Tucatinib (Tukysa)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses tucatinib (Tukysa), 50 mg and 150 mg tablets, orally. Tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and T-DM1 separately or in combination.

Azacitidine (Onureg)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses azacitidine (Onureg), tablet 300 mg, oral. Indication: Maintenance therapy in adult patients with acute myeloid leukemia who achieved complete remission or complete remission with incomplete blood count recovery following induction therapy with or without consolidation treatment, and who are not eligible for hematopoietic stem cell transplantation.

Place of imidazoline receptor agonists in the treatment of hypertension

The review is devoted to selective I1-imidazoline-receptor agonists. An analysis of Russian and foreign studies is presented, the results of which indicate that this drug class not only provides adequate and long-term control of blood pressure, but also has a number of favorable metabolic effects. Therefore, it contributes to reducing insulin resistance (weight loss) and has organ protective properties (endothelial function improvement, left ventricular hypertrophy regression, microalbuminuria reduction). At the same time, selective I1-imidazoline-receptor agonists are much less likely to cause side effects characteristic of old-generation sympatholytic agents. This class of drugs is invariably included in Russian guidelines for the diagnosis and treatment of hypertension.

A Study on Pharmacist Mediated Intervention in Identifying and Reporting of Adverse Drug Reactions at a Tertiary Care Hospital

Background: Adverse drug reactions are major problem in health care system due to its consequences - morbidity, mortality and health care cost. Recent epidemiologic research reveals that the total incidence rate of ADRs was 6.7%, with an overall fatality rate of 0.32%. Method: A prospective observational study was carried out for 6 months in a tertiary care hospital. Patients admitted to the department of medicine, Pediatrics, orthopedics & surgery were selected randomly and followed from date of admission to date of discharge by enrolling into the study by considering the study criteria. Results: During the research about 27 ADRs were recognized & reported. Among them 14 (51.86%) patients were male and 13(48.14%) were female patients. The system or organ most commonly involved was Blood disorders were 8 (29.62%). Type A were 16(57.25%) reactions followed by Type B were 8 (29.62%); Type C were 3 (11.11%). Study depicts drug class usually implicated with ADRs was Antibiotics and antineoplastic drugs were 6 (22.22%) followed by Anti-Tubercular were 3 (11.11%); NSAIDS and Antidiabetic drugs were 2 (7.4%); The least implicated (3.7%) drug class are Anti-Pyretic, Diuretics and Antiretroviral. Causality was assessed for all the reported reactions are found to be PROBABLE according to WHO-UMC Scale. Conclusion: The study report shows that incidence of ADRs is steadily increasing. Under reporting of ADR is a major problem in India. Clinical Pharmacist plays a vital role in surveillance and prevention of ADRs. Keywords: Adverse Drug Reactions, Pharmacovigilance, Causality.

Anticoagulation Changes Following Major and Clinically Relevant Nonmajor Bleeding Events in Non-valvular Atrial Fibrillation Patients

Background Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown. Methods Patients with non-valvular atrial fibrillation from six anticoagulation clinics taking warfarin or DOAC therapy who experienced an International Society of Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant non-major (CRNM) bleeding event were identified between 2016 and 2020. The primary outcome was management of the anticoagulant following bleeding (discontinuation, change in drug class, and restarting of same drug class). DOAC- and warfarin-treated patients were propensity matched based on the individual elements of the CHA2DS2-VASc and HAS-BLED scores as well as the severity of the bleeding event. Results Of the 509 patients on warfarin therapy and 246 on DOAC therapy who experienced a major or CRNM bleeding event, the majority of patients continued anticoagulation therapy. The majority of warfarin (231, 62.6%) and DOAC patients (201, 81.7%) restarted their previous anticoagulation. Conclusion Following a bleeding event, most patients restarted anticoagulation therapy, most often with the same type of anticoagulant that they previously had been taking.

