, high oral doses of magnesium (> 10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. There are 3 types of indications: specific (for the treatment of some forms of magnesium deficit i.e. acute), pharmacological (i.e. without alterations of magnesium status) and mixed--pharmacological and aetiopathogenic--(for example complications of chronic alcoholism). Today pharmacological magnesium therapy mainly concerns the obstetrical, cardiological and anaesthesiological fields. The main indications are eclampsia, some dysrhythmias (torsades de pointe particularly) and myocardial ischaemias. But it is now difficult to situate the exact place of the pharmacological indications of magnesium. Magnesium infusions can only be envisaged in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis, electrocardiogram and respiratory recordings. High oral magnesium doses besides their laxative action may bring latent complications which may reduce lifespan. There may remain some indications of the laxative and antacid properties of non soluble magnesium, particularly during intermittent haemodialysis. Lastly local use of the mucocutaneous and cytoprotective properties of magnesium is still valid, in cardioplegic solutions and for preservation of transplants particularly." ], "offsets": [ [ 0, 2901 ] ] } ]

[ { "id": "7786695_T1", "type": "DRUG", "text": [ "Magnesium" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "7786695_T2", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 64, 73 ] ], "normalized": [] }, { "id": "7786695_T3", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 103, 112 ] ], "normalized": [] }, { "id": "7786695_T4", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 172, 181 ] ], "normalized": [] }, { "id": "7786695_T5", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 221, 230 ] ], "normalized": [] }, { "id": "7786695_T6", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 258, 267 ] ], "normalized": [] }, { "id": "7786695_T7", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 330, 339 ] ], "normalized": [] }, { "id": "7786695_T8", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 372, 381 ] ], "normalized": [] }, { "id": "7786695_T9", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 448, 457 ] ], "normalized": [] }, { "id": "7786695_T10", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 561, 570 ] ], "normalized": [] }, { "id": "7786695_T11", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 607, 616 ] ], "normalized": [] }, { "id": "7786695_T12", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 651, 660 ] ], "normalized": [] }, { "id": "7786695_T13", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 727, 736 ] ], "normalized": [] }, { "id": "7786695_T14", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 803, 812 ] ], "normalized": [] }, { "id": "7786695_T15", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 916, 925 ] ], "normalized": [] }, { "id": "7786695_T16", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 974, 983 ] ], "normalized": [] }, { "id": "7786695_T17", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1051, 1060 ] ], "normalized": [] }, { "id": "7786695_T18", "type": "DRUG", "text": [ "magnesium salt" ], "offsets": [ [ 1142, 1156 ] ], "normalized": [] }, { "id": "7786695_T19", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1262, 1271 ] ], "normalized": [] }, { "id": "7786695_T20", "type": "GROUP", "text": [ "magnesium sparing diuretics" ], "offsets": [ [ 1311, 1338 ] ], "normalized": [] }, { "id": "7786695_T21", "type": "DRUG", "text": [ "vitamin B6" ], "offsets": [ [ 1365, 1375 ] ], "normalized": [] }, { "id": "7786695_T22", "type": "GROUP", "text": [ "vitamin D" ], "offsets": [ [ 1400, 1409 ] ], "normalized": [] }, { "id": "7786695_T23", "type": "DRUG", "text": [ "selenium" ], "offsets": [ [ 1417, 1425 ] ], "normalized": [] }, { "id": "7786695_T24", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1534, 1543 ] ], "normalized": [] }, { "id": "7786695_T25", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1738, 1747 ] ], "normalized": [] }, { "id": "7786695_T26", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1814, 1823 ] ], "normalized": [] }, { "id": "7786695_T27", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 1953, 1962 ] ], "normalized": [] }, { "id": "7786695_T28", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 2253, 2262 ] ], "normalized": [] }, { "id": "7786695_T29", "type": "DRUG", "text": [ "Magnesium" ], "offsets": [ [ 2264, 2273 ] ], "normalized": [] }, { "id": "7786695_T30", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 2478, 2487 ] ], "normalized": [] }, { "id": "7786695_T31", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 2670, 2679 ] ], "normalized": [] }, { "id": "7786695_T32", "type": "DRUG", "text": [ "magnesium" ], "offsets": [ [ 2800, 2809 ] ], "normalized": [] }, { "id": "7786695_T33", "type": "DRUG", "text": [ "cardioplegic solutions" ], "offsets": [ [ 2829, 2851 ] ], "normalized": [] } ]

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[ { "id": "11219477__text", "type": "abstract", "text": [ "Sildenafil citrate: a therapeutic update. BACKGROUND: Since its approval by the US Food and Drug Administration in March 1998, sildenafil citrate has been used by millions of men for the treatment of erectile dysfunction. Recent studies and consensus reports have expanded our understanding of its efficacy, safety, contraindications, and drug interactions. OBJECTIVE: This paper reviews recent studies of the efficacy of sildenafil, its adverse effects and drug interactions, and socioeconomic factors involved in its use, with a focus on specific patient populations (prostate cancer, diabetes mellitus, ischemic heart disease, spinal cord injuries, neurologic disorders). METHODS: Clinical studies, case reports, and commentaries and editorials concerning sildenafil published in the international literature between January 1999 and August 2000 were identified through searches of MEDLINE, PREMEDLINE, and International Pharmaceutical Abstracts, using the terms sildenafil, Viagra, and erectile dysfunction. RESULTS: Sildenafil has demonstrated effectiveness in men with erectile dysfunction associated with prostatectomy, radiation therapy, diabetes mellitus, certain neurologic disorders, and drug therapy (eg, selective serotonin reuptake inhibitors [SSRIs]). It has not been as effective in women with sexual dysfunction, with the exception of SSRI-associated sexual dysfunction. Some disorders unrelated to sexual dysfunction (eg, esophageal motility dysfunction) may also respond to sildenafil. In the general population, sildenafil is considered to have an acceptable tolerability profile; however, patients with moderate to severe cardiovascular disease or those taking nitrate therapy are at increased risk for potentially serious cardiovascular adverse effects with sildenafil therapy. In addition, patients taking drugs that inhibit the cytochrome P450 3A4 isozyme, which metabolizes sildenafil, may experience increased drug concentrations and possible toxicity from normal doses of sildenafil. CONCLUSIONS: Sildenafil is an effective first-line therapy for erectile dysfunction in men. The decision to prescribe this agent should include such considerations as the cost-risk-benefit balance, patient access, drug distribution pathways, and prescription drug coverage." ], "offsets": [ [ 0, 2284 ] ] } ]

[ { "id": "11219477_T1", "type": "DRUG", "text": [ "Sildenafil citrate" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "11219477_T2", "type": "DRUG", "text": [ "sildenafil citrate" ], "offsets": [ [ 127, 145 ] ], "normalized": [] }, { "id": "11219477_T3", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 422, 432 ] ], "normalized": [] }, { "id": "11219477_T4", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 759, 769 ] ], "normalized": [] }, { "id": "11219477_T5", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 966, 976 ] ], "normalized": [] }, { "id": "11219477_T6", "type": "BRAND", "text": [ "Viagra" ], "offsets": [ [ 978, 984 ] ], "normalized": [] }, { "id": "11219477_T7", "type": "DRUG", "text": [ "Sildenafil" ], "offsets": [ [ 1021, 1031 ] ], "normalized": [] }, { "id": "11219477_T8", "type": "GROUP", "text": [ "selective serotonin reuptake inhibitors" ], "offsets": [ [ 1217, 1256 ] ], "normalized": [] }, { "id": "11219477_T9", "type": "GROUP", "text": [ "SSRIs" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "11219477_T10", "type": "GROUP", "text": [ "SSRI" ], "offsets": [ [ 1352, 1356 ] ], "normalized": [] }, { "id": "11219477_T11", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 1493, 1503 ] ], "normalized": [] }, { "id": "11219477_T12", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 1532, 1542 ] ], "normalized": [] }, { "id": "11219477_T13", "type": "GROUP", "text": [ "nitrate" ], "offsets": [ [ 1682, 1689 ] ], "normalized": [] }, { "id": "11219477_T14", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 1780, 1790 ] ], "normalized": [] }, { "id": "11219477_T15", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 1899, 1909 ] ], "normalized": [] }, { "id": "11219477_T16", "type": "DRUG", "text": [ "sildenafil" ], "offsets": [ [ 1999, 2009 ] ], "normalized": [] }, { "id": "11219477_T17", "type": "DRUG", "text": [ "Sildenafil" ], "offsets": [ [ 2024, 2034 ] ], "normalized": [] } ]

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[ { "id": "11219477_R1", "type": "EFFECT", "arg1_id": "11219477_T13", "arg2_id": "11219477_T14", "normalized": [] } ]

[ { "id": "11211460__text", "type": "abstract", "text": [ "Pharmacological treatment of depression: the role of paroxetine. Depression is reaching epidemic proportions in the western world. With each successive generation more people are becoming more severely depressed at a younger age." ], "offsets": [ [ 0, 229 ] ] } ]

