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fe175754297258a1f3caa314f0949acf

We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition ; this phenomenon was associated with altered conductance through Ca²⁺ and voltage-activated K⁺ ( BK ) channels , and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling .

Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules. melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition ; this phenomenon was associated with altered conductance through Ca²⁺ and voltage-activated K⁺ ( BK ) channels , and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling . The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer.

https://pubmed.ncbi.nlm.nih.gov/22532966/

e609fcfa45531012af6f10e72c76a75b

It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration .

Treatment of adult acute lymphoblastic leukemia with cytosine arabinoside, vincristine, and prednisone. Thirteen adults with acute lymphoblastic leukemia were entered into a protocol in which cytosine arabinoside infusion was added to vincristine and prednisone as remission induction and periodic intensification therapy. Central nervous system prophylaxis consisting of cranial irradiation and intrathecal methotrexate was given, and all patients received continuous oral 6-mercaptopurine and methotrexate as maintenance treatment. Myelotoxicity was severe during induction, with prolonged granulocyte and platelet count nadirs noted. Nine of 13 patients (69%) obtained a complete remission and one (8%) obtained a partial remission. The median duration of complete remission was 38.1 weeks. It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration .

https://pubmed.ncbi.nlm.nih.gov/356988/

c178c4c3b519362980989cb290ad3e8e

Patients were categorized into 10 groups according to the index OAC ( warfarin , rivaroxaban , dabigatran , apixaban , and edoxaban ) and whether or not they received PPI co-therapy , and were followed up for incidence of major GIB .

Proton Pump Inhibitor Co-Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulants and a Prior History of Upper Gastrointestinal Tract Bleeding. The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. ### methods Using a nationwide claims database, OAC-naïve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC ( warfarin , rivaroxaban , dabigatran , apixaban , and edoxaban ) and whether or not they received PPI co-therapy , and were followed up for incidence of major GIB . ### results Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6 years (interquartile ranges 0.2-1.7 years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. ### conclusion Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.

https://pubmed.ncbi.nlm.nih.gov/33730289/

9d6fcba2e6520c9c80bdedbaa4495ed7

Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin , etoposide , irinotecan or vincristine in vitro .

Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo. Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2-specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. ### Experimental Design Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. ### results Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin , etoposide , irinotecan or vincristine in vitro . In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. ### conclusions celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. celecoxib could also be a potential drug for treatment of minimal residual disease.

https://pubmed.ncbi.nlm.nih.gov/17289900/

67c22a91de33a9ba2240f12810ebef2e

In vivo , midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments .

Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis. An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-κB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo , midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments . Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.

https://pubmed.ncbi.nlm.nih.gov/30584254/

f67b8b02b47a8036885907fa7d3afd2b

Treatment of GIST882-R with imatinib in combination with gefitinib , an EGFR inhibitor , partially prevented cell growth , implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST .

Augmentation of multiple protein kinase activities associated with secondary imatinib resistance in gastrointestinal stromal tumors as revealed by quantitative phosphoproteome analysis. Mutations in the Kit receptor tyrosine kinase gene (KIT), which result in constitutive activation of the protein (KIT), are causally related to the development of gastrointestinal stromal tumors (GISTs). imatinib, a targeted anticancer drug, exerts a therapeutic effect against GISTs by repressing the kinase activity of KIT. Long-term administration of this drug, however, causes the emergence of imatinib-resistant GISTs. We performed quantitative phosphoproteome analysis using a cell-based GIST model system comprising an imatinib-sensitive GIST cell line (GIST882), GIST882 under treatment with imatinib (GIST882-IM), and secondary imatinib-resistant GIST882 (GIST882-R). Phosphorylated peptides were purified from each cell line using titania-based affinity chromatography or anti-phosphotyrosine immunoprecipitation, and then subjected to LC-MS/MS based quantitative phosphoproteome analysis. Using this method we identified augmentation of the kinase activities of multiple elements of the signal transduction pathway, especially KIT and EGFR. Although, these elements were up-regulated in GIST882-R, no additionally mutated KIT mRNA was found in secondary imatinib-resistant GIST cells. Treatment of GIST882-R with imatinib in combination with gefitinib , an EGFR inhibitor , partially prevented cell growth , implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST . ### Biological Significance In this study, we performed a quantitative phosphoproteome analysis using a cell culture-based GIST model system. The goal of the study was to investigate the mechanism of acquired resistance in GISTs against imatinib, a molecularly targeted drug that inhibits kinase activity of the KIT protein and that has been approved for the treatment of GISTs. In imatinib-resistant GIST cells, we observed elevated expression of KIT and restoration of its kinase activity, as well as activation of multiple proliferative signaling pathways. Our results indicate that the effects of even so-called 'molecularly targeted' drugs, are broad rather than convergent, and that the mechanisms of action of such drugs during continuous administration are extremely complex.

https://pubmed.ncbi.nlm.nih.gov/25554490/

2e01a54adda80b3e1acdce028954a1a4

This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients , providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer .

Combination treatment of tamoxifen with risperidone in breast cancer. tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients , providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer .

https://pubmed.ncbi.nlm.nih.gov/24886861/

e94ef24785140b8074e7ae63e5a592e8

Amoxicillin , erythromycin , and levofloxacin at supra-MIC concentrations were very active against planktonic cells of 3 selected strains but lower on biofilm-associated organisms in 2 strains and null against the third .

Biofilm formation by Streptococcus pneumoniae strains and effects of human serum albumin, ibuprofen, N-acetyl-l-cysteine, amoxicillin, erythromycin, and levofloxacin. Streptococcus pneumoniae ability to produce biofilms may induce persistent infections and difficulties for eradication in vivo. We investigated the ability of 11 pneumococcal strains (serotypes 3, 6B, 9V, 19F, and 23F) to form biofilms on polystyrene plates at 16 and 24 h. The extent of biofilm was greater at 24 h in 10 strains, being the highest magnitude for serotype 3 strains. Human serum albumin at 25,000 microg/mL and ibuprofen at 128 microg/mL significantly reduced biofilm formation in 7 and 5 strains, respectively. Amoxicillin , erythromycin , and levofloxacin at supra-MIC concentrations were very active against planktonic cells of 3 selected strains but lower on biofilm-associated organisms in 2 strains and null against the third . Although N-acetyl-l-cysteine had very little activity against both planktonic and biofilm-forming organisms, when combined with the 3 antibiotics, a slightly enhanced activity against biofilm-embedded organisms in 1 strain and combined with amoxicillin in another one was observed.

https://pubmed.ncbi.nlm.nih.gov/20638597/

e3f8061263e9c92e36bbc4142eefa57f

A double-blind , parallel , placebo-controlled study was performed to assess the efficacy of a combination drug product containing the antihistamine , triprolidine , and the sympathomimetic , pseudoephedrine , in the treatment of allergic rhinitis .

An evaluation of triprolidine and pseudoephedrine in the treatment of allergic rhinitis. A double-blind , parallel , placebo-controlled study was performed to assess the efficacy of a combination drug product containing the antihistamine , triprolidine , and the sympathomimetic , pseudoephedrine , in the treatment of allergic rhinitis . Allergic rhinitis was defined on the basis of coexistent nasal congestion and an aggregate symptom complex score which exceeded a pre-established value. pseudoephedrine and triprolidine were shown to make distinct and separate contributions to the treatment of allergic rhinitis defined in this manner.

https://pubmed.ncbi.nlm.nih.gov/7258744/

cd58d1b74e20986d75608ae49ee926e2

After surgery , 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide ( EC ; 90 and 600 mg/m(2 ) , respectively , × four cycles ) , followed by docetaxel ( 100 mg/m(2 ) × four cycles ; EC-T ) or epirubicin plus docetaxel ( ET ; 90 and 75 mg/m(2 ) , respectively , × four cycles ) , followed by capecitabine ( 1,250 mg/m(2 ) twice a day on days 1 to 14 , × four cycles ; ET-X ) ; all regimens were given every 3 weeks .

Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study. capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. ### Patients And Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery , 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide ( EC ; 90 and 600 mg/m(2 ) , respectively , × four cycles ) , followed by docetaxel ( 100 mg/m(2 ) × four cycles ; EC-T ) or epirubicin plus docetaxel ( ET ; 90 and 75 mg/m(2 ) , respectively , × four cycles ) , followed by capecitabine ( 1,250 mg/m(2 ) twice a day on days 1 to 14 , × four cycles ; ET-X ) ; all regimens were given every 3 weeks . The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). ### results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). ### conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

https://pubmed.ncbi.nlm.nih.gov/26416999/

978592058e063b76a9516013aa601c76

This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab .

Association of HER-2 copy number and HER-2/CEP-17 ratio with neoadjuvant taxane-containing chemotherapy sensitivity in locally advanced breast cancer. Aneusomy 17 causes inconsistency in fluorescence in situ hybridization (FISH)-based human epidermal growth factor receptor (HER)-2 status assessment using different algorithms (copy number or the HER-2/centromere enumerator probe 17 [CEP-17] ratio). We investigated the effects of FISH-based HER-2 status assessment and aneusomy 17 on responsiveness to neoadjuvant chemotherapy (NAC). ### Patients And Methods This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab . ### results The pathologic complete remission (pCR) rate in the breast and axilla was 24.3% (95% confidence interval [CI], 17.7%-32.0%). Although HER-2 status, assessed by either HER-2/CEP-17 ratio-based FISH or copy number-based FISH, was a predictor of NAC sensitivity, ratio-assessed HER-2 status had a poorer performance in determining patients' responsiveness to NAC (p = .029). Patients who were not HER-2 amplified when assessed using the HER-2/CEP-17 ratio but were HER-2 amplified when assessed using copy number (~5%) were eventually proven to be responsive to NAC, with a pCR rate of 57% (95% CI, 18.4%-90.1%). In contrast, patients who were HER-2 amplified when assessed by the ratio but not HER-2 amplified when assessed using copy number (~3%) were completely irresponsive. Higher HER-2 copy numbers represented increasing chances of a pCR (adjusted odds ratio, 3.09; 95% CI, 1.35-7.08), with an apparent gene-dose effect (p for trend < .001). ### conclusion It is likely that HER-2 copy number but not the HER-2/CEP-17 ratio determines NAC sensitivity. Additional studies to validate our findings are warranted.

https://pubmed.ncbi.nlm.nih.gov/22561335/

702912841ec686e82c8e3e19682f76d9

High response rate and acceptable toxicity of a combination of rituximab , vinorelbine , ifosfamide , mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study .

High response rate and acceptable toxicity of a combination of rituximab , vinorelbine , ifosfamide , mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study . The optimal management of relapsed diffuse large B-cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leucémies et aAutres Maladies du Sang developed a combination of vinorelbine, ifosfamide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18-75 years. Patients received rituximab 375 mg/m² day 1, ifosfamide 1000 mg/m² days 1-5, vinorelbine 25 mg/m² days 1 and 15, mitoxantrone 10 mg/m² day 1, and prednisone 1 mg/kg days 1-5, every 28 days for three cycles. Responding patients underwent autologous transplantation or received three additional R-NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non-germinal centre B immunophenotype was associated with shorter progression-free survival. in conclusion, the R-NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.

https://pubmed.ncbi.nlm.nih.gov/23692641/

de1bf6c32ec082fe4cb33f57d88827ee

A second complete remission was obtained with RFC chemotherapy regimen ( rituximab , fludarabine , and cyclophosphamide ) .

Bing and neel syndrome. Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenström's macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen ( rituximab , fludarabine , and cyclophosphamide ) . In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM.

https://pubmed.ncbi.nlm.nih.gov/22988532/

974b0e10447488e9814e90bc4e274dcc

At a median duration of follow-up of 18.2 months , anastrozole was at least equivalent to tamoxifen in terms of median TTP ( 8.5 and 7.0 months , respectively ; estimated hazard ratio [ tamoxifen relative to anastrozole ] , 1.13 [ lower 95 % confidence level , 1.00 ] ) .

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. ### methods The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. ### results At a median duration of follow-up of 18.2 months , anastrozole was at least equivalent to tamoxifen in terms of median TTP ( 8.5 and 7.0 months , respectively ; estimated hazard ratio [ tamoxifen relative to anastrozole ] , 1.13 [ lower 95 % confidence level , 1.00 ] ) . In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. ### conclusions In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.

https://pubmed.ncbi.nlm.nih.gov/11745278/

393ff550cc8686a0aa016fefad4777bc

A favourable response to chemotherapy can be expected in up to 60 % of patients receiving a combination of streptozocin plus doxorubicin , and in up to 40 % of patients receiving dacarbazine .

Endocrine tumours of the gastrointestinal tract: Chemotherapy. Malignant neuroendocrine tumours are less sensitive to chemotherapy than other epithelial malignancies. If chemotherapy is considered, tumours of pancreatic origin have a higher sensitivity than tumours from the gastrointestinal tract ('carcinoids'). Chemotherapy with streptozocin combinations and with dacarbazine should be considered in patients with progressive malignant neuroendocrine tumours of the pancreas. A favourable response to chemotherapy can be expected in up to 60 % of patients receiving a combination of streptozocin plus doxorubicin , and in up to 40 % of patients receiving dacarbazine . A survival benefit has been shown for streptozocin combinations. Treatment regimens are effective in functioning and non-functioning tumours. The response to treatment cannot be predicted. Poorly differentiated neuroendocrine tumours, independent of their origin, respond to a combination of etoposide plus cisplatin. Chemotherapy is, however, almost ineffective in patients with well-differentiated neuroendocrine tumours originating in the gastrointestinal tract ('carcinoids').

https://pubmed.ncbi.nlm.nih.gov/16183533/

fa9ceb85fec23bbd0522dd1f81e97f53

A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B ) and 5-HT(2C ) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine .

