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Copyright of Canadian Journal of Hospital Pharmacy / Journal Canadien de la Pharmacie Hospitalière is the property of Canadian Society of Hospital Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The treatment of multiple myeloma has dramatically improved due to the availability of novel therapies that are highly effective and are quickly moving into first-line therapy. The Canadian Agency for Drugs and Technologies in Health (CADTH) recently recommended that patients who receive daratumumab should only be eligible to receive either carfilzomib or pomalidomide but not both, for relapsed MM. In order to assess the efficacy of these two agents in the relapsed setting, we utilized our national myeloma database. A total of 121 patients were reviewed, 49 patients received CAR- before POM-based (CAR-POM), and 73 patients received POM- before CAR-based (POM-CAR) therapy. In the groups selected, the median PFS was 4.93 months (95% CI, 2.76–7.07) and 5.36 months (95% CI, 3.75–6.94) for CAR-POM and POM-CAR, respectively. The median OS for patients treated with CAR-POM was 11.01 months (95% CI, 4.50–19.13), and for patients treated with POM-CAR the median OS was 10.98 months (95% CI, 8.98–19.17). In this real-world observational study, we demonstrated that both CAR- and POM-based therapies, irrespective of the order in which they were used, were effective treatment options for patients with advanced relapsed MM. [ABSTRACT FROM AUTHOR]

Background: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis—ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab—and to identify clinical predictors that can influence the drug survival of these drugs. Methods: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models. Results: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418–0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257–1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective. Conclusion: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower. [ABSTRACT FROM AUTHOR]

Objectives: Primary: To explore anti-Müllerian Hormone (AMH) levels in community dwelling women following TBI. Secondary: To explore the relation of AMH to menstrual cycle, cognition, distress and symptoms of menopause. Setting: Large adult TBI outpatient clinic in Toronto Canada. Research design: Prospective study of 10 women with persistent symptoms who were one or more years post TBI. Methods: Consenting participants provided a serum sample for AMH levels, and completed the Menopause Rating Scale (MRS), Symptom Checklist-90 r (SCL-90 r), Repeatable Battery for the Assessment of Neurological Status (RBANS) and a health questionnaire. Main outcomes and results: This study found lower than expected levels of AMH in 50% of participants relative to age matched norms and 50% of participants experienced new onset of menstrual changes. Also notable were findings of lower-than-expected cognitive scores in women over 35 and reports of menopause-related symptoms across all ages groups. Conclusions: As our understanding of the role of AMH grows, examining changes in this novel biomarker in the long-term post-TBI is warranted. Future research should be sufficiently powered to expand on and validate the study's findings. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.Methods: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.Findings: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.Interpretation: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.Funding: Pfizer. [ABSTRACT FROM AUTHOR]

Importance: To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms.Objective: To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.Design, Setting, and Participants: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis.Interventions: Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study.Main Outcomes and Measures: The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes.Results: A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04).Conclusions and Relevance: Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo.Trial Registration: ClinicalTrials.gov identifier: NCT02363738. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the discontinuation of tumor necrosis factor inhibitors (TNFi) during pregnancy is associated with any changes of the disease course in women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Methods: Pregnant women with RA and JIA from the US and Canada were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Information about medication and disease activity (patient‐reported outcome measures) was collected prior to gestational week 20 and at gestational week 32. Associations between patterns of TNFi continuation or discontinuation and disease activity changes were tested in unadjusted and multivariate analyses. Results: Among 490 women (397 with RA, 93 with JIA) enrolled between 2005 and 2017, 122 (24.9%) discontinued a TNFi before gestational week 20, 201 (41.0%) received a TNFi beyond week 20, and 167 (34.1%) did not receive a TNFi during pregnancy. At the time of enrollment, disease activity was low to minimal in 72.9% of women. TNFi discontinuation was not associated with a clinically important worsening of patient reported outcome measures at the third trimester. Univariate but not multivariate analysis showed that women receiving TNFi beyond week 20 were more likely to experience improved disease activity scores at the third trimester. Conclusion: Discontinuing TNFi before gestational week 20 seems feasible in women with RA and JIA who enter pregnancy with well‐controlled disease. [ABSTRACT FROM AUTHOR]

