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[ { "id": "passage-100", "type": "abstract", "text": [ "Dronedarone: a new treatment for atrial fibrillation. Dronedarone. Dronedarone is a benzofuran derivative pharmacologically related to amiodarone but without the iodine moiety. It is designed for the treatment of atrial fibrillation and atrial flutter. Historically, amiodarone has proved most effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure. However, its use has been limited by cumulative and often irreversible organ toxicity, especially in younger patients. Dronedarone was developed in an effort to provide equivalent efficacy and safety with less toxicity. Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but remaining concerns exist regarding its use in patients with advanced heart failure." ], "offsets": [ [ 0, 810 ] ] } ]

[ { "id": "entity-100-0", "type": "DISEASE", "text": [ "atrial fibrillation" ], "offsets": [ [ 33, 52 ] ], "normalized": [] }, { "id": "entity-100-1", "type": "DISEASE", "text": [ "atrial fibrillation" ], "offsets": [ [ 214, 233 ] ], "normalized": [] }, { "id": "entity-100-2", "type": "DISEASE", "text": [ "atrial flutter" ], "offsets": [ [ 238, 252 ] ], "normalized": [] }, { "id": "entity-100-3", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 384, 397 ] ], "normalized": [] }, { "id": "entity-100-4", "type": "ADVERSE", "text": [ "irreversible organ toxicity" ], "offsets": [ [ 457, 484 ] ], "normalized": [] }, { "id": "entity-100-5", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 796, 809 ] ], "normalized": [] } ]

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[ { "id": "passage-101", "type": "abstract", "text": [ "Do doctors discuss fertility issues before they treat young patients with cancer? BACKGROUND: Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS: Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS: Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS: These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys." ], "offsets": [ [ 0, 1436 ] ] } ]

[ { "id": "entity-101-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 74, 80 ] ], "normalized": [] }, { "id": "entity-101-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 121, 127 ] ], "normalized": [] }, { "id": "entity-101-2", "type": "ADVERSE", "text": [ "infertility" ], "offsets": [ [ 143, 154 ] ], "normalized": [] }, { "id": "entity-101-3", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 335, 341 ] ], "normalized": [] }, { "id": "entity-101-4", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 616, 622 ] ], "normalized": [] }, { "id": "entity-101-5", "type": "ADVERSE", "text": [ "infertility" ], "offsets": [ [ 957, 968 ] ], "normalized": [] } ]

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[ { "id": "passage-102", "type": "abstract", "text": [ "Risk of thrombogenicity among nonionic radiocontrast agents. Several contrast agents have been approved in the United States for radiographic imaging purposes. Most of the older ionic, high-osmolar contrast agents are no longer used because of their side effect profile. Therefore, newer nonionic, low or iso-osmolar contrast agents have been widely accepted as an alternative due to their improved tolerability and safety. We investigated the thrombogenicity of the 6 different nonionic radiocontrast media in terms of their platelet reactivity and noted some minor differences among them. In the 50% contrast concentration group, all of the nonionic contrast agents inhibited aggregation, whereas in the 10% contrast concentration group, all agents showed similar aggregation curves in comparison to the normal control. At 50% contrast concentration, the inhibitory effect of aggregation appeared to be related to the inhibition of calcium mobilization, which may be one of the mechanistic effects." ], "offsets": [ [ 0, 1001 ] ] } ]

[ { "id": "entity-102-0", "type": "ADVERSE", "text": [ "thrombogenicity" ], "offsets": [ [ 8, 23 ] ], "normalized": [] }, { "id": "entity-102-1", "type": "ADVERSE", "text": [ "thrombogenicity" ], "offsets": [ [ 445, 460 ] ], "normalized": [] } ]

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[ { "id": "passage-103", "type": "abstract", "text": [ "Natural anti-Siglec autoantibodies mediate potential immunoregulatory mechanisms: implications for the clinical use of intravenous immunoglobulins (IVIg). Human intravenous immunoglobulins (IVIg) contain natural autoantibodies against the inhibitory lectin-receptors Siglec-8 and Siglec-9. These two members of the Siglec family are known to mediate both inhibitory and death signals. Here, we discuss recent findings regarding the cytotoxic effects of natural anti-Siglec autoantibodies on both neutrophils and eosinophils, and present the concept of a novel regulatory mechanism exhibiting anti-inflammatory properties. Consequently, IVIg may amplify this regulatory pathway by increasing the concentration of natural anti-Siglec autoantibodies in blood and tissues." ], "offsets": [ [ 0, 769 ] ] } ]

[ { "id": "entity-103-0", "type": "ADVERSE", "text": [ "cytotoxic effects" ], "offsets": [ [ 433, 450 ] ], "normalized": [] } ]

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[ { "id": "passage-104", "type": "abstract", "text": [ "Orally administered apple procyanidins protect against experimental inflammatory bowel disease in mice. Apple procyanidins (ACT) is a natural biologically active compound extracted from apple. Our recent studies have shown that ACT ameliorates the symptoms of atopic dermatitis and inhibits food-allergen-induced oral sensitization. The aim of this study was to investigate the potential protective effect and mechanism of action of ACT in a murine model of inflammatory bowel disease. We investigated the preventive effects of ACT in experimental models of colitis induced by dextran sulfate sodium (DSS) or oxazolone. Oral administration of ACT before DSS treatment attenuated the DSS-induced mortality rate and decreased body weight loss. ACT also prevented the body weight loss associated with oxazolone-induced colitis. Next we examined the effect of ACT on intraepithelial lymphocytes (IEL), which is a major T cell population in the intestine. Oral administration of ACT increased the proportions of TCRgammadelta and TCRalphabeta-CD8alphaalpha T cells in IEL and suppressed interferon gamma synthesis in stimulated IEL. In addition, ACT inhibited phorbol 12-myristate 13-acetate-induced secretion of interleukin 8 (IL-8) in intestinal epithelial cells. The combined anti-inflammatory and immunomodulatory effects of ACT on intestinal epithelial cells and IEL suggest that it may be an effective oral preventive agent for inflammatory bowel diseases." ], "offsets": [ [ 0, 1458 ] ] } ]

[ { "id": "entity-104-0", "type": "DISEASE", "text": [ "inflammatory bowel disease" ], "offsets": [ [ 68, 94 ] ], "normalized": [] }, { "id": "entity-104-1", "type": "DISEASE", "text": [ "atopic dermatitis" ], "offsets": [ [ 261, 278 ] ], "normalized": [] }, { "id": "entity-104-2", "type": "DISEASE", "text": [ "inflammatory bowel disease" ], "offsets": [ [ 459, 485 ] ], "normalized": [] }, { "id": "entity-104-3", "type": "ADVERSE", "text": [ "colitis" ], "offsets": [ [ 559, 566 ] ], "normalized": [] }, { "id": "entity-104-4", "type": "ADVERSE", "text": [ "colitis" ], "offsets": [ [ 817, 824 ] ], "normalized": [] }, { "id": "entity-104-5", "type": "DISEASE", "text": [ "inflammatory bowel diseases" ], "offsets": [ [ 1430, 1457 ] ], "normalized": [] } ]

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[ { "id": "passage-105", "type": "abstract", "text": [ "Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection. BACKGROUND: The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat. METHODS: Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan probes and normalized to nuclear-encoded ribosomal L13. RESULTS: ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [P=0.017] and 2.5 versus 4.6 [P=0.006], respectively). No difference was found between ART-naive patients and controls (P>0.70). ND6/L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [P=0.02] and 726 versus 1,372 copies/cell [P=0.03], respectively), but no difference was found between ART-naive and controls. In a multiple regression analysis, limb fat correlated with all three mitochrondrial RNA, whereas mitochondrial DNA did not correlate with mitochondrial RNA or limb fat. CONCLUSIONS: In contrast to ART-naive patients, HIV-positive patients on ART with lipoatrophy had significant depletion in mitochondrial DNA in fat and mitochondrial RNAs. This suggests that mitochondrial toxicity in lipoatrophy could be driven by ART and not by HIV itself. In addition, mitochondrial RNA abnormalities, and not mitochondrial DNA depletion, could be a key driving force behind lipoatrophy." ], "offsets": [ [ 0, 1835 ] ] } ]

[ { "id": "entity-105-0", "type": "DISEASE", "text": [ "HIV lipoatrophy" ], "offsets": [ [ 41, 56 ] ], "normalized": [] }, { "id": "entity-105-1", "type": "DISEASE", "text": [ "HIV infection" ], "offsets": [ [ 105, 118 ] ], "normalized": [] }, { "id": "entity-105-2", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 329, 340 ] ], "normalized": [] }, { "id": "entity-105-3", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 702, 713 ] ], "normalized": [] }, { "id": "entity-105-4", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 1058, 1069 ] ], "normalized": [] }, { "id": "entity-105-5", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 1511, 1522 ] ], "normalized": [] }, { "id": "entity-105-6", "type": "ADVERSE", "text": [ "mitochondrial toxicity" ], "offsets": [ [ 1620, 1642 ] ], "normalized": [] }, { "id": "entity-105-7", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 1646, 1657 ] ], "normalized": [] }, { "id": "entity-105-8", "type": "DISEASE", "text": [ "lipoatrophy" ], "offsets": [ [ 1823, 1834 ] ], "normalized": [] } ]

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[ { "id": "passage-106", "type": "abstract", "text": [ "Environmental ozone exposure and oxidative DNA damage in adult residents of Florence, Italy. In 71 adults residing in Florence, Italy, enrolled in a prospective study, we investigated the correlation between individual levels of oxidative DNA damage detected by the Comet assay in circulating lymphocytes, and a specific ozone exposure score calculated in 10 different time-windows (0-5 to 0-90 days) before blood drawing, based on daily measurements provided by the local environmental monitoring system. Overall, statistically significant positive correlations between average ozone concentrations and DNA damage emerged in almost all time-windows considered; correlations were more evident among males, non-smokers, and traffic-exposed workers. Multivariate regression analyses taking into account selected individual characteristics, showed an independent effect on DNA damage of average ozone concentrations in the last 60-90 days before blood drawing. Local residents showed a divergent pattern with correlations restricted to shorter time-windows. Our results suggest that ozone concentrations at ground levels modulate oxidative DNA damage in circulating lymphocytes of residents of polluted areas." ], "offsets": [ [ 0, 1207 ] ] } ]

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[ { "id": "passage-107", "type": "abstract", "text": [ "Methods to evaluate the pharmacology of oral antiplatelet drugs. Principally, there are two reasons why the pharmacological response to antiplatelet drugs should be measured: on the one hand, an insufficient inhibition of platelet function may result in atherothrombotic complications; on the other hand, an excessive inhibition of platelet function may lead to bleeding complications. The clinical importance to measure the effects of antiplatelet drugs is demonstrated by increasingly growing evidence for an association of resistance to antiplatelet drugs with thromboembolic events. It is often claimed that there is no generally accepted definition of \"resistance\" and, instead, there is an ongoing semantic discussion about the correct term to be used to describe this phenomenon. From the pharmacological point of view, there is only one acceptable definition of \"resistance\" to antiplatelet drugs: the term \"resistance\" should be used when a drug is unable to hit its pharmacological target. Thus, laboratory methods used to evaluate the effects of antiplatelet drugs should be designed to measure the direct pharmacodynamic effect of a drug, rather than the consequences for global platelet function. Based on physiological/pathophysiological, pharmacological, and practical considerations, the authors propose the following assays to be used to measure the effects of oral antiplatelet drugs: for the detection of aspirin actions, thromboxane or arachidonic acid-induced responses (light aggregometry, whole-blood aggregometry) should be measured; for the detection of clopidogrel actions, VASP (vasodilator-stimulated phosphoprotein) phosphorylation (flow cytometry) or ADP-(adenosine diphosphate-)induced responses (light aggregometry, whole-blood aggregometry, possibly also flow cytometry) should be measured." ], "offsets": [ [ 0, 1824 ] ] } ]

[ { "id": "entity-107-0", "type": "DISEASE", "text": [ "atherothrombotic complications" ], "offsets": [ [ 255, 285 ] ], "normalized": [] }, { "id": "entity-107-1", "type": "DISEASE", "text": [ "bleeding complications" ], "offsets": [ [ 363, 385 ] ], "normalized": [] }, { "id": "entity-107-2", "type": "DISEASE", "text": [ "thromboembolic events" ], "offsets": [ [ 565, 586 ] ], "normalized": [] } ]

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[ { "id": "passage-108", "type": "abstract", "text": [ "Comparison of three different chemotherapy regimens containing epirubicin in hormone-refractory prostate cancer patients. We compared three different chemotherapy regimens containing epirubicin in hormone-refractory prostate cancer (HRPC) patients. Sixty-nine patients with HRPC were randomized into three groups. The first group (22 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks. The second group (24 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks followed by monthly maintenance therapy for 4-6 months. The third group (23 patients) received oral estramustine phosphate (EMP) at a dose of 840 mg/day together with weekly and monthly maintenance epirubicin. The response rates, mean survival times, and toxicity were determined. Within the first 3 months, pain and performance scores were improved by at least one degree in all the groups. One patient in group two and three patients in group three had complete response. Partial response rates were 23% in group 1, 25% in group 2, and 17% in group 3. Stable disease rates were 41% in group 1, 33% in group 2, and 26% in group 3. The progression rates within the first 3 months were 36% in group 1, 38% in group 2, and 44% in group 3. None of the patients developed complications that were significant enough to terminate the treatment. Two patients in group 3 died of cardiotoxicity. The mean survival times were 10.1, 15.8, and 16.1 months in groups 1, 2, and 3, respectively. It was determined that weekly and maintenance epirubicin treatment protocol, and estramustine treatment protocol in addition to this treatment, was only meaningfully more effective against weekly epirubicin treatment in the statistical sense (0.01 < p < 0.05). However, due to the complications of EMP, which influence the quality of life, we believe that this was usable only when measures were adopted against these effects." ], "offsets": [ [ 0, 1886 ] ] } ]

[ { "id": "entity-108-0", "type": "DISEASE", "text": [ "hormone-refractory prostate cancer" ], "offsets": [ [ 77, 111 ] ], "normalized": [] }, { "id": "entity-108-1", "type": "DISEASE", "text": [ "hormone-refractory prostate cancer" ], "offsets": [ [ 198, 232 ] ], "normalized": [] }, { "id": "entity-108-2", "type": "DISEASE", "text": [ "HRPC" ], "offsets": [ [ 234, 238 ] ], "normalized": [] }, { "id": "entity-108-3", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 787, 791 ] ], "normalized": [] }, { "id": "entity-108-4", "type": "ADVERSE", "text": [ "cardiotoxicity" ], "offsets": [ [ 1350, 1364 ] ], "normalized": [] } ]

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[ { "id": "passage-109", "type": "abstract", "text": [ "Prognostic role of glutathione S-transferase polymorphisms in acute myeloid leukemia. Glutathione S-transferases (GSTs) are phase II detoxification enzymes involved in the metabolism of carcinogens and anticancer drugs, known also to interact with kinase complexes during oxidative or chemical stress-induced apoptosis. We were interested whether their polymorphic variants may account for differences in outcome of patients with acute myeloid leukemia (AML) following chemotherapy. We studied the prognostic role of polymorphisms in three GST genes (GSTP1/M1/T1) in a large patient cohort of the German Austrian Acute Myeloid Leukemia Study Group, treated according to prospective multicenter clinical trials (AML HD98A: 254 patients; AML HD98-B: 100 patients), with a median follow-up of 46 months. Looking at short-term adverse drug reactions, homozygous carriers of the GSTP1*105 Val allele had a faster neutrophil and platelet recovery (P=0.002 and 0.02, respectively) and a reduced need of red cell and platelet transfusions (P=0.01 and 0.03, respectively). Response to induction chemotherapy did not vary according to GST polymorphisms. Multivariable Cox regression models revealed a significant better relapse-free (RFS) and overall survival for the GSTP1(*)105 Val (P=0.003 and 0.03, respectively), whereas GSTT1 and GSTM1 genotypes had no significant impact. The favorable impact of GSTP1(*)105 Val on RFS seems to be restricted to the subgroup of patients exhibiting a normal karyotype." ], "offsets": [ [ 0, 1498 ] ] } ]

[ { "id": "entity-109-0", "type": "DISEASE", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 62, 84 ] ], "normalized": [] }, { "id": "entity-109-1", "type": "DISEASE", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 431, 453 ] ], "normalized": [] }, { "id": "entity-109-2", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 455, 458 ] ], "normalized": [] }, { "id": "entity-109-3", "type": "DISEASE", "text": [ "Acute Myeloid Leukemia" ], "offsets": [ [ 614, 636 ] ], "normalized": [] }, { "id": "entity-109-4", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 712, 715 ] ], "normalized": [] }, { "id": "entity-109-5", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 737, 740 ] ], "normalized": [] } ]

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[ { "id": "passage-110", "type": "abstract", "text": [ "Increased damage of exon 5 of p53 gene in workers from an arsenic plant. Mutagenesis is a multistage process. Substitution mutations can be induced by base modified through alteration of pairing property. Mutations of exon 5 and 8 of p53 gene have been found in most arsenicosis patients with precarcinomas and carcinomas, but never in arsenicosis individuals without precarcinomas and carcinomas. This study investigates whether base modification exists in exon 5 and 8 of p53 gene, and explores the dose-effect relationship between damage of exon 5 of p53 gene and urinary arsenic. Concentrations of urinary 8-hydroxydeoxyguanine (8-OHdG) are analyzed to identify the occurrence of DNA damage. The real-time PCR developed by Sikorsky et al. is applied to detect base modification in exon 5 and 8 of p53 gene for apparently healthy participants. Our results show that the mean total arsenic concentrations of two exposed groups from an arsenic plant are significantly elevated compared with the control group, and the damage level of exon 5 of the high-exposed group is significantly higher than that of the control group, but which does not happen in exon 8. The closely correlation between the damage index of exon 5 and urinary organic arsenic concentration are found. Concentration of 8-OHdG of the high-exposed group is significantly higher than that of the control group. These results imply that base modification in exon 5 of p53 gene can be induced by arsenic. In addition, our study suggests that the damage level of exon 5 is a useful biomarker to assess adverse health effect levels caused by chronic exposure to arsenic." ], "offsets": [ [ 0, 1635 ] ] } ]

[ { "id": "entity-110-0", "type": "DISEASE", "text": [ "precarcinomas" ], "offsets": [ [ 294, 307 ] ], "normalized": [] }, { "id": "entity-110-1", "type": "DISEASE", "text": [ "carcinomas" ], "offsets": [ [ 312, 322 ] ], "normalized": [] }, { "id": "entity-110-2", "type": "DISEASE", "text": [ "precarcinomas" ], "offsets": [ [ 369, 382 ] ], "normalized": [] }, { "id": "entity-110-3", "type": "DISEASE", "text": [ "carcinomas" ], "offsets": [ [ 387, 397 ] ], "normalized": [] } ]

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[ { "id": "passage-111", "type": "abstract", "text": [ "Genotoxic damage in pathology anatomy laboratory workers exposed to formaldehyde. Formaldehyde (FA) is a chemical traditionally used in pathology and anatomy laboratories as a tissue preservative. Several epidemiological studies of occupational exposure to FA have indicated an increased risk of nasopharyngeal cancers in industrial workers, embalmers and pathology anatomists. There is also a clear evidence of nasal squamous cell carcinomas from inhalation studies in the rat. The postulated mode of action for nasal tumours in rats was considered biologically plausible and considered likely to be relevant to humans. Based on the available data IARC, the International Agency for Research on Cancer, has recently classified FA as a human carcinogen. Although the in vitro genotoxic as well as the in vivo carcinogenic potentials of FA are well documented in mammalian cells and in rodents, evidence for genotoxic effects and carcinogenic properties in humans is insufficient and conflicting thus remains to be more documented. To evaluate the genetic effects of long-term occupational exposure to FA a group of 30 Pathological Anatomy laboratory workers was tested for a variety of biological endpoints, cytogenetic tests (micronuclei, MN; sister chromatid exchange, SCE) and comet assay. The level of exposure to FA was evaluated near the breathing zone of workers, time weighted average of exposure was calculated for each subject. The association between the biomarkers and polymorphic genes of xenobiotic metabolising and DNA repair enzymes was also assessed. The mean level of exposure was 0.44+/-0.08ppm (0.04-1.58ppm). MN frequency was significantly higher (p=0.003) in the exposed subjects (5.47+/-0.76) when compared with controls (3.27+/-0.69). SCE mean value was significantly higher (p<0.05) among the exposed group (6.13+/-0.29) compared with control group (4.49+/-0.16). Comet assay data showed a significant increase (p<0.05) of TL in FA-exposed workers (60.00+/-2.31) with respect to the control group (41.85+/-1.97). A positive correlation was found between FA exposure levels and MN frequency (r=0.384, p=0.001) and TL (r=0.333, p=0.005). Regarding the genetic polymorphisms studied, no significant effect was found on the genotoxic endpoints. The results of the present biomonitoring study emphasize the need to develop safety programs." ], "offsets": [ [ 0, 2360 ] ] } ]

[ { "id": "entity-111-0", "type": "ADVERSE", "text": [ "Genotoxic damage" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "entity-111-1", "type": "ADVERSE", "text": [ "nasopharyngeal cancers" ], "offsets": [ [ 297, 319 ] ], "normalized": [] }, { "id": "entity-111-2", "type": "ADVERSE", "text": [ "nasal squamous cell carcinomas" ], "offsets": [ [ 413, 443 ] ], "normalized": [] }, { "id": "entity-111-3", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 697, 703 ] ], "normalized": [] }, { "id": "entity-111-4", "type": "ADVERSE", "text": [ "genotoxic effects" ], "offsets": [ [ 908, 925 ] ], "normalized": [] } ]

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[ { "id": "passage-112", "type": "abstract", "text": [ "A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans." ], "offsets": [ [ 0, 1524 ] ] } ]

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[ { "id": "passage-113", "type": "abstract", "text": [ "Paraquat and maneb induced neurotoxicity. Parkinson's disease is a progressive neurological disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. Though the exact cause of the neurodegeneration is unknown, it has been shown that environmental factors can contribute to the onset of Parkinson's disease. Parkinsonian symptoms are seen following exposure to the herbicide paraquat, and the fungicide maneb. Furthermore, evidence clearly shows that neurodegeneration develops in environments where workers are co-exposed to paraquat and maneb. These neurotoxins cause a pesticide-induced loss of dopaminergic neurons, inducing a Parkinsonian phenotype. The specific mechanisms by which these environmental neurotoxins affect the nigral dopaminergic neurons are unknown. This gap in mechanistic understanding raises a need for further examination of their cytotoxic effects. Despite advances in pharmacotherapy that have improved quality of life, the mortality rate among Parkinson's disease sufferers remains largely unchanged. There is need for a proactive treatment strategy that could provide neuroprotection or neurorestoration. Since evidence has shown that environmental neurotoxins play an important role in nigral degeneration, there is obviously a need to take a closer look at such toxins since a greater understanding could aid in development of novel pharmacological agents with anti-parkinson and neuroprotective effects. In this review, we intend to examine the role of environmental toxins, namely paraquat and maneb, in the neurotoxicity that leads to dopamine depletion." ], "offsets": [ [ 0, 1743 ] ] } ]

[ { "id": "entity-113-0", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 27, 40 ] ], "normalized": [] }, { "id": "entity-113-1", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 43, 62 ] ], "normalized": [] }, { "id": "entity-113-2", "type": "DISEASE", "text": [ "neurological disorder" ], "offsets": [ [ 80, 101 ] ], "normalized": [] }, { "id": "entity-113-3", "type": "DISEASE", "text": [ "neurodegenerative movement disorders" ], "offsets": [ [ 209, 245 ] ], "normalized": [] }, { "id": "entity-113-4", "type": "DISEASE", "text": [ "neurodegeneration" ], "offsets": [ [ 335, 352 ] ], "normalized": [] }, { "id": "entity-113-5", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 441, 460 ] ], "normalized": [] }, { "id": "entity-113-6", "type": "DISEASE", "text": [ "Parkinsonian symptoms" ], "offsets": [ [ 462, 483 ] ], "normalized": [] }, { "id": "entity-113-7", "type": "DISEASE", "text": [ "neurodegeneration" ], "offsets": [ [ 605, 622 ] ], "normalized": [] }, { "id": "entity-113-8", "type": "ADVERSE", "text": [ "cytotoxic effects" ], "offsets": [ [ 1011, 1028 ] ], "normalized": [] }, { "id": "entity-113-9", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 1127, 1146 ] ], "normalized": [] }, { "id": "entity-113-10", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 1696, 1709 ] ], "normalized": [] } ]