[ { "id": "11211460_T1", "type": "DRUG", "text": [ "paroxetine" ], "offsets": [ [ 53, 63 ] ], "normalized": [] } ]

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[ { "id": "11219023__text", "type": "abstract", "text": [ "Prescribing. Keys to maximizing benefit while avoiding adverse drug effects. When prescribing for older patients, some physicians are overly cautious, and this strategy can result in a less than optimal treatment outcome. The reluctance to treat aggressively is understandable because the geriatric population is susceptible to adverse drug reactions. The key to maximizing therapy lies in individualizing it as much as possible. There are a number of steps physicians can take to ensure that their patients are not being undertreated. These steps include regular reevaluations of dosages and plasma drug concentrations, recognition and understanding of drug side effects, and avoidance of certain agents. Close monitoring allows physicians to minimize risks, maximize benefits, and get the most out of what modern medications can do to help older patients." ], "offsets": [ [ 0, 857 ] ] } ]

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[ { "id": "17894105__text", "type": "abstract", "text": [ "The effects of chlordiazepoxide, amphetamine and cocaine on bar-press behavior in normal and genetically nervous dogs. Studies on two strains of pointer dogs have demonstrated that administration of a benzodiazepine (chlordiazepoxide) facilitates acquisition of goal-directed behavior in \"genetically nervous\" subjects. Continued admistration of the drug is required to maintain barpress response in this strain of dogs. The concomitant administration of either cocaine or amphetamine, compounds which inhibit neuronal reuptake of norepinephrine, disrupts the behavioral response of the genetically nervous E-strain subjects to a far greater extent than the stable A-strain subjects. It is also shown that after 14 days of daily administration of chlordiazepoxide, withdrawal of the drug not only re-results in almost complete loss of bar-press response in the E-strain subjects but also results in a temporary decrease in the acquired behavioral response of the stable A-strain subjects." ], "offsets": [ [ 0, 988 ] ] } ]

[ { "id": "17894105_T1", "type": "DRUG", "text": [ "chlordiazepoxide" ], "offsets": [ [ 15, 31 ] ], "normalized": [] }, { "id": "17894105_T2", "type": "DRUG", "text": [ "amphetamine" ], "offsets": [ [ 33, 44 ] ], "normalized": [] }, { "id": "17894105_T3", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 49, 56 ] ], "normalized": [] }, { "id": "17894105_T4", "type": "GROUP", "text": [ "benzodiazepine" ], "offsets": [ [ 201, 215 ] ], "normalized": [] }, { "id": "17894105_T5", "type": "DRUG", "text": [ "chlordiazepoxide" ], "offsets": [ [ 217, 233 ] ], "normalized": [] }, { "id": "17894105_T6", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 462, 469 ] ], "normalized": [] }, { "id": "17894105_T7", "type": "DRUG", "text": [ "amphetamine" ], "offsets": [ [ 473, 484 ] ], "normalized": [] }, { "id": "17894105_T8", "type": "DRUG", "text": [ "chlordiazepoxide" ], "offsets": [ [ 747, 763 ] ], "normalized": [] } ]

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[ { "id": "11170315__text", "type": "abstract", "text": [ "The mode of toxic action of the pesticide gliftor: the metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate. The biochemical toxicology of 1,3-difluoroacetone, a known metabolite of the major ingredient of the pesticide Gliftor (1,3-difluoro-2-propanol), was investigated in vivo and in vitro. Rat kidney homogenates supplemented with coenzyme A, ATP, oxaloacetate, and Mg2+ converted 1,3-difluoroacetone to (-)-erythro-fluorocitrate in vitro. Administration of 1,3-difluoroacetone (100 mg kg(-1) body weight) to rats in vivo resulted in (-)-erythro-fluorocitrate synthesis in the kidney, which was preceded by an elevation in fluoride levels and followed by citrate accumulation. Animals dosed with 1,3-difluoroacetone did not display the 2-3 hour lag phase in either (-)-erythro-fluorocitrate synthesis or in citrate and fluoride accumulation characteristic of animals dosed with 1,3-difluoro-2-propanol. We demonstrate that the conversion of 1,3-difluoro-2-propanol to 1,3-difluoroacetone by an NAD+-dependent oxidation is the rate-limiting step in the synthesis of the toxic product, (-)-erythro-fluorocitrate from 1,3-difluoro-2-propanol. Prior administration of 4-methylpyrazole (90 mg kg(-1) body weight) was shown to prevent the conversion of 1,3-difluoro-2-propanol (100 mg kg(-1) body weight) to (-)-erythro-fluorocitrate in vivo and to eliminate the fluoride and citrate elevations seen in 1,3-difluoro-2-propanol-intoxicated animals. However, administration of 4-methylpyrazole (90 mg kg(-1) body weight) to rats 2 hours prior to 1,3-difluoroacetone (100 mg kg(-1) body weight) was ineffective in preventing (-)-erythro-fluorocitrate synthesis and did not diminish fluoride or citrate accumulation in vivo. We conclude that the prophylactic and antidotal properties of 4-methylpyrazole seen in animals treated with 1,3-difluoro-2-propanol derive from its capacity to inhibit the NAD+-dependent oxidation responsible for converting 1,3-difluoro-2-propanol to 1,3-difluoroacetone in the committed step of the toxic pathway." ], "offsets": [ [ 0, 2043 ] ] } ]

[ { "id": "11170315_T1", "type": "DRUG_N", "text": [ "gliftor" ], "offsets": [ [ 42, 49 ] ], "normalized": [] }, { "id": "11170315_T2", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 69, 88 ] ], "normalized": [] }, { "id": "11170315_T3", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 92, 117 ] ], "normalized": [] }, { "id": "11170315_T4", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 149, 168 ] ], "normalized": [] }, { "id": "11170315_T5", "type": "DRUG_N", "text": [ "Gliftor" ], "offsets": [ [ 230, 237 ] ], "normalized": [] }, { "id": "11170315_T6", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 239, 262 ] ], "normalized": [] }, { "id": "11170315_T7", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 395, 414 ] ], "normalized": [] }, { "id": "11170315_T8", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 418, 443 ] ], "normalized": [] }, { "id": "11170315_T9", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 472, 491 ] ], "normalized": [] }, { "id": "11170315_T10", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 548, 573 ] ], "normalized": [] }, { "id": "11170315_T11", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 710, 729 ] ], "normalized": [] }, { "id": "11170315_T12", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 779, 804 ] ], "normalized": [] }, { "id": "11170315_T13", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 892, 915 ] ], "normalized": [] }, { "id": "11170315_T14", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 955, 978 ] ], "normalized": [] }, { "id": "11170315_T15", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 982, 1001 ] ], "normalized": [] }, { "id": "11170315_T16", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 1098, 1123 ] ], "normalized": [] }, { "id": "11170315_T17", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 1129, 1152 ] ], "normalized": [] }, { "id": "11170315_T18", "type": "DRUG", "text": [ "4-methylpyrazole" ], "offsets": [ [ 1178, 1194 ] ], "normalized": [] }, { "id": "11170315_T19", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 1261, 1284 ] ], "normalized": [] }, { "id": "11170315_T20", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 1316, 1341 ] ], "normalized": [] }, { "id": "11170315_T21", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 1411, 1434 ] ], "normalized": [] }, { "id": "11170315_T22", "type": "DRUG", "text": [ "4-methylpyrazole" ], "offsets": [ [ 1483, 1499 ] ], "normalized": [] }, { "id": "11170315_T23", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 1552, 1571 ] ], "normalized": [] }, { "id": "11170315_T24", "type": "DRUG_N", "text": [ "(-)-erythro-fluorocitrate" ], "offsets": [ [ 1630, 1655 ] ], "normalized": [] }, { "id": "11170315_T25", "type": "DRUG", "text": [ "4-methylpyrazole" ], "offsets": [ [ 1791, 1807 ] ], "normalized": [] }, { "id": "11170315_T26", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 1837, 1860 ] ], "normalized": [] }, { "id": "11170315_T27", "type": "DRUG_N", "text": [ "1,3-difluoro-2-propanol" ], "offsets": [ [ 1953, 1976 ] ], "normalized": [] }, { "id": "11170315_T28", "type": "DRUG_N", "text": [ "1,3-difluoroacetone" ], "offsets": [ [ 1980, 1999 ] ], "normalized": [] } ]

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[ { "id": "11170315_R1", "type": "EFFECT", "arg1_id": "11170315_T18", "arg2_id": "11170315_T19", "normalized": [] }, { "id": "11170315_R2", "type": "EFFECT", "arg1_id": "11170315_T25", "arg2_id": "11170315_T26", "normalized": [] } ]