Background Patients with cancer have an elevated risk of venous thromboembolism. Importantly, patients with cancer, who have metastatic disease, renal insufficiency, or are receiving anticancer therapy, have an even higher risk of a recurrent event. Similarly, the risk of recurrent venous thromboembolism is higher than the risk of an initial event. To reduce the risk, extended duration of prophylaxis for up to six months with low-molecular-weight heparins such as dalteparin, enoxaparin, nadroparin, and tinzaparin is recommended by international guidelines. In this paper, the clinical and economic literature is reviewed to provide evidenced based recommendations based on clinical benefit and economic value. Methods A systematic review of major databases was conducted from January 1996 to October 2016 for randomized controlled trials evaluating the four distinct low-molecular-weight heparins against a vitamin K antagonists control group for the prevention of recurrent venous thromboembolism in patients with active cancer. This was then followed by the application of the National Institute of Health and Clinical Excellence guidance to assess the quality of all trials that met the inclusion criteria. Finally, the cost-effectiveness literature supporting the value proposition of each product was reviewed. Results Six randomized trials met the inclusion criteria. There were one, two, and three trials that compared dalteparin, tinzaparin, and enoxaparin to a vitamin K antagonists control group. However, there were no trials for nadroparin in the setting of secondary venous thromboembolism prevention. In addition, only the dalteparin and one of the tinzaparin trials were of high quality and adequately powered. Of the two studies, only the dalteparin trial reported a statistically significant benefit in terms of venous thromboembolism absolute risk reduction when compared to a vitamin K antagonists control group (HR = 0.48; p = 0.002). In addition, there was robust pharmacoeconomic data from Canada, the Netherlands, France, and Austria supporting the cost-effectiveness of dalteparin for this indication. There were no such studies for any of the other agents. Conclusions The totality of high-quality clinical and cost-effectiveness data supports the use of dalteparin over other low-molecular-weight heparins for preventing recurrent venous thromboembolism in patients with cancer. [ABSTRACT FROM AUTHOR]

Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC. [ABSTRACT FROM AUTHOR]

Aim To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. Methods This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. Results In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib C increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). Conclusions Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal. [ABSTRACT FROM AUTHOR]

Abstract: Background: Abatacept, a soluble human fusion protein that selectively modulates the costimulatory signal required for full T-cell activation, is approved for the treatment of rheumatoid arthritis (RA) in the United States, Canada, and the European Union. Because rare but serious adverse effects have been associated with biologic therapies, it is important to assess the safety profiles of these agents on an ongoing basis. Objective: This article reviews current evidence on the safety profile of abatacept in patients with RA. Methods: PubMed/MEDLINE was searched for clinical trials of abatacept using the terms abatacept OR CTLA4Ig, rheumatoid arthritis, and safety. Searches of abstracts presented at the 2007–2009 annual meetings of the American College of Rheumatology, European League Against Rheumatism, and Canadian Rheumatology Association were also conducted. Reports from clinical trials of at least 6 months'' duration that evaluated abatacept in adults with RA were included in the review. Results: Seven placebo-controlled trials and 1 open- label trial were included in the review, as were the long-term extensions of 5 of the studies and an integrated safety analysis. Abatacept added to methotrexate had an acceptable safety profile in patients with RA who had an inadequate response to methotrexate or other traditional disease-modifying antirheumatic drugs, or who failed to respond to treatment with anti-tumor necrosis factor agents. In the 5 core trials, discontinuations due to adverse events ranged from 1.9% to 8.7% of abatacept recipients and 0.9% to 4.3% of placebo recipients. In the integrated safety analysis, serious infections were reported in 3.0% of abatacept recipients and 1.9% of placebo recipients; the corresponding rates of malignancies were 3.7% and 2.9%. No additional safety concerns emerged during up to 7 years of exposure in the long-term extension studies. Antibodies to abatacept developed in ≤3% of patients, with no association found between immunogenicity and adverse events. Conclusion: Based on the evidence reviewed, abatacept had an acceptable safety profile and was well tolerated in patients with RA. [Copyright &y& Elsevier]