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[ { "id": "passage-114", "type": "abstract", "text": [ "Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. INTRODUCTION: The combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin. PATIENTS AND METHODS: Patients with AOC were randomised to either six courses of Paclitaxel 175mg/m(2) plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75mg/m(2) plus Doxorubicin 40mg/m(2). RESULTS: Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. CONCLUSION: The combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen." ], "offsets": [ [ 0, 1605 ] ] } ]

[ { "id": "entity-114-0", "type": "DISEASE", "text": [ "ovarian cancer" ], "offsets": [ [ 112, 126 ] ], "normalized": [] }, { "id": "entity-114-1", "type": "DISEASE", "text": [ "Ovarian Cancer" ], "offsets": [ [ 314, 328 ] ], "normalized": [] }, { "id": "entity-114-2", "type": "DISEASE", "text": [ "AOC" ], "offsets": [ [ 330, 333 ] ], "normalized": [] }, { "id": "entity-114-3", "type": "DISEASE", "text": [ "AOC" ], "offsets": [ [ 460, 463 ] ], "normalized": [] }, { "id": "entity-114-4", "type": "ADVERSE", "text": [ "febrile neutropaenia" ], "offsets": [ [ 942, 962 ] ], "normalized": [] } ]

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[ { "id": "passage-115", "type": "abstract", "text": [ "Use of flow cytometry in an apoptosis assay to determine pH and temperature stability of shiga-like toxin 1. Shiga toxins and Shiga-like toxins (Stx) are a relatively large group of cytotoxins produced by certain serotypes of Shigella and E. coli (STEC). These toxins are responsible for diarrhea, hemorrhagic colitis and may induce hemolytic uremic syndrome (HUS) with serious consequences in young children. The toxins are proteins made up of 5 small B subunits responsible for binding to an outer membrane ligand on host cells and surround the larger, biologically active A subunit. For Shiga-like toxin 1 (Stx1), the cellular receptor is the carbohydrate globotriose. Stx1was purified from STEC. We utilized induction of apoptosis in the human monocyte cell line THP-1, as a biological endpoint to test the stability of Stx1 activity added to fruit punch at different pH (2-9) and temperatures (4 and 20 degrees C). A flow cytometric method was used to test for early and late apoptotic events based on binding of R-phycoerytherin-labeled annexin V to exposed membrane phosphatidyl serine. Membrane permeability to 7-Amino-actinomycin corresponds with late apoptosis or necrosis. The combination of acid pH and higher storage temperature resulted in greatest degree of toxin inactivation. This approach provides a rapid and high throughput method to determine the functional activity of Stx1, and related toxins in a food matrix." ], "offsets": [ [ 0, 1434 ] ] } ]

[ { "id": "entity-115-0", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 289, 297 ] ], "normalized": [] }, { "id": "entity-115-1", "type": "ADVERSE", "text": [ "hemorrhagic colitis" ], "offsets": [ [ 299, 318 ] ], "normalized": [] }, { "id": "entity-115-2", "type": "ADVERSE", "text": [ "hemolytic uremic syndrome" ], "offsets": [ [ 334, 359 ] ], "normalized": [] }, { "id": "entity-115-3", "type": "ADVERSE", "text": [ "HUS" ], "offsets": [ [ 361, 364 ] ], "normalized": [] } ]

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[ { "id": "passage-116", "type": "abstract", "text": [ "Immunocompromised hosts: perspectives in the treatment and prophylaxis of cytomegalovirus disease in solid-organ transplant recipients. Cytomegalovirus (CMV) infection is an important complication of solid-organ transplantation. The availability of potent antiviral therapies has decreased the incidence of CMV disease among solid-organ transplant recipients but has also led to challenges, including ganciclovir resistance, late-onset CMV disease, and uncertainty about the optimal duration of prophylaxis or therapy for CMV disease. Specific therapies and management of CMV resistance will be addressed here. The best approach for CMV disease in solid-organ transplant recipients is prevention, but which strategy--prophylaxis or preemptive therapy--is optimal remains debatable. Ganciclovir and valganciclovir remain the best options for prevention and treatment of CMV disease in solid-organ transplant recipients, but they are costly and associated with toxicity. Foscarnet and cidofovir, indicated for the treatment of patients who fail to respond to ganciclovir, are less attractive alternatives because of renal toxicity. Therefore, new therapeutic agents for CMV and an immunogenic, safe CMV vaccine are critically needed." ], "offsets": [ [ 0, 1232 ] ] } ]

[ { "id": "entity-116-0", "type": "DISEASE", "text": [ "cytomegalovirus disease" ], "offsets": [ [ 74, 97 ] ], "normalized": [] }, { "id": "entity-116-1", "type": "DISEASE", "text": [ "Cytomegalovirus (CMV) infection" ], "offsets": [ [ 137, 168 ] ], "normalized": [] }, { "id": "entity-116-2", "type": "DISEASE", "text": [ "CMV disease" ], "offsets": [ [ 308, 319 ] ], "normalized": [] }, { "id": "entity-116-3", "type": "DISEASE", "text": [ "CMV disease" ], "offsets": [ [ 437, 448 ] ], "normalized": [] }, { "id": "entity-116-4", "type": "DISEASE", "text": [ "CMV disease" ], "offsets": [ [ 523, 534 ] ], "normalized": [] }, { "id": "entity-116-5", "type": "DISEASE", "text": [ "CMV" ], "offsets": [ [ 573, 576 ] ], "normalized": [] }, { "id": "entity-116-6", "type": "DISEASE", "text": [ "CMV disease" ], "offsets": [ [ 634, 645 ] ], "normalized": [] }, { "id": "entity-116-7", "type": "DISEASE", "text": [ "CMV disease" ], "offsets": [ [ 870, 881 ] ], "normalized": [] }, { "id": "entity-116-8", "type": "ADVERSE", "text": [ "renal toxicity" ], "offsets": [ [ 1115, 1129 ] ], "normalized": [] }, { "id": "entity-116-9", "type": "DISEASE", "text": [ "CMV" ], "offsets": [ [ 1169, 1172 ] ], "normalized": [] }, { "id": "entity-116-10", "type": "DISEASE", "text": [ "CMV" ], "offsets": [ [ 1198, 1201 ] ], "normalized": [] } ]

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[ { "id": "passage-117", "type": "abstract", "text": [ "Hepatocyte growth factor and granulocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy. BACKGROUND: Myocardial infarction (MI) is a significant cause of heart failure. Current therapies are limited and, therefore, the development of novel revascularization methods is potentially important. We investigated whether hepatocyte growth factor (HGF), expressed by genetically modified mesenchymal stromal cells (MSC), in combination with granulocyte colony-stimulating factor (G-CSF), exhibited a synergistic therapeutic benefit, as measured 8 weeks after MI induction in a rat model. METHODS: Four weeks after MI, rats were randomly divided into a control group (n=11), HGF group (Adenovirus vector carrying human HGF (Ad-HGF)-transfected MSC transplanted into the infarct zone; n=11), G-CSF group (intraperitoneal injection with G-CSF; n=11), and HGF + G-CSF group (Ad-HGF-transfected MSC transplanted into the infarct zone and intraperitoneal injection with G-CSF; n=11). Four weeks later, hearts were analyzed for endothelial cell density and angiogenesis, ventricular geometry, myocardial function and levels of VCAM-1 and MMP-9 protein. RESULTS: The HGF + G-CSF group exhibited improved left ventricular systolic and diastolic function and experienced less adverse ventricular remodeling, as manifested by decreased left ventricular dilatation and increased border zone wall thickness. Angiogenesis was significantly enhanced in HGF + G-CSF rats by inducing the proliferation of endothelial cells. Furthermore, HGF induced expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression in ischemic hearts. DISCUSSION: The combination of G-CSF and HGF exhibited a significant synergistic effect and enhanced myocardial endothelial density, angiogenesis, geometric preservation and heart function in an ischemic cardiomyopathy model." ], "offsets": [ [ 0, 1923 ] ] } ]

[ { "id": "entity-117-0", "type": "DISEASE", "text": [ "ischemic cardiomyopathy" ], "offsets": [ [ 111, 134 ] ], "normalized": [] }, { "id": "entity-117-1", "type": "DISEASE", "text": [ "Myocardial infarction" ], "offsets": [ [ 149, 170 ] ], "normalized": [] }, { "id": "entity-117-2", "type": "DISEASE", "text": [ "MI" ], "offsets": [ [ 172, 174 ] ], "normalized": [] }, { "id": "entity-117-3", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 202, 215 ] ], "normalized": [] }, { "id": "entity-117-4", "type": "DISEASE", "text": [ "MI" ], "offsets": [ [ 601, 603 ] ], "normalized": [] }, { "id": "entity-117-5", "type": "DISEASE", "text": [ "MI" ], "offsets": [ [ 656, 658 ] ], "normalized": [] }, { "id": "entity-117-6", "type": "DISEASE", "text": [ "infarct" ], "offsets": [ [ 811, 818 ] ], "normalized": [] }, { "id": "entity-117-7", "type": "DISEASE", "text": [ "infarct" ], "offsets": [ [ 958, 965 ] ], "normalized": [] }, { "id": "entity-117-8", "type": "DISEASE", "text": [ "ischemic cardiomyopathy" ], "offsets": [ [ 1893, 1916 ] ], "normalized": [] } ]

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[ { "id": "passage-118", "type": "abstract", "text": [ "Sildenafil citrate and Torsade de pointes. Sildenafil citrate is a drug used in the treatment of erectile dysfunction. It is an inhibitor of the enzyme phosphordiesterase-5; it slows down the breakdown of c-GMP and nitrous oxide. The cardiac effects associated with Sildenafil citrate have been extensively studied in medical literature, especially its potent vasodilatory effect when combined with nitrate-based medications, producing intractable hypotension, but a lesser known and potentially lethal side effect is prolonged cardiac repolarization when used at dosage greater than recommended, leading to QT prolongation that could theoretically lead to dangerous cardiac dysrrhythmias and sudden death in men with coronary artery disease. The authors present the case of a 49-year-old hypertensive Hispanic man who arrived to our emergency department with the chief complaint of acute epigastric pain for 3 hours of evolution after ingestion of Sildenafil citrate 50 milligrams (mg). The patient was found to have an acute ST elevation inferior myocardial infarction (STEMI). Shortly after diagnosis the patient developed a polymorphic ventricular tachycardia (Torsade de pointes) before thrombolytic administration. We present this case followed by a brief discussion, to heighten awareness of the possible association of acute inferior STEMI and the development of Torsade de Pointes after the use of Sildenafil citrate." ], "offsets": [ [ 0, 1427 ] ] } ]

[ { "id": "entity-118-0", "type": "DISEASE", "text": [ "Torsade de pointes" ], "offsets": [ [ 23, 41 ] ], "normalized": [] }, { "id": "entity-118-1", "type": "DISEASE", "text": [ "erectile dysfunction" ], "offsets": [ [ 98, 118 ] ], "normalized": [] }, { "id": "entity-118-2", "type": "DISEASE", "text": [ "hypotension" ], "offsets": [ [ 449, 460 ] ], "normalized": [] }, { "id": "entity-118-3", "type": "DISEASE", "text": [ "sudden death" ], "offsets": [ [ 694, 706 ] ], "normalized": [] }, { "id": "entity-118-4", "type": "DISEASE", "text": [ "coronary artery disease" ], "offsets": [ [ 719, 742 ] ], "normalized": [] }, { "id": "entity-118-5", "type": "DISEASE", "text": [ "hypertensive" ], "offsets": [ [ 790, 802 ] ], "normalized": [] }, { "id": "entity-118-6", "type": "DISEASE", "text": [ "epigastric pain" ], "offsets": [ [ 890, 905 ] ], "normalized": [] }, { "id": "entity-118-7", "type": "DISEASE", "text": [ "inferior myocardial infarction" ], "offsets": [ [ 1041, 1071 ] ], "normalized": [] }, { "id": "entity-118-8", "type": "DISEASE", "text": [ "STEMI" ], "offsets": [ [ 1073, 1078 ] ], "normalized": [] }, { "id": "entity-118-9", "type": "DISEASE", "text": [ "polymorphic ventricular tachycardia" ], "offsets": [ [ 1129, 1164 ] ], "normalized": [] }, { "id": "entity-118-10", "type": "DISEASE", "text": [ "Torsade de pointes" ], "offsets": [ [ 1166, 1184 ] ], "normalized": [] }, { "id": "entity-118-11", "type": "DISEASE", "text": [ "STEMI" ], "offsets": [ [ 1343, 1348 ] ], "normalized": [] }, { "id": "entity-118-12", "type": "DISEASE", "text": [ "Torsade de Pointes" ], "offsets": [ [ 1372, 1390 ] ], "normalized": [] } ]

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[ { "id": "passage-119", "type": "abstract", "text": [ "Descriptive study on the circumstances concerning confirmation of contraindications and careful administration upon purchasing over-the-counter cold medication and manifestation of after-use urinary disorders. Over-the-counter medications are primarily for self-medication, where the seller, such as a pharmacist, provides the necessary information and the consumer uses the medication at his or her own discretion based on the information provided. A Web survey was conducted from February 8 to 13, 2006, involving 500 men and women, ranging in age from 50 to 69 years, who had purchased over-the-counter medications for the common cold within the past 3 years. Upon consultation with and purchase of a cold medication from a pharmacist, 84.2% of respondents reported \"being asked my symptoms,\" and less frequently (12.3-21.3%) being asked about contraindications/careful administration. Most respondents (60.8%) when asked whether they confirmed \"contraindications/careful administration\" responded negatively, stating they \"occasionally do not confirm\" or \"do not confirm.\" In addition, among men aged 50-69 years, it became clear that 6.0% had experienced aggravation of prostatic hypertrophy symptoms after taking a cold medication. It is assumed that symptoms are usually confirmed upon the sale of over-the-counter medications, but the rate of confirming whether the consumer may need to consider contraindications/careful administration is low. Urinary retention is a preventable side effect because the confirmation prior to taking the medication can be made. Accordingly, some of those side effects can be avoided by ensuring the environment for confirming whether the individual corresponds to \"contraindications/careful administration\" before taking the medication." ], "offsets": [ [ 0, 1778 ] ] } ]

[ { "id": "entity-119-0", "type": "DISEASE", "text": [ "cold" ], "offsets": [ [ 144, 148 ] ], "normalized": [] }, { "id": "entity-119-1", "type": "DISEASE", "text": [ "urinary disorders" ], "offsets": [ [ 191, 208 ] ], "normalized": [] }, { "id": "entity-119-2", "type": "DISEASE", "text": [ "common cold" ], "offsets": [ [ 627, 638 ] ], "normalized": [] }, { "id": "entity-119-3", "type": "DISEASE", "text": [ "cold" ], "offsets": [ [ 705, 709 ] ], "normalized": [] }, { "id": "entity-119-4", "type": "ADVERSE", "text": [ "prostatic hypertrophy" ], "offsets": [ [ 1176, 1197 ] ], "normalized": [] }, { "id": "entity-119-5", "type": "DISEASE", "text": [ "cold" ], "offsets": [ [ 1222, 1226 ] ], "normalized": [] }, { "id": "entity-119-6", "type": "ADVERSE", "text": [ "Urinary retention" ], "offsets": [ [ 1454, 1471 ] ], "normalized": [] } ]

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[ { "id": "passage-120", "type": "abstract", "text": [ "Amiodarone increases the accumulation of DEA in a human alveolar epithelium-derived cell line. Amiodarone (AMD)-induced pulmonary toxicity (AIPT) is the most life-threatening side-effect of AMD treatment. N-Monodesethylamiodarone (DEA), an active metabolite of AMD, also exhibits cytotoxicity and tends to accumulate in the lung more intensively than AMD. In this study, we characterized the mechanism of DEA accumulation using A549 cells as a model of the alveolar epithelium. Typical ATP-depletion compounds caused an approximately 30% increase in the accumulation of DEA in A549 cells, although these effects were less than those in Caco-2 cells. Triiodothyronine (T(3)), which exhibited an inhibitory effect on DEA efflux in Caco-2 cells, did not affect the accumulation of DEA in A549 cells. On the other hand, 100 microM AMD caused an approximately 200% increase in DEA content in A549 cells, although AMD accumulation was not affected by 100 microM DEA. Since the reducing effect of AMD on cellular ATP levels and that of FCCP were similar, the mechanism by which DEA accumulation is increased by AMD might be different from the ATP-dependent DEA efflux mechanism. The decrease in cell viability by DEA in the presence of AMD (IC(50) value of DEA for A549 cell viability: 25.4+/-2.4 microM) was more pronounced than that by DEA alone (IC(50) value: 11.5+/-3.0 microM). This further DEA accumulation by AMD might be a factor responsible for the greater accumulation of DEA than that of AMD in the lung in long-term AMD-treated patients." ], "offsets": [ [ 0, 1543 ] ] } ]

[ { "id": "entity-120-0", "type": "ADVERSE", "text": [ "pulmonary toxicity" ], "offsets": [ [ 121, 139 ] ], "normalized": [] }, { "id": "entity-120-1", "type": "ADVERSE", "text": [ "AIPT" ], "offsets": [ [ 141, 145 ] ], "normalized": [] } ]

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[ { "id": "passage-121", "type": "abstract", "text": [ "Sexual dysfunction in women with epilepsy: role of antiepileptic drugs and psychotropic medications. Sexual dysfunction is a frequently encountered comorbid disorder in patients with neurological and psychiatric disorders. Importantly, sexual dysfunction can also occur as a treatment emergent adverse effect of a number of commonly used psychotropic and antiepileptic medications, and can include decreased libido, erectile dysfunction, disordered arousal, delayed orgasm, and anorgasmia. These effects can occur in both men and women, and can be seen across age groups. Understanding the neurobiology of normal sexual response, as well as the pharmacologic mechanisms of these commonly used medications can enable the clinician to predict how medication use may impact different phases of sexual response. Discussion of the current treatment strategies for female sexual dysfunction is also elucidated in this chapter." ], "offsets": [ [ 0, 921 ] ] } ]

[ { "id": "entity-121-0", "type": "DISEASE", "text": [ "Sexual dysfunction" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "entity-121-1", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 33, 41 ] ], "normalized": [] }, { "id": "entity-121-2", "type": "DISEASE", "text": [ "Sexual dysfunction" ], "offsets": [ [ 102, 120 ] ], "normalized": [] }, { "id": "entity-121-3", "type": "DISEASE", "text": [ "psychiatric disorders" ], "offsets": [ [ 201, 222 ] ], "normalized": [] }, { "id": "entity-121-4", "type": "ADVERSE", "text": [ "sexual dysfunction" ], "offsets": [ [ 237, 255 ] ], "normalized": [] }, { "id": "entity-121-5", "type": "ADVERSE", "text": [ "decreased libido" ], "offsets": [ [ 399, 415 ] ], "normalized": [] }, { "id": "entity-121-6", "type": "ADVERSE", "text": [ "erectile dysfunction" ], "offsets": [ [ 417, 437 ] ], "normalized": [] }, { "id": "entity-121-7", "type": "ADVERSE", "text": [ "disordered arousal" ], "offsets": [ [ 439, 457 ] ], "normalized": [] }, { "id": "entity-121-8", "type": "ADVERSE", "text": [ "delayed orgasm" ], "offsets": [ [ 459, 473 ] ], "normalized": [] }, { "id": "entity-121-9", "type": "ADVERSE", "text": [ "anorgasmia" ], "offsets": [ [ 479, 489 ] ], "normalized": [] }, { "id": "entity-121-10", "type": "DISEASE", "text": [ "female sexual dysfunction" ], "offsets": [ [ 860, 885 ] ], "normalized": [] } ]

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[ { "id": "passage-122", "type": "abstract", "text": [ "Conjugated chitosan as a novel platform for oral delivery of paclitaxel. A new platform for oral delivery of paclitaxel (PTX) was developed through chemical conjugation of PTX to a low molecular weight chitosan (LMWC). The LMWC-PTX conjugate contained approximately 12 wt % PTX and showed greatly enhanced water solubility (>1 mg/mL) as compared to native PTX. The conjugate showed comparable IC 50 values to that of the parent PTX against human cancer cell lines. The pharmacokinetic data revealed approximately 42% of bioavailability after oral administration of 5 mg PTX/kg of the conjugate. When the conjugate (10 mg/kg based on PTX content) was administered orally to mice bearing xenograft or allograft tumors, the conjugate-treated group showed significant inhibition of tumor growth, which was comparable to that seen with PTX of the clinically available injected form, formulated in cremophor EL/ethanol (iv) but with much lower toxicity. Tracking I (125)-labeled conjugate showed that LMWC-PTX was likely to be absorbed mainly from the ileum and reach the blood as the intact conjugate." ], "offsets": [ [ 0, 1097 ] ] } ]

[ { "id": "entity-122-0", "type": "DISEASE", "text": [ "tumors" ], "offsets": [ [ 710, 716 ] ], "normalized": [] }, { "id": "entity-122-1", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 779, 784 ] ], "normalized": [] } ]

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[ { "id": "passage-123", "type": "abstract", "text": [ "Polyanhydrides as localized drug delivery carrier: an update. BACKGROUND: There is a continuing thrust to increase the efficacy and reduce the toxicity of existing and new drug molecules for their better usage to treat disease. Localized drug delivery has been explored in the same way, which can provide a platform to target local diseased tissues and can reduce the burden on the body by reducing the dose size and hence the dose-related toxicity of the molecules. Various polymers have evolved for the purpose of localized drug delivery, however, polyanhydrides are considered the best, supported by products in the clinical phases. OBJECTIVE: To demonstrate the advantages of localized delivery using basic concepts and describing polyanhydride carrier with products such as Gliadel and Septacin. METHODS: The rationale behind localized drug delivery and the carrier for the same are dealt with. Polyanhydrides discussed in detail are those from subclasses that have been given less emphasis previously and have been developed or investigated in the last 5 years. RESULTS/CONCLUSION: From the recent update on polyanhydrides, it can be concluded that these polymers have great potential as localized drug delivery carriers due to the versatility of their properties. However, the quest to stabilize the system in order to achieve a long shelf life remains ongoing." ], "offsets": [ [ 0, 1369 ] ] } ]

[ { "id": "entity-123-0", "type": "ADVERSE", "text": [ "dose-related toxicity" ], "offsets": [ [ 428, 449 ] ], "normalized": [] } ]

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[ { "id": "passage-124", "type": "abstract", "text": [ "Antimicrobial and cytotoxic arylazoenamines. Part III: antiviral activity of selected classes of arylazoenamines. Eighty-five arylazoenamines, characterized by different types of aryl and basic moieties, have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of ten RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, RSV, BVDV, YFV, and Sb-1; the remaining viruses were either not affected (HIV-1, VSV, and VV) or susceptible only to a very few compounds (Reo-1 and HSV-1). Thirty-five compounds exhibited high activity, with EC(50) in the range 0.8-10 microM, and other 28 compounds had EC(50) between 11 and 30 microM, thus indicating that the arylazoenamine molecular pattern is an interesting novel pharmacophore for antiviral agents against ssRNA viruses. Moreover, some compounds (as 28, 32, 42, and 53) appear of high interest, being devoid of toxicity on the human MT-4 cells (CC(50)>100 microM). A ligand-based computational approach was employed to identify highly predictive pharmacophore models for the most frequently affected viruses CVB-2, RSV, and BVDV. These models should allow the design of second generation of more potent inhibitors of these human and veterinary pathogens." ], "offsets": [ [ 0, 1292 ] ] } ]