[ { "id": "15986716__text", "type": "abstract", "text": [ "Behavioral mechanisms underlying the link between smoking and drinking. Many people use both alcohol and nicotine (i.e., cigarettes and other tobacco products). The behavioral effects of these two drugs differ, and they do not act on the same target sites in the brain, although they may share, or partly share, certain properties. The initiation of alcohol or nicotine use may be precipitated by similar personality characteristics in the user, such as impulsivity and sensation seeking. Moreover, the mechanisms underlying the development of dependence may be similar for alcohol and nicotine. Thus, certain factors, such as reinforcing drug effects, conditioning processes, automatic behavior, and stress, may influence the development of dependence on both drugs. Other factors, such as tolerance and sensitization to the drugs' actions and the development of withdrawal symptoms, may also contribute to dependence. This review discusses the actions of the two drugs on certain brain chemical (i.e., neurotransmitter) systems and the extent to which the effects of the two drugs may interact." ], "offsets": [ [ 0, 1096 ] ] } ]

[ { "id": "15986716_T1", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 93, 100 ] ], "normalized": [] }, { "id": "15986716_T2", "type": "DRUG", "text": [ "nicotine" ], "offsets": [ [ 105, 113 ] ], "normalized": [] }, { "id": "15986716_T3", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 350, 357 ] ], "normalized": [] }, { "id": "15986716_T4", "type": "DRUG", "text": [ "nicotine" ], "offsets": [ [ 361, 369 ] ], "normalized": [] }, { "id": "15986716_T5", "type": "DRUG", "text": [ "alcohol" ], "offsets": [ [ 574, 581 ] ], "normalized": [] }, { "id": "15986716_T6", "type": "DRUG", "text": [ "nicotine" ], "offsets": [ [ 586, 594 ] ], "normalized": [] } ]

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[ { "id": "2578597__text", "type": "abstract", "text": [ "Analgesic effects of antihistaminics. The literature provides considerable evidence indicating that several, but not all antihistaminics, are indeed analgesic agents and some are analgesic adjuvants as well. Those for which effectiveness is reported includes diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyltoloxamine, promethazine, methdilazine, and tripelennamine. The proposed mechanisms of analgesic action of antihistaminics are reviewed and discussed. The literature suggests that more than one mechanism of action exists for them. There is considerable evidence suggesting that histaminergic and serotoninergic central pathways are involved in nociception and that antihistaminic drugs can modulate their responses (1). The evidence for a role for norepinephrine and dopamine and the effects of antihistaminics on them are less well established. Still other pathways have been proposed. A greater understanding of pain mechanisms will aid in elucidating the role of antihistaminics in analgesia." ], "offsets": [ [ 0, 1016 ] ] } ]

[ { "id": "2578597_T1", "type": "GROUP", "text": [ "antihistaminics" ], "offsets": [ [ 21, 36 ] ], "normalized": [] }, { "id": "2578597_T2", "type": "GROUP", "text": [ "antihistaminics" ], "offsets": [ [ 121, 136 ] ], "normalized": [] }, { "id": "2578597_T3", "type": "GROUP", "text": [ "analgesic agents" ], "offsets": [ [ 149, 165 ] ], "normalized": [] }, { "id": "2578597_T4", "type": "GROUP", "text": [ "analgesic adjuvants" ], "offsets": [ [ 179, 198 ] ], "normalized": [] }, { "id": "2578597_T5", "type": "DRUG", "text": [ "diphenhydramine" ], "offsets": [ [ 259, 274 ] ], "normalized": [] }, { "id": "2578597_T6", "type": "DRUG", "text": [ "hydroxyzine" ], "offsets": [ [ 276, 287 ] ], "normalized": [] }, { "id": "2578597_T7", "type": "DRUG", "text": [ "orphenadrine" ], "offsets": [ [ 289, 301 ] ], "normalized": [] }, { "id": "2578597_T8", "type": "DRUG", "text": [ "pyrilamine" ], "offsets": [ [ 303, 313 ] ], "normalized": [] }, { "id": "2578597_T9", "type": "DRUG_N", "text": [ "phenyltoloxamine" ], "offsets": [ [ 315, 331 ] ], "normalized": [] }, { "id": "2578597_T10", "type": "DRUG", "text": [ "promethazine" ], "offsets": [ [ 333, 345 ] ], "normalized": [] }, { "id": "2578597_T11", "type": "DRUG", "text": [ "methdilazine" ], "offsets": [ [ 347, 359 ] ], "normalized": [] }, { "id": "2578597_T12", "type": "DRUG", "text": [ "tripelennamine" ], "offsets": [ [ 365, 379 ] ], "normalized": [] }, { "id": "2578597_T13", "type": "GROUP", "text": [ "antihistaminics" ], "offsets": [ [ 428, 443 ] ], "normalized": [] }, { "id": "2578597_T14", "type": "GROUP", "text": [ "antihistaminic" ], "offsets": [ [ 686, 700 ] ], "normalized": [] }, { "id": "2578597_T15", "type": "GROUP", "text": [ "antihistaminics" ], "offsets": [ [ 816, 831 ] ], "normalized": [] }, { "id": "2578597_T16", "type": "GROUP", "text": [ "antihistaminics" ], "offsets": [ [ 987, 1002 ] ], "normalized": [] } ]

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[ { "id": "1109556__text", "type": "abstract", "text": [ "Serum digoxin levels using an 125I-labelled antigen: Validation of method and observations on cardiac patients. 1. Determinations of serum digoxin levels utilizing commercially available kits with an 125I-labelled antigen were precise and not materially different from results obtained with a 3H-labelled antigen. 2. In order to approximate the steady state level, serum digoxin levels should be drawn either before or at least six hours following the administration of an oral tablet. 3. Concomitantly given thiazide diuretics did not interfere with the absorption of a tablet of digoxin. 4. In the digitalized patient, slow alterations in serum levels after oral administration appeared well correlated with, at least, the negative chronotropic effects of the drug. 5. Maximal exercise testing, a maneuver often applied to cardiac patients, does not significantly alter the serum digoxin level." ], "offsets": [ [ 0, 896 ] ] } ]

[ { "id": "1109556_T1", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 6, 13 ] ], "normalized": [] }, { "id": "1109556_T2", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 139, 146 ] ], "normalized": [] }, { "id": "1109556_T3", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 371, 378 ] ], "normalized": [] }, { "id": "1109556_T4", "type": "GROUP", "text": [ "thiazide diuretics" ], "offsets": [ [ 509, 527 ] ], "normalized": [] }, { "id": "1109556_T5", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 581, 588 ] ], "normalized": [] }, { "id": "1109556_T6", "type": "DRUG", "text": [ "digoxin" ], "offsets": [ [ 882, 889 ] ], "normalized": [] } ]

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[ { "id": "11198959__text", "type": "abstract", "text": [ "[Importance of pharmacogenetics];Pharmacogenetics deals with the differences in effect of drugs caused by genetic variation. Differences can occur in therapeutic effect and in adverse events. Genetic variation in metabolism may result in high concentrations of drugs and an increased risk of adverse effects in slow metabolizers, which is important when using for example antidepressants or chemotherapy. Genetic variation also occurs in proteins interacting with drugs, which may change the effect of e.g. asthma drugs and antipsychotics. The selection of drugs and their dosages may be improved, and the number of adverse effects reduced by pharmacogenetic investigations. However, it may be important also in case of medical examinations for insurances and job appointments, since some patients may turn out to need expensive drugs or to be susceptible to a certain disease. Therefore, the use of genetic data in these instances has to be regulated." ], "offsets": [ [ 0, 952 ] ] } ]

[ { "id": "11198959_T1", "type": "GROUP", "text": [ "antidepressants" ], "offsets": [ [ 372, 387 ] ], "normalized": [] }, { "id": "11198959_T2", "type": "GROUP", "text": [ "antipsychotics" ], "offsets": [ [ 524, 538 ] ], "normalized": [] } ]

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[ { "id": "7476793__text", "type": "abstract", "text": [ "Drug-lab interactions: implications for nutrition support. Acetylcysteine interference with urine ketone test. It is important that health care professionals be aware of the potential for medications to interfere with clinical laboratory tests. Medications can cause in vivo effects when the concentration or activity of the analyte is altered before the analysis and therefore the assay result is true and accurate. An in vitro effect occurs when the medication interferes with the assay, and the result is erroneous and cannot be interpreted. This report describes a recently identified case of interference of acetylcysteine with the urine test for ketones and demonstrates the importance of a thorough medication review in evaluating abnormal laboratory tests." ], "offsets": [ [ 0, 764 ] ] } ]

[ { "id": "7476793_T1", "type": "DRUG", "text": [ "Acetylcysteine" ], "offsets": [ [ 59, 73 ] ], "normalized": [] }, { "id": "7476793_T2", "type": "DRUG", "text": [ "acetylcysteine" ], "offsets": [ [ 613, 627 ] ], "normalized": [] } ]