1. The ductus venosus is actively regulated in the fetus, but questions remain on the presence of a functional sphincter at its inlet. Using fetal sheep (0.6-0.7 gestation onwards), we have examined the morphology of the vessel and have also determined whether endothelin-1 (ET-1) qualifies as a natural constrictor being modulated by prostaglandins (PGs). 2. Masson's staining and alpha-actin immunohistochemistry showed a muscular, sphincter-like formation at the ductus inlet and a muscle layer within the wall of the vessel proper. This muscle cell component increased with age. 3. ET-1 contracted dose-dependently isolated sphincter and extrasphincter preparations of the ductus from term fetus. This ET-1 effect also occurred in the premature, but its threshold was higher. 4. BQ123 (1 microm) caused a rightward shift in the ET-1 dose-response curve, while indomethacin at a threshold concentration (28 nm) tended to have an opposite effect. 5. Big ET-1 also contracted the ductus sphincter but differed from ET-1 for its lesser potency and inhibition by phosphoramidon (50 microm). 6. The ductus sphincter (term and preterm) and extrasphincter (term) released 6-keto-PGF(1alpha) (hence PGI(2)) and, to a lesser degree, PGE(2) at rest and their release increased dose-dependently upon ET-1 treatment. Both basal and stimulated release was curtailed by endothelium removal. 7. BQ123 and phosphoramidon reduced slightly the contraction of ductus sphincter to indomethacin (2.8 microm). 8. We conclude that the ductus contains a contractile mechanism in the sphincter and extrasphincter regions. ET-1 lends itself to a role in the generation of contractile tone and its action may be modulated by prostaglandins. [ABSTRACT FROM AUTHOR]

Abstract Background: Two programs to reduce expenditures for common gastrointestinal drugs were introduced simultaneously by British Columbia (BC) Pharmacare in 1995. Reference-based pricing restricted reimbursement for all histamine-2 receptor antagonists (H[sub2]RAs) to the cost of the least expensive H[sub2]RA available, generic cimetidine. Special authority restricted reimbursement for proton pump inhibitors (PPIs) to patients who met certain eligibility criteria. We evaluated the effect of reference-based pricing for H[sub2]RAs and special authority for PPIs on dispensing and reimbursement for senior citizen beneficiaries of BC Pharmacare. Methods: Itemized monthly claims data for upper gastrointestinal drugs were obtained from BC Pharmacare for all beneficiaries 65 years of age or older. Periods before and after implementation of reference-based pricing and special authority were compared with respect to defined daily doses dispensed per 100 000 beneficiaries, BC Pharmacare reimbursement per 100 000 beneficiaries, BC Pharmacare reimbursement per defined daily dose and beneficiary contributions per defined daily dose. We used regression models to project forward trends in expenditures observed before implementation of the new policies and hence to estimate accrued cost savings. Results: Before reference-based pricing and special authority, the numbers of defined daily doses that were dispensed and total BC Pharmacare reimbursements for H[sub2]RAs appeared to be declining gradually, whereas those for PPIs were rising. With reference-based pricing, the monthly defined daily dose of cimetidine dispensed increased more than 4-fold, to 116 257 per 100 000 beneficiaries, while those of other restricted H[sub2]RAs decreased by more than half, to 50 927 per 100 000 beneficiaries. Special authority immediately reduced the dispensed volumes of PPIs by one-fourth, but growth in volume then appeared to resume at its previous rate. The estimated annualized cost savings... [ABSTRACT FROM AUTHOR]