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[ { "id": "passage-125", "type": "abstract", "text": [ "An approach to defining the upper safe limits of amino acid intake. The existing data on the safe upper limits of amino acid intake in humans is essentially observational; how much do individuals ingest and what side effects do they have? There are numerous studies in humans comparing the effects of high doses of amino acids given as protein bound vs. as free amino acids. These studies have shown that protein-bound amino acids have much less effect on plasma levels of the test amino acid, because protein intake stimulates protein synthesis as another sink for the increased amino acid intake. In practice, the highest amino acid intakes occur with free amino acid supplements that may be ingested by athletes who believe that the amino acids will benefit them in training and/or performance. Previously, in a piglet study, we were able to define the point at which maximal phenylalanine oxidation occurred, above which plasma phenylalanine concentration and body balance rose exponentially. We regard this value of maximal disposal (oxidation) of an amino acid as one metabolic marker of the upper limit of intake. Recently, others have demonstrated a similar maximal oxidation rate for leucine in rats. Based on these experimental data and the paucity of published human data in controlled experiments, we think that a systematic approach needs to be undertaken to define the maximal oxidation rate for all dietary indispensable amino acids and other amino acids that may be ingested in excess by humans. We believe that this will provide a rational basis to begin to define the upper limits of tolerance for dietary amino acids. However, some amino acids, such as threonine and methionine, will be more difficult to study, because they have more than 1 route of disposal or very complex metabolic regulation, in which case defining their upper limits will be more multifaceted." ], "offsets": [ [ 0, 1886 ] ] } ]

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[ { "id": "passage-126", "type": "abstract", "text": [ "Lentiviral short hairpin RNA screen of genes associated with multidrug resistance identifies PRP-4 as a new regulator of chemoresistance in human ovarian cancer. Published reports implicate a variety of mechanisms that may contribute to drug resistance in ovarian cancer. The chief aim of this study is to understand the relationship between overexpression of drug resistance associated genes and multidrug resistance in ovarian cancer. Using lentiviral short hairpin RNA collections targeting 132 genes identified from transcriptional profiling of drug-resistant cancer cell lines, individual knockdown experiments were done in the presence of sublethal doses of paclitaxel. Specific genes whose knockdown was found to be associated with cellular toxicity included MDR1 (ABCB1), survivin, and pre-mRNA processing factor-4 (PRP-4). These genes, when repressed, can reverse paclitaxel resistance in the multidrug-resistant cell line SKOV-3(TR) and OVCAR8(TR). Both MDR1 and survivin have been reported previously to play a role in multidrug resistance and chemotherapy-induced apoptosis; however, the effect of PRP-4 expression on drug sensitivity is currently unrecognized. PRP-4 belongs to the serine/threonine protein kinase family, plays a role in pre-mRNA splicing and cell mitosis, and interacts with CLK1. Northern analysis shows that PRP-4 is overexpressed in several paclitaxel-resistant cell lines and confirms that PRP-4 expression could be significantly repressed by PRP-4 lentiviral short hairpin RNA. Both clonogenic and MTT assays confirm that transcriptional repression of PRP-4 could reverse paclitaxel resistance 5-10-fold in SKOV-3(TR). Finally, overexpression of PRP-4 in drug-sensitive cells could induce a modest level of drug resistance to paclitaxel, doxorubicin, and vincristine." ], "offsets": [ [ 0, 1804 ] ] } ]

[ { "id": "entity-126-0", "type": "DISEASE", "text": [ "ovarian cancer" ], "offsets": [ [ 146, 160 ] ], "normalized": [] }, { "id": "entity-126-1", "type": "DISEASE", "text": [ "ovarian cancer" ], "offsets": [ [ 257, 271 ] ], "normalized": [] }, { "id": "entity-126-2", "type": "DISEASE", "text": [ "ovarian cancer" ], "offsets": [ [ 422, 436 ] ], "normalized": [] }, { "id": "entity-126-3", "type": "ADVERSE", "text": [ "cellular toxicity" ], "offsets": [ [ 740, 757 ] ], "normalized": [] } ]

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[ { "id": "passage-127", "type": "abstract", "text": [ "Local tissue destruction and procoagulation properties of Echis carinatus venom: inhibition by Vitis vinifera seed methanol extract. Plant extracts are extensively used against snakebites in Indian folk medicine. In this study, one such traditionally used plant, Vitis vinifera L. (Vitaceae) seed methanol extract has been studied for its ability to neutralize Indian Echis carinatus (saw-scaled viper) venom. The extract effectively inhibited toxic effects, such as oedema, haemorrhage, myonecrosis and coagulation of citrated human plasma. Further, the extract inhibited the caseinolytic, hyaluronolytic and fibrinogenolytic activities of the venom. The extract caused dose dependent inhibition of the toxic activities studied, suggesting venom inhibition. Thus, the anti-snake venom property of the extract appears to be highly promising for further investigation in order to achieve better neutralization of Indian E. carinatus venom poisoning." ], "offsets": [ [ 0, 949 ] ] } ]

[ { "id": "entity-127-0", "type": "ADVERSE", "text": [ "oedema" ], "offsets": [ [ 468, 474 ] ], "normalized": [] }, { "id": "entity-127-1", "type": "ADVERSE", "text": [ "haemorrhage" ], "offsets": [ [ 476, 487 ] ], "normalized": [] }, { "id": "entity-127-2", "type": "ADVERSE", "text": [ "myonecrosis" ], "offsets": [ [ 489, 500 ] ], "normalized": [] }, { "id": "entity-127-3", "type": "ADVERSE", "text": [ "coagulation of citrated human plasma" ], "offsets": [ [ 505, 541 ] ], "normalized": [] }, { "id": "entity-127-4", "type": "DISEASE", "text": [ "venom poisoning" ], "offsets": [ [ 933, 948 ] ], "normalized": [] } ]

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[ { "id": "passage-128", "type": "abstract", "text": [ "An in vivo evaluation of Brilliant Blue G in animals and humans. BACKGROUND/AIMS: To evaluate the retinal toxicity of Brilliant Blue G (BBG) following intravitreal injection in rat eyes and examine the biocompatibility and the staining properties in humans. METHODS: BBG was injected into the 11 rat eyes to evaluate toxic effects with balanced salt solution (BSS) serving as control. Retinal toxicity was assessed by retinal ganglion cell (RGC) counts and by light microscopy 7 days later. In addition, BBG was applied during vitrectomy for macular hole (MH) (n = 15) or epiretinal membranes (ERM) (n = 3) in a prospective, non-comparative consecutive series of patients. Before and after surgery, all patients underwent a complete clinical examination including measurement of best corrected visual acuity (VA) and intraocular pressure, perimetry, fundus photography and optical coherence tomography. Patients were seen 1 day before surgery and then in approximately four weeks intervals. RESULTS: No significant reduction in RGC numbers and no morphological alterations were noted. A sufficient staining of the internal limiting membrane (ILM) was seen in patients with MH, while the staining pattern in ERM cases was patchy, indicating that parts of the ILM were peeled off along with the ERM in a variable extent. All MHs could be closed successfully. VA improved in 10 eyes (56%; 8/15 MH patients, 2/3 ERM patients), was unchanged in four eyes (22%; all MH patients) and was reduced in four eyes (22%; 3/15 MH, 1/3 ERM). No toxic effects attributable to the dye were noted during patient follow-up. The ultrastructure of tissue harvested during surgery was unremarkable. CONCLUSION: Brilliant Blue provides a sufficient and selective staining of the ILM. No retinal toxicity or adverse effects related to the dye were observed in animal and human studies. The long-term safety of this novel dye will have to be evaluated in larger patient series and a longer follow-up." ], "offsets": [ [ 0, 1976 ] ] } ]

[ { "id": "entity-128-0", "type": "ADVERSE", "text": [ "retinal toxicity" ], "offsets": [ [ 99, 115 ] ], "normalized": [] }, { "id": "entity-128-1", "type": "ADVERSE", "text": [ "Retinal toxicity" ], "offsets": [ [ 386, 402 ] ], "normalized": [] }, { "id": "entity-128-2", "type": "ADVERSE", "text": [ "retinal toxicity" ], "offsets": [ [ 1765, 1781 ] ], "normalized": [] } ]

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[ { "id": "passage-129", "type": "abstract", "text": [ "Koshikamide B, a cytotoxic peptide lactone from a marine sponge Theonella sp. Koshikamide B (1) has been isolated from two separate collections of the marine sponge Theonella sp. as the major cytotoxic constituent. Koshikamide B is a 17-residue peptide lactone composed of six proteinogenic amino acids, two D-isomers of proteinogenic amino acids, seven N-methylated amino acids, and two unusual amino acid residues. The unusual amino acids are N(delta)-carbamoylasparagine and 2-(3-amino-2-hydroxy-5-oxopyrrolidin-2-yl)propionic acid (AHPP); the former is first found as the constituent of peptides, whereas the latter is a new amino acid residue. The N-terminus of koshikamide B is blocked by a methoxyacetyl group. The structure of koshikamide B (1) has been determined by interpretation of spectral data and analysis of chemical degradation products. Koshikamide B (1) exhibits cytotoxicity against P388 murine leukemia cells and the human colon tumor (HCT-116) cell line with an IC50 value of 0.45 and 7.5 microg/mL, respectively." ], "offsets": [ [ 0, 1036 ] ] } ]

[ { "id": "entity-129-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 883, 895 ] ], "normalized": [] } ]

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[ { "id": "passage-130", "type": "abstract", "text": [ "Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. Long-term outcomes after kidney transplantation remain suboptimal, despite the great achievements observed in recent years with the use of modern immunosuppressive drugs. Currently, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the cornerstones of immunosuppressive regimens in many centers worldwide, regardless of their well described side-effects, including nephrotoxicity. In this article, we review recent CNI-minimization strategies in kidney transplantation, while emphasizing on the importance of long-term follow-up and patient monitoring. Finally, accumulating data indicate that low-dose CNI-based regimens would provide an interesting balance between efficacy and toxicity." ], "offsets": [ [ 0, 804 ] ] } ]

[ { "id": "entity-130-0", "type": "ADVERSE", "text": [ "nephrotoxicity" ], "offsets": [ [ 480, 494 ] ], "normalized": [] } ]

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[ { "id": "passage-131", "type": "abstract", "text": [ "Zebrafish whole-adult-organism chemogenomics for large-scale predictive and discovery chemical biology. The ability to perform large-scale, expression-based chemogenomics on whole adult organisms, as in invertebrate models (worm and fly), is highly desirable for a vertebrate model but its feasibility and potential has not been demonstrated. We performed expression-based chemogenomics on the whole adult organism of a vertebrate model, the zebrafish, and demonstrated its potential for large-scale predictive and discovery chemical biology. Focusing on two classes of compounds with wide implications to human health, polycyclic (halogenated) aromatic hydrocarbons [P(H)AHs] and estrogenic compounds (ECs), we generated robust prediction models that can discriminate compounds of the same class from those of different classes in two large independent experiments. The robust expression signatures led to the identification of biomarkers for potent aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) agonists, respectively, and were validated in multiple targeted tissues. Knowledge-based data mining of human homologs of zebrafish genes revealed highly conserved chemical-induced biological responses/effects, health risks, and novel biological insights associated with AHR and ER that could be inferred to humans. Thus, our study presents an effective, high-throughput strategy of capturing molecular snapshots of chemical-induced biological states of a whole adult vertebrate that provides information on biomarkers of effects, deregulated signaling pathways, and possible affected biological functions, perturbed physiological systems, and increased health risks. These findings place zebrafish in a strategic position to bridge the wide gap between cell-based and rodent models in chemogenomics research and applications, especially in preclinical drug discovery and toxicology." ], "offsets": [ [ 0, 1894 ] ] } ]

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[ { "id": "passage-132", "type": "abstract", "text": [ "Fragrance material review on 2-(1-methylpropyl)-1-vinylcyclohexyl acetate. A toxicologic and dermatologic review of 2-(1-methylpropyl)-1-vinylcyclohexyl acetate when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 211 ] ] } ]

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[ { "id": "passage-133", "type": "abstract", "text": [ "QT prolongation and safety in the Indian population. The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled 'Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products' [1, 2]. In addition, USFDA adopted the guideline 'Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs' [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation." ], "offsets": [ [ 0, 1892 ] ] } ]

[ { "id": "entity-133-0", "type": "ADVERSE", "text": [ "polymorphic ventricular tachycardia" ], "offsets": [ [ 373, 408 ] ], "normalized": [] }, { "id": "entity-133-1", "type": "ADVERSE", "text": [ "torsade de pointes" ], "offsets": [ [ 416, 434 ] ], "normalized": [] }, { "id": "entity-133-2", "type": "ADVERSE", "text": [ "TdP" ], "offsets": [ [ 436, 439 ] ], "normalized": [] }, { "id": "entity-133-3", "type": "DISEASE", "text": [ "TdP" ], "offsets": [ [ 442, 445 ] ], "normalized": [] }, { "id": "entity-133-4", "type": "DISEASE", "text": [ "ventricular fibrillation" ], "offsets": [ [ 466, 490 ] ], "normalized": [] }, { "id": "entity-133-5", "type": "DISEASE", "text": [ "sudden cardiac death" ], "offsets": [ [ 507, 527 ] ], "normalized": [] }, { "id": "entity-133-6", "type": "ADVERSE", "text": [ "arrhythmias" ], "offsets": [ [ 1648, 1659 ] ], "normalized": [] } ]

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[ { "id": "passage-134", "type": "abstract", "text": [ "Testosterone and the breast. Although women have been treated with testosterone (T) for female sexual dysfunction since the 1950s, the role of T in normal female physiology is not yet fully defined. One of the major safety concerns of androgen therapy is whether androgens have a stimulatory effect on the breast that could lead to breast carcinomas. The proposed mechanisms for such stimulation include local estrogen production from the aromatase enzyme complex present in the breast tissue or by the direct stimulation of the androgen receptor. Predominant data from in vitro studies have shown that androgens actually have apoptotic and antiproliferative effects and not stimulatory effects. Animal models have shown similar results to in vitro studies, finding that androgens inhibit breast cancer growth. Prospective and retrospective epidemiological analyses have shown mixed outcomes, with no clear consensus regarding androgen use and breast cancer risk. Hyperandrogenism in patients with polycystic ovarian syndrome with elevated levels of endogenous T is not associated with an increased risk of breast cancer and may, in fact, be protective. Another human model with excess of T is female-to-male transgenderism, in which genotypic women are treated with large doses of exogenous T with no increased risk. High-dose androgen therapy also has been effective in treating patients with advanced breast cancer. Thus, the preponderance of data suggests that T use in females is not associated with an increased risk of breast carcinoma." ], "offsets": [ [ 0, 1544 ] ] } ]

[ { "id": "entity-134-0", "type": "DISEASE", "text": [ "female sexual dysfunction" ], "offsets": [ [ 89, 114 ] ], "normalized": [] }, { "id": "entity-134-1", "type": "ADVERSE", "text": [ "breast carcinomas" ], "offsets": [ [ 333, 350 ] ], "normalized": [] }, { "id": "entity-134-2", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 790, 803 ] ], "normalized": [] }, { "id": "entity-134-3", "type": "ADVERSE", "text": [ "breast cancer" ], "offsets": [ [ 945, 958 ] ], "normalized": [] }, { "id": "entity-134-4", "type": "DISEASE", "text": [ "Hyperandrogenism" ], "offsets": [ [ 965, 981 ] ], "normalized": [] }, { "id": "entity-134-5", "type": "DISEASE", "text": [ "polycystic ovarian syndrome" ], "offsets": [ [ 999, 1026 ] ], "normalized": [] }, { "id": "entity-134-6", "type": "ADVERSE", "text": [ "breast cancer" ], "offsets": [ [ 1108, 1121 ] ], "normalized": [] }, { "id": "entity-134-7", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1405, 1418 ] ], "normalized": [] }, { "id": "entity-134-8", "type": "DISEASE", "text": [ "breast carcinoma" ], "offsets": [ [ 1527, 1543 ] ], "normalized": [] } ]

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[ { "id": "passage-135", "type": "abstract", "text": [ "Does chemotherapy modify the immune surveillance of hematological malignancies? Malignant diseases induce immune responses against them which have variable success in controlling progression of disease. A variety of congenital and acquired disorders provide evidence in support of T cell or NK cell immune surveillance mechanisms in human hematological malignancies. Furthermore, clinical experience with stem cell transplantation underlines the potential for both T and NK cell-mediated antileukemia effects. Animal models of tumor surveillance and viral-driven lymphoproliferative diseases in man emphasize the dynamic nature of the equilibrium between tumors and the immune system, which can lead to tumor escape in individuals with normal immune function. In hematological malignancies the implication of a dynamic immune surveillance model is that chemotherapy may disrupt potentially competent immune surveillance mechanisms leading to disease recurrence following successful tumor bulk reduction by chemotherapy. This possibility deserves further investigation with a view to developing strategies to boost immune function following chemotherapy so as to combine the beneficial effect of chemotherapy with an immune response capable of sustaining remissions." ], "offsets": [ [ 0, 1266 ] ] } ]

[ { "id": "entity-135-0", "type": "DISEASE", "text": [ "hematological malignancies" ], "offsets": [ [ 52, 78 ] ], "normalized": [] }, { "id": "entity-135-1", "type": "DISEASE", "text": [ "Malignant diseases" ], "offsets": [ [ 81, 99 ] ], "normalized": [] }, { "id": "entity-135-2", "type": "DISEASE", "text": [ "hematological malignancies" ], "offsets": [ [ 340, 366 ] ], "normalized": [] }, { "id": "entity-135-3", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 528, 533 ] ], "normalized": [] }, { "id": "entity-135-4", "type": "DISEASE", "text": [ "lymphoproliferative diseases" ], "offsets": [ [ 564, 592 ] ], "normalized": [] }, { "id": "entity-135-5", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "entity-135-6", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 983, 988 ] ], "normalized": [] } ]

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[ { "id": "passage-136", "type": "abstract", "text": [ "Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss." ], "offsets": [ [ 0, 1861 ] ] } ]

[ { "id": "entity-136-0", "type": "DISEASE", "text": [ "multiple sclerosis" ], "offsets": [ [ 77, 95 ] ], "normalized": [] }, { "id": "entity-136-1", "type": "DISEASE", "text": [ "multiple sclerosis" ], "offsets": [ [ 240, 258 ] ], "normalized": [] }, { "id": "entity-136-2", "type": "DISEASE", "text": [ "MS" ], "offsets": [ [ 260, 262 ] ], "normalized": [] }, { "id": "entity-136-3", "type": "DISEASE", "text": [ "MS" ], "offsets": [ [ 406, 408 ] ], "normalized": [] }, { "id": "entity-136-4", "type": "ADVERSE", "text": [ "edema" ], "offsets": [ [ 963, 968 ] ], "normalized": [] }, { "id": "entity-136-5", "type": "ADVERSE", "text": [ "chemotoxicity" ], "offsets": [ [ 1001, 1014 ] ], "normalized": [] }, { "id": "entity-136-6", "type": "DISEASE", "text": [ "MS" ], "offsets": [ [ 1248, 1250 ] ], "normalized": [] }, { "id": "entity-136-7", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 1346, 1358 ] ], "normalized": [] }, { "id": "entity-136-8", "type": "DISEASE", "text": [ "pseudoatrophy" ], "offsets": [ [ 1559, 1572 ] ], "normalized": [] }, { "id": "entity-136-9", "type": "DISEASE", "text": [ "MS" ], "offsets": [ [ 1738, 1740 ] ], "normalized": [] } ]

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[ { "id": "passage-137", "type": "abstract", "text": [ "Dioxin interferes in chromosomal positioning through the aryl hydrocarbon receptor. Each chromosome occupies its own-specific space called a 'territory' within the interphase nucleus, and the arrangement of chromosome territories (CTs) is important in epigenetic mechanisms. The molecular mechanism to determine the positioning of CTs, however, remains unknown. On the other hand, dioxin is known to be the typical environmental pollutant that affects a wide variety of biological events in many species. Here, we show that dioxin enlarges the minimum distance between chromosome 12 and chromosome 16 territories in human preadipocyte cells, and the alteration of chromosome positioning is canceled by an aryl hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone. Thus, AhR may be a key molecule to regulate chromosome positioning. Our results suggest a novel effect of dioxin toxicity, and demonstrate a clue to reveal the novel molecular mechanism for the arrangement of CTs." ], "offsets": [ [ 0, 984 ] ] } ]

[ { "id": "entity-137-0", "type": "ADVERSE", "text": [ "dioxin toxicity" ], "offsets": [ [ 877, 892 ] ], "normalized": [] } ]

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[ { "id": "passage-138", "type": "abstract", "text": [ "Contraception in women with epilepsy: pharmacokinetic interactions, contraceptive options, and management. Contraceptive counseling is a critical component of the management of the female patient with epilepsy because of the increased risk of pregnancy associated with epilepsy and the multitude of interactions between antiepileptic drugs (AEDs) and hormonal contraception. Steroid hormones and many of the AEDs are substrates for the cytochrome P450 enzyme system, in particular, the 3A4 isoenzyme. As a result, concomitant use of hormonal contraceptives and AEDs may pose a risk for unexpected pregnancy, seizures, and drug-related adverse effects. The risk of combined oral contraceptive (COC) failure is slightly increased in the presence of cytochrome P450 3A4 enzyme-inducing AEDs. Several AEDs induce the production of sex hormone binding globulin (SHBG) to which the progestins are tightly bound, resulting in lower concentrations of free progestin that may also lead to COC failure. There is no increase in the risk of COC failure in women taking nonenzyme-inducing AEDs. Oral contraceptives significantly increase the metabolism of lamotrigine, posing a risk of seizures when hormonal agents are initiated and/or toxicity during pill-free weeks. There is no evidence that COCs increase seizures in women with epilepsy. While higher dose COCs are one contraceptive option for women on enzyme-inducing AEDs, a variety of other options are available. Injectable contraception (depot medroxyprogesterone acetate) appears effective with AED use, but the potential for bone mineral density loss is a concern. Intrauterine devices (IUDs) and barrier methods do not rely on hormonal components for contraceptive efficacy, and are therefore appropriate to recommend for use in women using enzyme-inducing medications. This chapter reviews the evidence regarding the pharmacokinetic interaction between AEDs and oral contraceptive hormones, the known or potential interactions with alternative contraceptive methods, and provides practical advice for management of contraceptive needs in reproductive-age women." ], "offsets": [ [ 0, 2113 ] ] } ]

[ { "id": "entity-138-0", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 28, 36 ] ], "normalized": [] }, { "id": "entity-138-1", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 202, 210 ] ], "normalized": [] }, { "id": "entity-138-2", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 270, 278 ] ], "normalized": [] }, { "id": "entity-138-3", "type": "ADVERSE", "text": [ "unexpected pregnancy" ], "offsets": [ [ 587, 607 ] ], "normalized": [] }, { "id": "entity-138-4", "type": "ADVERSE", "text": [ "seizures" ], "offsets": [ [ 609, 617 ] ], "normalized": [] }, { "id": "entity-138-5", "type": "ADVERSE", "text": [ "seizures" ], "offsets": [ [ 1174, 1182 ] ], "normalized": [] }, { "id": "entity-138-6", "type": "ADVERSE", "text": [ "seizures" ], "offsets": [ [ 1298, 1306 ] ], "normalized": [] }, { "id": "entity-138-7", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 1321, 1329 ] ], "normalized": [] } ]