Behavioural satiety sequence (BSS): separating wheat from chaff in the behavioural pharmacology of appetite. The history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use. In view of recent progress in our understanding of the multiplicity of signalling pathways involved in appetite regulation, and the resultant deluge of reports on the anorectic efficacy of novel therapies, it seems timely to stress the need to differentiate treatments that suppress intake by primary means from those that only indirectly achieve this endpoint. The current article reviews the conceptual history of the behavioural satiety sequence (BSS), also known as the behavioural sequence of satiety, post-ingestive satiety, and the postprandial satiety sequence. Early research confirmed that natural satiation, produced by a caloric load on the gut, is associated with a predictable transition from feeding through grooming to resting. Although many less naturalistic manipulations are also capable of reducing food intake, very few do so without disrupting the normal structure of this feeding cycle. Thus, while CCK and d-fenfluramine reduce intake by accelerating but otherwise maintaining the integrity of the BSS, other anorectic interventions disrupt the BSS through response competition (e.g. d-amphetamine), nausea/discomfort (e.g. lithium chloride) and/or interference with taste-mediated positive feedback (e.g. quinine adulteration of the diet). A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B ) and 5-HT(2C ) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine . Recent BSS analyses have also identified rather selective anorectic profiles for the dual noradrenaline and 5-HT reuptake inhibitor sibutramine, the orexin-1 receptor antagonist SB-334867, and the broad spectrum opioid receptor antagonist naloxone. However, similar analyses have offered little/no support for the anorectic potential of the gut peptide PYY(3-36) while the acute anorectic efficacy of cannabinoid CB1 receptor antagonist/inverse agonists appears largely to be secondary to response competition. In contrast, studies with low-dose combinations of naloxone and CB1 receptor antagonist/inverse agonists have very recently confirmed the potential of drug polytherapies not only in appetite suppression but also in attenuating/eliminating unwanted side-effects. In sum, as BSS analysis offers a reliable means of differentiating the wheat (primary anorectics) from the chaff (secondary anorectics), it should form an integral part of early phase testing in any anti-obesity drug screening programme.

https://pubmed.ncbi.nlm.nih.gov/20214921/

3333180a9b1fedb5e1a21a31df3b039a

Pilocarpine also induced secretion at a concentration as low as 1 μM and was the most powerful secretagogue at 10 μM. Secretion was induced by carbachol at 0.1 μM , with maximum secretion at 1.0 μM.

Cevimeline-induced monophasic salivation from the mouse submandibular gland: decreased Na+ content in saliva results from specific and early activation of Na+/H+ exchange. cevimeline and pilocarpine are muscarinic agonists used clinically to treat dry mouth. In this study, we explored fluid secretion from mouse submandibular glands to determine the mechanism of cevimeline, pilocarpine, and an experimentally used agent carbachol. cevimeline evoked almost the same amount of secretion at concentrations from 30 μM to 1 mM. Pilocarpine also induced secretion at a concentration as low as 1 μM and was the most powerful secretagogue at 10 μM. Secretion was induced by carbachol at 0.1 μM , with maximum secretion at 1.0 μM. cevimeline induced monophasic secretion at all concentrations tested, whereas higher concentrations of pilocarpine and carbachol induced secretion with variable kinetics, i.e., an initial transient high flow rate, followed by decreased secretion after 2 to 3 min. In the presence of an epithelial Na(+) channel blocker, amiloride, neither carbachol nor pilocarpine affected the Na(+) level of secreted saliva; however, it significantly increased the Na(+) content of cevimeline-induced saliva. The intracellular Ca(2+) response of acinar cells was almost identical among all three agents, although recovery after drug removal was slower for cevimeline and pilocarpine. A profound decrease in intracellular pH was observed during pilocarpine and carbachol treatment, whereas intracellular acidification induced by cevimeline was only seen in the presence of a Na(+)/H(+) exchange inhibitor. When external HCO(3)(-) was removed, cevimeline-induced saliva significantly decreased. These findings suggest that cevimeline specifically activates Na(+)/H(+) exchange and may promote Na(+) reabsorption by stabilizing epithelial sodium channel activity.

https://pubmed.ncbi.nlm.nih.gov/21239510/

342b18aa94a0107a5f0487598f751b34

This phase II study was conducted to establish whether induction chemotherapy with carboplatin ( CBDCA ) and paclitaxel ( PTX ) plus bevacizumab prior to surgery reduces the risk of progression .

Phase II trial of induction chemotherapy with carboplatin and paclitaxel plus bevacizumab in patients with stage IIIA to IV nonsquamous non-small cell lung cancer. Surgery remains the best curative treatment option for non-small cell lung cancer (NSCLC), but is of benefit only to patients with localized disease. A meta-analysis showed a significant beneficial effect of induction chemotherapy on survival, but there is still no clear evidence. This phase II study was conducted to establish whether induction chemotherapy with carboplatin ( CBDCA ) and paclitaxel ( PTX ) plus bevacizumab prior to surgery reduces the risk of progression . ### methods The subjects of this study were 29 patients with treatment-naive nonsquamous NSCLC (clinical stages IIIA to IV). Patients received PTX (200 mg/m ### results The overall response rate was 72.4%. Of the 29 patients, ten underwent surgery after the induction chemotherapy and complete resection was achieved in 7 (70%). The median progression-free-survival (PFS) time and the 3-year PFS rate were 0.92 years and 16.2%, respectively. The median overall survival (OS) time and the 3-year OS rate were 1.96 years and 44.9%, respectively. ### conclusion Combined modality therapy with surgery after induction chemotherapy with CBDCA and PTX plus bevacizumab is clinically feasible and tolerable for patients with unknown or negative molecular profiles.

https://pubmed.ncbi.nlm.nih.gov/30826861/

8caeec4c972d1568c6153dc1fac3df09

In women of childbearing potential , valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage .

Treatment options in juvenile myoclonic epilepsy. Juvenile myoclonic epilepsy (JME) is characterized by excellent response to treatment, if diagnosed correctly. Lifestyle advice is an integral part of the treatment of JME; it should include recommendations on avoidance of common triggers such as sleep deprivation and alcohol excess and emphasis on the importance of compliance with medication. The drug of first choice in the treatment of JME is sodium valproate, which has a response rate of up to 80%. Valproate should be avoided in women of childbearing age because of significantly increased risks of fetal malformations and neurodevelopmental delay. levetiracetam or lamotrigine are alternative first-line options if valproate is contraindicated. With limited data from trials to support either of these drugs, the choice should take into account comorbidity factors and patient priorities. Because of its low side effect profile, excellent tolerability, and lack of interactions with other drugs, levetiracetam is our preferred alternative first-line agent. lamotrigine is another first-line option but may exacerbate myoclonus. The failure of valproate or failure of two first-line antiepileptic drugs suggests that combination therapy is indicated. Drug interactions and the patient's gender, age, and comorbidities need to be considered. levetiracetam, lamotrigine, and valproate are suitable adjuncts, with a synergistic effect reported from the combination of valproate and lamotrigine. clonazepam is a useful adjunct for myoclonus and can be used in combination with lamotrigine to avoid lamotrigine's myoclonic effects. In women of childbearing potential , valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage . topiramate is a cost-effective alternative monotherapy, but because of its poor tolerability, we recommend it as add-on treatment only. zonisamide should remain a second-line adjunct in the treatment of JME, owing to the lack of supportive data. Phenobarbital is the most cost-effective drug and can be used to control the seizures of JME when antiepileptic drugs are limited or too costly. carbamazepine, oxcarbazepine, and phenytoin can exacerbate absences and myoclonus and are therefore contraindicated, although they can improve control of tonic-clonic seizures when these are refractory to other medication. gabapentin, pregabalin, tiagabine, and vigabatrin are contraindicated and can worsen seizures. (tiagabine and vigabatrin have been reported to induce absence status epilepticus.) Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.

https://pubmed.ncbi.nlm.nih.gov/21494841/

f257c53b718d4eaaa73be8c3ff25c60d

Patients with clinically localized , intermediate- or high-grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) .

Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. Patients with clinically localized , intermediate- or high-grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) . Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. ### methods We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. ### results Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). ### conclusions Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

https://pubmed.ncbi.nlm.nih.gov/9647875/

8b8d94ebd51dba1ac76a5865fda14eb7

To evaluate the effects of a fixed combination of olmesartan/amlodipine compared with olmesartan or amlodipine alone on some parameters of endothelial damage in diabetic , hypertensive patients .

Olmesartan Combined With Amlodipine on Oxidative Stress Parameters in Type 2 Diabetics, Compared With Single Therapies: A Randomized, Controlled, Clinical Trial. To evaluate the effects of a fixed combination of olmesartan/amlodipine compared with olmesartan or amlodipine alone on some parameters of endothelial damage in diabetic , hypertensive patients .We enrolled 221 patients; 74 were randomized to olmesartan 20 mg, 72 to amlodipine 10 mg, and 75 to olmesartan/amlodipine fixed combination 20/5 mg for 12 months. We assessed blood pressure monthly; in addition, we also assessed at baseline, and after 6 and 12 months, the following parameters: lipoprotein (a), myeloperoxidase (MPO), isoprostanes, and paraoxonase-1 (PON-1). Blood pressure values obtained with fixed olmesartan/amlodipine combination were significantly lower than those reached with single monotherapies. There was a reduction of lipoprotein (a), and isoprostanes levels with olmesartan/amlodipine fixed combination, both compared with baseline, and with single monotherapies. On the other hand, there was an increase of PON-1 with fixed olmesartan/amlodipine combination, both compared with baseline, and with single drugs. All treatments reduced MPO compared with baseline; however, in group-to-group comparison, MPO reduction was greater with olmesartan/amlodipine fixed combination. Fixed combination of olmesartan/amlodipine was more effective than single monotherapies in reducing oxidative stress, especially in increasing PON-1, and reducing isoprostanes levels in diabetic and hypertensive patients.

https://pubmed.ncbi.nlm.nih.gov/27043671/

8ae99858bbece53f14785ea1295dd424

Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer ( NSCLC ) than that of both agents in monotherapy .

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study. Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer ( NSCLC ) than that of both agents in monotherapy . ### methods This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m(2) (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. ### results Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1-6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29-59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3-4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3-4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). ### conclusion gemcitabine 1,000 mg/m(2) on days 1 and 8 in combination with docetaxel 85 mg/m(2) on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.

https://pubmed.ncbi.nlm.nih.gov/17273825/

b2f45e953ebd8acc0d2d99a6ed60565c

The use of HDCT-SCT in CNS metastases needs to be carefully considered , possibly by adding thiotepa or topotecan to improve tumor control .

Stem-Cell Therapy Following High-Dose Chemotherapy in Advanced Retinoblastoma: A Systematic Review. To analyze the risk and benefit of high-dose chemotherapy followed by stem cell transplantation (HDCT-SCT) treatment in patients with advanced retinoblastoma. ### design Systematic review. ### methods A comprehensive literature search from 4 online databases, including PubMed, Scopus, EBSCO, and Cochrane was done for original studies evaluating the use of HDCT followed by SCT in the treatment of patients with advanced retinoblastoma. The last search was performed on April 15, 2020. ### results A total of 35 studies consisting of 160 patients were considered suitable for inclusion. After HDCT-SCT treatment, 108/160 (67.5%) patients were alive with no evidence of disease at the last follow-up. The incidence of secondary malignancy in our data was also relatively low, which was 16/160 (10%) patients. The side effects were mainly hematological and gastrointestinal toxicities. The prognosis for metastatic cases especially the one to the central nervous system (CNS) remains poor, as shown in our data that 22 of 44 (50%) patients died due to the evidence of disease, and 12 of 44 (27%) patients acquired CNS relapse and died. ### conclusions HDCT-SCT is a promising treatment option in patients with advanced retinoblastoma. The use of HDCT-SCT in CNS metastases needs to be carefully considered , possibly by adding thiotepa or topotecan to improve tumor control . Further randomized clinical trials are needed to draw firm conclusion regarding its safety and efficacy.

https://pubmed.ncbi.nlm.nih.gov/33481395/

8030e5249393be52f9d124dfc63acd8d

Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors ( Cetuximab , Panitumumab , Zalutumumab ) , EGFR tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( Bevacizumab , Vandetanib ) , and various inhibitors of , e.g. , Src-family kinase , PARP , proteasome , mTOR , COX , and heat shock protein .

Targeted therapy in head and neck cancer. Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors ( Cetuximab , Panitumumab , Zalutumumab ) , EGFR tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( Bevacizumab , Vandetanib ) , and various inhibitors of , e.g. , Src-family kinase , PARP , proteasome , mTOR , COX , and heat shock protein . Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.

https://pubmed.ncbi.nlm.nih.gov/22373581/

782510b8d68226471251395f40f1440b

We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors ( phenylephrine , norepinephrine , dopamine , vasopressin or epinephrine ) to increase blood pressure

Vasopressor use and effect on blood pressure after severe adult traumatic brain injury. We describe institutional vasopressor usage, and examine the effect of vasopressors on hemodynamics: heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation (PbtO(2)), and jugular venous oximetry (SjVO(2)) in adults with severe traumatic brain injury (TBI). ### methods We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors ( phenylephrine , norepinephrine , dopamine , vasopressin or epinephrine ) to increase blood pressure ### results phenylephrine was the most commonly used vasopressor (43%), followed by norepinephrine (30%), dopamine (22%), and vasopressin (5%). Adjusted for age, gender, injury severity score, vasopressor dose, baseline blood pressure, fluid administration, propofol sedation, and hypertonic saline infusion, phenylephrine use was associated with 8 mmHg higher mean arterial pressure (MAP) than dopamine (P = 0.03), and 12 mmHg higher cerebral perfusion pressure (CPP) than norepinephrine (P = 0.02) during the 3 h after vasopressor start. There was no difference in ICP between the drug groups, either at baseline or after vasopressor treatment. ### conclusions Most severe TBI patients received phenylephrine. Patients who received phenylephrine had higher MAP and CPP than patients who received dopamine and norepinephrine, respectively.

https://pubmed.ncbi.nlm.nih.gov/20878264/

66de547f7916f338742dbd5bdb9fea53

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20 % , the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival .

FOLFOX/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy. While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20 % , the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival . However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.

https://pubmed.ncbi.nlm.nih.gov/25132748/

ad310a73917f2a65c49f1c5740a1b604

Chemotherapy was given in 405 of 410 treatment periods with dacarbazine , fotemustine , vindesine , carboplatin and temozolomide in different schedules .