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of patients with HIV infection. Both US and British treatment guidelines for HIV infection recommend NNRTI- or protease inhibitor-based combinations [i.e. with nucleoside reverse transcriptase inhibitors (NRTIs)] as first-line treatment options in the management of HIV disease. Results of a pivotal randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection (the majority of whom were antiretroviral therapy-naive) showed the efavirenz-based regimen was better tolerated and had greater success in achieving reductions in viral load below the limit of detection. These and other clinical data were incorporated into economic models in 2 analyses, one conducted in the US and the other in Canada. The US analysis examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy. The efavirenz-based regimen was the dominant treatment strategy as it was predicted to improve survival and reduce direct medical costs in the US healthcare system. Compared with the indinavir-containing regimen, survival was increased by 11% (absolute difference) and cumulative costs were reduced by $US10 326 per patient (1998 discounted costs) at 5 years after starting treatment with efavirenz-based therapy. The Canadian analysis was conducted from the perspective of the Ontario healthcare system. This study did not consider differences in clinical efficacy between treatment groups, costs of study medication or outcomes beyond 1 year - all factors that would have favoured the efavirenz-based regimen. Of the 2 treatment options, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs, primarily because of greater costs associated with adverse clinical events with the indinavir-based regimen. In conclusion, current treatment guidelines for HIV infection recognise efavirenz-based combination regimens as a first-line treatment option. A pivotal comparative clinical trial (DMP 266-006) showed a significantly greater virological response to efavirenz- than indinavir-based triple combination therapy, and the efavirenz-based regimen was better tolerated. These clinical data are supported by pharmacoeconomic analyses conducted in the US and Canada, both of which showed lower medical care costs with the efavirenz-based regimen. The US analysis also predicted long term health benefits, such as improved survival, with efavirenz- versus indinavir-based triple combination therapy. These results must be weighed against the inherent difficulties of predicting long term treatment failure rates from short term data, and the limited number of pharmacoeconomic analyses conducted with efavirenz to date. [ABSTRACT FROM AUTHOR]

Compares mortality and AIDS-free survival among HIV-infected patients in British Columbia who were treated with double- and triple-drug regimes. Methods; Results; Interpretation that treatment with a triple-drug antiretroviral regimen comprising 2 nucleoside analogue reverse transcriptase inhibitors (NRTI) plus a protease inhibitor or a non-NRTI have a lower risk of morbidity and death.

Abstract: In the present study, the role of phosphoproteinphosphatase in the regulation of L-type Ca[sup 2+] channel currents inrat pinealocytes was investigated using the whole-cell version of thepatch-clamp technique. The effects of three phosphatase inhibitors, calyculinA, tautomycin, and okadaic acid, were compared. Although all three inhibitorswere effective in inhibiting the L-type Ca[sup 2+] channel current,calyculin A was more potent than either tautomycin or okadaic acid, suggestingthe involvement of phosphoprotein phosphatase-1. To determine the kinaseinvolved in the regulation of these channels, cells were pretreated with H7 (anonspecific kinase inhibitor), H89 (a specific inhibitor of cyclicAMP-dependent kinase), KT5823 (a specific inhibitor of cyclic GMP-dependentkinase), or calphostin C (a specific inhibitor of protein kinase C).Pretreatment with either H7 or calphostin C decreased the inhibitory effect ofcalyculin A on the L-type Ca[sup 2+] channel current. In contrast,pretreatment with H89 or KT5823 had no effect on the inhibition caused bycalyculin A. Based on these observations, we conclude that basal phosphataseactivity, probably phosphoprotein phosphatase-1, plays an important role inthe regulation of L-type Ca[sup 2+] channel currents in rat pinealocytesby counteracting protein kinase C-mediated phosphorylation. [ABSTRACT FROM AUTHOR]

Background: Around 20% of venous thromboembolism (VTE) cases occur in patients with cancer. Current guidelines recommend low molecular weight heparin (LMWH) as the preferred anticoagulant for VTE treatment. However, some guidelines state that vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are acceptable alternatives for long-term therapy in some patients if LMWHs are not available. LMWHs and VKAs have a number of drawbacks that can increase the burden on patients. DOACs, such as rivaroxaban, can ameliorate some burdens and may offer an opportunity to increase patient satisfaction and health-related quality of life (HRQoL). The Cancer-associated thrOmboSIs – patient-reported outcoMes with rivarOxaban (COSIMO) study is designed to provide real-world information on treatment satisfaction in patients with active cancer who switch from LMWH or VKA to rivaroxaban for the treatment of acute VTE or to prevent recurrent VTE. Methods: COSIMO is a prospective, non-interventional, single-arm cohort study that aims to recruit 500 patients in Europe, Canada and Australia. Adults with active cancer who are switching to rivaroxaban having received LMWH/VKA for the treatment and secondary prevention of recurrent VTE for at least the previous 4 weeks are eligible. Patients will be followed for 6 months. The primary outcome is treatment satisfaction assessed as change in the Anti-Clot Treatment Scale (ACTS) Burdens score at week 4 after enrolment compared with baseline. Secondary outcomes include treatment preferences, measured using a discrete choice experiment, change in ACTS Burdens score at months 3 and 6, and change in HRQoL (assessed using the Functional Assessment of Chronic Illness Therapy – Fatigue questionnaire). COSIMO will collect data on patients’ medical history, patterns of anticoagulant use and incidence of bleeding and thromboembolic events. Study recruitment started in autumn 2016. Conclusions: COSIMO will provide information on outcomes associated with switching from LMWH or VKA therapy to rivaroxaban for the treatment or secondary prevention of cancer-associated thrombosis in a real-life setting. The key goal is to assess whether there is a change in patient-reported treatment satisfaction. In addition, COSIMO will facilitate the evaluation of the safety and effectiveness of rivaroxaban in preventing recurrent VTE in this patient population. Trial registration: NCT02742623. Registered 19 April 2016. [ABSTRACT FROM AUTHOR]