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[ { "id": "passage-139", "type": "abstract", "text": [ "Styrene induces an inflammatory response in human lung epithelial cells via oxidative stress and NF-kappaB activation. Styrene is a volatile organic compound (VOC) that is widely used as a solvent in many industrial settings. Chronic exposure to styrene can result in irritation of the mucosa of the upper respiratory tract. Contact of styrene with epithelial cells stimulates the expression of a variety of inflammatory mediators, including the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1). To characterise the underlying mechanisms of the induction of inflammatory signals by styrene, we investigated the influence of this compound on the induction of oxidative stress and the activation of the nuclear factor-kappa B (NF-kappaB) signalling pathway in human lung epithelial cells (A549). The results demonstrate that styrene-induced MCP-1 expression, as well as the expression of the oxidative stress marker glutathione S-transferase (GST), is associated with a concentration dependent pattern of NF-kappaB activity. An inhibitor of NF-kappaB, IKK-NBD, and the anti-inflammatory antioxidant N-acetylcysteine (NAC) were both effective in suppressing styrene-induced MCP-1 secretion. In addition, NAC was capable of inhibiting the upregulation of GST expression. Our findings suggest that the activation of the NF-kappaB signalling pathway by styrene is mediated via a redox-sensitive mechanism." ], "offsets": [ [ 0, 1415 ] ] } ]

[ { "id": "entity-139-0", "type": "ADVERSE", "text": [ "irritation of the mucosa" ], "offsets": [ [ 269, 293 ] ], "normalized": [] } ]

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[ { "id": "passage-140", "type": "abstract", "text": [ "Mutual stimulation of beta-amyloid fibrillogenesis by clioquinol and divalent metals. As reported by some authors, clioquinol (CQ), a 8-hydroxyquinoline derivative, has produced very encouraging results in the treatment of Alzheimer's disease (AD). Its biological effects are most likely ascribed to complexation of specific metal ions, such as copper (II) and zinc (II), critically associated with beta-amyloid (A beta) aggregation/fibrillogenesis and degeneration processes in the brain. The present study was aimed at assessing the in vitro effects of CQ on the aggregation/fibrillogenesis properties of human A beta either alone or complexed with Cu(2+) and Zn(2+). Surprisingly, our data indicated that CQ promoted rather than inhibited the formation of A beta fibrillar aggregates when added metal ions were present. To understand whether the latter effects were related to the peptide amino acid sequence, we also investigated the aggregational profile of rat A beta, which differs from the human homologous for three amino acidic substitutions. Such a sequence alteration drastically reduced the tendency of the peptide to undergo spontaneous aggregation/fibrillization. In the presence of CQ and metals, however, also rat A beta showed a strong propensity to generate fibrillar aggregates. In agreement with the pro-aggregation effects observed in solution, studies with neuroblastoma cells demonstrated an impairment of cell functioning only in the presence of CQ + A beta-metals. Based on the present findings, the literature data on the potential effectiveness of CQ-based chelation therapy in AD should be re-interpreted." ], "offsets": [ [ 0, 1635 ] ] } ]

[ { "id": "entity-140-0", "type": "DISEASE", "text": [ "Alzheimer's disease" ], "offsets": [ [ 224, 243 ] ], "normalized": [] }, { "id": "entity-140-1", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 245, 247 ] ], "normalized": [] }, { "id": "entity-140-2", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 1607, 1609 ] ], "normalized": [] } ]

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[ { "id": "passage-141", "type": "abstract", "text": [ "Effect of an ibuprofen-releasing foam dressing on wound pain: a real-life RCT. OBJECTIVE: To compare an ibuprofen-releasing foam dressing (Biatain Ibu, ColoplastA/S) with local best practice in the treatment of painful exuding wounds. METHOD: In this large-scale randomised comparative study, 853 patients were randomised to either ibuprofen-releasing foam (test) dressing (n=467) or local best practice (n=386). Primary endpoint was wound pain relief from day 1-7, assessed by the patients twice daily using a five-point verbal rating scale. Secondary endpoints were reduction in pain intensity from day 0-7 (assessed using an 11-point numeric box scale), quality of life (assessed using the WHO-5 well-being index and effect on health-related activities of daily living) and the incidence of adverse events. RESULTS: After seven days significantly more patients in the experimental group experienced relief from temporary and persistent pain and a reduction in pain intensity,when compared with patients in the local best practice group (p<0.0001). They also experienced a greater improvement in quality of life. The number of adverse events in both groups was low. CONCLUSION: The test dressing provided an appropriate wound healing environment, relieved temporary and persistent wound pain, and decreased pain intensity. It was also associated with an improvement in quality of life." ], "offsets": [ [ 0, 1388 ] ] } ]

[ { "id": "entity-141-0", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 50, 60 ] ], "normalized": [] }, { "id": "entity-141-1", "type": "DISEASE", "text": [ "painful exuding wounds" ], "offsets": [ [ 212, 234 ] ], "normalized": [] }, { "id": "entity-141-2", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 435, 445 ] ], "normalized": [] }, { "id": "entity-141-3", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 582, 586 ] ], "normalized": [] }, { "id": "entity-141-4", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 940, 944 ] ], "normalized": [] }, { "id": "entity-141-5", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 964, 968 ] ], "normalized": [] }, { "id": "entity-141-6", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 1223, 1228 ] ], "normalized": [] }, { "id": "entity-141-7", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 1284, 1294 ] ], "normalized": [] }, { "id": "entity-141-8", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 1310, 1314 ] ], "normalized": [] } ]

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[ { "id": "passage-142", "type": "abstract", "text": [ "A multiple-center phase II study of biweekly oxaliplatin and tegafur-uracil/leucovorin for chemonaive patients with advanced gastric cancer. PURPOSE: The current study assessed the efficacy and safety of biweekly oxaliplatin combining oral tegafur-uracil/leucovorin in treating chemonaive patients with advanced gastric cancer. METHODS: Eligible patients were 18-75 years old, had stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0-2. Patients in the current study received 2-h i.v. infusion of oxaliplatin at a dose of 100 mg/m(2) after diluting in 500 mL 5% dextrose/water (dexan premedication), and 5-HT3 antagonist biweekly. Oral tegafur-uracil and leucovorin was given at a dose of 300 mg/m(2)/day and 60 mg/day three times daily from day 1 to 21, respectively, followed by a 1-week rest. Response assessment was based on the RECIST criteria and was performed every two courses. Toxicity was assessed according to NCI common toxicity criteria version 2. RESULTS: From October 2003 to April 2006, 57 patients were evaluated (55 eligible) with a median age of 61 years (range 31-75). According to the assessment of response in 48 evaluable patients, partial response rate was 24/48 (50.0%) (95% CI: 35.23-64.73%) and stable disease was observed in 11 patients (22.92%), and diseased progressed in 13 patients (27.08%). Mean number of oxaliplatin cycles was 3 (0.5-6.5). Median time to progression was 177 days. Median overall survival was 318 days. Major-grade (III/IV) toxicities were diarrhea 25.5%, vomiting 16.5%, anemia 10.9%, numbness 12.7%, thrombocytopenia 7.3%, neutropenia 3.6% and leucopenia 1.8%. CONCLUSIONS: Biweekly, oxaliplatin combining oral tegafur-uracil/leucovorin in treating patients with advanced gastric cancer showed acceptable activity and manageable toxicity." ], "offsets": [ [ 0, 1854 ] ] } ]

[ { "id": "entity-142-0", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 125, 139 ] ], "normalized": [] }, { "id": "entity-142-1", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 313, 327 ] ], "normalized": [] }, { "id": "entity-142-2", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1554, 1562 ] ], "normalized": [] }, { "id": "entity-142-3", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 1570, 1578 ] ], "normalized": [] }, { "id": "entity-142-4", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 1586, 1592 ] ], "normalized": [] }, { "id": "entity-142-5", "type": "ADVERSE", "text": [ "numbness" ], "offsets": [ [ 1600, 1608 ] ], "normalized": [] }, { "id": "entity-142-6", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1616, 1632 ] ], "normalized": [] }, { "id": "entity-142-7", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1639, 1650 ] ], "normalized": [] }, { "id": "entity-142-8", "type": "ADVERSE", "text": [ "leucopenia" ], "offsets": [ [ 1660, 1670 ] ], "normalized": [] }, { "id": "entity-142-9", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 1788, 1802 ] ], "normalized": [] } ]

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[ { "id": "passage-143", "type": "abstract", "text": [ "Insulin glargine versus intermediate-acting insulin as the basal component of multiple daily injection regimens for adolescents with type 1 diabetes mellitus. OBJECTIVES: To compare long-acting insulin glargine (Lantus) with intermediate-acting insulin (neutral protamine Hagedorn [NPH]/Lente) when used as the basal component of a multiple daily injection (MDI) regimen with prandial insulin lispro (Humalog) in adolescents with type 1 diabetes mellitus (T1DM). STUDY DESIGN: This was an active-controlled, randomized, open-label, sex-stratified, 2-arm, parallel-group comparison of once-daily insulin glargine with twice-daily NPH/Lente in an MDI regimen. Changes in glycated hemoglobin A1C (A1C), occurrence of hypoglycemia, and adverse events were assessed in 175 patients (age 9 to 17 years) with T1DM. RESULTS: The overall mean change in A1C from baseline to week 24 was similar in the 2 groups: insulin glargine (n = 76), -0.25% +/- 0.14%; NPH/Lente (n = 81), 0.05% +/- 0.13% (P = .1725). However, an analysis of covariance, adjusting for baseline A1C, revealed a strong study arm effect on the slopes of the regression lines, indicating that the reduction in A1C was significantly greater with insulin glargine in those patients with higher baseline A1C values. The rate of confirmed glucose values <70 mg/dL was higher in the patients receiving insulin glargine (P = .0298). No differences in the rate of severe hypoglycemia (P = .1814) or the occurrence of glucose levels <50 mg/dL (P = .82) or <36 mg/dL (P = .32) were found between the 2 groups. CONCLUSIONS: Insulin glargine is well tolerated in MDI regimens for pediatric patients with T1DM and may be more efficacious than NPH/Lente in those with elevated A1C." ], "offsets": [ [ 0, 1726 ] ] } ]

[ { "id": "entity-143-0", "type": "DISEASE", "text": [ "type 1 diabetes mellitus" ], "offsets": [ [ 133, 157 ] ], "normalized": [] }, { "id": "entity-143-1", "type": "DISEASE", "text": [ "type 1 diabetes mellitus" ], "offsets": [ [ 431, 455 ] ], "normalized": [] }, { "id": "entity-143-2", "type": "DISEASE", "text": [ "T1DM" ], "offsets": [ [ 457, 461 ] ], "normalized": [] }, { "id": "entity-143-3", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 715, 727 ] ], "normalized": [] }, { "id": "entity-143-4", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 1422, 1434 ] ], "normalized": [] }, { "id": "entity-143-5", "type": "DISEASE", "text": [ "T1DM" ], "offsets": [ [ 1651, 1655 ] ], "normalized": [] } ]

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[ { "id": "passage-144", "type": "abstract", "text": [ "Novel therapies in lupus - focus on nephritis. Lupus nephritis (LN) is one of the major complications of Systemic Lupus Erythematosus (SLE) and its treatment remains a challenge. Although the classical and widely used immunosuppressive agents have accounted for a significant improvement in the survival and decreased the progression to end-stage renal failure they lack selectivity for the underlying immune dysregulation. In addition the toxicity related to their use and the relapses after treatment are of major concern not least because of the adverse effect on the prognosis of the patients with SLE who have kidney involvement. The development of more specific pharmacological agents for patients with SLE is still a major research goal. Ideally these agents should provide a better long-term prognosis for SLE patients and be less toxic. In this review we summarise the mechanism of action and the results obtained with a variety of drugs that have recently been utilized in the treatment of patients with lupus especially those with nephritis. We discuss the clinical usefulness of B- -cell depletion principally anti-CD20 antibodies blockage of co-stimulatory pathways (anti-CD40 ligand antibody CTLA4Ig) the induction of immune tolerance (LJP 394 peptide specific vaccination) and therapy targeting cytokines (anti-IL10 antibody BLyS blockage) and the complement system (anti-C5 antibody). Immunoablative doses of Cyclophosphamide (CyC) with or without Haematopoietic Stem Cell Transplantation (HSCT) and the possibilities of gene therapy are also reviewed. The use of intravenous immunoglobulin (IVIg) and plasmapheresis are not discussed because these treatments have been used in clinical practice for several years." ], "offsets": [ [ 0, 1731 ] ] } ]

[ { "id": "entity-144-0", "type": "DISEASE", "text": [ "nephritis" ], "offsets": [ [ 36, 45 ] ], "normalized": [] }, { "id": "entity-144-1", "type": "DISEASE", "text": [ "Lupus nephritis" ], "offsets": [ [ 48, 63 ] ], "normalized": [] }, { "id": "entity-144-2", "type": "DISEASE", "text": [ "LN" ], "offsets": [ [ 65, 67 ] ], "normalized": [] }, { "id": "entity-144-3", "type": "DISEASE", "text": [ "Systemic Lupus Erythematosus" ], "offsets": [ [ 106, 134 ] ], "normalized": [] }, { "id": "entity-144-4", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 136, 139 ] ], "normalized": [] }, { "id": "entity-144-5", "type": "DISEASE", "text": [ "renal failure" ], "offsets": [ [ 348, 361 ] ], "normalized": [] }, { "id": "entity-144-6", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 603, 606 ] ], "normalized": [] }, { "id": "entity-144-7", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 710, 713 ] ], "normalized": [] }, { "id": "entity-144-8", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 815, 818 ] ], "normalized": [] }, { "id": "entity-144-9", "type": "DISEASE", "text": [ "nephritis" ], "offsets": [ [ 1043, 1052 ] ], "normalized": [] } ]

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[ { "id": "passage-145", "type": "abstract", "text": [ "A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma. Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42-51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22-31%), constipation (37%, 95% CI 32-42%) and peripheral neuropathy (27%, 95% CI 23-32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3-8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy." ], "offsets": [ [ 0, 1050 ] ] } ]

[ { "id": "entity-145-0", "type": "DISEASE", "text": [ "refractory multiple myeloma" ], "offsets": [ [ 117, 144 ] ], "normalized": [] }, { "id": "entity-145-1", "type": "DISEASE", "text": [ "relapsed/refractory multiple myeloma" ], "offsets": [ [ 174, 210 ] ], "normalized": [] }, { "id": "entity-145-2", "type": "DISEASE", "text": [ "MM" ], "offsets": [ [ 212, 214 ] ], "normalized": [] }, { "id": "entity-145-3", "type": "DISEASE", "text": [ "relapsed/refractory MM" ], "offsets": [ [ 487, 509 ] ], "normalized": [] }, { "id": "entity-145-4", "type": "ADVERSE", "text": [ "Therapy-related toxicity" ], "offsets": [ [ 621, 645 ] ], "normalized": [] }, { "id": "entity-145-5", "type": "ADVERSE", "text": [ "somnolence" ], "offsets": [ [ 701, 711 ] ], "normalized": [] }, { "id": "entity-145-6", "type": "ADVERSE", "text": [ "constipation" ], "offsets": [ [ 734, 746 ] ], "normalized": [] }, { "id": "entity-145-7", "type": "ADVERSE", "text": [ "peripheral neuropathy" ], "offsets": [ [ 772, 793 ] ], "normalized": [] }, { "id": "entity-145-8", "type": "ADVERSE", "text": [ "venous thromboembolism" ], "offsets": [ [ 821, 843 ] ], "normalized": [] }, { "id": "entity-145-9", "type": "DISEASE", "text": [ "relapsed/refractory MM" ], "offsets": [ [ 967, 989 ] ], "normalized": [] } ]

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[ { "id": "passage-146", "type": "abstract", "text": [ "Bendamustine, but not fludarabine, exhibits a low stem cell toxicity in vitro. PURPOSE: We investigated the in vitro toxicity of bendamustine and fludarabine to hematopoietic progenitors and stem cells from healthy donors. METHODS: Clonogenic agar colony assays, non-clonogenic long-term liquid cultures (LTC) and apoptosis assays were used to assess the cytotoxicity of both the agents. RESULTS: Total colony-forming units (CFU) were more sensitive to fludarabine than to bendamustine in agar colony assays (IC(50) 0.7 microM/L and 8.5 microM/L, respectively). Using the Bliss independence model and combining the two agents yielded additive inhibition of progenitors. Non-clonogenic assays, including LTC and an apoptosis assay detecting activated caspases showed that stem cells are characterized by low sensitivity to bendamustine. In contrast, fludarabine strongly inhibited the viability and growth of stem cells in LTC. CONCLUSIONS: Our data show that bendamustine is characterized by lower in vitro toxicity to hematopoietic progenitors and stem cells than fludarabine and might thus be preferable in regimens prior to stem cells apheresis." ], "offsets": [ [ 0, 1149 ] ] } ]

[ { "id": "entity-146-0", "type": "ADVERSE", "text": [ "stem cell toxicity" ], "offsets": [ [ 50, 68 ] ], "normalized": [] }, { "id": "entity-146-1", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 356, 368 ] ], "normalized": [] } ]

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[ { "id": "passage-147", "type": "abstract", "text": [ "Lisdexamfetamine dimesylate for childhood ADHD. Stimulants are extremely effective and safe and have been the mainstay for the pharmacological treatment of attention deficit hyperactivity disorder (ADHD) for many years. However, there have been some concerns regarding their abuse, especially by teenagers and young adults. Lisdexamfetamine was recently approved for the treatment of ADHD in 6-12-year-olds and provides a novel approach to the treatment of ADHD. Lisdexamfetamine is a prodrug comprised of dextroamphetamine covalently attached to an essential amino acid, L-lysine. Following oral administration, the amide linkage between the two molecules is enzymatically hydrolyzed in the gastrointestinal tract, thus releasing active dextroamphetamine, which mediates the therapeutic effect in a fashion similar to other stimulants. The parent drug does not bind to sites responsible for the reuptake of norepinephrine and dopamine in vitro. Lisdexamfetamine does not produce high dextroamphetamine levels when injected or snorted, and thus may have lower abuse potential compared to conventional stimulants. Lisdexamfetamine appears to have efficacy and tolerability comparable to other extended-release stimulant formulations used to treat ADHD, but reduced potential for abuse-related liking effects. Compared to equivalent amounts of immediate-release dextroamphetamine." ], "offsets": [ [ 0, 1379 ] ] } ]

[ { "id": "entity-147-0", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 42, 46 ] ], "normalized": [] }, { "id": "entity-147-1", "type": "DISEASE", "text": [ "attention deficit hyperactivity disorder" ], "offsets": [ [ 157, 197 ] ], "normalized": [] }, { "id": "entity-147-2", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 199, 203 ] ], "normalized": [] }, { "id": "entity-147-3", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 385, 389 ] ], "normalized": [] }, { "id": "entity-147-4", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 458, 462 ] ], "normalized": [] }, { "id": "entity-147-5", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 1247, 1251 ] ], "normalized": [] } ]

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[ { "id": "passage-148", "type": "abstract", "text": [ "Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. Since the manufacture and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufactured nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were determined using the comet assay, and intracellular production of reactive oxygen species (ROS) was measured using the oxidation-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was observed, but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by soluble metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles." ], "offsets": [ [ 0, 2052 ] ] } ]

[ { "id": "entity-148-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 802, 814 ] ], "normalized": [] }, { "id": "entity-148-1", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1266, 1278 ] ], "normalized": [] }, { "id": "entity-148-2", "type": "ADVERSE", "text": [ "cytotoxic effects" ], "offsets": [ [ 1845, 1862 ] ], "normalized": [] } ]

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[ { "id": "passage-149", "type": "abstract", "text": [ "Down-regulation of asymmetric arginine methylation during replicative and H2O2-induced premature senescence in WI-38 human diploid fibroblasts. Protein arginine methylation is one of the post-translational modifications which yield monomethyl and dimethyl (asymmetric or symmetric) arginines in proteins. In the present study, we investigated the status of protein arginine methylation during human diploid fibroblast senescence. When the expression of protein arginine methyltransferases (PRMTs), namely PRMT1, PRMT4, PRMT5 and PRMT6 was examined, a significant reduction was found in replicatively senescent cells as well as their catalytic activities against histone mixtures compared with the young cells. Furthermore, when the endogenous level of arginine-dimethylated proteins was determined, asymmetric modification (the product of type I PRMTs including PRMT1, PRMT4 and PRMT6) was markedly down-regulated. In contrast, both up- and down-regulations of symmetrically arginine-methylated proteins (the product of type II PRMTs including PRMT5) during replicative senescence were found. Furthermore, when young fibroblasts were induced to premature senescence by sub-cytotoxic H2O2 treatment, results similar to replicative senescence were obtained. Finally, we found that SV40-mediated immortalized WI-38 and HeLa cell lines maintained a higher level of asymmetrically modified proteins as well as type I PRMTs than young fibroblasts. These results suggest that the maintenance of asymmetric modification in the expressed target proteins of type I PRMTs might be critical for cellular proliferation." ], "offsets": [ [ 0, 1607 ] ] } ]

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[ { "id": "passage-150", "type": "abstract", "text": [ "Anti-inflammatory activity of Crinum asiaticum Linne var. japonicum extract and its application as a cosmeceutical ingredient. Crinum asiaticum Linne var. japonicum has long been used as a rheumatic remedy, as an anti-pyretic and as an anti-ulcer treatment, and for the alleviation of local pain and fever in Korea and Malaysia. In order to investigate the possibility of Crinum asiaticum Linne var. japonicum extract as a cosmetic ingredient, we measured its anti-inflammatory effect by its inhibition of iNOS (inducible nitric oxide synthase) and the release of PGE2, IL-6, and IL-8. We also measured its anti-allergic effect by its inhibition of beta-hexosamidase release. An HPLC experiment after extraction with 95% EtOH at pH 3.5 showed that Crinum asiaticum Linne var. japonicum was mainly composed of lycorine (up to 1%), a well-known immunosuppressor. The content of lycorine varied, depending on the type of plant tissue analyzed and the extraction method. In an anti-inflammatory assay for inhibition of nitric oxide formation on lipopolysaccharide (LPS)-activated mouse macrophage RAW 264.7 cells, the ethanol extract of Crinum asiaticum showed an inhibitory activity of NO production in a dose-dependent manner (IC50 = 58.5 microg/ml). Additional study by RT-PCR demonstrated that the extract of Crinum asiaticum significantly suppressed the expression of the iNOS gene. Moreover, the extract of Crinum asiaticum did not show any cytotoxicity, but did show a cell proliferation effect against LPS (a 10 approximately 60% increase in cell viability). In an assay to determine inhibition of the H2O2-activated release of PGE2, IL-6, and IL-8 in human normal fibroblast cell lines, the release of PGE2 and IL-6 was almost completely inhibited above concentrations of 0.05% and 1%, respectively. Moreover, the release of IL-8 was completely inhibited over the entire range of concentration (>0.0025%). In order to investigate the skin-sensitizing potentials of the extract of Crinum asiaticum, a human clinical test was performed after repeated epicutaneous 48-h applications under an occlusive patch (RIPT). The repeated and single cutaneous applications of Crinum asiaticum Linne var. japonicum extract under the occlusive patch did not provoke any cumulative irritation and sensitization reactions. The result showed that the extract of Crinum asiaticum Linne var. japonicum has a sufficient anti-inflammatory effect. Therefore, Crinum asiaticum Linne var. japonicum extract may be useful for development as an ingredient in cosmetic products." ], "offsets": [ [ 0, 2556 ] ] } ]

[ { "id": "entity-150-0", "type": "DISEASE", "text": [ "local pain" ], "offsets": [ [ 286, 296 ] ], "normalized": [] }, { "id": "entity-150-1", "type": "DISEASE", "text": [ "fever" ], "offsets": [ [ 301, 306 ] ], "normalized": [] }, { "id": "entity-150-2", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1444, 1456 ] ], "normalized": [] } ]