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[ { "id": "8996605__text", "type": "abstract", "text": [ "Determinants of cellular sensitivity to topoisomerase-targeting antitumor drugs. It is now clear that topoisomerase activity level is an important determinant of sensitivity to topo drugs. The regulation of topoisomerases is no doubt complex and multifaceted and is probably accomplished through redundancy at many control levels. The mechanism(s) of altered topo I expression in certain tumor types is unknown, but may be related to the central importance of topoisomerases in proliferating cell functions (transcription, replication, etc.), and the aberrant and chronic activation of these functions as a result of specific tumorigenic alterations. Small differences in sensitivity to chemotherapy can have a dramatic effect on cure rates, and therefore subtle cell type-specific differences may be important determinants of drug sensitivity. Whether abnormal topoisomerase quantity and specific activity are associated with resistance or sensitivity to topoisomerase-targeted chemotherapy in the clinic is now being studied. Determinants downstream of cleavable complex formation that affect the sensitivity of tumor versus normal cells to topo drugs in particular and DNA-damaging agents in general are little known. The goal of enhancing selective tumor cell killing relative to the normal cells that are dose limiting may be achieved either by overcoming tumor cell resistance or by protecting normal cells. Both of these strategies will become more feasible as specific molecular differences between tumor and normal cells are being rapidly identified and new combination therapies that take advantage of these differences are being designed and tested." ], "offsets": [ [ 0, 1660 ] ] } ]

[ { "id": "8996605_T1", "type": "GROUP", "text": [ "topoisomerase-targeting antitumor drugs" ], "offsets": [ [ 40, 79 ] ], "normalized": [] } ]

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[ { "id": "11085336__text", "type": "abstract", "text": [ "18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action. 18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine." ], "offsets": [ [ 0, 1834 ] ] } ]

[ { "id": "11085336_T1", "type": "DRUG_N", "text": [ "18-Methoxycoronaridine" ], "offsets": [ [ 0, 22 ] ], "normalized": [] }, { "id": "11085336_T2", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 24, 29 ] ], "normalized": [] }, { "id": "11085336_T3", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 35, 43 ] ], "normalized": [] }, { "id": "11085336_T4", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 119, 124 ] ], "normalized": [] }, { "id": "11085336_T5", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 242, 250 ] ], "normalized": [] }, { "id": "11085336_T6", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 263, 268 ] ], "normalized": [] }, { "id": "11085336_T7", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 329, 337 ] ], "normalized": [] }, { "id": "11085336_T8", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 342, 349 ] ], "normalized": [] }, { "id": "11085336_T9", "type": "DRUG", "text": [ "ethanol" ], "offsets": [ [ 386, 393 ] ], "normalized": [] }, { "id": "11085336_T10", "type": "DRUG", "text": [ "nicotine" ], "offsets": [ [ 398, 406 ] ], "normalized": [] }, { "id": "11085336_T11", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 423, 431 ] ], "normalized": [] }, { "id": "11085336_T12", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 433, 438 ] ], "normalized": [] }, { "id": "11085336_T13", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 505, 513 ] ], "normalized": [] }, { "id": "11085336_T14", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 518, 523 ] ], "normalized": [] }, { "id": "11085336_T15", "type": "GROUP", "text": [ "opioid" ], "offsets": [ [ 535, 541 ] ], "normalized": [] }, { "id": "11085336_T16", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 565, 573 ] ], "normalized": [] }, { "id": "11085336_T17", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 578, 583 ] ], "normalized": [] }, { "id": "11085336_T18", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 661, 669 ] ], "normalized": [] }, { "id": "11085336_T19", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 745, 753 ] ], "normalized": [] }, { "id": "11085336_T20", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 758, 763 ] ], "normalized": [] }, { "id": "11085336_T21", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 770, 778 ] ], "normalized": [] }, { "id": "11085336_T22", "type": "DRUG", "text": [ "nicotine" ], "offsets": [ [ 791, 799 ] ], "normalized": [] }, { "id": "11085336_T23", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 856, 864 ] ], "normalized": [] }, { "id": "11085336_T24", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 874, 881 ] ], "normalized": [] }, { "id": "11085336_T25", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 927, 935 ] ], "normalized": [] }, { "id": "11085336_T26", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 940, 945 ] ], "normalized": [] }, { "id": "11085336_T27", "type": "DRUG_N", "text": [ "Ibogaine" ], "offsets": [ [ 1010, 1018 ] ], "normalized": [] }, { "id": "11085336_T28", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "11085336_T29", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1085, 1093 ] ], "normalized": [] }, { "id": "11085336_T30", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1120, 1128 ] ], "normalized": [] }, { "id": "11085336_T31", "type": "DRUG", "text": [ "morphine" ], "offsets": [ [ 1151, 1159 ] ], "normalized": [] }, { "id": "11085336_T32", "type": "DRUG_N", "text": [ "Ibogaine" ], "offsets": [ [ 1178, 1186 ] ], "normalized": [] }, { "id": "11085336_T33", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1273, 1278 ] ], "normalized": [] }, { "id": "11085336_T34", "type": "DRUG_N", "text": [ "Ibogaine" ], "offsets": [ [ 1311, 1319 ] ], "normalized": [] }, { "id": "11085336_T35", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1329, 1334 ] ], "normalized": [] }, { "id": "11085336_T36", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1378, 1383 ] ], "normalized": [] }, { "id": "11085336_T37", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 1388, 1396 ] ], "normalized": [] }, { "id": "11085336_T38", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1472, 1477 ] ], "normalized": [] }, { "id": "11085336_T39", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 1509, 1517 ] ], "normalized": [] }, { "id": "11085336_T40", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1598, 1603 ] ], "normalized": [] }, { "id": "11085336_T41", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 1608, 1616 ] ], "normalized": [] }, { "id": "11085336_T42", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 1650, 1658 ] ], "normalized": [] }, { "id": "11085336_T43", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1660, 1665 ] ], "normalized": [] }, { "id": "11085336_T44", "type": "DRUG_N", "text": [ "18-MC" ], "offsets": [ [ 1723, 1728 ] ], "normalized": [] }, { "id": "11085336_T45", "type": "DRUG_N", "text": [ "ibogaine" ], "offsets": [ [ 1825, 1833 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11085336_R1", "type": "EFFECT", "arg1_id": "11085336_T19", "arg2_id": "11085336_T21", "normalized": [] }, { "id": "11085336_R2", "type": "EFFECT", "arg1_id": "11085336_T19", "arg2_id": "11085336_T22", "normalized": [] }, { "id": "11085336_R3", "type": "EFFECT", "arg1_id": "11085336_T20", "arg2_id": "11085336_T21", "normalized": [] }, { "id": "11085336_R4", "type": "EFFECT", "arg1_id": "11085336_T20", "arg2_id": "11085336_T22", "normalized": [] }, { "id": "11085336_R5", "type": "EFFECT", "arg1_id": "11085336_T23", "arg2_id": "11085336_T24", "normalized": [] }, { "id": "11085336_R6", "type": "EFFECT", "arg1_id": "11085336_T27", "arg2_id": "11085336_T29", "normalized": [] }, { "id": "11085336_R7", "type": "EFFECT", "arg1_id": "11085336_T28", "arg2_id": "11085336_T29", "normalized": [] } ]

[ { "id": "11197767__text", "type": "abstract", "text": [ "Toxicity of cadmium and zinc to encystment and in vitro excystment of Parorchis acanthus (Digenea: Philophthalmidae). The toxicity of cadmium, zinc and cadmium/zinc mixtures at concentrations ranging from 1000 to 50000 microg/l were investigated against cercariae and metacercariae of Parorchis acanthus obtained from the dog whelk Nucella lapillus. Cercarial encystment at concentrations of 25000 microg/l or higher was significantly impaired by all test metals; however, at lower concentrations only zinc demonstrated toxicity. Mixtures of cadmium and zinc had a synergistic effect compared with single metal toxicity but only at 50000 microg/l. Excystment in vitro was only significantly affected by cercariae exposed to cadmium/zinc mixtures whilst encysting. Twenty-four h exposures of fully formed cysts had no effect on excystment in vitro. Effects on in vitro excystment rates over a 2 h period demonstrated widespread effects for cercariae-exposed P. acanthus. No effects were evident on excystment rates of cyst-exposed parasites." ], "offsets": [ [ 0, 1040 ] ] } ]

[ { "id": "11197767_T1", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "11197767_T2", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 143, 147 ] ], "normalized": [] }, { "id": "11197767_T3", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 502, 506 ] ], "normalized": [] }, { "id": "11197767_T4", "type": "DRUG", "text": [ "zinc" ], "offsets": [ [ 554, 558 ] ], "normalized": [] } ]