Background: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. Methods: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). Findings: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). Interpretation: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. Funding: Myriad Pharmaceuticals. [ABSTRACT FROM AUTHOR]

The article reports on the treatment of early breast cancer through adjuvant therapy with aromatase inhibitors. Experiment results showed improved event-free survival and a trend for improved survival in women who switched to aromatase inhibitor therapy. The clinical trial run by the National Cancer Institute of Canada suggests the proper dosage for the inhibitor.

Reports research which concluded that the desire to drink alcohol may be related to neuropeptide Y (NPY) levels in the brain. Research in this issue by Thiele et al; Genetic influences on sensitivity to ethanol in humans; Supporting research; Consumption of ethanol by NPY knockout mice; Traits of mice overexpressing NPY; Possible use of antagonists against NPY receptors as anti-obesity agents.

The article offers information on an agent that may prevent Alzheimer's disease. It is stated that thiamet-G, an enzyme inhibitor designed by the scientists, can be preventive of the tangling of brain protein that attributes to disorders such as Alzheimer's disease. The study stated that the removal of sugar groups is being stopped by the said inhibitor, where the attachment of phosphate groups that leads to complication is being blocked. Prior to the information, it is stated that thiamet-G has been tested to healthy rats by the team led by David Vocadlo of Simon Fraser University in British Columbia, Canada, finding out that thiamet-G is the first inhibitor that can be delivered to the brain through the bloodstream, thus saying that it can be a therapeutic agent.

West Nile virus (WNV) has spread throughout the United States and Canada and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to acute flaccid paralysis and lethal encephalitis. No therapy or vaccine is currently approved for use in humans. Using high-throughput screening assays that included a luciferase expressing WNV subgenomic replicon and an NS1 capture enzyme-linked immunosorbent assay, we evaluated a chemical library of over 80,000 compounds for their capacity to inhibit WNV replication. We identified 10 compounds with strong inhibitory activity against genetically diverse WNV and Kunjin virus isolates. Many of the inhibitory compounds belonged to a chemical family of secondary sulfonamides and have not been described previously to inhibit WNV or other related or unrelated viruses. Several of these compounds inhibited WNV infection in the submicromolar range, had selectivity indices of greater than 10, and inhibited replication of other flaviviruses, including dengue and yellow fever viruses. One of the most promising compounds, AP30451, specifically blocked translation of a yellow fever virus replicon but not a Sindbis virus replicon or an internal ribosome entry site containing mRNA. Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans. [ABSTRACT FROM AUTHOR]

Reports on a breakthrough made by researchers at the British Columbia Cancer Agency (BCCA) in the discovery of an agent that is capable of inhibiting tumor cell growth. How integrin-linked kinase (ILK) prevents tumor cell death; How ILK is suppressed by the gene PTEN in non-cancerous cells; How the absence of PTEN in cancerous cells leads to the spread and growth of tumors; Study methods; Results; Discussion of the finding that ILK-inhibiting compounds prevent both the growth and spread of tumor cells.

Presents an abstract `Kinetics and Chain Termination Studies Performed with Recombinant Mutated M184V and K65R HIV Reverse Transcriptase,' by M.A. Wainberg, Y. Quan, et al from the McGill University AIDS Centre, Jewish General Hospital, Montreal, Canada.