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[ { "id": "passage-151", "type": "abstract", "text": [ "Acute interstitial nephritis due to deferasirox: a case report. Deferasirox is a new oral iron chelator used to treat transfusional iron overload. Pre-marketing clinical trials revealed little organ-specific toxicity. Increases in serum creatinine were noted in one-third of patients but were mild and non-progressive. We describe a 62-year-old man with myelodysplastic syndrome who developed a progressive decline in renal function after starting deferasirox. A kidney biopsy showed acute interstitial nephritis with increased eosinophils, suggesting drug hypersensitivity. Deferasirox was discontinued and renal function returned to baseline. This is the first pathological description of deferasirox-related acute kidney injury in humans, which differs from tubular vacuolization observed in animals." ], "offsets": [ [ 0, 804 ] ] } ]

[ { "id": "entity-151-0", "type": "ADVERSE", "text": [ "Acute interstitial nephritis" ], "offsets": [ [ 0, 28 ] ], "normalized": [] }, { "id": "entity-151-1", "type": "DISEASE", "text": [ "transfusional iron overload" ], "offsets": [ [ 119, 146 ] ], "normalized": [] }, { "id": "entity-151-2", "type": "ADVERSE", "text": [ "organ-specific toxicity" ], "offsets": [ [ 194, 217 ] ], "normalized": [] }, { "id": "entity-151-3", "type": "DISEASE", "text": [ "myelodysplastic syndrome" ], "offsets": [ [ 355, 379 ] ], "normalized": [] }, { "id": "entity-151-4", "type": "ADVERSE", "text": [ "progressive decline in renal function" ], "offsets": [ [ 396, 433 ] ], "normalized": [] }, { "id": "entity-151-5", "type": "ADVERSE", "text": [ "acute interstitial nephritis" ], "offsets": [ [ 485, 513 ] ], "normalized": [] }, { "id": "entity-151-6", "type": "ADVERSE", "text": [ "eosinophils" ], "offsets": [ [ 529, 540 ] ], "normalized": [] }, { "id": "entity-151-7", "type": "ADVERSE", "text": [ "drug hypersensitivity" ], "offsets": [ [ 553, 574 ] ], "normalized": [] }, { "id": "entity-151-8", "type": "ADVERSE", "text": [ "acute kidney injury" ], "offsets": [ [ 712, 731 ] ], "normalized": [] } ]

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[ { "id": "passage-152", "type": "abstract", "text": [ "Gluten ataxia. Gluten ataxia is an immune-mediated disease triggered by the ingestion of gluten in genetically susceptible individuals. It should be considered in the differential diagnosis of all patients with idiopathic sporadic ataxia. Early diagnosis and treatment with a gluten free diet can improve ataxia and prevent its progression. Readily available and sensitive markers of gluten ataxia include antigliadin antibodies. IgA deposits against TG2 in the small bowel and at extraintestinal sites are proving to be additional reliable and perhaps more specific markers of the whole spectrum of gluten sensitivity. They may also hold the key to its pathogenesis." ], "offsets": [ [ 0, 668 ] ] } ]

[ { "id": "entity-152-0", "type": "DISEASE", "text": [ "Gluten ataxia" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "entity-152-1", "type": "DISEASE", "text": [ "Gluten ataxia" ], "offsets": [ [ 16, 29 ] ], "normalized": [] }, { "id": "entity-152-2", "type": "DISEASE", "text": [ "idiopathic sporadic ataxia" ], "offsets": [ [ 212, 238 ] ], "normalized": [] }, { "id": "entity-152-3", "type": "DISEASE", "text": [ "ataxia" ], "offsets": [ [ 306, 312 ] ], "normalized": [] }, { "id": "entity-152-4", "type": "DISEASE", "text": [ "gluten ataxia" ], "offsets": [ [ 385, 398 ] ], "normalized": [] } ]

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[ { "id": "passage-153", "type": "abstract", "text": [ "Effect of the frequency of self-monitoring blood glucose in patients with type 2 diabetes treated with oral antidiabetic drugs-a multi-centre, randomized controlled trial. OBJECTIVE: Recommendations on the frequency of self-monitoring of blood glucose (SMBG) vary widely among physicians treating patients with type 2 diabetes (T2D). Aim of this study was to investigate two testing regimen of SMBG in patients with stable metabolic control. RESEARCH DESIGN AND METHODS: Patients with T2D treated with oral antidiabetic drugs were randomized to two groups: either one SMBG (low) or four SMBG (high) per week. Subjects were followed up after 3, 6 and 12 months. Primary outcome parameter was the change in HbA1c between baseline and 6 months. Primary outcome criterion was tested by a one-sided t- test for non- inferiority. Secondary outcome parameters were safety, compliance and HbA1c at 3 and 12 months. RESULTS: There were no differences in the 202 subjects for demographic and sociodemographic parameters and drug treatment. HbA(1)c (%) at baseline was similar in both groups (7.2+/-1.4 vs. 7.2+/-1.0). Non- inferiority was demonstrated for the low group (p = 0.0022) with a difference from baseline to 6 months of 0.24 in the low and of 0.16 in the high group. Compliance with the testing regimen was 82-90% in both groups. There were no statistical significant differences for compliance, HbA(1)c at 3 and 12 months and serious adverse events (SAE). CONCLUSION: One SMBG per week is as sufficient and safe as four SMBG per week to maintain HbA(1)c in non-insulin treated T2D close to metabolic target. The results of this study are in contrast to current international consensus guidelines. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN79164268." ], "offsets": [ [ 0, 1756 ] ] } ]

[ { "id": "entity-153-0", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 74, 89 ] ], "normalized": [] }, { "id": "entity-153-1", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 312, 327 ] ], "normalized": [] }, { "id": "entity-153-2", "type": "DISEASE", "text": [ "T2D" ], "offsets": [ [ 329, 332 ] ], "normalized": [] }, { "id": "entity-153-3", "type": "DISEASE", "text": [ "T2D" ], "offsets": [ [ 486, 489 ] ], "normalized": [] }, { "id": "entity-153-4", "type": "DISEASE", "text": [ "T2D" ], "offsets": [ [ 1579, 1582 ] ], "normalized": [] } ]

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[ { "id": "passage-154", "type": "abstract", "text": [ "Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women. RATIONALE: The pharmacokinetics and behavioral effects of isoallopregnanolone (3beta-hydoxy-5alpha-pregnan-20-one) in women are not known. OBJECTIVES: Allopregnanolone (3alpha-hydoxy-5alpha-pregnan-20-one) is a well-known neurosteroid, acting via the GABA(A) receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3beta-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA(A) receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA(A) receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans. MATERIALS AND METHODS: Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle. RESULTS: Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle. CONCLUSIONS: After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements." ], "offsets": [ [ 0, 1990 ] ] } ]

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[ { "id": "passage-155", "type": "abstract", "text": [ "Fragrance material review on l-borneol. A toxicologic and dermatologic review of l-borneol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 141 ] ] } ]

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[ { "id": "passage-156", "type": "abstract", "text": [ "In vitro evaluation of the chemoprotective action mechanisms of leontopodic acid against aflatoxin B1 and deoxynivalenol-induced cell damage. Several in vitro studies showed that free radical scavengers possess chemopreventive properties against mycotoxin-induced cell damage which are at least partially associated with the induction of phase II detoxifying enzymes and antioxidant enzymes like glutathione S-transferase (GST) and glutathione peroxidase (GPx). The aim of this project was to study the chemopreventive effects of leontopodic acid (LA), a potent natural occurring free radical scavenger isolated from the aerial parts of Leontopodium alpinum. Different mycotoxins were evaluated in two different cell lines on the basis of their specific toxicity: aflatoxin B1 (AFB1) on HepG2 cells and deoxynivalenol (DON) on U937 cells. Cell viability and reactive oxygen species concentration were determined, and the effects of pre-treatment with LA on these parameters were investigated together with the GST and GPx activity as well as the concentration of reduced glutathione. The results show that LA protects U937 cells from DON-induced cell damage but not HepG2 cells from AFB1. Moreover LA is able to enhance GPx activity in U937, but not GST activity in HepG2. We hypothesize that the increase in detoxifying enzymes is probably the main mechanism of antioxidant mediated chemoprevention." ], "offsets": [ [ 0, 1401 ] ] } ]

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[ { "id": "passage-157", "type": "abstract", "text": [ "Sibutramine: current status as an anti-obesity drug and its future perspectives. BACKGROUND: Obesity has become a global epidemic with recent estimates of > 400 million obese adults. Despite this, there are few safe and effective pharmacological interventions for obesity. Sibutramine is a weight loss agent, for use as an adjuvant to a comprehensive program of calorie restriction, exercise and behavioral therapy. OBJECTIVE: The goal of this article is to review the available literature of pharmacological interventions for obesity and specifically to examine data with sibutramine for the short term on safety and efficacy for weight loss. METHODS: The literature on sibutramine was reviewed after a PubMed and Medline search in March 2008. All randomized clinical trails were reviewed. RESULTS/CONCLUSIONS: Sibutramine appears to be safe and effective in producing clinically significant weight loss for up to 1 year. Longer prospective clinical studies with sibutramine are needed to evaluate its safety (effect on blood pressure) and ability to maintain weight loss, improve metabolic profiles and reduce the risk of cardiovascular diseases." ], "offsets": [ [ 0, 1149 ] ] } ]

[ { "id": "entity-157-0", "type": "DISEASE", "text": [ "Obesity" ], "offsets": [ [ 94, 101 ] ], "normalized": [] }, { "id": "entity-157-1", "type": "DISEASE", "text": [ "obesity" ], "offsets": [ [ 265, 272 ] ], "normalized": [] }, { "id": "entity-157-2", "type": "DISEASE", "text": [ "obesity" ], "offsets": [ [ 528, 535 ] ], "normalized": [] }, { "id": "entity-157-3", "type": "DISEASE", "text": [ "cardiovascular diseases" ], "offsets": [ [ 1125, 1148 ] ], "normalized": [] } ]

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[ { "id": "passage-158", "type": "abstract", "text": [ "Bisphosphonate-induced necrosis of the jaws: a reconstructive nightmare. PURPOSE OF REVIEW: Bisphosphonates are used for the management of metastatic bone disease, prevention and treatment of osteoporosis and Paget's disease of bone. An increasing number of reports have associated the use of bisphosphonates with the occurrence of osteoradionecrosis of the jaw. The purpose of this review is to summarize the recent literature in this area, specifically focusing on its management. RECENT FINDINGS: Osteoradionecrosis of the jaw mostly results from the use of intravenous bisphosphonates for metastatic bone disease and multiple myeloma; cases from oral treatment for osteoporosis and Paget's disease have also been reported. It mostly affects the posterior maxilla, followed by the posterior mandible. In more than half of the affected patients, there has been preceding dental trauma or procedure. Many treatment modalities have been attempted in order to limit disease progression. Conservative management with antibiotic therapy and mouthwashes seems to be most beneficial. Surgery should be reserved for refractory and symptomatic cases. SUMMARY: It is important for the reconstructive head and neck surgeon to recognize the clinical presentation of bisphosphonate-induced osteoradionecrosis of the jaw and the role of conservative management in consistently achieving good results." ], "offsets": [ [ 0, 1389 ] ] } ]

[ { "id": "entity-158-0", "type": "ADVERSE", "text": [ "necrosis of the jaws" ], "offsets": [ [ 23, 43 ] ], "normalized": [] }, { "id": "entity-158-1", "type": "DISEASE", "text": [ "metastatic bone disease" ], "offsets": [ [ 140, 163 ] ], "normalized": [] }, { "id": "entity-158-2", "type": "DISEASE", "text": [ "osteoporosis" ], "offsets": [ [ 193, 205 ] ], "normalized": [] }, { "id": "entity-158-3", "type": "DISEASE", "text": [ "Paget's disease" ], "offsets": [ [ 210, 225 ] ], "normalized": [] }, { "id": "entity-158-4", "type": "ADVERSE", "text": [ "osteoradionecrosis of the jaw" ], "offsets": [ [ 333, 362 ] ], "normalized": [] }, { "id": "entity-158-5", "type": "ADVERSE", "text": [ "Osteoradionecrosis of the jaw" ], "offsets": [ [ 501, 530 ] ], "normalized": [] }, { "id": "entity-158-6", "type": "DISEASE", "text": [ "metastatic bone disease" ], "offsets": [ [ 594, 617 ] ], "normalized": [] }, { "id": "entity-158-7", "type": "DISEASE", "text": [ "multiple myeloma" ], "offsets": [ [ 622, 638 ] ], "normalized": [] }, { "id": "entity-158-8", "type": "DISEASE", "text": [ "osteoporosis" ], "offsets": [ [ 670, 682 ] ], "normalized": [] }, { "id": "entity-158-9", "type": "DISEASE", "text": [ "Paget's disease" ], "offsets": [ [ 687, 702 ] ], "normalized": [] }, { "id": "entity-158-10", "type": "DISEASE", "text": [ "dental trauma" ], "offsets": [ [ 874, 887 ] ], "normalized": [] }, { "id": "entity-158-11", "type": "ADVERSE", "text": [ "osteoradionecrosis of the jaw" ], "offsets": [ [ 1280, 1309 ] ], "normalized": [] } ]

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[ { "id": "passage-159", "type": "abstract", "text": [ "Pharmacokinetic interaction between everolimus and antifungal triazoles in a liver transplant patient. OBJECTIVE: To describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. CASE SUMMARY: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (C(min)) of everolimus was achieved (approximately 5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus C(min) averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, C(min) reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean +/- SD, 3.49 +/- 0.29 vs 11.05 +/- 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patient's condition continued to deteriorate and he died on day 84 posttransplant. DISCUSSION: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The interaction is due to the inhibition of CYP3A4-mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. CONCLUSIONS: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment." ], "offsets": [ [ 0, 2446 ] ] } ]

[ { "id": "entity-159-0", "type": "ADVERSE", "text": [ "iatrogenic retroperitoneal duodenal perforation" ], "offsets": [ [ 398, 445 ] ], "normalized": [] }, { "id": "entity-159-1", "type": "ADVERSE", "text": [ "sepsis" ], "offsets": [ [ 524, 530 ] ], "normalized": [] }, { "id": "entity-159-2", "type": "ADVERSE", "text": [ "acute renal failure" ], "offsets": [ [ 535, 554 ] ], "normalized": [] }, { "id": "entity-159-3", "type": "ADVERSE", "text": [ "impaired renal function" ], "offsets": [ [ 635, 658 ] ], "normalized": [] }, { "id": "entity-159-4", "type": "ADVERSE", "text": [ "nephrotoxicity" ], "offsets": [ [ 702, 716 ] ], "normalized": [] }, { "id": "entity-159-5", "type": "ADVERSE", "text": [ "invasive aspergillosis" ], "offsets": [ [ 991, 1013 ] ], "normalized": [] }, { "id": "entity-159-6", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 1161, 1174 ] ], "normalized": [] } ]

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[ { "id": "passage-160", "type": "abstract", "text": [ "An update on clinical drug interactions with the herbal antidepressant St. John's wort. St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. Limited clinical trials suggest that hypericum and standard antidepressants have similar beneficial effects, but current evidence regarding the antidepression effects of SJW extracts is inconsistent. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs. This review highlights and updates the knowledge regarding drug interactions with SJW by a systematic review of all the available evidence, including worldwide published literature and spontaneous case reports. A number of clinically significant interactions of SJW have been identified with conventional drugs. These interactions often result in a decrease in the concentration or effect of the combined drug, most probably due to the induction of cytochrome P450s (CYPs) and the key drug transporter P-glycoprotein (P-gp) by the major active constituents in SJW. SJW is a potent inducer of human CYP3A4 and P-gp in vitro and in vivo. In addition, pharmacodynamic interactions of SJW with some drugs (e.g. selective serotonin re-uptake inhibitors) have been identified, which are associated with an increased risk of adverse reactions. Since potential interactions of SJW with conventional drugs is a major safety concern, it is important to minimize and avoid these interactions by taking appropriate approaches. These include systematic research to identify SJW-drug interaction; close therapeutic drug monitoring when SJW is combined with conventional drugs with a narrow therapeutic window; proper dose and regimen adjustment; patient education and communication between the patient and physician; design of new preparations of SJW without inducing ability of CYP3A4 and P-gp while retaining its bioactivity; and appropriate regulation in herbal safety and efficacy. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and clinical significance." ], "offsets": [ [ 0, 2201 ] ] } ]

[ { "id": "entity-160-0", "type": "DISEASE", "text": [ "depression" ], "offsets": [ [ 228, 238 ] ], "normalized": [] } ]

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[ { "id": "passage-161", "type": "abstract", "text": [ "Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth. Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity." ], "offsets": [ [ 0, 1617 ] ] } ]

[ { "id": "entity-161-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 102, 114 ] ], "normalized": [] }, { "id": "entity-161-1", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 142, 147 ] ], "normalized": [] }, { "id": "entity-161-2", "type": "DISEASE", "text": [ "neuroblastoma" ], "offsets": [ [ 1370, 1383 ] ], "normalized": [] }, { "id": "entity-161-3", "type": "DISEASE", "text": [ "small cell carcinoma" ], "offsets": [ [ 1385, 1405 ] ], "normalized": [] }, { "id": "entity-161-4", "type": "DISEASE", "text": [ "medulloblastoma" ], "offsets": [ [ 1410, 1425 ] ], "normalized": [] }, { "id": "entity-161-5", "type": "ADVERSE", "text": [ "chemotherapeutic toxicity" ], "offsets": [ [ 1591, 1616 ] ], "normalized": [] } ]

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[ { "id": "passage-162", "type": "abstract", "text": [ "Phase II study of 9-aminocamptothecin in previously treated lymphomas: results of Cancer and Leukemia Group B 9551. PURPOSE: To evaluate the efficacy and toxicity of the topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), in patients with relapsed lymphoma and to correlate 9-AC plasma concentrations with response and toxicity. METHODS: Eligible patients had relapsed Hodgkin lymphoma (HL) treated with one or two prior regimens, low grade non-Hodgkin's lymphoma (NHL) treated with one or two prior regimens, or aggressive NHL treated with one prior regimen. The first nine patients received 9-AC dimethylacetamide 0.85 mg/m(2) per day intravenously over 72 h every 2 weeks and the remaining 27 patients received 9-AC/colloidal dispersion 1.1 mg/m(2) per day. Patients received a minimum of three cycles unless progression or intolerable toxicity occurred. Responding patients received two cycles past best response with a minimum of six cycles. RESULTS: CALGB 9551 accrued 37 patients from April 1996 through October 2000; one patient with HD, 18 patients with indolent lymphoma, and 17 patients with aggressive lymphoma. The overall response rate was 17%, with response rates of 11% (2 partial responses) in patients with indolent histologies and 23% (1 complete response, 3 partial responses) in patients with aggressive histologies. The patient with HD did not respond. Response rates were similar for both drug formulations. The median remission duration for the six responders was 6.5 months, with one remission lasting longer than 12 months. Significant grade 3 and 4 toxicities included neutropenia (66%), anemia (31%), and thrombocytopenia (36%), with 20% of patients experiencing grade 3 or 4 infection. No treatment related deaths occurred. Steady state serum concentrations did not correlate with patient response or toxicity. CONCLUSION: Single agent 9-AC has modest activity in aggressive non-Hodgkin's lymphomas." ], "offsets": [ [ 0, 1932 ] ] } ]

[ { "id": "entity-162-0", "type": "DISEASE", "text": [ "lymphomas" ], "offsets": [ [ 60, 69 ] ], "normalized": [] }, { "id": "entity-162-1", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 82, 88 ] ], "normalized": [] }, { "id": "entity-162-2", "type": "DISEASE", "text": [ "Leukemia" ], "offsets": [ [ 93, 101 ] ], "normalized": [] }, { "id": "entity-162-3", "type": "DISEASE", "text": [ "relapsed lymphoma" ], "offsets": [ [ 243, 260 ] ], "normalized": [] }, { "id": "entity-162-4", "type": "DISEASE", "text": [ "relapsed Hodgkin lymphoma" ], "offsets": [ [ 364, 389 ] ], "normalized": [] }, { "id": "entity-162-5", "type": "DISEASE", "text": [ "HL" ], "offsets": [ [ 391, 393 ] ], "normalized": [] }, { "id": "entity-162-6", "type": "DISEASE", "text": [ "non-Hodgkin's lymphoma" ], "offsets": [ [ 445, 467 ] ], "normalized": [] }, { "id": "entity-162-7", "type": "DISEASE", "text": [ "NHL" ], "offsets": [ [ 469, 472 ] ], "normalized": [] }, { "id": "entity-162-8", "type": "DISEASE", "text": [ "NHL" ], "offsets": [ [ 528, 531 ] ], "normalized": [] }, { "id": "entity-162-9", "type": "DISEASE", "text": [ "HD" ], "offsets": [ [ 1046, 1048 ] ], "normalized": [] }, { "id": "entity-162-10", "type": "DISEASE", "text": [ "lymphoma" ], "offsets": [ [ 1076, 1084 ] ], "normalized": [] }, { "id": "entity-162-11", "type": "DISEASE", "text": [ "lymphoma" ], "offsets": [ [ 1118, 1126 ] ], "normalized": [] }, { "id": "entity-162-12", "type": "DISEASE", "text": [ "HD" ], "offsets": [ [ 1359, 1361 ] ], "normalized": [] }, { "id": "entity-162-13", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1600, 1611 ] ], "normalized": [] }, { "id": "entity-162-14", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 1619, 1625 ] ], "normalized": [] }, { "id": "entity-162-15", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1637, 1653 ] ], "normalized": [] }, { "id": "entity-162-16", "type": "ADVERSE", "text": [ "infection" ], "offsets": [ [ 1708, 1717 ] ], "normalized": [] }, { "id": "entity-162-17", "type": "DISEASE", "text": [ "non-Hodgkin's lymphomas" ], "offsets": [ [ 1908, 1931 ] ], "normalized": [] } ]

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[ { "id": "passage-163", "type": "abstract", "text": [ "Safe use of rectal suppositories and enemas with adult patients. Medications that are given via the rectal route are prescribed for a variety of reasons and have either a local or systemic effect. The administration of suppositories and enemas is an intimate procedure which has the potential to cause embarrassment and discomfort for the patient. This article outlines the reasons for the use of rectal medications and recommends a procedure to be followed when giving them." ], "offsets": [ [ 0, 476 ] ] } ]

[ { "id": "entity-163-0", "type": "ADVERSE", "text": [ "embarrassment" ], "offsets": [ [ 303, 316 ] ], "normalized": [] }, { "id": "entity-163-1", "type": "ADVERSE", "text": [ "discomfort" ], "offsets": [ [ 321, 331 ] ], "normalized": [] } ]

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[ { "id": "passage-164", "type": "abstract", "text": [ "Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. PURPOSE: The toxicity of radiotherapy (RT) combined with weekly carboplatin and adjuvant carboplatin and etoposide was prospectively assessed in a group of patients with high-risk Stage I and II Merkel cell carcinoma of the skin. This regimen was compared with the Trans-Tasman Radiation Oncology Group 96:07 study, which used identical eligibility criteria but carboplatin and etoposide every 3 weeks during RT. PATIENTS AND METHODS: Patients were eligible if they had disease localized to the primary site and lymph nodes, with high-risk features. RT was delivered to the primary site and lymph nodes to a dose of 50 Gy and weekly carboplatin (area under the curve of 2) was given during RT. This was followed by three cycles of carboplatin and etoposide. A total of 18 patients were entered into the study, and their data were compared with the data from 53 patients entered into the Trans-Tasman Radiation Oncology Group 96:07 study. RESULTS: Involved lymph nodes (Stage II) were present in 14 patients (77%). Treatment was completed as planned in 16 patients. The weekly carboplatin dose was delivered in 17 patients, and 15 were able to complete all three cycles of adjuvant carboplatin and etoposide. Grade 3 and 4 neutrophil toxicity occurred in 7 patients, but no cases of febrile neutropenia developed. Compared with the Trans-Tasman Radiation Oncology Group 96:07 protocol (19 of 53 cases of febrile neutropenia), the reduction in the febrile neutropenia rate (p = 0.003) and decrease in Grade 3 skin toxicity (p = 0.006) were highly statistically significant. CONCLUSION: The results of our study have shown that weekly carboplatin at this dosage is a safe way to deliver synchronous chemotherapy during RT for MCC and results in a marked reduction of febrile neutropenia and Grade 3 skin toxicity compared with the three weekly regimen." ], "offsets": [ [ 0, 1958 ] ] } ]