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[ { "id": "2857100__text", "type": "abstract", "text": [ "[Stimulation by cerulein--an analog of the octapeptide cholecystokinin--of 3H-spiroperidol binding after the long-term administration of neuroleptics] It has been established in experiments on white male rats that prolonged administration (twice a day for 14 days) of haloperidol (0.25 mg/kg) and pyreneperone (0.25 mg/kg) resulted in the reduced interaction between 3H-spiroperidol and low affinity binding sites for apomorphine in subcortical structures, whereas 3H-spiroperidol binding with high affinity binding sites for apomorphine increased both in the frontal cortex and subcortical structures of the forebrain. After prolonged administration of neuroleptics the displacing effect of cerulein, an analog of cholecystokinin octapeptide, was replaced by the stimulant action on 3H-spiroperidol binding. It is assumed that increased interaction between 3H-spiroperidol and high affinity binding sites for apomorphine on dopamine2- and serotonin2-receptors underlies the antipsychotic action of neuroleptics after their prolonged administration. Cholecystokinin octapeptide is a necessary factor for realization of this action of neuroleptics." ], "offsets": [ [ 0, 1147 ] ] } ]

[ { "id": "2857100_T1", "type": "DRUG_N", "text": [ "cerulein" ], "offsets": [ [ 16, 24 ] ], "normalized": [] }, { "id": "2857100_T2", "type": "DRUG_N", "text": [ "3H-spiroperidol" ], "offsets": [ [ 75, 90 ] ], "normalized": [] }, { "id": "2857100_T3", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 137, 149 ] ], "normalized": [] }, { "id": "2857100_T4", "type": "DRUG", "text": [ "haloperidol" ], "offsets": [ [ 268, 279 ] ], "normalized": [] }, { "id": "2857100_T5", "type": "DRUG_N", "text": [ "pyreneperone" ], "offsets": [ [ 297, 309 ] ], "normalized": [] }, { "id": "2857100_T6", "type": "DRUG_N", "text": [ "3H-spiroperidol" ], "offsets": [ [ 367, 382 ] ], "normalized": [] }, { "id": "2857100_T7", "type": "DRUG", "text": [ "apomorphine" ], "offsets": [ [ 418, 429 ] ], "normalized": [] }, { "id": "2857100_T8", "type": "DRUG_N", "text": [ "3H-spiroperidol" ], "offsets": [ [ 465, 480 ] ], "normalized": [] }, { "id": "2857100_T9", "type": "DRUG", "text": [ "apomorphine" ], "offsets": [ [ 526, 537 ] ], "normalized": [] }, { "id": "2857100_T10", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 654, 666 ] ], "normalized": [] }, { "id": "2857100_T11", "type": "DRUG_N", "text": [ "cerulein" ], "offsets": [ [ 692, 700 ] ], "normalized": [] }, { "id": "2857100_T12", "type": "DRUG_N", "text": [ "3H-spiroperidol" ], "offsets": [ [ 784, 799 ] ], "normalized": [] }, { "id": "2857100_T13", "type": "DRUG_N", "text": [ "3H-spiroperidol" ], "offsets": [ [ 858, 873 ] ], "normalized": [] }, { "id": "2857100_T14", "type": "DRUG", "text": [ "apomorphine" ], "offsets": [ [ 910, 921 ] ], "normalized": [] }, { "id": "2857100_T15", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 999, 1011 ] ], "normalized": [] }, { "id": "2857100_T16", "type": "GROUP", "text": [ "neuroleptics" ], "offsets": [ [ 1134, 1146 ] ], "normalized": [] } ]

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[ { "id": "11120981__text", "type": "abstract", "text": [ "If taken 1 hour before indinavir (IDV), didanosine does not affect IDV exposure, despite persistent buffering effects. Concurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine." ], "offsets": [ [ 0, 897 ] ] } ]

[ { "id": "11120981_T1", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 23, 32 ] ], "normalized": [] }, { "id": "11120981_T2", "type": "DRUG", "text": [ "IDV" ], "offsets": [ [ 34, 37 ] ], "normalized": [] }, { "id": "11120981_T3", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 40, 50 ] ], "normalized": [] }, { "id": "11120981_T4", "type": "DRUG", "text": [ "IDV" ], "offsets": [ [ 67, 70 ] ], "normalized": [] }, { "id": "11120981_T5", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 148, 157 ] ], "normalized": [] }, { "id": "11120981_T6", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 162, 172 ] ], "normalized": [] }, { "id": "11120981_T7", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 220, 229 ] ], "normalized": [] }, { "id": "11120981_T8", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 264, 274 ] ], "normalized": [] }, { "id": "11120981_T9", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 290, 299 ] ], "normalized": [] }, { "id": "11120981_T10", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 333, 342 ] ], "normalized": [] }, { "id": "11120981_T11", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 448, 457 ] ], "normalized": [] }, { "id": "11120981_T12", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 481, 490 ] ], "normalized": [] }, { "id": "11120981_T13", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 514, 524 ] ], "normalized": [] }, { "id": "11120981_T14", "type": "DRUG", "text": [ "indinavir" ], "offsets": [ [ 589, 598 ] ], "normalized": [] }, { "id": "11120981_T15", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 615, 625 ] ], "normalized": [] }, { "id": "11120981_T16", "type": "DRUG", "text": [ "Indinavir" ], "offsets": [ [ 799, 808 ] ], "normalized": [] }, { "id": "11120981_T17", "type": "DRUG", "text": [ "didanosine" ], "offsets": [ [ 886, 896 ] ], "normalized": [] } ]

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[]

[ { "id": "11120981_R1", "type": "MECHANISM", "arg1_id": "11120981_T5", "arg2_id": "11120981_T6", "normalized": [] }, { "id": "11120981_R2", "type": "MECHANISM", "arg1_id": "11120981_T14", "arg2_id": "11120981_T15", "normalized": [] }, { "id": "11120981_R3", "type": "ADVISE", "arg1_id": "11120981_T16", "arg2_id": "11120981_T17", "normalized": [] } ]

[ { "id": "10150268__text", "type": "abstract", "text": [ "The fluoroquinolones for urinary tract infections: a review. The fluoroquinolones are a rapidly growing class of antibiotics with a broad spectrum of activity against gram-negative and some gram-positive aerobic bacteria. These agents, including norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin, have been extensively studied and have demonstrated efficacy and safety profiles comparable to those of other traditional agents for the treatment of complicated or uncomplicated urinary tract infections and prostatitis. Advantages offered by this class of antibiotics include optimal pharmacokinetics, effectiveness against multidrug-resistant organisms, and oral administration even when parenteral antibiotics are generally used. The fluoroquinolones are also extensively used in urologic surgery." ], "offsets": [ [ 0, 813 ] ] } ]

[ { "id": "10150268_T1", "type": "GROUP", "text": [ "fluoroquinolones" ], "offsets": [ [ 4, 20 ] ], "normalized": [] }, { "id": "10150268_T2", "type": "GROUP", "text": [ "fluoroquinolones" ], "offsets": [ [ 65, 81 ] ], "normalized": [] }, { "id": "10150268_T3", "type": "GROUP", "text": [ "antibiotics" ], "offsets": [ [ 113, 124 ] ], "normalized": [] }, { "id": "10150268_T4", "type": "DRUG", "text": [ "norfloxacin" ], "offsets": [ [ 246, 257 ] ], "normalized": [] }, { "id": "10150268_T5", "type": "DRUG", "text": [ "ciprofloxacin" ], "offsets": [ [ 259, 272 ] ], "normalized": [] }, { "id": "10150268_T6", "type": "DRUG", "text": [ "ofloxacin" ], "offsets": [ [ 274, 283 ] ], "normalized": [] }, { "id": "10150268_T7", "type": "DRUG", "text": [ "enoxacin" ], "offsets": [ [ 285, 293 ] ], "normalized": [] }, { "id": "10150268_T8", "type": "DRUG", "text": [ "lomefloxacin" ], "offsets": [ [ 299, 311 ] ], "normalized": [] }, { "id": "10150268_T9", "type": "GROUP", "text": [ "antibiotics" ], "offsets": [ [ 570, 581 ] ], "normalized": [] }, { "id": "10150268_T10", "type": "DRUG", "text": [ "antibiotics" ], "offsets": [ [ 714, 725 ] ], "normalized": [] }, { "id": "10150268_T11", "type": "GROUP", "text": [ "fluoroquinolones" ], "offsets": [ [ 750, 766 ] ], "normalized": [] } ]

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[ { "id": "11085305__text", "type": "abstract", "text": [ "Activation of an effector immediate-early gene arc by methamphetamine. As immediate-early genes (IEGs) are thought to play a critical role in mediating stimulus-induced neural plasticity, IEG response induced by methamphetamine (METH) has been characterized to define the changes in gene expression that may underlie its long-lasting behavioral effects. Although activation of several transcription factor IEGs has been described, little is known about effector IEGs. Here, we have examined whether METH administration affects expression of an effector IEG arc (activity-regulated, cytoskeleton-associated) that encodes a protein with homology to spectrin. Using in situ hybridization, we observed that METH caused a rapid and transient dose-dependent increase in arc mRNA level in the striatum and cortex that was abolished by pretreatment with the specific dopamine D1 receptor antagonist SCH-23390 but not by an atypical neuroleptic clozapine. METH induced arc mRNA in layers IV and VI of the cortex which dopamine receptor are localized to. These results suggest that D1 receptors are coupled to activation of arc gene, which may be involved in functional or structural alterations underlying neural plasticity triggered by METH." ], "offsets": [ [ 0, 1233 ] ] } ]