Organ- and treatment-specific local response rates to systemic and local treatment modalities in stage IV melanoma. Metastatic melanoma shows different local response rates in organs to systemic or local treatment modalities. Whereas skin, soft tissue, lymph node and lung metastases seem to have better local response rates, the local response of metastases localized in the liver, brain and bone seems to be low. ### objectives The organ-specific response rate, local response rate of each therapeutic measure and survival of 68 patients with stage IV disease were evaluated. ### methods Four hundred and ten treatment periods (1-18 per patient) in 17 different organs of 43 men and 25 women (mean age 55 years, range 19-79) with measurable, widespread, surgically incurable disease were analysed. Chemotherapy was given in 405 of 410 treatment periods with dacarbazine , fotemustine , vindesine , carboplatin and temozolomide in different schedules . Local treatment modalities comprising radiotherapy, gamma knife radiosurgery and local hyperthermia were given in 71 of 410 treatment periods. ### results Local response (complete or partial local remission) was achieved in 52 treatment periods (12.7%). When local treatment modalities, either combined with systemic therapy or not, were compared with systemic therapeutic modalities alone, a local response of 24% was achieved with local measures, compared with 10% in systemic treatment only (P = 0.003). When a spontaneous remission rate of less than 5% is considered, however, local as well as systemic treatments had a significant effect (P < 0.001). Organ-specific response rates to local therapies showed no statistically significant differences between the various organs involved. When systemic treatments without local measures were taken into account, lung metastases, cutaneous/subcutaneous metastases and adrenal metastases performed significantly better than liver metastases. When different treatment modalities were considered, there was no significant difference between the three local measures applied (radiotherapy, gamma knife radiosurgery and hyperthermia). Among the systemic therapies, dacarbazine high dose and carboplatin monochemotherapy were superior to combined regimens using fotemustine. A local response, irrespective of the mode of therapy, was significantly associated with longer survival (median 16 months) compared with no local response or local progressive disease (median 7 months; P < 0.0001). When the first treatment period of each patient was considered, local response was no longer a significant predictor. ### conclusions The study shows that local therapeutic measures are superior in inducing a local response than systemic therapies alone. Induction of remission may be associated with longer survival. Chemotherapy, despite limited local response rates, is still statistically superior to an estimated spontaneous remission rate.

https://pubmed.ncbi.nlm.nih.gov/16225601/

c4e685add5c386bede07d3d0e7c7d983

[ Effect of nedaplatin , 5-FU , and leucovorin combined with radiation therapy in unresectable esophageal carcinoma ] .

[ Effect of nedaplatin , 5-FU , and leucovorin combined with radiation therapy in unresectable esophageal carcinoma ] . A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.

https://pubmed.ncbi.nlm.nih.gov/12795101/

77936ab1257411c5c8d55a4b43f4afca

After 5 years , approximately 30.8 % of etanercept patients and 68.8 % of monoclonal antibody patients ( adalimumab 71.2 % ; infliximab 67.2 % ) were still being treated .

Psoriatic arthritis treated by anti-TNFs: a monocentric trial of 102 cases in Auvergne, France. While several registries have already evaluated the retention of anti-TNF therapy in psoriatic arthritis (PsA), they sometimes reach divergent conclusions. Our study therefore sought to assess therapeutic retention rates and predictive factors of response in a patient cohort from Auvergne, France, followed up in routine clinical practice. ### methods Medical records of all PsA patients treated from 2002 to May 2015 were analysed. PsA diagnosis was established based on the CASPAR criteria. ### results In total, 102 patients were analysed, comprising 62 men (44.6±12.6 years) and 40 women (37.8±13.4). Mean PsA evolution was 2.7 years (0.8-11.2). The most common forms were peripheral (47/102, 45.1%) and mixed (46/102, 46.1%) PsA. The anti-TNF treatment initiated was etanercept in 47 cases (45.2%), adalimumab in 29 (27.9%), infliximab in 20 (19.2%), and golimumab in six [5.8%]. In 28 cases (27.4%), anti-TNF was associated with methotrexate (MTX). Overall, the median duration of anti-TNF retention was 76.5 months. The hazard ratios (HR) for treatment cessation did not significantly differ between the etanercept and monoclonal antibody groups (HR=1.35[0.96-1.93], p=0.08). After 5 years , approximately 30.8 % of etanercept patients and 68.8 % of monoclonal antibody patients ( adalimumab 71.2 % ; infliximab 67.2 % ) were still being treated . Combining with MTX did not prolong the overall retention rate (HR=0.85[0.37-1.96], p=0.71). Tobacco use was predictive of discontinuation (p=0.03). ### conclusions Our study demonstrates good anti-TNF treatment retention in PsA patients, as well as confirming the deleterious effect of smoking while providing no argument in favour of combined treatment with MTX to improve maintenance.

https://pubmed.ncbi.nlm.nih.gov/27607233/

bcf8beb68f7f3a805ddcdc34243375e9

( 4 mg/day ) ; in group 3 , 69 patients administered metformin ( 1,000 mg/day ) and rosiglitazone ( 4 mg/day ) for 6 months ,

Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial. To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. ### design Prospective randomized controlled trail. ### setting Tertiary teaching hospital. ### Patient S Obese Chinese women (body mass index [BMI] ≥25 kg/m ### Intervention S In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone ( 4 mg/day ) ; in group 3 , 69 patients administered metformin ( 1,000 mg/day ) and rosiglitazone ( 4 mg/day ) for 6 months , all with the same diet and regular exercise lifestyle recommendation. ### Main Outcome Measure S Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. ### Result S The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. ### Conclusion S Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. ### Clinical Trial Registration Number ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).

https://pubmed.ncbi.nlm.nih.gov/31718828/

080a1f6daab8cdd048d02a1e2eaf5a0d

In the intention-to-treat analysis , 57 % of patients that received tenecteplase and 53 % of patients that received alteplase reached good functional outcome ( modified Rankin Scale score of 0 - 1 ) at 3 months ( odds ratio , 1.19 ; 95 % CI , 0.68 - 2.10 ) .

Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Background and Purpose- Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods- The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results- The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2-6). In the intention-to-treat analysis , 57 % of patients that received tenecteplase and 53 % of patients that received alteplase reached good functional outcome ( modified Rankin Scale score of 0 - 1 ) at 3 months ( odds ratio , 1.19 ; 95 % CI , 0.68 - 2.10 ) . The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26-2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65-2.37). Conclusions- tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.

https://pubmed.ncbi.nlm.nih.gov/30602354/

a2068802121405329956c2ab8aeac3ce

The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy .

Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman. This is the first report of congenital adrenal hyperplasia (CAH) due to combined 17α-hydroxylase/17,20 lyase deficiency in an Omani patient who was initially treated for many years as a case of hypertension. CAH is an uncommon disorder that results from a defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and the types of accumulated steroid precursors. A 22-year-old woman who was diagnosed to have hypertension since the age of 10 years who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study were performed and the diagnosis was confirmed by molecular mutation study. Laboratory investigations revealed adrenal steroids and pituitary hormones profile in addition to 46XY karyotype that are consistent with the diagnosis of CAH due to 17α-hydroxylase deficiency. Extensive laboratory workup revealed low levels of serum cortisol (and its precursors 17α-hydroxyprogesterone and 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone sulfate and androstenedione), and estrogen (estradiol); and high levels of mineralocorticoids precursors (11-deoxycorticosterone and corticosterone) with high levels of ACTH, FSH and LH. Mutation analysis revealed CYP17A1-homozygous mutation (c.287G>A p.Arg96Gln) resulting in the complete absence of 17α-hydroxylase/17,20-lyase activity. The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy . A review of the literature was conducted to identify previous studies related to this subtype of CAH. This is the first biochemically and genetically proven case of CAH due to 17α-hydroxylase/17,20-lyase deficiency in Oman and in the Arab World described in the literature.

https://pubmed.ncbi.nlm.nih.gov/24498484/

b951d4bad97758b8d64e9f2a728d3f9a

Exposure of bss1 to clinically-used antiepileptic drugs ( phenytoin or gabapentin ) significantly reduces synchrony .

Calcium Imaging of Neuronal Activity in Drosophila Can Identify Anticonvulsive Compounds. Although there are now a number of antiepileptic drugs (AEDs) available, approximately one-third of epilepsy patients respond poorly to drug intervention. The reasons for this are complex, but are probably reflective of the increasing number of identified mutations that predispose individuals to this disease. Thus, there is a clear requirement for the development of novel treatments to address this unmet clinical need. The existence of gene mutations that mimic a seizure-like behaviour in the fruit fly, Drosophila melanogaster, offers the possibility to exploit the powerful genetics of this insect to identify novel cellular targets to facilitate design of more effective AEDs. In this study we use neuronal expression of GCaMP, a potent calcium reporter, to image neuronal activity using a non-invasive and rapid method. Expression in motoneurons in the isolated CNS of third instar larvae shows waves of calcium-activity that pass between segments of the ventral nerve cord. Time between calcium peaks, in the same neurons, between adjacent segments usually show a temporal separation of greater than 200 ms. Exposure to proconvulsants (picrotoxin or 4-aminopyridine) reduces separation to below 200 ms showing increased synchrony of activity across adjacent segments. Increased synchrony, characteristic of epilepsy, is similarly observed in genetic seizure mutants: bangsenseless1 (bss1) and paralyticK1270T (paraK1270T). Exposure of bss1 to clinically-used antiepileptic drugs ( phenytoin or gabapentin ) significantly reduces synchrony . In this study we use the measure of synchronicity to evaluate the effectiveness of known and novel anticonvulsive compounds (antipain, isethionate, etopiside rapamycin and dipyramidole) to reduce seizure-like CNS activity. We further show that such compounds also reduce the Drosophila voltage-gated persistent Na+ current (INaP) in an identified motoneuron (aCC). Our combined assays provide a rapid and reliable method to screen unknown compounds for potential to function as anticonvulsants.

https://pubmed.ncbi.nlm.nih.gov/26863447/

c01c2daec942afc34c5c4f3a1dafef29

When compared with the combination of amphotericin B plus flucytosine , fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis .

Effects of preventive, early, and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. To investigate the potential use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, its in vivo antifungal activity was studied in three models of disseminated candidiasis in persistently granulocytopenic rabbits: acute, subacute, and chronic disseminated candidiasis. fluconazole was compared with the combination of amphotericin B and flucytosine for preventive, early, and late treatment of disseminated candidiasis, depending on the model. fluconazole was most effective when used for preventive or early treatment of acute and subacute disseminated candidiasis. When compared with the combination of amphotericin B plus flucytosine , fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis . When treatment was delayed 6 days after established infection, fluconazole was less active in clearing tissues in comparison with its activity in preventive and early treatment. The combination of amphotericin B plus flucytosine, however, was significantly more active than fluconazole in treatment of chronic disseminated candidiasis in all tissues. In summary, fluconazole was most effective against disseminated candidiasis in persistently granulocytopenic rabbits when used for prevention or early treatment.

https://pubmed.ncbi.nlm.nih.gov/2138654/

f4198d736bd1ac7d37b16e95d79eb3a8

Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside , vincristine , and prednisone ( ROAP ) .

Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside , vincristine , and prednisone ( ROAP ) . We administered a combination of rubidazone, cytosine arabinoside, vincristine, and prednisone (ROAP) to 91 patients with acute myelogenous leukemia who were 50 yr of age or older. These patients had been identified in previous studies to be a group with a relatively poor prognosis. One-third of the patients had an antecedent hematologic disorder prior to treatment. Forty patients (48%) obtained a complete hematologic and clinical remission. A history of an antecedent hematologic disorder, male sex, and absence of Auer rods were adverse factors for achieving remission in this older population. More than half of the patients achieved remission in one course. The major cause of failure to obtain a remission was death due to infection, 40% of which were caused by fungi. Resistance to chemotherapy, although uncommon, was noted more frequently in patients with an antecedent hematologic disorder. Univariate and multivariate prognostic factor analysis was used to compare these patients with a historical control group treated with a program in which adriamycin was used instead of rubidazone (AdOAP). No significant difference in remission rate was detected. Cyclocytidine was used as a maintenance agent in this study, and while the median remission duration was only 37 wk, 30% of patients are expected to be in remission for 2 yr. Chemotherapy programs combining an anthracycline with cytosine arabinoside, given to older patients in similar fasion to younger patients will achieve remissions in one-half of a group of older patients. These remissions are of comparable quality to those of younger patients. Mathematical models derived from analysis of prognostic factors are of use in identifying patients likely to fail these programs who are in need of innovative approaches to treatment.

https://pubmed.ncbi.nlm.nih.gov/6942848/

fdcac5bfcc99b822df604cef2bffb127

Patients progressing after first-line chemotherapy are treated with docetaxel , pemetrexed or erlotinib .

Chemotherapy of advanced non-small cell lung cancer. Patients with advanced NSCLC receive palliative chemotherapy with platinum-based doublets. Cisplatin-based doublets are preferred in patients with good performance status, whereas carboplatin-based protocols are preferred in patients with impaired organ functions (kidney, heart). Customized chemotherapy appears promising but still remains experimental. Improvements of the outcome of first-line chemotherapy have been achieved by the addition of cetuximab in patients with EGFR-positive NSCLC and of bevacizumab in selected patients with non-squamous cell NSCLC. The optimal combination of chemotherapy with targeted therapies remains a challenge. Maintenance therapy and early second-line chemotherapy might improve outcome but are not yet considered as standard treatments. Patients progressing after first-line chemotherapy are treated with docetaxel , pemetrexed or erlotinib . Finally, the efficacy of new anticancer treatments should be assessed by several clinical endpoints with overall survival remaining the most important endpoint in patients with advanced NSCLC.

https://pubmed.ncbi.nlm.nih.gov/19955802/

6c805952d028fae25b74c03c73e50488

To compare the therapeutic effect of α(2 ) and α(4 ) integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate , 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model .

Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy. To compare the therapeutic effect of α(2 ) and α(4 ) integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate , 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model . ### methods Colitis was induced in balb/c mice with 2.5-3.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. ### results Treatment with anti-α(2) antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-α(2) antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-α(2) antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1β at the mRNA level, while the anti-α(2) antibody group displayed decreased protein expression of iNOS and IL-1β. ### conclusions Specific blocking of extravascular trafficking of leucocytes with α(2)-antibodies could be a new beneficial drug target in inflammatory bowel disease.

https://pubmed.ncbi.nlm.nih.gov/23009282/

543d288140376a20b71334d3c0ffcfcf

Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine .

Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis. paclitaxel, the first member of taxanes, is one of the most active chemotherapeutic agents developed in the last decade for the treatment of advanced breast cancer and many other types of solid tumors. The promising clinical activity of paclitaxel has also promoted considerable interest in combining this drug with other anti-tumor agents. In this study, we assessed the cytotoxic interaction between paclitaxel and gemcitabine administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, DNA fragmentation, and flow cytometric analyses, we found that gemcitabine could significantly antagonize the cytotoxic effects of paclitaxel when tumor cells were exposed to the two drugs simultaneously or exposed to gemcitabine before paclitaxel. However, there was little antagonistic interaction observed when paclitaxel was administered before gemcitabine. Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine . In addition, biochemical examinations revealed that pretreatment or cotreatment of gemcitabine inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation that are believed to play critical roles in the signal pathways leading to apoptotic cell death. These results indicate that the interaction between paclitaxel and gemcitabine is highly schedule dependent. Exposure of tumor cells to gemcitabine before paclitaxel or two drugs simultaneously could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to paclitaxel followed by gemcitabine.

https://pubmed.ncbi.nlm.nih.gov/16855376/

d4af3bd7f0037132c5d1b2c3bd96e0c4

Standard anticonvulsants such as phenytoin , the barbiturates , carbamazepine , and the succinimides have been ineffective .

Treatment of infantile spasms. To summarize and evaluate the literature regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms. ### Data Sources A literature search of articles from January 1966 to July 1993 using MEDLINE, EM-Base, and Current Concepts/Life Sciences, as well as bibliographies of relevant articles. ### Study Selection All identified original and review publications regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms were reviewed. Emphasis was placed on original studies published since 1975. ### Data Extraction Data from published research were extracted and evaluated according to study design, sample size, dosing regimen, outcome measures, and treatment efficacy and safety. ### Data Synthesis Infantile spasms constitute a rare epileptic syndrome with a poor long-term prognosis for normal intellectual development. The spasms are characterized by a brief symmetric contraction of the muscles of the neck, trunk, and/or extremities, often occurring in a series of 2 to more than 100 spasms during a single episode. The disorder is age-specific, with the peak onset of symptoms occurring between 2 and 8 months of age. Spasms of no identifiable cause in infants with normal development prior to the onset of infantile spasms are classified as cryptogenic or idiopathic, whereas those with an identifiable cause are classified as symptomatic. Long-term prognosis is best in cryptogenic cases, with 30-70 percent attaining normal intellect compared with 5-19 percent in symptomatic cases. The etiology and pathophysiology are not well understood. Recent theory postulates that infantile spasms may be caused by an excess of corticotropin-releasing hormone activity during infancy. The suspected association between the whole-cell pertussis vaccine and infantile spasms is coincidental. Few well-designed, prospective, controlled clinical trials for the treatment of infantile spasms have been conducted. ### conclusions Standard anticonvulsants such as phenytoin , the barbiturates , carbamazepine , and the succinimides have been ineffective . Of the anticonvulsants, only the benzodiazepines, valproic acid, and vigabatrin have shown efficacy in reducing spasm frequency and severity. Hormonal therapy with adrenocorticotropic hormone (ACTH) and/or prednisone has been the most frequently studied treatment modality and appears to be the most effective. Hormonal therapy achieves complete spasm control in 50-75 percent of infants within four weeks of initiation. Opinions differ regarding the relative efficacy between ACTH and prednisone, the need for early initiation of hormonal treatment, and the benefits of high dosages of ACTH (> 40 units/d). No treatment has been shown conclusively to improve the long-term intellectual development of these infants. Neurosurgery may be the treatment of choice in select cases when a localized central nervous system abnormality can be demonstrated. Well-designed, blind, prospective clinical trials are needed to answer definitively many lingering questions regarding the treatment of infantile spasms.

https://pubmed.ncbi.nlm.nih.gov/7919570/

6ae0095c9a8f6cbc8960a54c0af639de

Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.

Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin, a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore. ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.

https://pubmed.ncbi.nlm.nih.gov/33773562/

eac9584c2367a897c3d5f005ad38e353

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma .

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma . lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. ### methods We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. ### results At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 ### conclusions Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

https://pubmed.ncbi.nlm.nih.gov/31141632/

ad06d06e0a0caf1864998ab4d0c1f297

Noninferiority was concluded if the lower limit of the 2-sided 95 % CI for the difference ( doripenem minus meropenem ) in the proportion of patients classified as clinical cures was > or=-15 % .

Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. ### objective This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. ### methods In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (>or=1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95 % CI for the difference ( doripenem minus meropenem ) in the proportion of patients classified as clinical cures was > or=-15 % . ### results A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. ### conclusions The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.

https://pubmed.ncbi.nlm.nih.gov/18555934/

a6b383436a2def1c9d1067bc8d6224bd

We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab .

Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. : Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab . A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. ### Implications For Practice Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.

https://pubmed.ncbi.nlm.nih.gov/27401894/

1907ac711e449549c62aa9eaa1332cb9

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV .

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV . This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). ### Patients And Methods We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. ### results 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)). ### conclusion The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

https://pubmed.ncbi.nlm.nih.gov/22564713/

414a3e5812a4517cf6870ce0c8570e17

One subject who received oxaprozin for 12 days and , in addition , aspirin for the last five days developed a rash that subsided after both drugs were discontinued ; one subject treated with aspirin experienced tinnitus .

Effects of oxaprozin alone or in combination with aspirin on hemostasis and plasma protein binding. oxaprozin, a new nonsteroidal antiinflammatory agent, was studied alone and in combination with aspirin for its effects on hemostasis and protein binding in 10 healthy adults. When both oxaprozin and aspirin were given separately for seven days and in combination for five days, both drugs prolonged bleeding time and inhibited collagen- and epinephrine-induced platelet aggregation to a similar degree. The effects of the combination of oxaprozin and aspirin were not additive. The data from the protein binding study showed that oxaprozin was more than 99 per cent bound to plasma proteins. aspirin displaced oxaprozin from its binding sites. As a result, the rate of plasma clearance of oxaprozin significantly increased from 20 to 26 ml/min/kg (P less than 0.05), and the plasma half-life decreased from 45 to 40 hours. Platelet count and the humoral clotting mechanism were not affected by either drug alone or in combination. There was no clinical evidence of bleeding. One subject who received oxaprozin for 12 days and , in addition , aspirin for the last five days developed a rash that subsided after both drugs were discontinued ; one subject treated with aspirin experienced tinnitus . These data suggest that oxaprozin, like aspirin and other nonsteroidal antiinflammatory drugs, should be used with caution when administered to patients who have suffered trauma, who undergo surgery, or who have known defects in hemostasis.

https://pubmed.ncbi.nlm.nih.gov/6863578/

85712f0944108b11c6b5f2c0e8251f98

To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis ( MDRTB ) after undergoing solid organ transplantation .

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population. To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis ( MDRTB ) after undergoing solid organ transplantation . ### design Retrospective analysis. ### setting Community outpatient clinic. ### patients Forty-eight recipients of solid organ transplants beginning prophylaxis for MDRTB during August 1999 after possible exposure to a single index case of multidrug-resistant Mycobacterium tuberculosis within our community ### intervention Prophylaxis consisted of pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day, administered for 1 year. ### Measurements And Main Results Thirteen (27.1%) of the 48 patients completed therapy; 27 (56.3%) discontinued therapy within 4 months due to adverse drug events. Gastrointestinal intolerance was the major adverse event resulting in early discontinuation. ### conclusion Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.

https://pubmed.ncbi.nlm.nih.gov/12066961/

e13b097056767107755caa524612eabc

Additive effect of the combination of griseofulvin and ketoconazole against Microsporum canis in vitro .

Additive effect of the combination of griseofulvin and ketoconazole against Microsporum canis in vitro . The susceptibility of 28 strains of Microsporum canis to griseofulvin, to ketoconazole and to a combination of both antifungal drugs was determined. griseofulvin proved to be more active than ketoconazole. The combination of both antifungal agents was found to exert an additive effect.

https://pubmed.ncbi.nlm.nih.gov/2608097/

78699e90df5077a96bf93983a2dc5f1e

Aprepitant plus ondansetron may increase acute-CR , may have benefit regarding CINV 's effect on QoL , and is safe for 5-day temozolomide compared to ondansetron .

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide. CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. ### methods One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m ### results Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. ### conclusions Aprepitant plus ondansetron may increase acute-CR , may have benefit regarding CINV 's effect on QoL , and is safe for 5-day temozolomide compared to ondansetron . This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

https://pubmed.ncbi.nlm.nih.gov/31440823/

04b11f4bbe48e806b7a55b77e37e351a

Finally , a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide , which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function .

Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the FcγRIIIa-158F allele or the FcγRIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the FcγRIIIa-158V allele or the FcγRIIa-131H allele. Finally , a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide , which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function .

https://pubmed.ncbi.nlm.nih.gov/25510242/

f3d33152454e31c6b54af84d22ec03f9

Both liposomal doxorubicin ( LD ) and docetaxel ( D ) have a broad range of activity against solid tumors , including advanced pancreatic cancer ( APC ) , as single agents , while their combination has produced encouraging response rates in the treatment of several malignancies .

A phase-II study of liposomal doxorubicin and docetaxel in patients with advanced pancreatic cancer. Both liposomal doxorubicin ( LD ) and docetaxel ( D ) have a broad range of activity against solid tumors , including advanced pancreatic cancer ( APC ) , as single agents , while their combination has produced encouraging response rates in the treatment of several malignancies . We have conducted a Phase-II study in order to evaluate the tolerance and efficacy of their combination as front-line treatment in patients with APC. ### Patients And Methods Twenty-one chemotherapy-naïve patients with unresectable, locally-advanced or metastatic pancreatic cancer were enrolled. These included 16 males and 5 females with median age 66 years (range 57-80). Performance status (PS) was 0 (n = 10 pts), 1 (n = 7 pts) and 2 (n = 4 pts). D (80 mg/m2), and LD (30 mg/m2) were administered on day 1, every 3 weeks. RhG-CSF s.c. was given to all patients. At the time of analysis, all included patients were evaluated for toxicity and for response. ### results A total of 92 cycles were administered (4.38 cycles/patient). Partial response was achieved in 6 patients, with a median duration of response of 3 months. Stable disease was observed in 7 patients and progressive disease in 8 patients. The median duration of survival was 10 months (95% CI, 6-14 months) and the actuarial 1-year survival rate was 33.33%. With regard to toxicity, grades 3,4 neutropenia occurred in 8 (38%) patients and grades 3,4 thrombocytopenia in 4 (19%) patients. Non-hematological toxicity was recorded in 15 (71%) patients: grades 3,4 diarrhea (3 pts, 14%), hypersensitivity reactions (3 pt, 14%), grade 2 neurotoxicity (6 pts, 29%) and palmar-plantar erythrodysesthesia (9 pts, 43%). ### conclusion The doxorubicin and docetaxel combination was well-tolerated by these poor prognosis patients. Although both drugs have a marginal activity in pancreatic cancer, most patients experienced significant clinical improvement, with acceptable toxicity.

https://pubmed.ncbi.nlm.nih.gov/12552960/

457ab486b502454d826a4ff1764c5a89

Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer .

Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer . The aim of this study was to verify the efficacy--in the cure of duodenal ulcer associated H. pylori infection--of ranitidine 300 mg taken late in the evening or lansoprazole 30 mg taken before breakfast, coupled with clarithromycin and metronidazole. ### methods Eighty patients with endoscopically proven active duodenal ulcer were randomized to take ranitidine or lansoprazole for 4-8 wk, together with clarithromycin 250 mg b.i.d. and metronidazole 500 mg b.id. for the first 2 wk. Endoscopic controls, as well as histological and urease tests for H. pylori, were performed at entry and after 4 and 8 wk. ### results According to intent-to-treat analysis, ulcers were healed after 4 wk in 36/40 patients (90%) with ranitidine and in 38/40 (95%) with lansoprazole. After 8 wk, the healing percentage with ranitidine and lansoprazole was 97% (39/40) and 95% (38/40), respectively. H. pylori was eradicated in 85% of the patients taking ranitidine and in 90% of those taking lanzoprazole. Side effects were reported in 25% of the patients in both groups. ### conclusions Our results confirm that the combination of ranitidine, clarithromycin, and metronidazole can be considered an alternative to proton pump inhibitors in terms of clinical efficacy and economy.

https://pubmed.ncbi.nlm.nih.gov/9128316/

2ee98ff750189143f9fb1bb9c9fb70ff

A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats .

A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats . Myoglobinuric acute renal failure is the most important life threatening complication of rhabdomyolysis. Iron, free radicals, nitric oxide and cytochrome p450 are involved in the pathogenesis of mARF. The aim of this study is to compare the effect of cimetidine, l-carnitine and both agents together on mARF in rats. Forty rats were divided into 5 groups; group I: control rats, group II: myoglobinuric ARF rats, group III: mARF rats received l-carnitine (200mg/kg, i.p.), group IV: mARF rats received cimetidine (150mg/kg i.p.) and group V: mARF rats received both agents together. 48h after glycerol injection, systolic blood pressure was measured. Urine and blood samples were collected to evaluate urine volume, GFR, BUN, creatinine, K, Na, serum creatine kinase, NO and glutathione levels. Kidney specimens were taken to investigate renal cytochrome p450 and for histological examinations. cimetidine treatment significantly decreased creatinine, BUN, K, Na, SBP and creatine kinase and increased GFR and urine volume compared to group II. l-carnitine exerted similar changes except for the effect on K and GFR. NO was significantly decreased, while renal glutathione and cytochrome p450 were significantly increased in groups treated with l-carnitine or cimetidine as compared to group II. Combined treatment further improved renal functions, creatine kinase, oxidative stress parameters and SBP as compared to each therapy alone. The histological changes confirmed the biochemical findings. cimetidine and l-carnitine have protective effects - almost equally - against mARF. Using both agents together, minimises the renal injury.

https://pubmed.ncbi.nlm.nih.gov/25930980/

c621f4b107fb4febd9bfe51738cd297d

Importantly , MAPK and/or MTOR complex1 ( MTORC1 ) activity were upregulated in AML cells made resistant to several FLT3 inhibitors , including crenolanib , quizartinib , or sorafenib .

Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia. Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly , MAPK and/or MTOR complex1 ( MTORC1 ) activity were upregulated in AML cells made resistant to several FLT3 inhibitors , including crenolanib , quizartinib , or sorafenib . These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.

https://pubmed.ncbi.nlm.nih.gov/33375770/

d39a99792670b3843d6e896df08acb30

We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts .

Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial. nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts . ### methods This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2-8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day. ### results varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal. ### conclusions varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence.

https://pubmed.ncbi.nlm.nih.gov/21652735/

666c22926567c3b45e26c9e0effa533e

However , combination of pioglitazone and sulfasalazine has shown greater efficacy .

Comparative evaluation of different doses of PPAR-γ agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory condition, which affects the gastrointestinal tract and has no curative treatment. The present study aimed to investigate the effect of different doses of pioglitazone alone and in combination with sulfasalazine in TNBS (trinitrobenzenesulfonic acid)-induced inflammatory bowel disease (IBD) in rats. ### methods A total of 36 animals were included in the study. Animals were divided into five groups (n = 6): group I--vehicle (ethanol), group II--TNBS + ethanol, group IIIA--TNBS + pioglitazone (15 mg/kg), group IIIB--TNBS + pioglitazone (30 mg/kg), group IV--TNBS + sulfasalazine (360 mg/kg), group V--TNBS + sulfasalazine (360 mg/kg) + pioglitazone (least effective dose found in group III). Group III was divided into two subgroups, namely IIIA and IIIB, on the basis of different doses of pioglitazone used. After completion of two weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay and TNF-α estimation. ### results All the drug-treated groups showed both gross morphological and microscopic score either 1 or 2. None of them showed score of > 2 on both gross and microscopic morphological examination. Both MDA levels and MPO activity were significantly reduced in the drug-treated groups, with maximum reduction seen in the combination group. TNF-α was reduced in pioglitazone group. It was highly reduced in sulfasalazine group (group V) as compared to TNBS group thereby indicating that pioglitazone is protective in TNBS-induced inflammatory bowel disease. ### conclusion The present study showed reduction in lipid peroxidation, malondialdehyde levels and TNF-α levels in pioglitazone-treated group and hence, there was significant improvement in gross and microscopic features, too. However , combination of pioglitazone and sulfasalazine has shown greater efficacy .

https://pubmed.ncbi.nlm.nih.gov/24145089/

2818609aab66d157161aa1f06d272dd5

At time 2 , genotypic resistance to zidovudine was found in 11 out of 12 cases ( 41L : two cases ; 41L , 215Y : six cases ; 41L , 210W , 215Y : two cases ; M41L , D67N , L210W , T215Y : one case ) with a mean 18.9 + /- 8.8-fold increase in the IC50 to zidovudine and 1.4 + /- 0.4-fold to stavudine

Phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors in HIV-1 clinical isolates. To assess phenotypic and genotypic cross-resistance to nucleoside reverse transcriptase inhibitors in patients treated with a combination including zidovudine, who were switched to a combination including stavudine. ### methods We analysed 24 clinical HIV-1 isolates from 12 patients before and several months after therapeutic switching. Plasma HIV-1 RNA was measured using quantitative polymerase chain reaction (Roche). Genotypic resistance was measured by sequencing the reverse transcriptase gene from plasma HIV-1 RNA. Phenotypic resistance was measured using a recombinant assay (Virco). ### results Patients were treated with a combination including zidovudine for a mean (+/- SEM) period of 21.8 +/- 3.5 months and had a plasma viral load of 4.1 +/- 0.2 log HIV-1 RNA copies/mL (time 1). After a mean period of 19.3 +/- 1.6 months following the therapeutic change, the plasma viral load was 3.6 +/- 0.1 log copies/mL (time 2). At time 1, genotypic resistance to zidovudine was found in all cases (41L: four cases; 41L, 215Y: five cases; 41L, 210W, 215Y: two cases; K70R: one case) with a mean 6.6 +/- 1.6-fold increase in the median inhibitory concentration (IC50) to zidovudine and 1.7 +/- 0.4-fold to stavudine. At time 2 , genotypic resistance to zidovudine was found in 11 out of 12 cases ( 41L : two cases ; 41L , 215Y : six cases ; 41L , 210W , 215Y : two cases ; M41L , D67N , L210W , T215Y : one case ) with a mean 18.9 + /- 8.8-fold increase in the IC50 to zidovudine and 1.4 + /- 0.4-fold to stavudine ### conclusions In this clinical series of patients with suboptimal control of plasma HIV-1 RNA using a combination including zidovudine, the presence of zidovudine-related mutations was associated with a decreased phenotypic sensitivity to this drug. Despite persistent HIV-1 replication, switching to stavudine was associated with a further decrease in phenotypic sensitivity to zidovudine but not to stavudine after 19 months. These data suggest that stavudine remains a possible option in zidovudine-experienced patients.

https://pubmed.ncbi.nlm.nih.gov/11737402/

c000680082dd039500d99d2aaec21834

Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin , 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis .

Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin , 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis . sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3 months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. ### methods Thirty five patients were treated with sorafenib 400 mg orally twice a day, oxaliplatin 85 mg/m ### results The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2 months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3-4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). ### conclusions The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).

https://pubmed.ncbi.nlm.nih.gov/29327075/

238e1815e2b060ff8c3b2f516404af28

Sprague-Dawley male rats were treated with levodopa ( LD ) , betaine ( Bet ) , levodopa plus betaine ( LD/Bet ) , levodopa plus benserazide ( LD/Ben ) , levodopa plus betaine-benserazide ( LD/Bet-Ben ) , and the controls with vehicle for 10 consecutive days , orally .

Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats. The aim of the present study was to evaluate antioxidant and methyl donor effects of betaine in cerebellum following levodopa and benserazide administration in rats. ### Materials And Methods Sprague-Dawley male rats were treated with levodopa ( LD ) , betaine ( Bet ) , levodopa plus betaine ( LD/Bet ) , levodopa plus benserazide ( LD/Ben ) , levodopa plus betaine-benserazide ( LD/Bet-Ben ) , and the controls with vehicle for 10 consecutive days , orally . ### results Treatment of rats with LD and benserazide significantly increased total homocysteine in plasma of the LD/Ben group when compared to the other groups. Lipid peroxidation of cerebellum increased significantly in LD-treated rats when compared to the other groups. In contrast, glutathione peroxidase activity and glutathione content in cerebellum were significantly higher in the betaine-treated rats when compared to the LD and LD/Ben groups. Serum dopamine concentration increased significantly in LD-treated rats in comparison with the LD/Ben group. LD/Bet-treated rats also demonstrated significantly higher dopamine levels when compared to the LD/Ben group. ### conclusion We observed valuable effects of Bet in combination with LD and benserazide, which routinely were used for Parkinson's disease (PD) treatment, in experimentally-induced oxidative stress and hyperhomocysteinemia in rats. Therefore, it seems that Bet is a vital and promising agent regarding PD for future clinical trials in humans.

https://pubmed.ncbi.nlm.nih.gov/26730328/

67d41e07c43f910f0d11c74aee20802b

We designed a phase I trial to determine the maximum-tolerated dose ( MTD ) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies .

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose ( MTD ) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies . A 3 + 3 Phase I design was chosen. Temsirolimus and cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.

https://pubmed.ncbi.nlm.nih.gov/23605083/

9579ba27f569c40ef0d7c0cb5560f8a8

Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole , 31 % received itraconazole alone , and 7 % received an amphotericin B-containing product only .

Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. To our knowledge, an institutional review of systemic histoplasmosis has not been conducted in the United States since the major outbreaks in Indianapolis in 1978-4982. We conducted a retrospective review of all patients with systemic histoplasmosis diagnosed at Mayo Clinic over a 15-year period. The case definitions employed were based on an international consensus statement by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG). One hundred eleven patients with systemic histoplasmosis were identified between January 1, 1991, and December 31, 2005. Of these, 78 patients had disseminated histoplasmosis and 55 patients had Histoplasma capsulatum fungemia. The mean age of patients was 55 years, 66% were male, and 98% were white. Fifty-nine percent of patients were immunocompromised. Fever was the most frequently reported symptom (63%), followed by respiratory complaints (43%) and weight loss (37%). The peripheral white blood cell count was <3000 cells/mm in 28%, hemoglobin was <10 g/dL in 29%, and platelet count was <150,000 cells/mm in 41% of patients. Liver enzymes were elevated (alanine aminotransferase >60 U/L in 39%, aspartate aminotransferase >60 U/L in 27%), alkaline phosphatase was >200 U/L in 55%, and albumin was <3.5 g/dL in 70%. Serologic and histopathologic examinations were each positive in 75% of cases, Histoplasma urine antigen screening was positive in 80%, and H. capsulatum was culture positive in 84%. Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole , 31 % received itraconazole alone , and 7 % received an amphotericin B-containing product only . Another 13% of patients did not receive antifungal treatment, and the remaining 2% did not have treatment data available. Sixty percent of patients required hospitalization, and in hospital mortality was 6% with a median survival time of 61 days. The relapse rate was 9%, with a median relapse-free survival of 857 days. Systemic histoplasmosis should be suspected in patients who have lived in endemic areas with fever, bone marrow suppression, and elevated hepatic enzymes, particularly if they are immunocompromised. Evaluation including a combination of Histoplasma serologic screening, urine antigen assay, and fungal culture will secure the diagnosis in most cases.

https://pubmed.ncbi.nlm.nih.gov/17505255/

9258ab4aee8b8684decb3d3c05c37ba1

From August 2008 to May 2011 , consecutive chemo-naïve patients with stage IV non-squamous non-small cell lung cancer ( NSCLC ) received pemetrexed 500mg/m(2 ) , oxaliplatin 100mg/m(2 ) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles , in the outpatient setting .

Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer. oxaliplatin has less haematological toxicity than cisplatin and carboplatin. The combination of pemetrexed, oxaliplatin and bevacizumab appeared well tolerated and active as second- or third-line treatment in a previous phase II study. Its role as first-line therapy remains to define. ### Patients And Methods From August 2008 to May 2011 , consecutive chemo-naïve patients with stage IV non-squamous non-small cell lung cancer ( NSCLC ) received pemetrexed 500mg/m(2 ) , oxaliplatin 100mg/m(2 ) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles , in the outpatient setting . Maintenance therapy including pemetrexed and bevacizumab was given to patients with non-progressive disease. The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, progression-free survival (PFS) and overall survival (OS). ### results Thirty-eight patients (50% males, median age: 55 years, range 38-76) received a total of 199 cycles (median per patient: 6, range 2-6), plus 98 cycles of maintenance therapy. Twenty patients (52.6%) had a PS of 2, and 6 (15.8%) had brain metastases. The most frequent toxicities were hypertension (all grades: 42.1%) and peripheral neuropathy (grade 2-3: 21.1%). Haematological toxicities included grade 4 neutropenia, grade 3 anaemia and thrombopenia (5.3% each). Neither febrile neutropenia nor arterial thrombo-embolic event occurred. The objective response rate was 55.3% (95%CI: 39.5-71.1). The median PFS and OS were 6.2 (95%CI: 5.4-9.0) and 14.6 (95%CI: 9.8-19.5) months, respectively. ### conclusions In this single centre experience, the combination of pemetrexed, oxaliplatin and bevacizumab was well tolerated and had promising activity as first-line therapy in unselected patients with stage IV non-squamous NSCLC.

https://pubmed.ncbi.nlm.nih.gov/22364783/

dc679fbc5a8701077814b90e659e7955

To determine if antiseptic central venous catheters impregnated with silver sulfadiazine and chlorhexidine ( antiseptic ) reduce bacterial adherence and biofilm formation without producing local or systemic toxicity .

Decreased bacterial adherence and biofilm formation on chlorhexidine and silver sulfadiazine-impregnated central venous catheters implanted in swine. To determine if antiseptic central venous catheters impregnated with silver sulfadiazine and chlorhexidine ( antiseptic ) reduce bacterial adherence and biofilm formation without producing local or systemic toxicity . ### design Prospective, randomized, controlled trial. ### setting Experimental laboratory in a university teaching hospital. ### subjects Ten outbred New Hampshire pigs. ### interventions Nonimpregnated (control) and antiseptic-impregnated catheters were inserted intravascularly into swine for 7 days. After explantation, the catheters were assessed for bacterial adherence and biofilm formation, and the surrounding tissue was assessed for signs of toxicity. Before retrieval, systemic concentrations of antimicrobials were determined. ### Measurements And Main Results Sequential roll plate and centrifuging were used to detect moderately and tightly adherent bacteria on the outer and luminal surfaces of the catheter. The presence of biofilm was detected by scanning electron microscopy. Tissues surrounding the catheters were examined histopathologically; systemic concentrations of chlorhexidine, sulfadiazine, and silver were determined by atomic absorption and high-performance liquid chromatography. As compared with the controls, antiseptic catheters had significantly (p < .01) fewer moderately and tightly adherent bacteria on outer and luminal surfaces, and fewer adherent bacteria when outer surfaces alone were examined (p < .01). Scanning electron microscopy showed bacterial biofilm and adherence on the control catheters but not on the antiseptic catheters. There were no abnormal histopathologic changes associated with the test catheter, and serum concentrations of the antibacterial agents were shown to be within nontoxic ranges. ### conclusion The antiseptic-impregnated catheters prevented bacterial adherence and biofilm formation and produced no local or systemic toxicity.

https://pubmed.ncbi.nlm.nih.gov/7736748/

b4f6178a851fbb8ac91841c9d9abd82d

In multivariate analysis , LDP and LAP were significantly associated with stavudine ( d4 T ) use , while LAP was also associated with zidovudine ( ZDV ) treatment .