[ { "id": "entity-164-0", "type": "DISEASE", "text": [ "Merkel cell carcinoma of skin" ], "offsets": [ [ 77, 106 ] ], "normalized": [] }, { "id": "entity-164-1", "type": "DISEASE", "text": [ "Merkel cell carcinoma of the skin" ], "offsets": [ [ 304, 337 ] ], "normalized": [] }, { "id": "entity-164-2", "type": "ADVERSE", "text": [ "neutrophil toxicity" ], "offsets": [ [ 1331, 1350 ] ], "normalized": [] }, { "id": "entity-164-3", "type": "ADVERSE", "text": [ "febrile neutropenia" ], "offsets": [ [ 1391, 1410 ] ], "normalized": [] }, { "id": "entity-164-4", "type": "ADVERSE", "text": [ "febrile neutropenia" ], "offsets": [ [ 1512, 1531 ] ], "normalized": [] }, { "id": "entity-164-5", "type": "ADVERSE", "text": [ "febrile neutropenia" ], "offsets": [ [ 1555, 1574 ] ], "normalized": [] }, { "id": "entity-164-6", "type": "ADVERSE", "text": [ "skin toxicity" ], "offsets": [ [ 1616, 1629 ] ], "normalized": [] }, { "id": "entity-164-7", "type": "ADVERSE", "text": [ "febrile neutropenia" ], "offsets": [ [ 1873, 1892 ] ], "normalized": [] }, { "id": "entity-164-8", "type": "ADVERSE", "text": [ "skin toxicity" ], "offsets": [ [ 1905, 1918 ] ], "normalized": [] } ]

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[ { "id": "passage-165", "type": "abstract", "text": [ "Considerations on the physiopathological mechanism of inner ear damage induced by intravenous cocaine abuse: cues from a case report. OBJECTIVE: Aim of the following paper is to discuss about the possible etiopathogenetic mechanisms of inner ear damage induced by cocaine abuse. Unfortunately the data concerning this topic are very limited; the authors are then presenting a literature review, also discussing the clinical presentation and the possible therapeutical approach of a clinical case of bilateral sudden sensorineural hearing loss following i.v. injection of cocaine. PATIENTS: Case report. INTERVENTION: A strictly audiological evaluation has been performed, in order to identify the cochlear lesion site(s) and to provide the best medical treatment. CONCLUSIONS: To our knowledge, this is the first report of acute cocaine intoxication with sudden bilateral hearing loss. Further studies are required in order to understand the effects of these substances on the inner ear cells and metabolism." ], "offsets": [ [ 0, 1009 ] ] } ]

[ { "id": "entity-165-0", "type": "ADVERSE", "text": [ "inner ear damage" ], "offsets": [ [ 54, 70 ] ], "normalized": [] }, { "id": "entity-165-1", "type": "ADVERSE", "text": [ "inner ear damage" ], "offsets": [ [ 237, 253 ] ], "normalized": [] }, { "id": "entity-165-2", "type": "ADVERSE", "text": [ "bilateral sudden sensorineural hearing loss" ], "offsets": [ [ 500, 543 ] ], "normalized": [] }, { "id": "entity-165-3", "type": "ADVERSE", "text": [ "acute cocaine intoxication" ], "offsets": [ [ 824, 850 ] ], "normalized": [] }, { "id": "entity-165-4", "type": "ADVERSE", "text": [ "bilateral hearing loss" ], "offsets": [ [ 863, 885 ] ], "normalized": [] } ]

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[ { "id": "passage-166", "type": "abstract", "text": [ "Lithium overdose with electrocardiogram changes suggesting ischemia. BACKGROUND: Lithium toxicity is associated with electrocardiogram (ECG) changes, but changes suggestive of an ST segment elevation myocardial infarction have not been reported. CASE REPORT: A 46-year-old incarcerated man suffering from diabetes, hypertension, and schizoaffective/bipolar disorder was treated with lithium 1,200 mg twice daily. Two days prior to presentation the patient became confused, ataxic, and anorexic in jail. Lithium level was 4.69 mmol/L. He was transferred to the emergency department. On arrival, vital signs were normal. The ECG showed a normal sinus rhythm. ST segments were elevated in the anterior leads with downward concavity. T waves were biphasic. Since these changes suggested cardiac ischemia and the patient was unable to respond to questions about chest pain, cardiac enzymes and an emergent echocardiogram were done. Troponin I was less than 0.1 microg/L. Echocardiogram was normal, without wall motion abnormalities. Treatment was with hemodialysis and whole-bowel irrigation. Postdialysis lithium level was 1.30 mmol/L. Over the next several days, electrocardiogram normalized. His speech gradually became coherent. After a 1-week hospitalization, he returned to jail. CONCLUSION: Lithium intoxication can cause transient ST segment elevations suggesting an acute myocardial infarction. In the absence of a clear history, echocardiogram and cardiac enzymes can be used to rule out a myocardial infarction." ], "offsets": [ [ 0, 1518 ] ] } ]

[ { "id": "entity-166-0", "type": "ADVERSE", "text": [ "ischemia" ], "offsets": [ [ 59, 67 ] ], "normalized": [] }, { "id": "entity-166-1", "type": "ADVERSE", "text": [ "Lithium toxicity" ], "offsets": [ [ 82, 98 ] ], "normalized": [] }, { "id": "entity-166-2", "type": "DISEASE", "text": [ "ST segment elevation myocardial infarction" ], "offsets": [ [ 180, 222 ] ], "normalized": [] }, { "id": "entity-166-3", "type": "DISEASE", "text": [ "diabetes" ], "offsets": [ [ 306, 314 ] ], "normalized": [] }, { "id": "entity-166-4", "type": "DISEASE", "text": [ "hypertension" ], "offsets": [ [ 316, 328 ] ], "normalized": [] }, { "id": "entity-166-5", "type": "DISEASE", "text": [ "bipolar disorder" ], "offsets": [ [ 350, 366 ] ], "normalized": [] }, { "id": "entity-166-6", "type": "DISEASE", "text": [ "cardiac ischemia" ], "offsets": [ [ 784, 800 ] ], "normalized": [] }, { "id": "entity-166-7", "type": "DISEASE", "text": [ "chest pain" ], "offsets": [ [ 858, 868 ] ], "normalized": [] }, { "id": "entity-166-8", "type": "ADVERSE", "text": [ "Lithium intoxication" ], "offsets": [ [ 1294, 1314 ] ], "normalized": [] }, { "id": "entity-166-9", "type": "ADVERSE", "text": [ "acute myocardial infarction" ], "offsets": [ [ 1371, 1398 ] ], "normalized": [] }, { "id": "entity-166-10", "type": "DISEASE", "text": [ "myocardial infarction" ], "offsets": [ [ 1496, 1517 ] ], "normalized": [] } ]

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[ { "id": "passage-167", "type": "abstract", "text": [ "Adverse effects of antiepileptic drugs. Adverse effects of antiepileptic drugs (AEDs) are considered by patients to be at least as important as repetitive seizures in terms of quality of life. AED toxicity is frequent and contributes to a high proportion of treatment failures. Despite its high prevalence and clinical relevance, screening for adverse reactions to AEDs is not systematically included in everyday clinical practice; therefore it is very likely that it remains underestimated. Because there is little difference among AEDs in terms of efficacy, drug selection is often based on the adverse effects profile. AED toxicity is classified according to different parameters, such as severity, time of occurrence, organ system involvement, and mechanisms of action. Although most toxic reactions to drugs can be predicted from cumulative experience, prevention is not always possible, since multiple mechanisms and individual susceptibility to each drug participate in the final outcome. However, adverse effects can be reduced and appropriate action can be taken in time by means of a high degree of suspicion, knowledge of risk factors, and close follow-up. This article highlights factors to consider for detecting and managing AED adverse effects." ], "offsets": [ [ 0, 1260 ] ] } ]

[ { "id": "entity-167-0", "type": "DISEASE", "text": [ "repetitive seizures" ], "offsets": [ [ 145, 164 ] ], "normalized": [] }, { "id": "entity-167-1", "type": "ADVERSE", "text": [ "AED toxicity" ], "offsets": [ [ 194, 206 ] ], "normalized": [] }, { "id": "entity-167-2", "type": "ADVERSE", "text": [ "AED toxicity" ], "offsets": [ [ 623, 635 ] ], "normalized": [] } ]

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[ { "id": "passage-168", "type": "abstract", "text": [ "Influence of nonsteroidal anti-inflammatory drugs on osseointegration. This paper reviews contemporary literature concerning the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on osseointegration. In vitro studies concerning the effect of NSAIDs on growth factors and bone-generating cells are the primary source of data pertaining to this issue because relatively few in vivo studies have been conducted. It is concluded that prescribing NSAIDs during the early postoperative period is likely not without negative effect, although any negative influence appears to be temporary and does not affect the final outcome of osseointegration." ], "offsets": [ [ 0, 659 ] ] } ]

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[ { "id": "passage-169", "type": "abstract", "text": [ "Drug-induced urinary incontinence. Physiological urinary continence depends on many factors that are potentially vulnerable to adverse drug effects, which may lead to incontinence. In principle, drugs could cause incontinence by lowering bladder outlet resistance and/or by increasing intravesical pressure, which disrupts the normal pressure relationship between the bladder and urethra and leads to urinary leakage; other possibilities include disturbances of central nervous control of voiding or an overproduction of urine. While many drug groups could theoretically induce urinary incontinence based upon pathophysiological considerations, evidence demonstrating a cause-effect relationship between drug usage and incontinence is sparse. Drug classes in which induction of incontinence has been proposed include alpha(1)-adrenoceptor antagonists, antipsychotics, benzodiazepines, antidepressants and hormone replacement therapy in postmenopausal women. However, other drug classes are not innocent in terms of causing urinary incontinence and physicians are well advised to closely monitor patients for the occurrence of incontinence after new prescriptions and/or major dosage changes." ], "offsets": [ [ 0, 1192 ] ] } ]

[ { "id": "entity-169-0", "type": "ADVERSE", "text": [ "urinary incontinence" ], "offsets": [ [ 13, 33 ] ], "normalized": [] }, { "id": "entity-169-1", "type": "ADVERSE", "text": [ "incontinence" ], "offsets": [ [ 168, 180 ] ], "normalized": [] }, { "id": "entity-169-2", "type": "ADVERSE", "text": [ "incontinence" ], "offsets": [ [ 214, 226 ] ], "normalized": [] }, { "id": "entity-169-3", "type": "ADVERSE", "text": [ "urinary incontinence" ], "offsets": [ [ 579, 599 ] ], "normalized": [] }, { "id": "entity-169-4", "type": "ADVERSE", "text": [ "incontinence" ], "offsets": [ [ 720, 732 ] ], "normalized": [] }, { "id": "entity-169-5", "type": "ADVERSE", "text": [ "incontinence" ], "offsets": [ [ 779, 791 ] ], "normalized": [] }, { "id": "entity-169-6", "type": "ADVERSE", "text": [ "urinary incontinence" ], "offsets": [ [ 1024, 1044 ] ], "normalized": [] }, { "id": "entity-169-7", "type": "ADVERSE", "text": [ "incontinence" ], "offsets": [ [ 1127, 1139 ] ], "normalized": [] } ]

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[ { "id": "passage-170", "type": "abstract", "text": [ "The effect of implementing computerized provider order entry on medication prescribing errors in an emergency department. Medication errors are a major concern in the Emergency Department (ED). We examined medication prescribing errors among consecutive adult ED patients during two 10-day periods before and during one 9-day period after implementing computerized provider order entry in an adult ED. 2,073 patients had 5,950, orders. Before (after) implementation there were 3.7 (2.8) potential adverse drug events, 222.0 (21.0) medication prescribing errors, and 5.1 (0) rule violations per 100 orders." ], "offsets": [ [ 0, 606 ] ] } ]

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[ { "id": "passage-171", "type": "abstract", "text": [ "A phase II trial of gemcitabine plus capecitabine for metastatic renal cell cancer previously treated with immunotherapy and targeted agents. PURPOSE: We assessed the clinical activity and safety of gemcitabine plus capecitabine in patients with metastatic renal cell cancer previously treated with immunotherapy. MATERIALS AND METHODS: In this phase II trial patients received 1,000 mg/m(2) gemcitabine intravenously on days 1, 8 and 15, plus 830 mg/m(2) capecitabine orally twice daily on days 1 to 21 of 28-day cycles. The primary end point was progression-free survival time. Secondary end points included overall survival time, objective response rate and toxicity. RESULTS: Of 84 patients enrolled 83 were evaluable for response and toxicity. A total of 65 patients had intermediate or poor risk prognosis. Median progression-free survival and overall survival were 4.6 (95% CI 3.7-7.3) and 17.9 months (95% CI 13.2-23.6), respectively. There were 6 partial responses and 1 complete response (objective response rate 8.4% [95% CI 3.5-16.6]). Two patients remain in unmaintained remission close to 3 years from the initiation of gemcitabine plus capecitabine treatment. On multivariate analysis more than 3 disease sites were significantly associated with shorter progression-free survival and patients with thrombocytosis, more than 3 disease sites or anemia had a significantly increased risk of death. Adverse events occurring at least once in more than 5% of patients included grade 3 or greater neutropenia (83%), grade 2 or greater hand-foot syndrome (13%), grade 3 or greater thrombocytopenia (12%), grade 3 or greater thromboembolic events (8%), grade 3 or greater fatigue (8%) and grade 2 or greater mucositis (6%). CONCLUSIONS: At the doses and schedule tested gemcitabine plus capecitabine demonstrated modest clinical activity in metastatic renal cell cancer after cytokine failure and produced significant neutropenia. A modified gemcitabine plus capecitabine regimen may be evaluated in patients with metastatic renal cell cancer after failure of approved targeted therapies." ], "offsets": [ [ 0, 2095 ] ] } ]

[ { "id": "entity-171-0", "type": "DISEASE", "text": [ "metastatic renal cell cancer" ], "offsets": [ [ 54, 82 ] ], "normalized": [] }, { "id": "entity-171-1", "type": "DISEASE", "text": [ "metastatic renal cell cancer" ], "offsets": [ [ 247, 275 ] ], "normalized": [] }, { "id": "entity-171-2", "type": "DISEASE", "text": [ "thrombocytosis" ], "offsets": [ [ 1314, 1328 ] ], "normalized": [] }, { "id": "entity-171-3", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 1359, 1365 ] ], "normalized": [] }, { "id": "entity-171-4", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1506, 1517 ] ], "normalized": [] }, { "id": "entity-171-5", "type": "ADVERSE", "text": [ "hand-foot syndrome" ], "offsets": [ [ 1544, 1562 ] ], "normalized": [] }, { "id": "entity-171-6", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1589, 1605 ] ], "normalized": [] }, { "id": "entity-171-7", "type": "ADVERSE", "text": [ "thromboembolic events" ], "offsets": [ [ 1632, 1653 ] ], "normalized": [] }, { "id": "entity-171-8", "type": "ADVERSE", "text": [ "fatigue" ], "offsets": [ [ 1679, 1686 ] ], "normalized": [] }, { "id": "entity-171-9", "type": "ADVERSE", "text": [ "mucositis" ], "offsets": [ [ 1715, 1724 ] ], "normalized": [] }, { "id": "entity-171-10", "type": "DISEASE", "text": [ "metastatic renal cell cancer" ], "offsets": [ [ 1848, 1876 ] ], "normalized": [] }, { "id": "entity-171-11", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1925, 1936 ] ], "normalized": [] }, { "id": "entity-171-12", "type": "DISEASE", "text": [ "metastatic renal cell cancer" ], "offsets": [ [ 2021, 2049 ] ], "normalized": [] } ]

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[ { "id": "passage-172", "type": "abstract", "text": [ "Pulmonary toxicity associated with vinorelbine-based chemotherapy in breast cancer. A 41-year-old woman had undergone a left mastectomy breast cancer three years prior to presentation. No for at six months she had recurrence, this time in the right breast and skin. Despite first-and second-line chemotherapy, the mass showed progression of the disease. Thereafter, a weekly treatment of vinorelbine and trastuzumab was started, but one month later, she developed a slight fever and dry cough. A chest CT scan revealed an infiltration shadow showing non-specific interstitial pattern in the right lung. A bronchoscopic examination showed lymphocyte dominance in bronchial lavage fluid, and lymphocyte infiltration into the interstium with fibrosis in the tissue specimens was found by transbronchial lung biopsy. After discontinuing the above vinorelbine therapy, the patient's condition improved. We therefore diagnosed this as a case of vinorelbine-and trastuzumab-induced interstitial pneumonia." ], "offsets": [ [ 0, 999 ] ] } ]

[ { "id": "entity-172-0", "type": "ADVERSE", "text": [ "Pulmonary toxicity" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "entity-172-1", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 69, 82 ] ], "normalized": [] }, { "id": "entity-172-2", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 137, 150 ] ], "normalized": [] }, { "id": "entity-172-3", "type": "ADVERSE", "text": [ "fever" ], "offsets": [ [ 474, 479 ] ], "normalized": [] }, { "id": "entity-172-4", "type": "ADVERSE", "text": [ "dry cough" ], "offsets": [ [ 484, 493 ] ], "normalized": [] }, { "id": "entity-172-5", "type": "DISEASE", "text": [ "fibrosis" ], "offsets": [ [ 740, 748 ] ], "normalized": [] }, { "id": "entity-172-6", "type": "ADVERSE", "text": [ "interstitial pneumonia" ], "offsets": [ [ 976, 998 ] ], "normalized": [] } ]

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[ { "id": "passage-173", "type": "abstract", "text": [ "Comparison of oxime reactivation and aging of nerve agent-inhibited monkey and human acetylcholinesterases. Non-human primates are valuable animal models that are used for the evaluation of nerve agent toxicity as well as antidotes and results from animal experiments are extrapolated to humans. It has been demonstrated that the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited acetylcholinesterase (AChE). If the in vitro oxime reactivation of nerve agent-inhibited animal AChE is similar to that of human AChE, it is likely that the results of an in vivo animal study will reliably extrapolate to humans. Therefore, the goal of this study was to compare the aging and reactivation of human and different monkey (Rhesus, Cynomolgus, and African Green) AChEs inhibited by GF, GD, and VR. The oximes examined include the traditional oxime 2-PAM, two H-oximes HI-6 and HLo-7, and the new candidate oxime MMB4. Results indicate that oxime reactivation of all three monkey AChEs was very similar to human AChE. The maximum difference in the second-order reactivation rate constant between human and three monkey AChEs or between AChEs from different monkey species was 5-fold. Aging rate constants of GF-, GD-, and VR-inhibited monkey AChEs were very similar to human AChE except for GF-inhibited monkey AChEs, which aged 2-3 times faster than the human enzyme. The results of this study suggest that all three monkey species are suitable animal models for nerve agent antidote evaluation since monkey AChEs possess similar biochemical/pharmacological properties to human AChE." ], "offsets": [ [ 0, 1616 ] ] } ]

[ { "id": "entity-173-0", "type": "ADVERSE", "text": [ "nerve agent toxicity" ], "offsets": [ [ 191, 211 ] ], "normalized": [] } ]

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[ { "id": "passage-174", "type": "abstract", "text": [ "The impact of olanzapine on tardive dyskinetic symptoms in a state hospital population. BACKGROUND: Tardive dyskinesia is a serious adverse event, which is associated mainly with the use of the first-generation antipsychotic agents. Convergent data from clinical trials suggest that second-generation antipsychotic agents are less likely to cause tardive dyskinesia. However, the data with regard to the effect of switching from first- to second-generation antipsychotic agents on pre-existing dyskinetic symptoms during routine clinical care is sparse. METHODS: Sixty-three patients with DSM-IV schizophrenia or schizoaffective disorder (n = 61) or bipolar I disorder (n = 2) consecutively admitted to a state hospital, who were treated either with olanzapine (n = 35) or conventional antipsychotic agents (n = 28) by physician choice, were enrolled in the study. The severity and frequency of tardive dyskinetic symptoms using the Abnormal Involuntary Movement Scale were assessed in the two medication groups at baseline, 8 weeks, and 6 months. RESULTS: There were statistically significant reductions in the prevalence and severity of dyskinetic symptoms at 8 weeks and 6 months for the group treated with olanzapine but not for those treated with conventional agents. CONCLUSIONS: These preliminary data suggest that olanzapine may be a treatment option for subjects with tardive dyskinesia. However, the question whether olanzapine treats, ameliorates, or masks preexisting tardive dyskinesia was difficult to answer, as no dosage reduction or withdrawal was undertaken." ], "offsets": [ [ 0, 1577 ] ] } ]

[ { "id": "entity-174-0", "type": "DISEASE", "text": [ "tardive dyskinetic symptoms" ], "offsets": [ [ 28, 55 ] ], "normalized": [] }, { "id": "entity-174-1", "type": "ADVERSE", "text": [ "Tardive dyskinesia" ], "offsets": [ [ 101, 119 ] ], "normalized": [] }, { "id": "entity-174-2", "type": "ADVERSE", "text": [ "tardive dyskinesia" ], "offsets": [ [ 348, 366 ] ], "normalized": [] }, { "id": "entity-174-3", "type": "DISEASE", "text": [ "DSM-IV schizophrenia" ], "offsets": [ [ 590, 610 ] ], "normalized": [] }, { "id": "entity-174-4", "type": "DISEASE", "text": [ "schizoaffective disorder" ], "offsets": [ [ 614, 638 ] ], "normalized": [] }, { "id": "entity-174-5", "type": "DISEASE", "text": [ "bipolar I disorder" ], "offsets": [ [ 651, 669 ] ], "normalized": [] }, { "id": "entity-174-6", "type": "ADVERSE", "text": [ "tardive dyskinetic symptoms" ], "offsets": [ [ 896, 923 ] ], "normalized": [] }, { "id": "entity-174-7", "type": "DISEASE", "text": [ "Abnormal Involuntary Movement" ], "offsets": [ [ 934, 963 ] ], "normalized": [] }, { "id": "entity-174-8", "type": "ADVERSE", "text": [ "dyskinetic symptoms" ], "offsets": [ [ 1140, 1159 ] ], "normalized": [] }, { "id": "entity-174-9", "type": "ADVERSE", "text": [ "tardive dyskinesia" ], "offsets": [ [ 1378, 1396 ] ], "normalized": [] }, { "id": "entity-174-10", "type": "ADVERSE", "text": [ "tardive dyskinesia" ], "offsets": [ [ 1481, 1499 ] ], "normalized": [] } ]

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[ { "id": "passage-175", "type": "abstract", "text": [ "Risk assessment of dietary exposures to compounds that are genotoxic and carcinogenic--an overview. The process of risk assessment of dietary exposures to genotoxic carcinogens is summarised. Exposures to six genotoxic carcinogens in food (acrylamide, aflatoxin B1, benzo(a)pyrene, dimethylnitrosamine, ethyl carbamate, PhIP) have been used to illustrate the process. The margin of exposure (MOE) approach is seen as a useful method to be used in the risk characterisation step of assessing exposures to genotoxic carcinogens. This approach combines information on animal potency and human exposure, and can be used to indicate levels of concern and also the ranking between various exposures to such agents. Both the T25 and the BMDL10 methods may be used as a reference point. Should a specific MOE value be developed as a cut-off between levels of concern and levels of low concern, the value using T25 data is proposed to be 2.5-times higher than using BMDL10 data. Linear low-dose extrapolation using either T25 or BMDL10, may also be applied. However, it should be understood that this approach should not be interpreted as giving a precise estimate of human risk. For exposures to mutagens in food lacking carcinogenicity data, it is proposed to apply the MOE approach to the lowest effective dose (LED) for in vivo genotoxicity." ], "offsets": [ [ 0, 1337 ] ] } ]