[ { "id": "11085305_T1", "type": "DRUG", "text": [ "methamphetamine" ], "offsets": [ [ 54, 69 ] ], "normalized": [] }, { "id": "11085305_T2", "type": "DRUG", "text": [ "methamphetamine" ], "offsets": [ [ 212, 227 ] ], "normalized": [] }, { "id": "11085305_T3", "type": "DRUG", "text": [ "METH" ], "offsets": [ [ 229, 233 ] ], "normalized": [] }, { "id": "11085305_T4", "type": "DRUG", "text": [ "METH" ], "offsets": [ [ 499, 503 ] ], "normalized": [] }, { "id": "11085305_T5", "type": "DRUG", "text": [ "METH" ], "offsets": [ [ 703, 707 ] ], "normalized": [] }, { "id": "11085305_T6", "type": "DRUG_N", "text": [ "SCH-23390" ], "offsets": [ [ 891, 900 ] ], "normalized": [] }, { "id": "11085305_T7", "type": "GROUP", "text": [ "atypical neuroleptic" ], "offsets": [ [ 915, 935 ] ], "normalized": [] }, { "id": "11085305_T8", "type": "DRUG", "text": [ "clozapine" ], "offsets": [ [ 936, 945 ] ], "normalized": [] }, { "id": "11085305_T9", "type": "DRUG", "text": [ "METH" ], "offsets": [ [ 947, 951 ] ], "normalized": [] }, { "id": "11085305_T10", "type": "DRUG", "text": [ "METH" ], "offsets": [ [ 1228, 1232 ] ], "normalized": [] } ]

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[]

[ { "id": "11085305_R1", "type": "EFFECT", "arg1_id": "11085305_T5", "arg2_id": "11085305_T6", "normalized": [] } ]

[ { "id": "11137703__text", "type": "abstract", "text": [ "Inhibitory effects of ruthenium red on inositol 1,4, 5-trisphosphate-induced responses in rat megakaryocytes. The effects of ruthenium red (RR) on inositol 1,4,5-trisphosphate (InsP(3))-induced responses were studied in rat bone marrow megakaryocytes with the patch-clamp whole-cell recording technique in combination with fura-2 microfluorometry. Internal application of InsP(3) (100 microM) increased intracellular Ca(2+) concentration ([Ca(2+)](i)) and activated the Ca(2+)-dependent K(+) current. Administering InsP(3) together with RR (100-500 microM) inhibited InsP(3)-induced responses (both Ca(2+) and current responses) in a dose-dependent fashion. Pretreatment of megakaryocytes with extracellular RR (50 microM) also inhibited InsP(3)-induced responses. Intracellular and extracellular application of RR reduced ADP-induced increases in [Ca(2+)](i). In contrast, in isolated single pancreatic acinar cells, RR had no effect on InsP(3)-induced responses. Taken together, these results suggest that the site of the inhibitory action of RR is at the InsP(3) receptor, or its closely associated proteins. In addition, we have shown that RR is a useful pharmacological tool with which to examine the InsP(3)-mediated responses of megakaryocytes." ], "offsets": [ [ 0, 1251 ] ] } ]

[ { "id": "11137703_T1", "type": "DRUG_N", "text": [ "ruthenium red" ], "offsets": [ [ 22, 35 ] ], "normalized": [] }, { "id": "11137703_T2", "type": "DRUG_N", "text": [ "ruthenium red" ], "offsets": [ [ 125, 138 ] ], "normalized": [] }, { "id": "11137703_T3", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 140, 142 ] ], "normalized": [] }, { "id": "11137703_T4", "type": "DRUG_N", "text": [ "inositol 1,4,5-trisphosphate" ], "offsets": [ [ 147, 175 ] ], "normalized": [] }, { "id": "11137703_T5", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 177, 184 ] ], "normalized": [] }, { "id": "11137703_T6", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 372, 379 ] ], "normalized": [] }, { "id": "11137703_T7", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 515, 522 ] ], "normalized": [] }, { "id": "11137703_T8", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 537, 539 ] ], "normalized": [] }, { "id": "11137703_T9", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 708, 710 ] ], "normalized": [] }, { "id": "11137703_T10", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 738, 745 ] ], "normalized": [] }, { "id": "11137703_T11", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 812, 814 ] ], "normalized": [] }, { "id": "11137703_T12", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 918, 920 ] ], "normalized": [] }, { "id": "11137703_T13", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 938, 945 ] ], "normalized": [] }, { "id": "11137703_T14", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 1045, 1047 ] ], "normalized": [] }, { "id": "11137703_T15", "type": "DRUG_N", "text": [ "RR" ], "offsets": [ [ 1144, 1146 ] ], "normalized": [] }, { "id": "11137703_T16", "type": "DRUG_N", "text": [ "InsP(3)" ], "offsets": [ [ 1206, 1213 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11137703_R1", "type": "EFFECT", "arg1_id": "11137703_T7", "arg2_id": "11137703_T8", "normalized": [] }, { "id": "11137703_R2", "type": "EFFECT", "arg1_id": "11137703_T9", "arg2_id": "11137703_T10", "normalized": [] } ]

[ { "id": "3967572__text", "type": "abstract", "text": [ "Enhanced theophylline clearance secondary to phenytoin therapy. This report describes two cases in which theophylline clearance accelerated markedly with concomitant phenytoin administration. Maximum calculated theophylline clearance ranged from 2 1/2 to 3 1/2 times baseline. Onset of the interaction began within five days of beginning concurrent therapy. With combined use, clinicians should be aware, when phenytoin is added, of the potential for reexacerbation of pulmonary symptomatology due to lowered serum theophylline concentrations." ], "offsets": [ [ 0, 543 ] ] } ]

[ { "id": "3967572_T1", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 9, 21 ] ], "normalized": [] }, { "id": "3967572_T2", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 45, 54 ] ], "normalized": [] }, { "id": "3967572_T3", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 105, 117 ] ], "normalized": [] }, { "id": "3967572_T4", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 166, 175 ] ], "normalized": [] }, { "id": "3967572_T5", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 211, 223 ] ], "normalized": [] }, { "id": "3967572_T6", "type": "DRUG", "text": [ "phenytoin" ], "offsets": [ [ 410, 419 ] ], "normalized": [] }, { "id": "3967572_T7", "type": "DRUG", "text": [ "theophylline" ], "offsets": [ [ 515, 527 ] ], "normalized": [] } ]

[]

[]

[ { "id": "3967572_R1", "type": "MECHANISM", "arg1_id": "3967572_T1", "arg2_id": "3967572_T2", "normalized": [] }, { "id": "3967572_R2", "type": "MECHANISM", "arg1_id": "3967572_T3", "arg2_id": "3967572_T4", "normalized": [] }, { "id": "3967572_R3", "type": "EFFECT", "arg1_id": "3967572_T6", "arg2_id": "3967572_T7", "normalized": [] } ]

[ { "id": "11134454__text", "type": "abstract", "text": [ "Carbamazepine overdose recognized by a tricyclic antidepressant assay. Altered mental status in an adolescent presents a diagnostic challenge, and the clinician depends on clinical evaluation and laboratory studies to determine therapy and prognosis. We report the case of an adolescent with altered consciousness caused by carbamazepine overdose with a positive tricyclic antidepressant level to alert clinicians to the cross-reactivity of carbamazepine with a toxicology screen for tricyclic antidepressants." ], "offsets": [ [ 0, 510 ] ] } ]

[ { "id": "11134454_T1", "type": "DRUG", "text": [ "Carbamazepine" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "11134454_T2", "type": "GROUP", "text": [ "tricyclic antidepressant" ], "offsets": [ [ 39, 63 ] ], "normalized": [] }, { "id": "11134454_T3", "type": "DRUG", "text": [ "carbamazepine" ], "offsets": [ [ 324, 337 ] ], "normalized": [] }, { "id": "11134454_T4", "type": "GROUP", "text": [ "tricyclic antidepressant" ], "offsets": [ [ 363, 387 ] ], "normalized": [] }, { "id": "11134454_T5", "type": "DRUG", "text": [ "carbamazepine" ], "offsets": [ [ 441, 454 ] ], "normalized": [] }, { "id": "11134454_T6", "type": "GROUP", "text": [ "tricyclic antidepressants" ], "offsets": [ [ 484, 509 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11134454_R1", "type": "EFFECT", "arg1_id": "11134454_T3", "arg2_id": "11134454_T4", "normalized": [] }, { "id": "11134454_R2", "type": "ADVISE", "arg1_id": "11134454_T5", "arg2_id": "11134454_T6", "normalized": [] } ]