Sustained HIV viral suppression with dolutegravir, tenofovir, and emtricitabine as initial therapy despite high-level transmitted multi-class resistance

Multi-class high-level transmitted HIV drug resistance is uncommon, and the selection of the optimal initial antiretroviral drug regimen may be challenging. We report a case of extensive transmitted multi-class resistance successfully treated with dolutegravir, tenofovir, and emtricitabine even though the baseline genotype demonstrated full susceptibility to only one drug class, the integrase strand transfer inhibitors. Our case highlights both the high resistance barrier of dolutegravir and the residual antiviral activity of nucleoside reverse transcriptase inhibitors despite extensive resistance on genotype.

Liraglutide (Saxenda)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses liraglutide 6 mg/mL (Saxenda). Indication under review : Indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of: 30 kg/m2 or greater (obesity), or 27 kg/m2 or greater (overweight) in the presence of at least 1 weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia) and who have failed a previous weight management intervention.

Pembrolizumab (Keytruda)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses pembrolizumab (Keytruda) 200 mg in adults or 2 mg/kg in pediatrics administered intravenously every 3 weeks. Indication: Treatment of adult and pediatric patients with refractory or relapsed cHL, as monotherapy, who have failed ASCT, or who are not candidates for multi-agent salvage chemotherapy and ASCT.

Investigating the Specific Interactions Between Microtubule Stabilising Agents and β-Tubulin

<p>Microtubule stabilising agents are a class of cytotoxic compounds that cause mitotic arrest through inhibition of microtubule function. They specifically target β-tubulin subunits promoting tubulin polymerisation, which eventually leads to cell death. Members of this drug class include the cancer chemotherapeutics paclitaxel and ixabepilone. However, like many cytotoxic agents, tumour cells often develop multi-drug resistance phenotypes limiting the effectiveness of such compounds. This results from the expulsion of these drugs from cells by efflux pumps, as well as mutation of their binding site. Much effort has been focused on improving the utility of this important drug class in the ongoing fight against cancer. The microtubule stabilising agents peloruside A and laulimalide originate from marine sponge species native to the South Pacific. They have similar pharmacological profiles to paclitaxel and ixabepilone, however with several unique properties. They are poor substrates for efflux pumps and target a different region on β-tubulin subunits, giving them the potential for treatment of resistant tumours. This represents a novel mechanism of action that may be exploited for drug development, and further characterisation of the binding site is warranted. The aim of this study is to investigate the contribution of two amino acids of human βItubulin to the interactions with peloruside A and laulimalide. Specifically, glu127 and lys124 have been predicted by computational modelling and analogue studies to form hydrogen bonds and other associations with the two compounds. These amino acids are located on β-tubulin subunits adjacent to the main binding pocket of peloruside A and laulimalide, and represent a potential inter-protofilament interaction that does not occur with other microtubule stabilising agents. This binding mechanism has not yet been shown by crystallography and is hence based solely on in silico work, requiring biological validation. HEK293 cells were transfected with βI-tubulin with these amino acids mutated to alanines to prevent hydrogen bond formation. Cell proliferation assays, flow cytometry, and immunoblotting were used to study the effect loss of the inter-protofilament interaction has on the bioactivity of peloruside A and laulimalide. These mutations did not significantly alter the concentration-response of cells to either drug in the cell proliferation assay. However, accumulation of cells in the G2/M phase of the cell cycle and the proportion of transfected cells showing signs of mitotic arrest significantly decreased for E127A mutant cells compared to wild type βI-tubulin transfected control cells treated with peloruside A. Furthermore, a similar reduction in cell cycle block was also seen in E127A mutant cells treated with the negative control ixabepilone, which binds to a different site on β-tubulin. No evidence seen in this study suggests that either amino acid plays a major role in peloruside A or laulimalide target binding. However, the amino acid E127 is important for inter-protofilament associations independent of drug treatment, as its mutation appeared to reduce global stability of microtubule structures. This information requires further validation, it may be useful in the design of future analogue syntheses as development of these promising drug candidates continues.</p>