[ { "id": "entity-175-0", "type": "ADVERSE", "text": [ "carcinogenicity" ], "offsets": [ [ 1214, 1229 ] ], "normalized": [] }, { "id": "entity-175-1", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 1324, 1336 ] ], "normalized": [] } ]

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[ { "id": "passage-176", "type": "abstract", "text": [ "The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. BACKGROUND AND AIM: Endothelial dysfunction in hypertensive type-2 diabetic patients is associated with increased levels of circulating soluble adhesion molecules (SAM). SAM participate in the development of diabetic macroangiopathy and microangiopathy. The aim of this study was to compare the effect of trandolapril (T) and its fixed-dose combination with verapamil (FDTV) on SAM levels in hypertensive type-2 diabetic patients. METHODS: Forty type-2 diabetic patients with never-treated hypertension were randomly assigned to two groups. One group (FDTV) received 2/180 mg once a day; the other group received T 2 mg once a day. Study drugs were administered for three months in both groups. VCAM-1, ICAM, and E-selectin were measured by ELISA at the beginning and end of the study. Patients were evaluated monthly for blood pressure, fasting serum glucose, and adverse events. Statistical analysis was performed with ANOVA. RESULTS: Both therapeutics regimens reduced significantly the levels of the SAM tested. When both groups were compared, we did not find a significant difference in ICAM and E-selectin reduction. However, VCAM-1 presented a significantly greater reduction (p = 0.022) in the trandolapril-verapamil group. No patient suffered adverse events. CONCLUSION: Our results show that FDTV produces a greater reduction of VCAM-1 circulating levels than trandolapril alone. This may explain some of the beneficial effects of this fixed dosed combination that are non-related to its antihypertensive effects." ], "offsets": [ [ 0, 1685 ] ] } ]

[ { "id": "entity-176-0", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 144, 159 ] ], "normalized": [] }, { "id": "entity-176-1", "type": "DISEASE", "text": [ "Endothelial dysfunction" ], "offsets": [ [ 182, 205 ] ], "normalized": [] }, { "id": "entity-176-2", "type": "DISEASE", "text": [ "diabetic macroangiopathy" ], "offsets": [ [ 370, 394 ] ], "normalized": [] }, { "id": "entity-176-3", "type": "DISEASE", "text": [ "microangiopathy" ], "offsets": [ [ 399, 414 ] ], "normalized": [] }, { "id": "entity-176-4", "type": "DISEASE", "text": [ "hypertension" ], "offsets": [ [ 652, 664 ] ], "normalized": [] } ]

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[ { "id": "passage-177", "type": "abstract", "text": [ "Incidence and predictors of activation syndrome induced by antidepressants. BACKGROUND: Activation syndrome is a side effect of antidepressants that is thought to carry a potentially increased risk of suicide. However, the incidence of activation syndrome has not been fully investigated and little has been reported on its predictors. The aim of this study was to survey the incidence of activation syndrome and clarify its predictors in a natural clinical setting. METHODS: Among 2,521 new outpatients visiting between August 2003 and March 2005, we retrospectively surveyed the case records of 729 patients who had not taken any antidepressants during the 1 month before presentation and were prescribed antidepressants for 3 months after the initial visit. Patients were classified as developing activation syndrome if they experienced any symptom of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania during the first 3 months. RESULTS: Of the 729 patients, 31 (4.3%) developed activation syndrome. The incidence was not significantly related to gender, age, class of antidepressant, combined use of benzodiazepine, or DSM-IV-TR diagnosis except for personality disorder. Diagnosis of personality disorder was significantly associated with the induction of activation syndrome (odds ratio=4.20, P=0.002). CONCLUSIONS: This study suggests that diagnosis of personality disorder may be a clinical predictor of activation syndrome." ], "offsets": [ [ 0, 1514 ] ] } ]

[ { "id": "entity-177-0", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 28, 47 ] ], "normalized": [] }, { "id": "entity-177-1", "type": "DISEASE", "text": [ "Activation syndrome" ], "offsets": [ [ 89, 108 ] ], "normalized": [] }, { "id": "entity-177-2", "type": "DISEASE", "text": [ "suicide" ], "offsets": [ [ 202, 209 ] ], "normalized": [] }, { "id": "entity-177-3", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 237, 256 ] ], "normalized": [] }, { "id": "entity-177-4", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 390, 409 ] ], "normalized": [] }, { "id": "entity-177-5", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 801, 820 ] ], "normalized": [] }, { "id": "entity-177-6", "type": "DISEASE", "text": [ "anxiety" ], "offsets": [ [ 856, 863 ] ], "normalized": [] }, { "id": "entity-177-7", "type": "DISEASE", "text": [ "agitation" ], "offsets": [ [ 865, 874 ] ], "normalized": [] }, { "id": "entity-177-8", "type": "DISEASE", "text": [ "panic attacks" ], "offsets": [ [ 876, 889 ] ], "normalized": [] }, { "id": "entity-177-9", "type": "DISEASE", "text": [ "insomnia" ], "offsets": [ [ 891, 899 ] ], "normalized": [] }, { "id": "entity-177-10", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 901, 913 ] ], "normalized": [] }, { "id": "entity-177-11", "type": "DISEASE", "text": [ "hostility" ], "offsets": [ [ 915, 924 ] ], "normalized": [] }, { "id": "entity-177-12", "type": "DISEASE", "text": [ "aggressiveness" ], "offsets": [ [ 926, 940 ] ], "normalized": [] }, { "id": "entity-177-13", "type": "DISEASE", "text": [ "akathisia" ], "offsets": [ [ 955, 964 ] ], "normalized": [] }, { "id": "entity-177-14", "type": "DISEASE", "text": [ "hypomania" ], "offsets": [ [ 966, 975 ] ], "normalized": [] }, { "id": "entity-177-15", "type": "DISEASE", "text": [ "mania" ], "offsets": [ [ 981, 986 ] ], "normalized": [] }, { "id": "entity-177-16", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 1064, 1083 ] ], "normalized": [] }, { "id": "entity-177-17", "type": "DISEASE", "text": [ "personality disorder" ], "offsets": [ [ 1236, 1256 ] ], "normalized": [] }, { "id": "entity-177-18", "type": "DISEASE", "text": [ "personality disorder" ], "offsets": [ [ 1271, 1291 ] ], "normalized": [] }, { "id": "entity-177-19", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 1343, 1362 ] ], "normalized": [] }, { "id": "entity-177-20", "type": "DISEASE", "text": [ "personality disorder" ], "offsets": [ [ 1442, 1462 ] ], "normalized": [] }, { "id": "entity-177-21", "type": "DISEASE", "text": [ "activation syndrome" ], "offsets": [ [ 1494, 1513 ] ], "normalized": [] } ]

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[ { "id": "passage-178", "type": "abstract", "text": [ "Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. L-asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is thought to result from depletion of asparagine in serum and cells. We investigated the clinical response in vivo of 1000 IU/m(2) pegylated (PEG)-asparaginase and its pharmacokinetic, pharmacodynamic and intracellular effects in children with newly diagnosed ALL before start of combination chemotherapy. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common/pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (P=0.01) and BCRABL-positive ALL (P=0.04). A poor in vivo clinical window response was related to in vitro resistance to L-asparaginase (P=0.02) and both were prognostic factors for long-term event-free survival (hazard ratio 6.4, P=0.004; hazard ratio 3.7, P=0.01). After administration of one in vivo dose of PEG-asparaginase no changes in apoptotic parameters or in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. One additional dose of PEG-asparaginase upfront ALL treatment did not lead to other severe toxicities." ], "offsets": [ [ 0, 1556 ] ] } ]

[ { "id": "entity-178-0", "type": "DISEASE", "text": [ "acute lymphoblastic leukemia" ], "offsets": [ [ 108, 136 ] ], "normalized": [] }, { "id": "entity-178-1", "type": "DISEASE", "text": [ "acute lymphoblastic leukemia" ], "offsets": [ [ 248, 276 ] ], "normalized": [] }, { "id": "entity-178-2", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 278, 281 ] ], "normalized": [] }, { "id": "entity-178-3", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 563, 566 ] ], "normalized": [] }, { "id": "entity-178-4", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 879, 882 ] ], "normalized": [] }, { "id": "entity-178-5", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1502, 1505 ] ], "normalized": [] } ]

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[ { "id": "passage-179", "type": "abstract", "text": [ "The assessment of genotoxic effects of wastewater from a fertilizer factory. In this study we investigated cytotoxic, mutagenic and genotoxic effects of different concentrations of wastewater from the phosphoric gypsum depot near the factory for fertilizing agents 'INA Petrokemija' (Kutina, Croatia). The Ames test was performed on Salmonella typhimurium TA98 and TA100 strains, in the presence of S9 mix, glutathione and buffer, respectively. Cytotoxicity was studied on human laryngeal carcinoma cells (HEp2) and human cervical cells (HeLa). The level of lipid peroxidation in these two cell lines was evaluated in parallel. To establish the levels of primary DNA damage, the alkaline comet assay was performed on treated human peripheral blood leukocytes. No mutagenic effects of phosphoric gypsum on Salmonella typhimurium strains in the presence of S9 mix, GSH or PBS were observed. However, strong cytotoxic effect was observed on both human cell lines when they were treated with different concentrations of wastewater. Lipid peroxidation was induced and increased by prolonged time of incubation, highlighting that the damage was not repaired, but increased with the time of incubation. The results of the alkaline comet assay indicate significant DNA damaging potential of wastewater for human leukocytes. Since phosphoric gypsum transport water in its present composition and acidity is highly toxic and acts as prooxidant, causing free radicals formation and DNA damage, urgent neutralization/purification of the wastewater to a level acceptable for disposal into the environment is mandatory." ], "offsets": [ [ 0, 1606 ] ] } ]

[ { "id": "entity-179-0", "type": "ADVERSE", "text": [ "genotoxic effects" ], "offsets": [ [ 18, 35 ] ], "normalized": [] }, { "id": "entity-179-1", "type": "ADVERSE", "text": [ "genotoxic effects" ], "offsets": [ [ 133, 150 ] ], "normalized": [] }, { "id": "entity-179-2", "type": "ADVERSE", "text": [ "Cytotoxicity" ], "offsets": [ [ 446, 458 ] ], "normalized": [] }, { "id": "entity-179-3", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 906, 922 ] ], "normalized": [] } ]

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[ { "id": "passage-180", "type": "abstract", "text": [ "Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin. AIMS: Indisulam and carboplatin have shown synergistic activity in preclinical studies. In a dose escalation study of the combination, a treatment delay was frequently required in a 3-weekly regimen to allow recovery from myelosuppression from previous cycles. A 4-weekly regimen was better tolerated, but had a decreased dose-intensity which may compromise efficacy. The aims of this study were (i) to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to describe the myelosuppressive effect of the combination, and (ii) to use this model to select a dosing regimen for Phase II evaluation. METHODS: Sixteen patients were treated at four different dose levels of indisulam (1-h infusion on day 1) and carboplatin (30-min infusion on day 2). Pharmacokinetic data were analysed with nonlinear mixed effects modelling. A semiphysiological model describing chemotherapy-induced myelosuppression characterized the relationship between the pharmacokinetics and the haematological toxicity of indisulam and carboplatin. A simulation study was performed to evaluate the tolerability and dose-intensity for 3-weekly and 4-weekly treatment regimens. RESULTS: The PK-PD model described the pharmacokinetics and the myelosuppressive effect of indisulam and carboplatin. The risk of a treatment delay at cycle 2 due to myelosuppression was unacceptably high (34-65%) in a 3-weekly regimen for various dose levels (350-600 mg m(-2) indisulam in combination with carboplatin to achieve an AUC of 4-6 mg min(-1) ml(-1)). This risk was acceptable for a 4-weekly regimen (9-24%), which is in line with the clinical study results. CONCLUSIONS: This PK-PD study supports the selection of indisulam 500 mg m(-2) and a dose of carboplatin to achieve an AUC of 6 mg min(-1) ml(-1) in a 4-weekly regimen as the recommended dose for future studies." ], "offsets": [ [ 0, 1981 ] ] } ]

[ { "id": "entity-180-0", "type": "ADVERSE", "text": [ "myelosuppression" ], "offsets": [ [ 373, 389 ] ], "normalized": [] }, { "id": "entity-180-1", "type": "ADVERSE", "text": [ "myelosuppressive effect" ], "offsets": [ [ 626, 649 ] ], "normalized": [] }, { "id": "entity-180-2", "type": "ADVERSE", "text": [ "myelosuppression" ], "offsets": [ [ 1032, 1048 ] ], "normalized": [] }, { "id": "entity-180-3", "type": "ADVERSE", "text": [ "haematological toxicity" ], "offsets": [ [ 1117, 1140 ] ], "normalized": [] }, { "id": "entity-180-4", "type": "ADVERSE", "text": [ "myelosuppressive effect" ], "offsets": [ [ 1362, 1385 ] ], "normalized": [] }, { "id": "entity-180-5", "type": "ADVERSE", "text": [ "myelosuppression" ], "offsets": [ [ 1464, 1480 ] ], "normalized": [] } ]

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[ { "id": "passage-181", "type": "abstract", "text": [ "Inhaled sodium pyruvate improved FEV1 and decreased expired breath levels of nitric oxide in patients with chronic obstructive pulmonary disease. Exogenously administered sodium pyruvate has a variety of biological effects including antioxidant/anti-inflammatory effects. Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways mediated in part by reactive oxygen species (ROS) and reactive nitrogen species (RNS). The current therapies for COPD have limited efficacy. This study was designed to test the safety and therapeutic efficacy of inhaled pyruvate in COPD patients. Subjects were randomized to receive either sodium pyruvate or placebo three times per day over a 6-week period. Long-term efficacy was evaluated by spirometry and expired breath nitric oxide (NO) levels taken at baseline, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks. In addition, acute assessments (1 h pre- and 1 h postinhalation of compound) were made at day 0 and at 4 weeks. Subjects receiving inhaled pyruvate showed significant (p < 0.02) improvement of approximately 11% in forced expiratory volume in 1 sec (FEV(1)) at 6 weeks, whereas subjects receiving placebo did not. The inhalation of pyruvate or placebo had no significant effect on expired breath NO levels at any of the long-term outcome time points; measurements were made 12 h after the last inhalation of the compound. In contrast, acute assessments (1 h pre-and 1 h postinhalation of compound) of expired breath NO made at 4 weeks demonstrated that inhalation of pyruvate resulted in a significant (p </= 0.01) decrease (-22.7 +/- 6%) in expired breath NO compared to placebo (5.0 +/- 7%). Inhalation of pyruvate was well tolerated and was associated with improvement in FEV(1) and expired breath NO, and was considered clinically important in COPD. These beneficial effects of inhaled pyruvate in COPD may be optimized with adjustments in both dose and length of treatment." ], "offsets": [ [ 0, 1953 ] ] } ]

[ { "id": "entity-181-0", "type": "DISEASE", "text": [ "chronic obstructive pulmonary disease" ], "offsets": [ [ 107, 144 ] ], "normalized": [] }, { "id": "entity-181-1", "type": "DISEASE", "text": [ "Chronic obstructive pulmonary disease" ], "offsets": [ [ 273, 310 ] ], "normalized": [] }, { "id": "entity-181-2", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 312, 316 ] ], "normalized": [] }, { "id": "entity-181-3", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 473, 477 ] ], "normalized": [] }, { "id": "entity-181-4", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 592, 596 ] ], "normalized": [] }, { "id": "entity-181-5", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 1823, 1827 ] ], "normalized": [] }, { "id": "entity-181-6", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 1877, 1881 ] ], "normalized": [] } ]

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[ { "id": "passage-182", "type": "abstract", "text": [ "Adverse effects of topical papaverine on auditory nerve function. BACKGROUND: Papaverine hydrochloride is a direct-acting vasodilator used to manage vasospasm during various neurosurgical operations. Transient cranial nerve dysfunction has been described in a few cases with topical papaverine. This study supports previous reports and provides neurophysiological evidence of an adverse effect on the auditory nerve. METHODS: We conducted a retrospective review of 70 consecutive microvascular decompression operations and studied those patients who received topical papaverine for vasospasm. Topical papaverine was used as a direct therapeutic action to manage vasospasm in a total of 11 patients. The timing of papaverine application and ongoing operative events was reviewed relative to changes in neurophysiological recordings. Brainstem auditory evoked potentials (BAEPs) were routinely used to monitor cochlear nerve function during these operations. FINDINGS: A temporal relationship was found between topical papaverine and BAEP changes leading to complete waveform loss. The average temporal delay between papaverine and the onset of an adverse BAEP change was 5 min. In 10 of 11 patients, BAEP waves II/III-V completely disappeared within 2 to 25 min after papaverine. Eight of these 10 patients had complete loss of BAEP waveforms within 10 min. One patient showed no recovery of later waves and a delayed profound sensorineural hearing loss. The average recovery time of BAEP waveforms to pre-papaverine baseline values was 39 min. CONCLUSIONS: Topical papaverine for the treatment of vasospasm was associated with the onset of a transient disturbance in neurophysiological function of the ascending auditory brainstem pathway. The complete disappearance of BAEP waveforms with a consistent temporal delay suggests a possible adverse effect on the proximal eighth nerve. Recommendations to avoid potential cranial nerve deficits from papaverine are provided." ], "offsets": [ [ 0, 1971 ] ] } ]

[ { "id": "entity-182-0", "type": "DISEASE", "text": [ "vasospasm" ], "offsets": [ [ 150, 159 ] ], "normalized": [] }, { "id": "entity-182-1", "type": "DISEASE", "text": [ "vasospasm" ], "offsets": [ [ 583, 592 ] ], "normalized": [] }, { "id": "entity-182-2", "type": "DISEASE", "text": [ "vasospasm" ], "offsets": [ [ 663, 672 ] ], "normalized": [] }, { "id": "entity-182-3", "type": "DISEASE", "text": [ "sensorineural hearing loss" ], "offsets": [ [ 1427, 1453 ] ], "normalized": [] }, { "id": "entity-182-4", "type": "DISEASE", "text": [ "vasospasm" ], "offsets": [ [ 1598, 1607 ] ], "normalized": [] } ]

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[ { "id": "passage-183", "type": "abstract", "text": [ "Neonatal nicotine exposure impairs development of auditory temporal processing. Accurate temporal processing of sound is essential for detecting word structures in speech. Maternal smoking affects speech processing in newborns and may influence child language development; however, it is unclear how neonatal exposure to nicotine, present in cigarettes, affects the normal development of temporal processing. The present study used the gap-induced prepulse inhibition (gap-PPI) of the acoustic startle response to investigate the effects of neonatal nicotine exposure on the normal development of gap detection, a behavioral testing procedure of auditory temporal resolution. Neonatal rats were injected twice per day with saline (control), 1mg/kg nicotine (N-1 mg) or 5 mg/kg nicotine (N-5 mg) from postnatal day 8-12 (P8-P12). During the first month after birth, rats showed poor gap-PPI in all three groups. At P45 and P60, gap-PPI in control rats improved significantly, whereas rats exposed to nicotine exhibited less improvement. At P60, the gap-detection threshold in the N-5 mg group was significantly higher than in the control group, suggesting that neonatal nicotine exposure affects the normal development of gap-detection acuity. Additionally, 1h after receiving an acute nicotine injection (1 mg/kg), gap-PPI recorded in adult rats from the N-5 mg group showed a temporary significant improvement. These results suggest that neonatal nicotine exposure reduces gap-PPI implying an impairment of the normal development of auditory temporal processing by inducing changes in cholinergic systems." ], "offsets": [ [ 0, 1607 ] ] } ]

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[ { "id": "passage-184", "type": "abstract", "text": [ "Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma. BACKGROUND: Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2-drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3-drug combination followed by maintenance treatment in patients with metastatic NPC. METHODS: Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1,000 mg/m(2), paclitaxel at a dose of 70 mg/m(2), and carboplatin at an area under the concentration-time-curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5-fluorouracil at a dose of 450 mg/m(2) and leucovorin at a dose of 30 mg/m(2) for 48 weeks. RESULTS: Twenty-eight patients were recruited. Twenty-two (79%) patients had >or=2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3-drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months. CONCLUSIONS: This regimen of a 3-drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival." ], "offsets": [ [ 0, 1680 ] ] } ]

[ { "id": "entity-184-0", "type": "DISEASE", "text": [ "metastatic nasopharyngeal carcinoma" ], "offsets": [ [ 137, 172 ] ], "normalized": [] }, { "id": "entity-184-1", "type": "DISEASE", "text": [ "Nasopharyngeal carcinoma" ], "offsets": [ [ 187, 211 ] ], "normalized": [] }, { "id": "entity-184-2", "type": "DISEASE", "text": [ "NPC" ], "offsets": [ [ 213, 216 ] ], "normalized": [] }, { "id": "entity-184-3", "type": "DISEASE", "text": [ "metastatic NPC" ], "offsets": [ [ 579, 593 ] ], "normalized": [] }, { "id": "entity-184-4", "type": "DISEASE", "text": [ "metastatic NPC" ], "offsets": [ [ 618, 632 ] ], "normalized": [] }, { "id": "entity-184-5", "type": "ADVERSE", "text": [ "bone marrow suppression" ], "offsets": [ [ 1151, 1174 ] ], "normalized": [] }, { "id": "entity-184-6", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1195, 1206 ] ], "normalized": [] }, { "id": "entity-184-7", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 1222, 1228 ] ], "normalized": [] }, { "id": "entity-184-8", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1248, 1264 ] ], "normalized": [] }, { "id": "entity-184-9", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 1292, 1298 ] ], "normalized": [] } ]

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[ { "id": "passage-185", "type": "abstract", "text": [ "Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: does body weight matter? Imatinib at a daily dose of 400 mg is the standard treatment for chronic myelogenous leukemia in the chronic phase. However, the feasibility of this dose for small Japanese adults has not been clarified. We prospectively investigated the toxicity and efficacy of this dose in adult Japanese patients. Among the 89 evaluable patients with a median body weight of 62.8 kg, imatinib therapy was held in 40 subjects (45%), due to Grade 3-4 toxicities in 30 patients (75%) and Grade 2 toxicities at the discretion of the attending physician in 10 patients (25%). However, treatment was resumed and the dose was gradually increased until 62 of the 89 patients tolerated a maintenance dose of 400 mg. Older age and lower body weight were significant independent risk factors for discontinuation of imatinib. After a median follow-up period of 31 months, 84 patients were alive without progression. The complete cytogenetic response rate was 60 and 90% at 6 months and 1 year after starting imatinib, respectively. Older patients and those with a lower body weight were less likely to achieve a complete cytogenetic response. These findings suggest that the body weight has a significant influence on the toxicity and efficacy of imatinib in patients with a small body size, although dose reduction in proportion to weight may result in an inadequate response to imatinib." ], "offsets": [ [ 0, 1538 ] ] } ]

[ { "id": "entity-185-0", "type": "DISEASE", "text": [ "chronic myelogenous leukemia" ], "offsets": [ [ 97, 125 ] ], "normalized": [] }, { "id": "entity-185-1", "type": "DISEASE", "text": [ "chronic myelogenous leukemia" ], "offsets": [ [ 239, 267 ] ], "normalized": [] } ]

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[ { "id": "passage-186", "type": "abstract", "text": [ "Magnetic resonance imaging appearance of the shoulder after subacromial injection with corticosteroids can mimic a rotator cuff tear. Subacromial injections have been used to treat rotator cuff problems. Previous studies have noted the difficulty in performing accurate injections into this area. In addition, one must also question the effects that misplaced corticosteroids could have on the surrounding tissues. In this case, a 51-year-old woman presented with several weeks of left shoulder pain and was diagnosed with rotator cuff tendonitis. After a subacromial injection with betamethasone and lidocaine, the patient noted 3 weeks of near complete pain relief, followed by a return of her symptoms. A magnetic resonance imaging scan obtained 7 weeks after the injection showed a full-thickness tear of the supraspinatus tendon. Five weeks later, the patient underwent arthroscopic evaluation of the shoulder and subacromial decompression. The rotator cuff tendons were noted to be intact and normal in appearance. The patient eventually had full resolution of her symptoms. Six months postoperatively, she underwent a new scan that showed a normal supraspinatus tendon. Apparently, the subacromial injection penetrated the anterior half of the supraspinatus tendon, causing a transient effect and signal change. One should use caution in the interpretation of magnetic resonance imaging scans of the shoulder soon after the injection of corticosteroids." ], "offsets": [ [ 0, 1461 ] ] } ]