[ { "id": "3881461__text", "type": "abstract", "text": [ "Dexamethasone and retinyl acetate similarly inhibit and stimulate EGF- or insulin-induced proliferation of prostatic epithelium. Prostatic epithelium proliferates in a defined medium consisting of basal medium RPMI1640 containing transferrin (1 microgram/ml), EGF (10 ng/ml), and insulin (3.7 micrograms/ml or 0.1 IU/ml). Although neither dexamethasone nor retinyl acetate affected the proliferation of prostatic epithelium in RPMI1640 containing transferrin alone, they modify the mitogenic effect of EGF and insulin. Dexamethasone at 10(-10) M or retinyl acetate at about 3 X 10(-9) M inhibits proliferation stimulated by EGF. Higher concentrations of dexamethasone (10(-8) - 10(-6) M) or retinyl acetate (3 X 10(-8) - 10(-7) M) enhance the mitogenic activity of EGF. Dexamethasone had a similar effect in the presence of insulin. However, retinyl acetate stimulated, but did not significantly inhibit, proliferation in the presence of insulin. These results suggest that both dexamethasone and retinyl acetate, and possibly other glucocorticoids and retinoids, may regulate the proliferation of prostate epithelium by a dose-dependent modification of the activity of insulin and EGF." ], "offsets": [ [ 0, 1186 ] ] } ]

[ { "id": "3881461_T1", "type": "DRUG", "text": [ "Dexamethasone" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "3881461_T2", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 18, 33 ] ], "normalized": [] }, { "id": "3881461_T3", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 66, 69 ] ], "normalized": [] }, { "id": "3881461_T4", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 74, 81 ] ], "normalized": [] }, { "id": "3881461_T5", "type": "DRUG_N", "text": [ "transferrin" ], "offsets": [ [ 230, 241 ] ], "normalized": [] }, { "id": "3881461_T6", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 260, 263 ] ], "normalized": [] }, { "id": "3881461_T7", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 280, 287 ] ], "normalized": [] }, { "id": "3881461_T8", "type": "DRUG", "text": [ "dexamethasone" ], "offsets": [ [ 339, 352 ] ], "normalized": [] }, { "id": "3881461_T9", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 357, 372 ] ], "normalized": [] }, { "id": "3881461_T10", "type": "DRUG_N", "text": [ "transferrin" ], "offsets": [ [ 447, 458 ] ], "normalized": [] }, { "id": "3881461_T11", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "3881461_T12", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 510, 517 ] ], "normalized": [] }, { "id": "3881461_T13", "type": "DRUG", "text": [ "Dexamethasone" ], "offsets": [ [ 519, 532 ] ], "normalized": [] }, { "id": "3881461_T14", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 549, 564 ] ], "normalized": [] }, { "id": "3881461_T15", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 624, 627 ] ], "normalized": [] }, { "id": "3881461_T16", "type": "DRUG", "text": [ "dexamethasone" ], "offsets": [ [ 654, 667 ] ], "normalized": [] }, { "id": "3881461_T17", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 691, 706 ] ], "normalized": [] }, { "id": "3881461_T18", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 765, 768 ] ], "normalized": [] }, { "id": "3881461_T19", "type": "DRUG", "text": [ "Dexamethasone" ], "offsets": [ [ 770, 783 ] ], "normalized": [] }, { "id": "3881461_T20", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 824, 831 ] ], "normalized": [] }, { "id": "3881461_T21", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 842, 857 ] ], "normalized": [] }, { "id": "3881461_T22", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 938, 945 ] ], "normalized": [] }, { "id": "3881461_T23", "type": "DRUG", "text": [ "dexamethasone" ], "offsets": [ [ 979, 992 ] ], "normalized": [] }, { "id": "3881461_T24", "type": "DRUG", "text": [ "retinyl acetate" ], "offsets": [ [ 997, 1012 ] ], "normalized": [] }, { "id": "3881461_T25", "type": "GROUP", "text": [ "glucocorticoids" ], "offsets": [ [ 1033, 1048 ] ], "normalized": [] }, { "id": "3881461_T26", "type": "GROUP", "text": [ "retinoids" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] }, { "id": "3881461_T27", "type": "DRUG", "text": [ "insulin" ], "offsets": [ [ 1170, 1177 ] ], "normalized": [] }, { "id": "3881461_T28", "type": "DRUG_N", "text": [ "EGF" ], "offsets": [ [ 1182, 1185 ] ], "normalized": [] } ]

[]

[]

[ { "id": "3881461_R1", "type": "EFFECT", "arg1_id": "3881461_T1", "arg2_id": "3881461_T3", "normalized": [] }, { "id": "3881461_R2", "type": "EFFECT", "arg1_id": "3881461_T1", "arg2_id": "3881461_T4", "normalized": [] }, { "id": "3881461_R3", "type": "EFFECT", "arg1_id": "3881461_T2", "arg2_id": "3881461_T3", "normalized": [] }, { "id": "3881461_R4", "type": "EFFECT", "arg1_id": "3881461_T2", "arg2_id": "3881461_T4", "normalized": [] }, { "id": "3881461_R5", "type": "EFFECT", "arg1_id": "3881461_T8", "arg2_id": "3881461_T11", "normalized": [] }, { "id": "3881461_R6", "type": "EFFECT", "arg1_id": "3881461_T8", "arg2_id": "3881461_T12", "normalized": [] }, { "id": "3881461_R7", "type": "EFFECT", "arg1_id": "3881461_T9", "arg2_id": "3881461_T11", "normalized": [] }, { "id": "3881461_R8", "type": "EFFECT", "arg1_id": "3881461_T9", "arg2_id": "3881461_T12", "normalized": [] }, { "id": "3881461_R9", "type": "EFFECT", "arg1_id": "3881461_T13", "arg2_id": "3881461_T15", "normalized": [] }, { "id": "3881461_R10", "type": "EFFECT", "arg1_id": "3881461_T14", "arg2_id": "3881461_T15", "normalized": [] }, { "id": "3881461_R11", "type": "EFFECT", "arg1_id": "3881461_T16", "arg2_id": "3881461_T18", "normalized": [] }, { "id": "3881461_R12", "type": "EFFECT", "arg1_id": "3881461_T17", "arg2_id": "3881461_T18", "normalized": [] }, { "id": "3881461_R13", "type": "EFFECT", "arg1_id": "3881461_T21", "arg2_id": "3881461_T22", "normalized": [] }, { "id": "3881461_R14", "type": "EFFECT", "arg1_id": "3881461_T23", "arg2_id": "3881461_T27", "normalized": [] }, { "id": "3881461_R15", "type": "EFFECT", "arg1_id": "3881461_T23", "arg2_id": "3881461_T28", "normalized": [] }, { "id": "3881461_R16", "type": "EFFECT", "arg1_id": "3881461_T24", "arg2_id": "3881461_T27", "normalized": [] }, { "id": "3881461_R17", "type": "EFFECT", "arg1_id": "3881461_T24", "arg2_id": "3881461_T28", "normalized": [] }, { "id": "3881461_R18", "type": "EFFECT", "arg1_id": "3881461_T25", "arg2_id": "3881461_T27", "normalized": [] }, { "id": "3881461_R19", "type": "EFFECT", "arg1_id": "3881461_T25", "arg2_id": "3881461_T28", "normalized": [] }, { "id": "3881461_R20", "type": "EFFECT", "arg1_id": "3881461_T26", "arg2_id": "3881461_T27", "normalized": [] }, { "id": "3881461_R21", "type": "EFFECT", "arg1_id": "3881461_T26", "arg2_id": "3881461_T28", "normalized": [] } ]

[ { "id": "7798493__text", "type": "abstract", "text": [ "Evidence for reduction of norepinephrine uptake sites in the failing human heart. OBJECTIVES. This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND. Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS. The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS. The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS. In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization." ], "offsets": [ [ 0, 2202 ] ] } ]