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition. This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. ### methods We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. ### results According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis , LDP and LAP were significantly associated with stavudine ( d4 T ) use , while LAP was also associated with zidovudine ( ZDV ) treatment . There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. ### conclusions The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.

https://pubmed.ncbi.nlm.nih.gov/11737398/

3312c85c700cfa1e3aa5d494128f7a6f

KARs , new semisynthetic antitumor bis-indole derivatives , were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine , used in chemotherapy .

A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y. KARs , new semisynthetic antitumor bis-indole derivatives , were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine , used in chemotherapy . Here, we compare the effect of KARs with those of vinblastine and vincristine on cell viability, cell proliferation, and cell cycle in neuroblastoma cell line (SH-SY5Y). At concentrations of the different compounds equivalent in causing 50% of inhibition of cell growth, KARs induced a complete arrest in the G2/M phase, whereas vinblastine and vincristine induced a partial arrest in both G0/G1 and G2/M. Moreover, a combination of KAR-2 and W13 (an anticalmodulin drug) qualitatively caused a similar arrest in both G0/G1 and G2/M than vinblastine. Levels of cyclin A and B1 were higher in KARs-treated cells than in vinblastine- or vincristine-treated cells. Cdc2 activity was much higher in KAR-2 than in vinblastine-treated cells, indicating a stronger mitotic arrest. The effect of KAR2 and vinblastine on microtubules network was analyzed by immunostaining with anti-tubulin antibody. Results indicated that KAR-2-induces the formation of aberrant mitotic spindles, with not apparent effect on interphase microtubules, whereas vinblastine partially destroyed interphase microtubules coexisting with normal and aberrant mitotic spindles.

https://pubmed.ncbi.nlm.nih.gov/11723230/

7a364d400198ab1388ee69dc9abe8494

More than one-third ( 36 % ) of AA patients in our study received Danazol as monotherapy , whereas less than a third ( 32 % ) each received standard doses of IST with equine Anti Thymocyte Globulin ( ATG ) and Cyclosporine combination , or Cyclosporine and Danazol combination , respectively .

Danazol increases T regulatory cells in patients with aplastic anemia. danazol is an attenuated androgen and is used in the treatment of aplastic anemia (AA) in resource constraint settings. We chose to study the role of CD4+ CD25 ### methods T-regs' percentages of 25 acquired idiopathic AA patients and 25 healthy controls who completed study protocol were analyzed by performing multicolor flowcytometry on peripheral blood samples. ### results More than one-third ( 36 % ) of AA patients in our study received Danazol as monotherapy , whereas less than a third ( 32 % ) each received standard doses of IST with equine Anti Thymocyte Globulin ( ATG ) and Cyclosporine combination , or Cyclosporine and Danazol combination , respectively . Results showed that all AA patients had a significantly lower percentage of T-regs at the time of diagnosis when compared to healthy controls (p < 0.0001), implicating their role in the pathophysiology. On treatment, all 25 patients showed a significant rise in the percentage of T-regs when compared to baseline (p < 0.0001). ### discussion The rise in T-regs' percentage was higher in patients treated with danazol alone when compared to standard IST (ATG with cyclosporine), or cyclosporine with danazol combinations (p = 0.585). ### conclusion We conclude that danazol also leads to increase in T-regs in acquired idiopathic AA.

https://pubmed.ncbi.nlm.nih.gov/29415633/

59a99e3c9b66f3a6dea60a3461efacf5

Similarly , antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity , but preimmune IgG had no effect .

Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly , antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity , but preimmune IgG had no effect . In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.

https://pubmed.ncbi.nlm.nih.gov/8960070/

9a9bc4ed3056eacaad4c006b6b3934eb

Furthermore , our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC .

First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group. To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). ### background paclitaxel is an active agent in ABC. Furthermore , our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC . ### Patients And Methods From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. ### results A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. ### conclusions The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.

https://pubmed.ncbi.nlm.nih.gov/9818080/

af9f9d821048ef780830cf1a5992726e

Cyclosporine ( 25 mg/kg per day , s.c . ) was given for 7 days to rats either alone or in combination with resveratrol ( 10 mg/kg per day , i.p . ) .

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system. cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine ( 25 mg/kg per day , s.c . ) was given for 7 days to rats either alone or in combination with resveratrol ( 10 mg/kg per day , i.p . ) . Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.

https://pubmed.ncbi.nlm.nih.gov/31613143/

ab077fde75c5127e2d3d623cc78f7d47

The diagnosis was confirmed by comparative double diagnostic block of the medial branch with bupivacaine and lidocaine .

Efficacy of combined treatment with medial branch radiofrequency neurotomy and steroid block in lumbar facet joint arthropathy. To evaluate the long-term efficacy of combined radiofrequency (RF) neurotomy and steroid nerve block in patients with lumbar facet joint arthropathy. ### Materials And Methods Combined RF neurotomy and steroid nerve block was performed in 34 patients with chronic paravertebral low back pain. The diagnosis was confirmed by comparative double diagnostic block of the medial branch with bupivacaine and lidocaine . Under fluoroscopy, RF thermal ablation of the medial branch was performed (at RF needle tip temperature 85°C for 90 seconds), three times for each target nerve. At the end of the procedure, 20 mg of methylprednisolone acetate (sustained-release preparation) was infiltrated on each ablated nerve. Outcome variable was the degree of improvement in pain using visual analog scale (VAS) and numerical rating scale (NRS). Improvement in the quality of life was assessed using the Roland-Morris (RM) questionnaire. The procedure was repeated in cases of unbearable pain (>5 VAS score). ### results Patients had a mean VAS score of 8.6 before the procedure. Thereafter, VAS score was 0.91 immediately after the procedure and 3.0, 2.8, 3.7, and 3.6 at 1 month, 2 months, 6 months, and 1 year. NRS showed pain relief after the procedure of 85%, 65%, 78%, 62%, and 59.5% at the same time points. RM score was 18 before the procedure, 7.6 at 6 months after the procedure, and 8.5 at 1 year after the procedure. No major complication was noted except local pain in all patients and numbness of the back in six patients after the procedure. ### conclusions Combined RF neurotomy and steroid nerve block produced substantial improvement in terms of long-term pain relief and quality of life.

https://pubmed.ncbi.nlm.nih.gov/23177113/

e9e11475fb4dfd19f99abf2096f282df

Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses .

Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors. ### methods Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500-600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7-1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0-1.6 mg/m2 on D1 and 8). ### results We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly. ### conclusions Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses . Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.

https://pubmed.ncbi.nlm.nih.gov/18090584/

f1cc7e30edeaee003ffd3a3b25b34687

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy ( TANIA ): an open-label , randomised phase 3 trial .

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy ( TANIA ): an open-label , randomised phase 3 trial . Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. ### methods In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. ### findings Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. ### interpretation These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. ### funding F Hoffmann-La Roche.

https://pubmed.ncbi.nlm.nih.gov/25273342/

88f525b0e33ed578e19041d6a770e6b1

Goserelin plus tamoxifen after cyclophosphamide , doxorubicin and 5-fluorouracil ( CAF ) chemotherapy resulted in improved disease-free survival compared with CAF alone .

Goserelin ('Zoladex')--offering patients more choice in early breast cancer. The luteinising hormone-releasing hormone analogue goserelin ('Zoladex') suppresses ovarian oestrogen production in pre- and perimenopausal women. goserelin is a biodegradable, sustained-release 3.6 mg depot that is administered by subcutaneous injection every 28 days. Clinical trials in premenopausal women with hormone-sensitive early breast cancer have demonstrated that goserelin alone, or in combination with tamoxifen, is at least as effective as cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. Goserelin plus tamoxifen after cyclophosphamide , doxorubicin and 5-fluorouracil ( CAF ) chemotherapy resulted in improved disease-free survival compared with CAF alone . These trials have also shown that goserelin is well tolerated and is associated with less acute toxicity than cytotoxic chemotherapy. Early improvements in quality of life over the first 3-6 months of goserelin treatment support the use of this agent as an alternative to chemotherapy in this patient population. Patients should be provided with information on the benefits and risks associated with available treatment options so that they can be involved in the decision-making process.

https://pubmed.ncbi.nlm.nih.gov/15590321/

b17be4a07cfbc24af81f8cd537f7184c

An 82-year-old white female developed a 36-hour episode of unresponsiveness/drowsiness after a single dose of triazolam 0.5 mg in combination with cimetidine .

Prolonged hypnotic response to triazolam-cimetidine combination in an elderly patient. An 82-year-old white female developed a 36-hour episode of unresponsiveness/drowsiness after a single dose of triazolam 0.5 mg in combination with cimetidine . This case illustrates the need for careful dose-titration of drug therapy in the elderly, particularly when a drug with the potential to impair drug metabolism is coadministered. cimetidine, when coadministered with triazolam, may increase the intensity and duration of action of single doses of triazolam.

https://pubmed.ncbi.nlm.nih.gov/6150838/

f459330ae9a018833fde1129b805d154

The combination of melatonin at concentrations of 50 μM with increasing doses of irinotecan ( 7.5 , 15 , 30 , and 60 μM ) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells , but was not effective in inducing DNA damage in healthy human lymphocytes .

The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells. Drug-target interactions can be modified by adding modulatory agents to increase treatment efficacy and clinical outcome. Combination chemotherapy has become increasingly important because drugs acting synergistically can achieve therapeutic effects at substantially lower doses and with a limited spectrum of side effects. irinotecan, known as one of the camptothecin analogs, has shown a broad spectrum of antitumor activity against various malignancies. In this study, we evaluated the effect of melatonin on the genotoxic activity of irinotecan in healthy human lymphocytes and a lung cancer cell line (A549) and a colorectal adenocarcinoma cell line (HT29) in vitro. irinotecan, as a single agent, was shown to induce DNA damage in all types of analyzed cells. The combination of melatonin at concentrations of 50 μM with increasing doses of irinotecan ( 7.5 , 15 , 30 , and 60 μM ) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells , but was not effective in inducing DNA damage in healthy human lymphocytes . Analysis of the efficacy of DNA repair, performed after 60 and 120 minutes of postincubation, showed the gradual decrease of DNA percentage in comet tails during repair postincubation in all experimental samples. Our results indicate that melatonin can modulate the genotoxic activity of irinotecan and DNA repair efficacy in human cancer cells in vitro. These findings may be supportive for the optimization of therapeutic efficacy in irinotecan treatment.

https://pubmed.ncbi.nlm.nih.gov/23126525/

698946285dc6e66a6520c401db987cc8

Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle .

Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. ### methods Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m2) followed by eight cycles of CMF (cyclophosphamide [600 mg/m2], methotrexate [50 mg/m2], and 5-fluorouracil [600 mg/m2]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m2), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m2) supported by filgrastim (300 microg/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle . Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. ### results At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (high-dose arm = 62%, 95% CI = 56% to 68%; conventional-dose arm = 64%, 95% CI = 57% to 70%) (P =.38). ### conclusion Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/15265969/

ebb16d45f12020fe397cb2924711fa22

Although cisplatin is generally the favoured platinum agent , gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile .

Gemcitabine and carboplatin in combination for the treatment of advanced, metastatic, non-small cell lung cancer. The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent , gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile . Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.

https://pubmed.ncbi.nlm.nih.gov/18035969/

0fa064ea7b31d4b077d6fbf11d1a921e

In group B , epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2 , given in the same manner as in group A.

Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B , epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2 , given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.

https://pubmed.ncbi.nlm.nih.gov/9374090/

87f36673a4e1cfaadef99fcdc642a0ed

We assessed the safety and activity of ceritinib plus nivolumab in these patients .

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study. Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients . ### methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. ### results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. ### conclusion ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

https://pubmed.ncbi.nlm.nih.gov/31634667/

789db177edc5cd5c6dfc1760f8ad5d0e

Incubation with somatostatin , 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells .

Incubation with somatostatin , 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells . somatostatin (SMS), binds to its specific receptors (SSTRs) and transduces growth inhibitory, anti-secretory and apoptotic signals. Several human cancers express SSTRs, including prostate cancer, and therefore SMS is of interest for anti-cancer therapy. DNA methylation and histone modifications are involved in normal cell development, gene imprinting and human carcinogenesis. Reversing DNA methylation is an attractive therapeutic possibility, since epigenetic modifications change gene expression without changing the gene function. DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (5'-aza, decitabine) have been used to treat several types of haematological malignancies. Histone deacetylase inhibitors such as trichostatin (TSA), are a new class of 'targeted anti-cancer agents'. TSA and decitabine can induce growth arrest, apoptosis or terminal differentiation in a variety of solid and haematological cancers in advanced disease patients. In the present study, the LNCaP cell line (prostate cancer) was incubated with SMS or Somadex (an SMS polymer conjugate) for three days, 1 nM per day, and the untreated cells were the negative control. For DNA demethylation, cells were grown in the presence of 2.5 microM 5-aza for 120 h, and re-fed with 5-aza-containing fresh medium at day 3. The total incubation time with 5-aza was 120 h. TSA at 1.0 microM was added into the cultured cells for 24 h. The combined treatment of 5-aza and TSA was performed by incubating the cells with 5-aza for 120 h followed by a 24-h exposure to TSA. Using cDNA obtained from these cell lines, the difference in the expression level of SSTR mRNA transcripts before and after 5-aza and TSA treatments was analyzed by RT-PCR. An increased induction of mRNA expression of the five SSTR subtypes was observed in the LNCaP cells when incubated with SMS/Somadex (dose-dependent). The inhibition of DNA methylation and histone acetylation resulted in the up-regulation of SSTR5 mRNA expression. The results demonstrate a positive feedback loop between SMS and its receptors. This regulation pathway may enhance the anti-tumor activity of somatostatin. To benefit from this effect in a clinical setting, the dose, dose frequency and pan affinity of the SMS derivative are important factors. The epigenetic manipulation with DNA methylation or histone deacetylase inhibitors, combined with SMS, may offer a novel alternative for the treatment of advanced prostate cancer.

https://pubmed.ncbi.nlm.nih.gov/18575731/

4e5dc5ce44c564c270b3f1ccdd19984e

This study was conducted to determine whether famotidine , a H2 antagonist , is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine .

Famotidine in the treatment of acute urticaria. Recent studies suggest that histamine H2-receptor antagonists may be useful in the treatment of urticaria. This study was conducted to determine whether famotidine , a H2 antagonist , is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine . In this prospective, double-blind, controlled trial, 25 patients with urticaria of less than 72 h duration were randomized to receive a single dose of either famotidine 20 mg i.m. or diphenhydramine 50 mg i.m. Prior to treatment and 30 min after treatment, patients rated pruritus and sedation using visual analogue scales, while physicians evaluated intensity of urticaria and percentage of body surface area involved by urticaria. famotidine was found to reduce pruritus associated with acute urticaria, intensity of urticaria, and body surface area affected by urticaria without causing sedation. famotidine was comparable to diphenhydramine in efficacy; however, there was a (nonsignificant) trend for diphenhydramine to be more effective than famotidine in the treatment of pruritus, and for famotidine to be more effective in the reduction of surface area of involvement. It is concluded that famotidine merits further investigation as a potential medication for treatment of urticaria.

https://pubmed.ncbi.nlm.nih.gov/10844490/

405908b1332efb919c7ee2252f499cb0

On the other hand , a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam ( with a high affinity for these sites ) and chlordiazepoxide ( with a low affinity ) were equipotent in the enhancement of the combined treatment efficacy .

Effect of combined treatment of diphenylhydantoin with clonazepam and chlordiazepoxide on the threshold for maximal electroconvulsions in mice. The anticonvulsant effect of either clonazepam (0.2-6.4 mg/kg) or chlordiazepoxide (2.5-40 mg/kg) alone or in combination with diphenylhydantoin (4-16 mg/kg) was studied against electroconvulsions in mice. All drugs were injected intraperitoneally, diphenylhydantoin - 75 min and the benzodiazepines - 60 min before the test. Adding either clonazepam or chlordiazepoxide (in doses moderately increasing the convulsive threshold) was more effective than doubling the dose of diphenylhydantoin. Both the interaction between benzodiazepines and diphenylhydantoin at the level of the receptor for picrotoxin-barbiturates and benzodiazepine-induced potentiation of specific diphenylhydantoin binding are likely to contribute to the observed phenomenon. On the other hand , a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam ( with a high affinity for these sites ) and chlordiazepoxide ( with a low affinity ) were equipotent in the enhancement of the combined treatment efficacy .

https://pubmed.ncbi.nlm.nih.gov/6855341/

697581868aee121b2c723980f6bb7cc0

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive , Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer ( NEO-ORB ) .

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive , Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer ( NEO-ORB ) . Addition of alpelisib to fulvestrant significantly extended progression-free survival in ### results In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the ### conclusions In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR

https://pubmed.ncbi.nlm.nih.gov/30723140/

b29c15bd2e8ad5f2e59d59be0b49ee8f

Treatment with bromocriptine and pyridoxine showed no improvement .

Aromatic amino Acid decarboxylase deficiency not responding to pyridoxine and bromocriptine therapy: case report and review of response to treatment. Aromatic L-amino acid decarboxylase (AADC) deficiency (MIM #608643) is an autosomal recessive inborn error of monoamines. It is caused by a mutation in the DDC gene that leads to a deficiency in the AADC enzyme. The clinical features of this condition include a combination of dopamine, noradrenaline, and serotonin deficiencies, and a patient may present with hypotonia, oculogyric crises, sweating, hypersalivation, autonomic dysfunction, and progressive encephalopathy with severe developmental delay. We report the case of an 8-month-old boy who presented with the abovementioned symptoms and who was diagnosed with AADC deficiency based on clinical, biochemical, and molecular investigations. Treatment with bromocriptine and pyridoxine showed no improvement . These data support the findings observed among previously reported cohorts that showed poor response of this disease to current regimens. Alternative therapies are needed to ameliorate the clinical complications associated with this disorder.

https://pubmed.ncbi.nlm.nih.gov/24453523/

15808b8203edebf1c7bd379a66f5135e

Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12 .

Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12 . The combined effects of trimethoprim and sulfamethoxazole on the viability of Escherichia coli K-12 and resistant strains possessing resistance plasmids were examined in minimal medium. When methionine, glycine, and adenine were present, sulfamethoxazole could enhance trimethoprim activity against E. coli K-12 so that the combination was bactericidal. However, this enhancement occurred over a narrow range of trimethoprim concentrations (0.04 to 0.2 mg liter-1) and only when the sulfamethoxazole concentration was more than 10 times that of trimethoprim. Under certain conditions, sulfamethoxazole enhanced trimethoprim bactericidal activity against E. coli K-12 carrying plasmid R1 at concentrations of sulfamethoxazole far below those required to inhibit the organism, but there was no such enhancement with the same host containing the SSu plasmid. Similar differences were found with strains possessing trimethoprim resistance plasmids R483 and R751. sulfamethoxazole can promote a bactericidal response with trimethoprim in E. coli K-12 and some of its resistant derivatives, but only under a narrow range of concentrations.

https://pubmed.ncbi.nlm.nih.gov/7041815/

842e788301534fc8e3bcc27876dd50ba

New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil , and real and perceived intolerance to standard drugs such as mefloquine .

Current status and replies to frequently posed questions on atovaquone plus proguanil (Malarone) for the prevention of malaria. Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil , and real and perceived intolerance to standard drugs such as mefloquine . A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.

https://pubmed.ncbi.nlm.nih.gov/12785875/

9569e93e22559dc03699092c070d4b6f

They were subsequently exposed to graded doses of cisplatin ( CP ) , etoposide ( VP-16 ) , Adriamycin ( ADR ) , cytarabine ( ara-C ) , cyclophosphamide ( CY ) , or camptothecin ( CAM ) .

Bcl-2 expression correlates with apoptosis induction but not tumor growth delay in transplantable murine lymphomas treated with different chemotherapy drugs. Previously, we have reported that the bcl-2-expressing murine lymphoma cell line LY-ar is resistant to chemotherapy-induced apoptosis when compared to the non-bcl-2-expressing LY-as cell line. The intent of the present study was to determine whether this relationship extends to lymphomas produced from these cell lines in syngeneic mice, after treatment with the same chemotherapy agents. ### methods LY-ar and LY-as tumors were grown in the hind legs of syngeneic mice. They were subsequently exposed to graded doses of cisplatin ( CP ) , etoposide ( VP-16 ) , Adriamycin ( ADR ) , cytarabine ( ara-C ) , cyclophosphamide ( CY ) , or camptothecin ( CAM ) . Apoptotic bodies were scored in histological sections of tumors that had been stained with hematoxylin and eosin. Tumor growth delay was determined on tumors that were treated when they were 8 mm in diameter. Thereafter, tumor diameter was measured daily with a vernier caliper until they had grown to a maximum of 16 mm in diameter. ### results When transplanted into host animals, tumors derived from these two cell lines and treated in vivo with CP, VP-16, ADR, ara-C, CY, and CAM displayed apoptotic propensities similar to those seen in the same cell lines when treated in vitro. Generally, for all the drugs tested, apoptotic indices in LY-as tumors were significantly higher than in LY-ar tumors. However, tumor growth delay measurements could not be predicted with any accuracy from the apoptotic indices. For some drugs LY-ar tumors were more sensitive than LY-as tumors (CP, Vp-16, ADR, ara-C), yet LY-ar tumors were more resistant to CY. ### conclusions Despite considerable interest in using apoptotic indices as predictors of treatment outcome, the data presented here suggest that these relationships are very complex. This may be especially true for chemotherapy agents for which effects in vivo are complicated by pharmacokinetics, host effects, and tumor cell heterogeneity.

https://pubmed.ncbi.nlm.nih.gov/10501909/

14dde51b22af3068e58463d286d5e956

In a phase II trial , patients with primary gastric cancer and clinical involvement of para-aortic nodes ( PAN ) were treated by neo-adjuvant chemotherapy with capecitabine and oxaliplatin combination , and responders were then submitted to gastrectomy with D2 lymphadenectomy .

Gastric cancer with para-aortic lymph node metastases: do not miss a chance of cure! This letter to editor is a comment to the paper by Wang et al. entitled: "A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis". In a phase II trial , patients with primary gastric cancer and clinical involvement of para-aortic nodes ( PAN ) were treated by neo-adjuvant chemotherapy with capecitabine and oxaliplatin combination , and responders were then submitted to gastrectomy with D2 lymphadenectomy . The diagnostic and therapeutic approach adopted in this protocol is discussed, with special reference to the potential limits of computed tomography scan for the clinical diagnosis of PAN metastases (false positive results), and the opportunity to perform a D2 plus para-aortic lymphadenectomy, to further increase the chance of cure in patients with suspected PAN metastases.

https://pubmed.ncbi.nlm.nih.gov/24889718/

e7b48bfc94dd35343e16291d3e96a8d4

More myelotoxicity is observed with palbociclib and ribociclib , but more gastrointestinal toxicity is observed with abemaciclib .

Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib , but more gastrointestinal toxicity is observed with abemaciclib . Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.

https://pubmed.ncbi.nlm.nih.gov/32145796/

e18b168a2e78aab4f991c16a7be994bd

Intraoperative epidural bupivacaine , intraoperative intravenous fentanyl use , time to first analgesia request , postoperative visual analogue scale pain scores , tramadol requirements and side-effects were recorded for 72 hours .

Subarachnoid morphine, bupivacaine and fentanyl as part of combined spinal-epidural analgesia for low anterior resection. A prospective, randomised, double-blind clinical trial. This study was designed to compare the efficacy of subarachnoid morphine alone or in combination with bupivacaine and fentanyl for combined spinal-epidural analgesia in colorectal surgery. This is a prospective, randomised, double-blind clinical trial. Sixty patients undergoing low anterior resection were assigned to one of three groups: subarachnoid morphine, bupivacaine and fentanyl, subarachnoid morphine and bupivacaine or subarachnoid morphine only. Epidural catheter placement and subarachnoid injection were done via a combined spinal-epidural Epistar needle at L2-3. The epidural catheter was used for scheduled intraoperative bupivacaine and intermittent postoperative bupivacaine and morphine administration. Intraoperative epidural bupivacaine , intraoperative intravenous fentanyl use , time to first analgesia request , postoperative visual analogue scale pain scores , tramadol requirements and side-effects were recorded for 72 hours . Postoperative analgesia was comparable in all groups. Intraoperative fentanyl and bupivacaine consumption was lowest in the morphine, bupivacaine and fentanyl group. Time to first analgesia request was longer in the morphine, bupivacaine and fentanyl compared to the morphine group (P = 0.009). tramadol use was lower in the morphine and bupivacaine group compared to morphine, bupivacaine and fentanyl (P = 0.017) on postoperative day two. There were no significant adverse effects. All patients ambulated the morning after surgery. The addition of bupivacaine and fentanyl to subarachnoid morphine did not confer any advantage on postoperative visual analogue scale scores and tramadol use, but lowered the need for additional intraoperative intravenous fentanyl and epidural bupivacaine and prolonged the time to first analgesia request.

https://pubmed.ncbi.nlm.nih.gov/19681410/

ad8aed5dc7fa01eb977f4265526c6c57

Three eyes had both bevacizumab and ranibizumab ( 1.58 % ) .

Intravitreal Anti Vascular Endothelial Growth Factor Agents in The Management of Retinal Diseases: An Audit. The study aimed to describe our initial experience with the use of anti vascular endothelial growth factors (anti-VEGFs) in the treatment of retinal diseases. ### methods The case records of all patients who had received at least 3 doses of intravitreal anti- VEGF injections between January 2012 to December 2016 were reviewed. Information culled from the data was age, sex, indications for treatment, type of injection, presenting visual acuity, post injection visual acuity, systemic and ocular co morbidities. Results were analyzed using Statistical Package for Social Sciences (SPSS) 20.0 for Windows statistical software. ### results A total of 190 injections were given during the study period, to 58 eyes of 50 patients. Twenty-eight females (56.00%) and twenty-two males (44.00%) were seen with a mean age of 59.6± 11.66. bevacizumab was the most frequently administered anti- VEGF, 142 (74.74%) while only 48(25.26%) injections of ranibizumab were given. Three eyes had both bevacizumab and ranibizumab ( 1.58 % ) . Retinal vein occlusion 61(32.11%) was the commonest indication for the injections followed by diabetic macular edema 43(22.63%) and proliferative diabetic retinopathy 42(22.11%). Others were neovascular age related macular degeneration, neovascular glaucoma, vitreous hemorrhage, myopic choroidal neovascularization and cystoid macular edema. There was an association between age and disease, (p = 0.001). There was an improvement in visual acuity after intervention in cases with retinal vein occlusion and diabetic macular edema, and this was statistically significant. Hypertension was the commonest systemic disorder in this series 81(42.36%) and the supero-temporal quadrant 131(68.95%) was the most preferred position to administer the injection. Floaters was the commonest complication seen. ### conclusion Anti VEGFs have become an invaluable tool in the management of a number of retinal diseases in our center. However, the cost implications are a hindrance to an increased uptake of this form of treatment. Cheaper alternative preparations should be made available to encourage the uptake. Government in developing countries should be encouraged to bear the health burden of the old aged pensioner (OAP).

https://pubmed.ncbi.nlm.nih.gov/29299078/

47739c6d1960e7f551fe386519ab6548

Newer treatment regimens , including etoposide , prednisone , vincristine , cyclophosphamide , doxorubicin , rituximab ( EPOCH-R ) , show promise for these patients .

Successful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report. Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens , including etoposide , prednisone , vincristine , cyclophosphamide , doxorubicin , rituximab ( EPOCH-R ) , show promise for these patients . However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.

https://pubmed.ncbi.nlm.nih.gov/30095692/

084dededdf9fc5e0f52c1576c4723fc4

In two groups of rats , propranolol or atropine were given before the venom administration .