[ { "id": "entity-186-0", "type": "DISEASE", "text": [ "rotator cuff tear" ], "offsets": [ [ 115, 132 ] ], "normalized": [] }, { "id": "entity-186-1", "type": "DISEASE", "text": [ "rotator cuff problems" ], "offsets": [ [ 182, 203 ] ], "normalized": [] }, { "id": "entity-186-2", "type": "DISEASE", "text": [ "shoulder pain" ], "offsets": [ [ 487, 500 ] ], "normalized": [] }, { "id": "entity-186-3", "type": "DISEASE", "text": [ "rotator cuff tendonitis" ], "offsets": [ [ 524, 547 ] ], "normalized": [] }, { "id": "entity-186-4", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 656, 660 ] ], "normalized": [] } ]

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[ { "id": "passage-187", "type": "abstract", "text": [ "Evaluation of cytotoxic properties of organometallic ferrocifens on melanocytes, primary and metastatic melanoma cell lines. Malignant melanoma is one of the most severe forms of skin cancer, and chemotherapeutic agents currently in use are poorly effective in curing the disease. Here we describe the properties of two organometallic ferrocenyl derivatives, ferrocifen (Fc-OH-Tam) and ferrociphenol (Fc-diOH) that show a specific antiproliferative effect on melanoma cells. After a short incubation period, Fc-OH-Tam is highly cytotoxic on melanoma cells but less toxic on melanocytes. Fc-diOH is slightly toxic at a high concentration but no discrepancy is observed between malignant and normal cells. After a long incubation time the latter is highly toxic for malignant cells but not for normal cells while the former was very highly toxic for primary malignant cells and significantly less toxic for normal cells. We also found that oxidative stress is not implicated in the mechanism of cytotoxicity, since both derivatives neither induce reactive oxygen species (ROS) level in melanocytes nor in melanoma cells. Finally, investigation on hair follicle growth revealed that the two organometallic derivatives induced an irreversible ejection of the hair shaft, thus predicting a potential hair loss side effect if used as a chemotherapeutic treatment." ], "offsets": [ [ 0, 1358 ] ] } ]

[ { "id": "entity-187-0", "type": "DISEASE", "text": [ "Malignant melanoma" ], "offsets": [ [ 126, 144 ] ], "normalized": [] }, { "id": "entity-187-1", "type": "DISEASE", "text": [ "skin cancer" ], "offsets": [ [ 180, 191 ] ], "normalized": [] }, { "id": "entity-187-2", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 994, 1006 ] ], "normalized": [] }, { "id": "entity-187-3", "type": "ADVERSE", "text": [ "hair loss" ], "offsets": [ [ 1296, 1305 ] ], "normalized": [] } ]

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[ { "id": "passage-188", "type": "abstract", "text": [ "Effect of Efalizumab on neutrophil and monocyte functions in patients with psoriasis. We evaluated the effect of efalizumab on neutrophil and monocyte functions. The in vitro pre-incubation with efalizumab concentrations similar to those reached during in vivo therapy almost completely saturated CD11a binding sites without affecting the membrane expression of CD11b, CD128a or CD128b. There was a significant reduction in the chemotactic activity of the pre-treated cells toward three different chemo-attractants, whereas their phagocytic capacity and production of oxygen radicals remained unchanged. One month after the administration of efalizumab to five patients with psoriasis (T1) circulating neutrophil counts increased by 34% from pre-therapy (T0) with no change in the number of monocytes. In the same patients the CD11a binding sites on phagocytes were >90% saturated, and there was also a significant down-modulation on neutrophils (44% of T0) and monocytes (63% of T0). In line with in vitro results, efalizumab treatment caused a significant deficiency in the chemotactic properties of neutrophils and monocytes, but no changes in phagocytosis, oxidative burst, production of pro-inflammatory cytokines or the membrane expression of CD11b, CD128a and CD128b. Our findings suggest that neutrophils and monocytes may be among the targets of efalizumab activity in patients with psoriasis." ], "offsets": [ [ 0, 1403 ] ] } ]

[ { "id": "entity-188-0", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 75, 84 ] ], "normalized": [] }, { "id": "entity-188-1", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 676, 685 ] ], "normalized": [] }, { "id": "entity-188-2", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 1393, 1402 ] ], "normalized": [] } ]

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[ { "id": "passage-189", "type": "abstract", "text": [ "Improving the applicability of (Q)SARs for percutaneous penetration in regulatory risk assessment. The new regulatory framework REACH (Registration, Evaluation, and Authorisation of Chemicals) foresees the use of non-testing approaches, such as read-across, chemical categories, structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs). Although information on skin absorption data are not a formal requirement under REACH, data on dermal absorption are an integral part of risk assessment of substances/products to which man is predominantly exposed via the dermal route. In this study, we assess the present applicability of publicly available QSARs on skin absorption for risk assessment purposes. We explicitly did not aim to give scientific judgments on individual QSARs. A total of 33 QSARs selected from the public domain were evaluated using the OECD (Organisation for Economic Co-operation and Development) Principles for the Validation of (Q)SAR Models. Additionally, several pragmatic criteria were formulated to select QSARs that are most suitable for their use in regulatory risk assessment. Based on these criteria, four QSARs were selected. The predictivity of these QSARs was evaluated by comparing their outcomes with experimentally derived skin absorption data (for 62 compounds). The predictivity was low for three of four QSARs, whereas one model gave reasonable predictions. Several suggestions are made to increase the applicability of QSARs for skin absorption for risk assessment purposes." ], "offsets": [ [ 0, 1555 ] ] } ]

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[ { "id": "passage-190", "type": "abstract", "text": [ "Comparative study of Helicobacter pylori eradication rates of twice-versus four-times-daily amoxicillin administered with proton pump inhibitor and clarithromycin: a randomized study. BACKGROUND: Proton pump inhibitor (PPI)-containing triple therapy with clarithromycin and amoxicillin is now a standard regimen for Helicobacter pylori eradication in Korea. Amoxicillin has time-dependent bactericidal activity against H. pylori; we therefore assumed a dosing schedule of amoxicillin would affect the eradication rate of H. pylori. The purpose of this study was to evaluate and compare the efficacy of different amoxicillin dosing schedules for the eradication of H. pylori. MATERIALS AND METHODS: One hundred and eighty-six patients with H. pylori infection were eligible for this study. Patients were randomly assigned to one of two regimens: amoxicillin 1000 mg with clarithromycin 500 mg and omeprazole 20 mg twice daily for 2 weeks (BID group, n = 93), or amoxicillin 500 mg four times daily with clarithromycin 500 mg and omeprazole 20 mg twice daily for 2 weeks (QID group, n = 93). The success of H. pylori eradication was evaluated 4-5 weeks after completing treatment. RESULTS: Overall eradication rate was 90.3%, and eradication rates were 91.4% in the BID group and 89.2% in the QID group (p = 0.62). Compliances was 95.7% in the BID group and 93.5% in the QID group (p = 0.516); this was the only factor that significantly affected H. pylori eradication in this study. Side effects in both groups were generally mild. CONCLUSIONS: Amoxicillin regimens with PPI and clarithromycin are found to be equally effective and safe in both the BID and QID groups for H. pylori eradication. Therefore, considering patient's comfort, we recommend a twice daily amoxicillin regimen." ], "offsets": [ [ 0, 1784 ] ] } ]

[ { "id": "entity-190-0", "type": "DISEASE", "text": [ "H. pylori infection" ], "offsets": [ [ 740, 759 ] ], "normalized": [] } ]

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[ { "id": "passage-191", "type": "abstract", "text": [ "Moxifloxacin for the treatment of HIV-associated tuberculosis in patients with contraindications or intolerance to rifamycins. Administration of rifampicin or rifabutin in the treatment of HIV-associated tuberculosis (TB) is made rather complex by the risk of drug-drug interactions with most antiretrovirals and/or for reasons of toxicity. While in selecting the appropriate concomitant regimens the priority usually goes to rifamycins with exclusion of interacting antiretrovirals, in some circumstances the former cannot be used and anti-TB rifamycin-free regimens must be administered. We describe here the clinical course of two patients with HIV-associated TB in whom the last generation fluorquinolone moxifloxacin (found to exert significant activity against Mycobacterium tuberculosis) successfully replaced rifamycins." ], "offsets": [ [ 0, 829 ] ] } ]

[ { "id": "entity-191-0", "type": "DISEASE", "text": [ "HIV-associated tuberculosis" ], "offsets": [ [ 34, 61 ] ], "normalized": [] }, { "id": "entity-191-1", "type": "DISEASE", "text": [ "HIV-associated tuberculosis" ], "offsets": [ [ 190, 217 ] ], "normalized": [] }, { "id": "entity-191-2", "type": "DISEASE", "text": [ "TB" ], "offsets": [ [ 219, 221 ] ], "normalized": [] }, { "id": "entity-191-3", "type": "DISEASE", "text": [ "HIV-associated TB" ], "offsets": [ [ 649, 666 ] ], "normalized": [] } ]

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[ { "id": "passage-192", "type": "abstract", "text": [ "Gene expression changes after exposure to six-mix in a mouse model. The exposure of Libby MT residents to amphibole-contaminated vermiculite is well known. To explore the gene-environment interactions in the development of asbestos-related diseases (ARD), a mouse model of asbestos exposure using Six-mix (a combination of amphibole fibers gathered from six sites at the Libby vermiculite mine), crocidolite asbestos, or saline as a negative control was used to determine both gene expression responses by using mouse 10,000 oligonucleotide array and to visualize these changes histologically. Mice were sacrificed and whole lungs harvested for histology and microarray analysis six months following exposure via intratracheal instillation. Using an arbitrary cutoff of 1.25-fold change, genes whose RNA expression levels were specifically altered in response to the different amphibole exposures were grouped into categories by a gene ontology analysis program, GoMiner. Our hypothesis was that assessment of asbestos-responsive genes would provide a better understanding of response mechanisms. These experiments have provided new candidates for genes involved in the asbestos response pathways." ], "offsets": [ [ 0, 1198 ] ] } ]

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[ { "id": "passage-193", "type": "abstract", "text": [ "Detailing the role of Bax translocation, cytochrome c release, and perinuclear clustering of the mitochondria in the killing of HeLa cells by TNF. Induction of cell death in HeLa cells with TNF and cycloheximide (CHX) required an adequate ATP supply and was accompanied by decrease in intracellular pH, translocation of Bax, perinuclear clustering of the mitochondria, and cytochrome c release. The chloride channel inhibitor furosemide prevented the intracellular acidification, the translocation of Bax and the cell death. Cyclosporin A (CyA) or bongkrekic acid (BK) inhibited the induction of the MPT, the release of cytochrome c and the cell death without affecting the perinuclear clustering of the mitochondria or the translocation of Bax. Energy depletion with the ATP synthase inhibitor oligomycin or the uncoupler FCCP in the presence of 2-deoxy-glucose prevented the perinuclear clustering of the mitochondria and the cell killing. However, mitochondrial translocation of Bax was still observed. By contrast, cytochrome c was released in the oligomycin-treated cells but not in the same cells treated with FCCP. The data demonstrate that apoptosis in HeLa cells is ATP dependent and requires the translocation of Bax. The movement of Bax to the mitochondria occurs before and during the perinuclear clustering of these organelles and does not require the presence of ATP. The release of cytochrome c depends on the induction of the mitochondrial permeability transition but not ATP content." ], "offsets": [ [ 0, 1501 ] ] } ]

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[ { "id": "passage-194", "type": "abstract", "text": [ "Management of bisphosphonate-induced osteonecrosis of the jaw. In conclusion, careful treatment planning minimizes BIONJ risk in patients with bisphosphonate exposure. The drug type, dose, potency, and duration are important factors in determining the cumulative effect on bone remodeling and resultant risk of BIONJ. Dentists and physicians should work closely to balance the risks of the oral and systemic conditions surrounding bisphosphonate use. A critical assessment of current literature is necessary to best serve our patients." ], "offsets": [ [ 0, 536 ] ] } ]

[ { "id": "entity-194-0", "type": "ADVERSE", "text": [ "osteonecrosis of the jaw" ], "offsets": [ [ 37, 61 ] ], "normalized": [] } ]

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[ { "id": "passage-195", "type": "abstract", "text": [ "Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. AIMS: To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS: Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94-->A and IVS2+21A-->C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS: Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A-->C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A-->C variants with thrombocytopenia (P = 0.012). CONCLUSIONS; Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization." ], "offsets": [ [ 0, 1952 ] ] } ]

[ { "id": "entity-195-0", "type": "DISEASE", "text": [ "acute lymphoblastic leukaemia" ], "offsets": [ [ 358, 387 ] ], "normalized": [] }, { "id": "entity-195-1", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 389, 392 ] ], "normalized": [] }, { "id": "entity-195-2", "type": "DISEASE", "text": [ "inflammatory bowel disease" ], "offsets": [ [ 397, 423 ] ], "normalized": [] }, { "id": "entity-195-3", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 425, 428 ] ], "normalized": [] }, { "id": "entity-195-4", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 495, 498 ] ], "normalized": [] }, { "id": "entity-195-5", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 526, 529 ] ], "normalized": [] }, { "id": "entity-195-6", "type": "ADVERSE", "text": [ "myelotoxicity" ], "offsets": [ [ 916, 929 ] ], "normalized": [] }, { "id": "entity-195-7", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1164, 1167 ] ], "normalized": [] }, { "id": "entity-195-8", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 1191, 1194 ] ], "normalized": [] }, { "id": "entity-195-9", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1264, 1267 ] ], "normalized": [] }, { "id": "entity-195-10", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1357, 1360 ] ], "normalized": [] }, { "id": "entity-195-11", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 1365, 1368 ] ], "normalized": [] }, { "id": "entity-195-12", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1476, 1479 ] ], "normalized": [] }, { "id": "entity-195-13", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 1503, 1506 ] ], "normalized": [] }, { "id": "entity-195-14", "type": "ADVERSE", "text": [ "leucopenia" ], "offsets": [ [ 1606, 1616 ] ], "normalized": [] }, { "id": "entity-195-15", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1621, 1632 ] ], "normalized": [] }, { "id": "entity-195-16", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1636, 1639 ] ], "normalized": [] }, { "id": "entity-195-17", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1746, 1762 ] ], "normalized": [] } ]

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[ { "id": "passage-196", "type": "abstract", "text": [ "Parkinsonism during cyclosporine treatment in liver transplantation: an unusual case report. OBJECTIVES: Cyclosporine (CyA) has been associated with various neurological reactions but parkinsonism is not generally recognized as a nervous system side effect. We describe herein a rare case, in that the patient developed parkinsonism with rest tremor after receiving CyA following orthotopic liver transplantation (OLT). METHODS: The patient was a 42-year-old man who had liver cirrhosis with hepatitis C. We performed OLT because of liver failure and started immunosuppressive therapy with CyA + methylprednisolone + CD25 antibody. Ten days after OLT, he developed parkinsonism with a rest tremor. The patient did not have a pre-existentneurological disorder, and had not received significant amounts of dopamine-blocking drugs. RESULTS: We administered levodopa with marked improvement. Three days after that event, the neurologist suggested the possibility of drug-induced parkinsonism. We converted the immunosuppressive drug from CyA to tacrolimus. After that, the symptom disappeared. At 75 days after OLT, he was discharged with no neurological medication and now he is completely recovered. CONCLUSION: We think that parkinsonism may be an occasional consequence of CyA because of its relation to withdrawal of the drug and the lack of another evident cause." ], "offsets": [ [ 0, 1367 ] ] } ]

[ { "id": "entity-196-0", "type": "ADVERSE", "text": [ "Parkinsonism" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "entity-196-1", "type": "ADVERSE", "text": [ "parkinsonism" ], "offsets": [ [ 185, 197 ] ], "normalized": [] }, { "id": "entity-196-2", "type": "ADVERSE", "text": [ "parkinsonism" ], "offsets": [ [ 321, 333 ] ], "normalized": [] }, { "id": "entity-196-3", "type": "ADVERSE", "text": [ "rest tremor" ], "offsets": [ [ 339, 350 ] ], "normalized": [] }, { "id": "entity-196-4", "type": "DISEASE", "text": [ "liver cirrhosis" ], "offsets": [ [ 472, 487 ] ], "normalized": [] }, { "id": "entity-196-5", "type": "DISEASE", "text": [ "hepatitis C" ], "offsets": [ [ 493, 504 ] ], "normalized": [] }, { "id": "entity-196-6", "type": "DISEASE", "text": [ "liver failure" ], "offsets": [ [ 534, 547 ] ], "normalized": [] }, { "id": "entity-196-7", "type": "ADVERSE", "text": [ "parkinsonism" ], "offsets": [ [ 666, 678 ] ], "normalized": [] }, { "id": "entity-196-8", "type": "ADVERSE", "text": [ "rest tremor" ], "offsets": [ [ 686, 697 ] ], "normalized": [] }, { "id": "entity-196-9", "type": "DISEASE", "text": [ " neurological disorder" ], "offsets": [ [ 738, 760 ] ], "normalized": [] }, { "id": "entity-196-10", "type": "ADVERSE", "text": [ "parkinsonism" ], "offsets": [ [ 977, 989 ] ], "normalized": [] }, { "id": "entity-196-11", "type": "ADVERSE", "text": [ "parkinsonism" ], "offsets": [ [ 1226, 1238 ] ], "normalized": [] } ]

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[ { "id": "passage-197", "type": "abstract", "text": [ "Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Statins have antiproliferative and anti-tumoral effects in MCF-7 cells. We determined the effect of statins upon MCF-7 cell cycle, toxicity, cell death, reactive oxygen species (ROS) production and mitochondrial membrane potential. Fluvastatin, simvastatin and atorvastatin inhibited cell proliferation. Antiproliferation was associated with a decrease in the DNA synthesis and a cell cycle arrest in the G1 and G2/M phases. A loss in the mitochondrial membrane potential was observed with fluvastatin. Statins induced increase in ROS production that was associated with cell death, which was abrogated by the antioxidant NAC. Our results suggest that the cytotoxic effect observed is mediated by an oxidative stress." ], "offsets": [ [ 0, 898 ] ] } ]

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[ { "id": "passage-198", "type": "abstract", "text": [ "Interactive transport, subcellular relocation and enhanced phototoxicity of hypericin encapsulated in guanidinylated liposomes via molecular recognition. Hypericin (HYP), a photocytotoxic phenanthroperylenquinone was encapsulated in liposomes outfitted with guanidinium-bearing lipids to ensure efficient cell binding through molecular recognition with anionic groups resident on the plasma membrane. The uptake of HYP encapsulated in these liposomes by DU145 human prostate cancer cells, was studied employing fluorescence, versus nonguadinylated liposomes and free HYP. The subcellular localization was in all cases studied by confocal microscopy employing specific subcellular organelle probes. The photocytotoxicity of HYP was assessed, 24 h following irradiation with 15 mWcm(-2) light through a GG 495 Schott filter, by a standard tetrazolium to formazan assay (XTT). HYP uptake by DU145 cells was found to be profoundly enhanced by using guanidinylated liposomes. Also the distance of the guanidinium group from the liposomal surface was found to significantly affect HYP loading, subcellular localization and phototoxicity. The two different modes of liposome cell internalization observed, i.e. plasma membrane fusion and endocytosis, were found to greatly affect the phototoxicity of HYP. Molecular recognition was overall appraised as a promising, novel route for photodynamic therapy, profoundly enhancing its efficacy. HYP encapsulated in liposomes-bearing guanidinium groups was more efficiently taken up by cells, leading to enhanced phototoxicity, in contrast to HYP encapsulated in their nonguanidinylated counterparts." ], "offsets": [ [ 0, 1637 ] ] } ]

[ { "id": "entity-198-0", "type": "ADVERSE", "text": [ "phototoxicity" ], "offsets": [ [ 59, 72 ] ], "normalized": [] }, { "id": "entity-198-1", "type": "DISEASE", "text": [ "phototoxicity" ], "offsets": [ [ 1118, 1131 ] ], "normalized": [] }, { "id": "entity-198-2", "type": "DISEASE", "text": [ "phototoxicity" ], "offsets": [ [ 1278, 1291 ] ], "normalized": [] }, { "id": "entity-198-3", "type": "DISEASE", "text": [ "phototoxicity" ], "offsets": [ [ 1550, 1563 ] ], "normalized": [] } ]

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[ { "id": "passage-199", "type": "abstract", "text": [ "Cutaneous adverse effects of biological therapies for psoriasis. Psoriasis is a common immune-mediated disease that affects approximately 2% of the world's population. Most patients require lifelong treatment and many of the current systemic therapies are complicated by significant toxicities or inconvenience when administered long-term. New biological psoriasis therapies have been developed, which are thought to act through targeted molecular pathways, so as to administer them continuously without causing any relevant toxicity. Nevertheless, acute and chronic dermatological adverse effects are frequently observed, but knowledge about them is limited and the potential pathogenic mechanisms have not yet been identified. We present 7 patients from our dermatological department who presented different cutaneous adverse effects (2 erythrodermias, 1 palmoplantar pustulosis, 1 flexural psoriasis, 1 eczema, 1 neutrophilic dermatosis and 1 papular eruption) during treatment with biological drugs (4 patients with efaluzimab, 2 patients with infliximab and 1 patient with etanercept). The use of biological agents is expanding worldwide as new alternative treatments for psoriasis and other chronic inflammatory diseases. The increased use of these treatments has allowed identification of their acute and chronic systemic adverse events. Nevertheless, the dermatological adverse events of these biological drugs are less well known due to few reports about them and lack of information about their pathogenic mechanisms. Exact diagnosis of these cutaneous eruptions is very important in order to decide the need for discontinuation of the biological treatment." ], "offsets": [ [ 0, 1668 ] ] } ]

[ { "id": "entity-199-0", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 54, 63 ] ], "normalized": [] }, { "id": "entity-199-1", "type": "DISEASE", "text": [ "Psoriasis" ], "offsets": [ [ 66, 75 ] ], "normalized": [] }, { "id": "entity-199-2", "type": "DISEASE", "text": [ "immune-mediated disease" ], "offsets": [ [ 88, 111 ] ], "normalized": [] }, { "id": "entity-199-3", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 356, 365 ] ], "normalized": [] }, { "id": "entity-199-4", "type": "ADVERSE", "text": [ "erythrodermias" ], "offsets": [ [ 840, 854 ] ], "normalized": [] }, { "id": "entity-199-5", "type": "ADVERSE", "text": [ "palmoplantar pustulosis" ], "offsets": [ [ 858, 881 ] ], "normalized": [] }, { "id": "entity-199-6", "type": "ADVERSE", "text": [ "flexural psoriasis" ], "offsets": [ [ 885, 903 ] ], "normalized": [] }, { "id": "entity-199-7", "type": "ADVERSE", "text": [ "eczema" ], "offsets": [ [ 907, 913 ] ], "normalized": [] }, { "id": "entity-199-8", "type": "ADVERSE", "text": [ "neutrophilic dermatosis" ], "offsets": [ [ 917, 940 ] ], "normalized": [] }, { "id": "entity-199-9", "type": "ADVERSE", "text": [ "papular eruption" ], "offsets": [ [ 947, 963 ] ], "normalized": [] }, { "id": "entity-199-10", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 1178, 1187 ] ], "normalized": [] }, { "id": "entity-199-11", "type": "DISEASE", "text": [ "chronic inflammatory diseases" ], "offsets": [ [ 1198, 1227 ] ], "normalized": [] } ]

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