[ { "id": "7798493_T1", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 26, 40 ] ], "normalized": [] }, { "id": "7798493_T2", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 149, 163 ] ], "normalized": [] }, { "id": "7798493_T3", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 403, 417 ] ], "normalized": [] }, { "id": "7798493_T4", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 476, 490 ] ], "normalized": [] }, { "id": "7798493_T5", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 664, 678 ] ], "normalized": [] }, { "id": "7798493_T6", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 804, 818 ] ], "normalized": [] }, { "id": "7798493_T7", "type": "DRUG", "text": [ "isoproterenol" ], "offsets": [ [ 998, 1011 ] ], "normalized": [] }, { "id": "7798493_T8", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 1042, 1056 ] ], "normalized": [] }, { "id": "7798493_T9", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1201, 1208 ] ], "normalized": [] }, { "id": "7798493_T10", "type": "DRUG", "text": [ "desipramine" ], "offsets": [ [ 1213, 1224 ] ], "normalized": [] }, { "id": "7798493_T11", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 1287, 1301 ] ], "normalized": [] }, { "id": "7798493_T12", "type": "DRUG", "text": [ "mazindol" ], "offsets": [ [ 1451, 1459 ] ], "normalized": [] }, { "id": "7798493_T13", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 1516, 1530 ] ], "normalized": [] }, { "id": "7798493_T14", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 1886, 1893 ] ], "normalized": [] }, { "id": "7798493_T15", "type": "DRUG", "text": [ "desipramine" ], "offsets": [ [ 1898, 1909 ] ], "normalized": [] }, { "id": "7798493_T16", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 1953, 1967 ] ], "normalized": [] }, { "id": "7798493_T17", "type": "DRUG", "text": [ "cocaine" ], "offsets": [ [ 2031, 2038 ] ], "normalized": [] }, { "id": "7798493_T18", "type": "DRUG", "text": [ "desipramine" ], "offsets": [ [ 2043, 2054 ] ], "normalized": [] }, { "id": "7798493_T19", "type": "DRUG", "text": [ "norepinephrine" ], "offsets": [ [ 2138, 2152 ] ], "normalized": [] } ]

[]

[]

[ { "id": "7798493_R1", "type": "EFFECT", "arg1_id": "7798493_T9", "arg2_id": "7798493_T11", "normalized": [] }, { "id": "7798493_R2", "type": "EFFECT", "arg1_id": "7798493_T10", "arg2_id": "7798493_T11", "normalized": [] } ]

[ { "id": "1109299__text", "type": "abstract", "text": [ "Effects of low temperatures on microtubules in the non-myelinated axons of post-ganglionic sympathetic nerves. The effect of temperature changes on the number of microtubules in non-myelinated axons has been studied in cat inferior mesenteric ganglion/hypogastric nerve preparations incubated at various temperatures in Eagles minimal essential tissue culture medium in vitro. At 37 degrees C the non-myelinated axons contained 28.4 plus or minus 0.8 S.E.M. (54) microtubules per axon. After incubation at 0 degrees C for 4 h this number fell to 2.3 plus or minus 0.1 S.E.M. (41) but returned to normal levels when the nerves were rewarmed. This loss of microtubules on cooling the nerves and their reappearance on rewarming was a rapid process; it was independent of the influence of the nueronal cell body and of protein synthesis within the axon. The preservation of the microtubules was improved when D2O was present in the incubation medium. Reformed microtubules appeared to function normally with respect to their possible role in the transport of noradrenaline storage vesicles along the axons." ], "offsets": [ [ 0, 1102 ] ] } ]

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[]

[]

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[ { "id": "8542840__text", "type": "abstract", "text": [ "Interaction of gentamycin and atracurium in anaesthetised horses. Evoked hind limb digital extensor tension (hoof twitch) was maintained at 40% of baseline for 1 h by atracurium infusion in 7 horses anaesthetised with halothane. After 1 h, atracurium was discontinued and hoof twitch allowed to recover to 75%. Atracurium was again given by infusion to maintain 40% twitch for a second hour, then 2 mg gentamycin/kg bwt were given i.v. Atracurium infusion was continued for a third hour, and then hoof twitch was again allowed to recover spontaneously to 75%. Gentamycin reduced twitch strength from 40 +/- 1% (mean +/- sem) to 29 +/- 4% within 7.0 +/- 1.5 min (P = 0.02). Twitch gradually returned to pre-gentamycin strength over the course of the next hour. Recovery of hoof twitch from 50% to 75% took 7.7 +/- 0.7 min for atracurium alone and 11.5 +/- 2.7 min for atracurium plus gentamycin (P = 0.03). Recovery from 50% twitch to 75% fade recovery took 13.8 +/- 0.8 min for atracurium alone and 13.7 +/- 1.2 min for atracurium plus gentamycin. At 75% recovery of fade, hoof twitch was 87 +/- 3% for atracurium alone and 82 +/- 4% for atracurium plus gentamycin. Reversal of the block with edrophonium and subsequent recovery of the horses from anaesthesia were uneventful. It was concluded that, although gentamycin did augment the neuromuscular blockade of atracurium, the effect was minimal." ], "offsets": [ [ 0, 1397 ] ] } ]

[ { "id": "8542840_T1", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 15, 25 ] ], "normalized": [] }, { "id": "8542840_T2", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 30, 40 ] ], "normalized": [] }, { "id": "8542840_T3", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 167, 177 ] ], "normalized": [] }, { "id": "8542840_T4", "type": "DRUG", "text": [ "halothane" ], "offsets": [ [ 218, 227 ] ], "normalized": [] }, { "id": "8542840_T5", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 240, 250 ] ], "normalized": [] }, { "id": "8542840_T6", "type": "DRUG", "text": [ "Atracurium" ], "offsets": [ [ 311, 321 ] ], "normalized": [] }, { "id": "8542840_T7", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 402, 412 ] ], "normalized": [] }, { "id": "8542840_T8", "type": "DRUG", "text": [ "Atracurium" ], "offsets": [ [ 436, 446 ] ], "normalized": [] }, { "id": "8542840_T9", "type": "DRUG", "text": [ "Gentamycin" ], "offsets": [ [ 560, 570 ] ], "normalized": [] }, { "id": "8542840_T10", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 706, 716 ] ], "normalized": [] }, { "id": "8542840_T11", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 825, 835 ] ], "normalized": [] }, { "id": "8542840_T12", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 867, 877 ] ], "normalized": [] }, { "id": "8542840_T13", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 883, 893 ] ], "normalized": [] }, { "id": "8542840_T14", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 978, 988 ] ], "normalized": [] }, { "id": "8542840_T15", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 1020, 1030 ] ], "normalized": [] }, { "id": "8542840_T16", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 1036, 1046 ] ], "normalized": [] }, { "id": "8542840_T17", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 1103, 1113 ] ], "normalized": [] }, { "id": "8542840_T18", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 1138, 1148 ] ], "normalized": [] }, { "id": "8542840_T19", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 1154, 1164 ] ], "normalized": [] }, { "id": "8542840_T20", "type": "DRUG", "text": [ "edrophonium" ], "offsets": [ [ 1193, 1204 ] ], "normalized": [] }, { "id": "8542840_T21", "type": "DRUG", "text": [ "gentamycin" ], "offsets": [ [ 1309, 1319 ] ], "normalized": [] }, { "id": "8542840_T22", "type": "DRUG", "text": [ "atracurium" ], "offsets": [ [ 1362, 1372 ] ], "normalized": [] } ]

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[ { "id": "8542840_R1", "type": "INT", "arg1_id": "8542840_T1", "arg2_id": "8542840_T2", "normalized": [] }, { "id": "8542840_R2", "type": "EFFECT", "arg1_id": "8542840_T12", "arg2_id": "8542840_T13", "normalized": [] }, { "id": "8542840_R3", "type": "EFFECT", "arg1_id": "8542840_T15", "arg2_id": "8542840_T16", "normalized": [] }, { "id": "8542840_R4", "type": "EFFECT", "arg1_id": "8542840_T18", "arg2_id": "8542840_T19", "normalized": [] }, { "id": "8542840_R5", "type": "EFFECT", "arg1_id": "8542840_T21", "arg2_id": "8542840_T22", "normalized": [] } ]

[ { "id": "2578306__text", "type": "abstract", "text": [ "Tumor phenotype and susceptibility to progression as an expression of subpopulations of initiated murine cells. Currently, it is conceived that a number of events, or hits, are required for the induction of tumors by chemical agents. The first phase of this sequence, initiation, is considered to result from at least one event in the genetic apparatus. Analyses of this sequence, however, usually give little consideration to the nature of the target cell or to the characteristics of the resultant tumors. Vesselinovitch et al. (Cancer Res., 38: 2003-2010, 1978) have reported that a single, small pulse of carcinogen can induce early and numerous liver tumors when administered neonatally to mice with a genetic predisposition to hepatotumorigenesis. In the current study, the nonpredisposed strain C57BL/6N was also shown to be highly susceptible to diethylnitrosamine during the neonatal period. C57BL/6N demonstrated large numbers of two of the three types of liver tumors seen in livers of genetically predisposed mice, one of which required the additional stimulus of dietary phenobarbital for growth. Tumors of more malignant phenotype were demonstrated only in genetically predisposed mice (C57BL/6N X C3H/HeN F1) that received one dose of carcinogen. These findings suggest that the phenotype of a tumor that results from a pulse of a chemical carcinogen may depend upon the target cell. The initiated cells that result from this hit may vary from those that demonstrate very little progression in cell type and may or may not require exogenous enhancement of growth to those that can progress very rapidly to fully malignant behavior. The latter might arise from a hit in a genetically initiated cell, the result of which is a more rapid progression in tumor type." ], "offsets": [ [ 0, 1776 ] ] } ]

[ { "id": "2578306_T1", "type": "DRUG", "text": [ "phenobarbital" ], "offsets": [ [ 1084, 1097 ] ], "normalized": [] } ]

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