Effect of scorpion Leiurus quinquestriatus (H&E) venom on rat's heart rate and blood pressure. The effects of scorpion Leiurus quinquestriatus (H&E) venom collected from the South Sinai region, Egypt, on heart rate (HR) and mean arterial pressure (MAP) were studied after intramuscular administration of 3 different doses (100, 200 and 400 micrograms/kg) to anesthetized rats. The effects of adrenergic and cholinergic blocking agents on the venom-induced HR and MAP changes were also evaluated. In two groups of rats , propranolol or atropine were given before the venom administration . In the third group the venom was given before the injection of propranolol and atropine in combination. HR was measured by using a cardiotachometer coupler connected to an ECG coupler. MAP was calculated from the recorded arterial blood pressure (ABP) after catheterization of the left common carotid artery. Venom doses of 100 and 200 micrograms/kg produced tachycardia with a dose-response relationship, whereas 400 micrograms/kg evoked sinus tachycardia followed by bradycardia then tachycardia. MAP was elevated after the administration of each dose and reached its maximum value after 60 min with a dose-response relationship. Sinus, atrial and ventricular arrhythmias were observed from the recorded ECG during the time studied. This study revealed that the venom has pressor and depressor effects which are mediated through the autonomic nervous system. propranolol reduced the stimulatory effects of the highest dose of the venom while atropine was effective in eliminating the depressor effect of the venom on HR. The arrhythmias induced by the venom were blocked by the injection of the two blockers and are assumed to be due to the release of catecholamines and acetylcholine.

https://pubmed.ncbi.nlm.nih.gov/1609434/

6c1237dfdedfde4c544691167964c0b4

Doxycycline and azithromycin were highly effective in restoring fertility .

Characteristics of murine model of genital infection with Chlamydia trachomatis and effects of therapy with tetracyclines, amoxicillin-clavulanic acid, or azithromycin. Following intravaginal inoculation of progesterone-treated outbred mice with Chlamydia trachomatis MoPn, 4 to 6 log10 inclusion-forming units were recovered in vaginal swabs for 21 days but all animals were culture negative after 28 days. Serum antibody titers were elevated and remained high for at least 70 days. Between 28 and 70 days, upper tract infection (inflammation and distension of the uterine horns, occlusion of oviducts with inflammatory exudate, pyosalpinx, and hydrosalpinx) was seen in > 80% of the animals. Mice were dosed orally, commencing at 7 days after infection, with minocycline, doxycycline, or amoxicillin-clavulanate. Further groups received azithromycin either as a single high dose or as lower once-daily doses. In addition, minocycline and amoxicillin-clavulanate were administered at 24 h after infection, and this early treatment prevented elevation of antibody titers whereas delayed therapy did not. Vaginal swabs from mice in all treatment regimens were culture negative except for 25% of mice receiving either early amoxicillin-clavulanate or low-dose azithromycin, which yielded low numbers (20 to 70 inclusion-forming units) of chlamydiae. Numbers of fertile mice in the early treatment regimens and their litter sizes were similar to those of noninfected controls, although 25% of amoxicillin-clavulanate-treated mice had unilateral hydrosalpinges. In comparison, 88% of untreated mice developed hydrosalpinges and only 25% conceived. Delayed dosing did not affect the outcome of amoxicillin-clavulanate therapy but did diminish the protective efficacy of minocycline such that 50% of treated mice had either unilateral hydrosalpinges or ovarian abscesses. Doxycycline and azithromycin were highly effective in restoring fertility . This model makes possible the study of both short- and long-term outcomes of chlamydial infection.

https://pubmed.ncbi.nlm.nih.gov/7811001/

c6eacb69cd79ef372a339fb7c864b630

The pupillary dilation caused by amantadine is not abolished by pretreatment with reserpine , or by combined pretreatment with reserpine and alpha-methyl-p-tyrosine , although the mydriasis is reduced by approximately 25 % .

Effect of amantadine on pupillary diameter in mice. amantadine, injected into mice, produces dose-dependent mydriasis. The pupillary dilation caused by amantadine is not abolished by pretreatment with reserpine , or by combined pretreatment with reserpine and alpha-methyl-p-tyrosine , although the mydriasis is reduced by approximately 25 % . Thus, release of catecholamines from nerve terminals can account for only 25% of amantadine-produced mydriasis. haloperidol and phentolamine can partially block the effect of amantadine, but, when given after reserpine, neither of the antagonists increases the blockade produced by reserpine alone. We conclude that the catecholaminergic system contributes only partially to the pupillary effect of amantadine, and that other mechanisms appear to be involved.

https://pubmed.ncbi.nlm.nih.gov/7068338/

a22b07f3cb48da03270484e2473ec013

Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment .

Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species. curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment . curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.

https://pubmed.ncbi.nlm.nih.gov/26893544/

2d36dba4e272f444c0a25809f4006d63

Combination Chemotherapy with Mitomycin C , Vinorelbine , and Cisplatin ( MVrP ) in Patients with Advanced Non-Small Cell Lung Cancer .

Combination Chemotherapy with Mitomycin C , Vinorelbine , and Cisplatin ( MVrP ) in Patients with Advanced Non-Small Cell Lung Cancer . A phase II study was conducted in patients with advanced non-small cell lung cancer (NSCLC) in order to evaluate the efficacy and toxicity of the combination chemotherapy regimen of mitomycin C, vinorelbine, and cisplatin (MVrP). ### Materials And Methods Between June 1996 and December 2000, fifty-nine patients with unresectable stage IIIB to IV, pathologically documented NSCLC were enrolled in this study. One cycle consisted of mitomycin C 10 mg/m2 i.v. day 1, vinorelbine 30 mg/m2 i.v. days 1 & 15, and cisplatin 80 mg/m2 i.v day 1 and the next cycle consisted of vinorelbine 30 mg/m2 i.v. days 29 & 43, and cisplatin 80 mg/m2 i.v day 29. Each cycle was alternated and treatments were repeated every 8 weeks. ### results We were able to evaluate fifty-three of 59 patients. Objective responses were seen in 22 (41.5%) patients (CR 0%, PR 41.5%). The median duration of response was 13.7 weeks and the median time to progression was 17.7 weeks. The median overall survival was 45.6 weeks. There was a significantly longer survival seen in responders (p=0.041). The toxicities of this regimen were acceptable without treatment related toxic death. ### conclusion This study suggests that a combination regimen of mitomycin C, vinorelbine, and cisplatin is relatively effective and well tolerated for the treatment of advanced NSCLC.

https://pubmed.ncbi.nlm.nih.gov/26680811/

ad6d1792a20b887be35ca92cb81ed90a

Bitches were also treated with amoxicillin ( 15 mg/kg body wt/48 h ) and/or gentamicin ( 4 mg/kg body wt/day ) administered as intramuscular ( i.m . ) injections .

Intravaginal prostaglandin F2 alpha for the treatment of metritis and pyometra in the bitch. The purpose of this study was to determine whether intravaginal prostaglandin F2 alpha (PGF2 alpha) would be effective for the treatment of metritis or pyometra in the bitch. Seventeen bitches with metritis or pyometra were treated with PGF2 alpha. Prostaglandin F2 alpha (150 micrograms/kg body weight) was administered once or twice daily by infusing 0.3 ml per 10 kg body wt into the vaginal lumen. Bitches were also treated with amoxicillin ( 15 mg/kg body wt/48 h ) and/or gentamicin ( 4 mg/kg body wt/day ) administered as intramuscular ( i.m . ) injections . Fifteen bitches were treated successfully with intravaginally administered PGF2 alpha for 3 to 12 days and with intramuscularly administered antibiotics for 4 to 12 days. Success of treatment was judged by cessation of vaginal discharge, the absence of fluid in the uterus as determined by ultrasonography, and the overall health status of the animal. As two bitches with pyometra showed clinical deterioration in spite of medical treatment, ovariohysterectomy was performed after the first and the second treatment, respectively. No side effects (salivation, vomiting, diarrhoea, hyperpnoea, ataxia, urination, anxiety, pupillary dilatation followed by contraction) were observed after PGF2 alpha treatment. The disease did not recur during the subsequent oestrous cycles within 12 months after the initial treatment. The results demonstrate that intravaginal administration of PGF2 alpha was effective in 13 dogs (86.6%) with metritis or pyometra, and caused no side effects. Although the study was based on a relatively small number of cases, it is concluded that prostaglandin F2 alpha can be a useful means of treating bitches with metritis or pyometra. However, in severe cases of pyometra ovariohysterectomy is needed.

https://pubmed.ncbi.nlm.nih.gov/10213934/

807f8268ae2d780c813d7fb26f9fdd0c

So far , chloroquine , lopinavir , hydroxychloroquine , azithromycin , favipiravir , ribavirin , darunavir , remdesivir , and umifenovir have been tested in COVID-19 clinical trials .

Tissue distributions of antiviral drugs affect their capabilities of reducing viral loads in COVID-19 treatment. Repurposing of approved antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising strategy to treat Coronavirus disease 2019 (COVID-19) patients. Previously we reported our hypothesis that the antiviral drugs with high lung distributions might benefit COVID-19 patients by reducing viral loads. So far , chloroquine , lopinavir , hydroxychloroquine , azithromycin , favipiravir , ribavirin , darunavir , remdesivir , and umifenovir have been tested in COVID-19 clinical trials . Here we validated our hypothesis by comparing the pharmacokinetics profiles of these drugs and their capabilities of reducing viral load in clinical trials. According to bulk RNA and single cell RNA sequencing analysis, we found that high expression of both angiotensin converting enzyme 2 (ACE2) and transmembrane Serine Protease 2 (TMPRSS2) makes the lung and intestine vulnerable to SARS-CoV-2. Hydroxychloroquine, chloroquine, and favipiravir, which were highly distributed to the lung, were reported to reduce viral loads in respiratory tract of COVID-19 patients. Conversely, drugs with poor lung distributions, including lopinavir/ritonavir, umifenovir and remdesivir, were insufficient to inhibit viral replication. lopinavir/ritonavir might inhibit SARS-CoV-2 in the GI tract according to their distribution profiles. We concluded here that the antiviral drugs should be distributed straight to the lung tissue for reducing viral loads in respiratory tract of COVID-19 patients. Additionally, to better evaluate antiviral effects of drugs that target the intestine, the stool samples should also be collected for viral RNA test in the future.

https://pubmed.ncbi.nlm.nih.gov/33031797/

a98224a670df50e4b56be6492f4addf1

Of the currently known pure antiandrogens , bicalutamide offers some advantages over flutamide as it possesses a much longer half-life , allowing a once daily regimen , and has advantages over nilutamide in terms of fewer adverse effects .

Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer. Prostatic cancer is the second most common cause of cancer death in males. Treatment by radical prostatectomy and radiotherapy is useful in the early stages of the disease. Whenever metastases occur, patients are usually treated by surgical (orchidectomy) or medical [gonadotropin releasing hormone (GnRH) analogue] castration. This form of treatment is, however, associated with unwanted adverse effects, such as flushing, loss of libido and potency and all patients ultimately escape therapy after a delay of 1 to 2 years. For this reason antiandrogens have been developed as another means of endocrine ablation therapy. Antiandrogens fall in 2 groups of which the first group, the steroidal antiandrogens such as cyproterone acetate (CPA), have a direct blocking effect at the cellular level but also inhibit testosterone production by their additional gestagenic properties blocking gonadotropin secretion. Except in preventing the flare-up associated with the start of GnRH analogue therapy and in reducing flushing, no evidence exist of any superiority for CPA over classical therapy in terms of adverse effects and survival. The second group, the nonsteroidal or 'pure' antiandrogens, only block androgens at the cellular level without any central effects. In contrast with other forms of castration, patients on pure antiandrogens as monotherapy preserve their sexual function and potency, at the expense of a slightly inferior androgen blockade and gynecomastia. These latter effects are explained by a compensatory rise in androgens as a result of the blockade at the central level, which weakens the androgen blockade, and by peripheral aromatisation of the increased androgens to oestrogens. In addition, some evidence exist that pure antiandrogens improve survival if combined with other forms of castration as they also inhibit the adrenal androgens, the so-called maximal androgen blockade (MAB). If patients escape control under MAB, a trial of stopping the antiandrogen must always be considered, as some tumours have 'learned' to be activated by these drugs. At the moment it is not yet clear if antiandrogens are of any benefit in downstaging the extent of disease before prostatectomy and/or radiotherapy. Of the currently known pure antiandrogens , bicalutamide offers some advantages over flutamide as it possesses a much longer half-life , allowing a once daily regimen , and has advantages over nilutamide in terms of fewer adverse effects .

https://pubmed.ncbi.nlm.nih.gov/9592622/

56f2acbe3d2bef73cccca2cb430faed2

Fifty-seven patients with advanced measurable urothelial tract cancer , 52 of whom had an adequate trial , were treated weekly with 3 to 4 mg . per m.2 vinblastine and 30 to 40 mg . per m.2 methotrexate .

Vinblastine and methotrexate for advanced bladder cancer. Fifty-seven patients with advanced measurable urothelial tract cancer , 52 of whom had an adequate trial , were treated weekly with 3 to 4 mg . per m.2 vinblastine and 30 to 40 mg . per m.2 methotrexate . Of 3 patients with unidimensional parameters 2 showed improvement lasting 16 and 27 months, which was documented by serial cystoscopic examinations. An additional 2 patients had measurable disease that could have been encompassed in a preoperative radiotherapy field. Both patients are free of disease at more than 12 and 14 months, respectively. Of the 47 patients with bidimensionally measurable parameters 19 (40 per cent) achieved a complete or partial remission lasting a median of 8 months, with a range of 1 to 24 months. Of 25 patients with intra-abdominal or pelvic disease 7 achieved a complete or partial remission and 5 also had a minor remission. Of note, 18 of 38 patients who had received no prior chemotherapy achieved a remission versus 1 of 9 who had been treated previously (p equals 0.06). Responders frequently obtained another remission with subsequent chemotherapy (4 of 9 versus 0 of 16, p equals 0.03). Responders lived 14 months versus 8 months for nonresponders (p equals 0.02). Four responders had brain metastases compared to none of 28 nonresponders. The combination of vinblastine and methotrexate is a well tolerated, effective outpatient regimen for patients with urothelial tract cancers.

https://pubmed.ncbi.nlm.nih.gov/3981708/