Modulation of the Renin-Angiotensin System against COVID-19: A path forward?

Soon after the pandemic outbreak in 2020, it was proposed that binding of SARS-CoV-2 to the angiotensin converting enzyme-2 may explain most of COVID-19's manifestations. Therefore, manipulation of the renin-angiotensin system (RAS) by using well known and commercialized blockers of its classical arm or by repurposing new stimulators of the alternative RAS pathway in clinical development was seen as a potentially effective strategy for the treatment of COVID-19. Moreover, this therapeutic approach had previously shown significant promise in the treatment of other respiratory viral respiratory infections and forms of acute respiratory distress syndrome.

BIO101 in Sarcopenic Seniors at Risk of Mobility Disability: Results of a Double-Blind Randomised Interventional Phase 2b Trial.

Background: Sarcopenia is a progressive muscle disorder that may lead to mobility disability. No pharmaceutical interventions are currently available, and treatment relies on physical exercise and nutrition. The aim of SARA-INT was to investigate whether BIO101 (20-hydroxyecdysone), an activator of the MAS receptor, is safe and improves muscle function and physical performance of community dwelling older sarcopenic patients.

Novel Potential Targets for Function-Promoting Therapies: Orphan Nuclear Receptors, Anti-inflammatory Drugs, Troponin Activators, Mas Receptor Agonists, and Urolithin A.

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy.

A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms ("KHENERGYC").

Background: METHODS: The KHENERGYC trial will be a phase II, randomised, double-blinded, placebo-controlled (DBPC), parallel-group study in the paediatric population (birth up to and including 17 years). The study will be recruiting 24 patients suffering from motor symptoms due to genetically confirmed PMD. The trial will be divided into two phases.

The use of mono- and combination drug therapy in men and women with lower urinary tract symptoms (LUTS) in the UK: a retrospective observational study.

Background: Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB).

Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE).

Background: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children.

Methods: Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily).

Efficacy and Safety of Combination Pharmacotherapy for Patients with Overactive Bladder: A Rapid Evidence Assessment.

Context: Oral pharmacotherapy consisting of antimuscarinics, β3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management.

Objective: To evaluate the efficacy and safety of combination therapy in patients with OAB.

Evidence Acquisition: A literature search was conducted in June 2018 using Embase, MEDLINE, and Cochrane databases via Ovid and relevant congress abstracts.

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

Aims: SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ≥65, <75, and ≥75 years).

Methods: Eligible patients were ≥18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ≥3 months.

Long-term Safety and Efficacy of Mirabegron and Solifenacin in Combination Compared with Monotherapy in Patients with Overactive Bladder: A Randomised, Multicentre Phase 3 Study (SYNERGY II).

Background: The long-term potential of solifenacin and mirabegron combination treatment for patients with overactive bladder (OAB) has not been previously assessed.

Objectives: To evaluate the safety and efficacy of solifenacin succinate 5mg plus mirabegron 50mg tablets (combination treatment) versus solifenacin or mirabegron monotherapy in patients with OAB over 12 mo.

Design, Setting, And Participants: Randomised, double-blind, multicentre, phase 3 trial (SYNERGY II) of patients with "wet" OAB symptoms (urinary frequency and urgency with incontinence) for ≥3 mo.

Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients.

Aims: To evaluate patient-reported outcomes (PROs) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder (OAB) from the SYNERGY trial.

Methods: Following a 4-week placebo run-in, period patients (≥18 years) with OAB were randomized 2:2:1:1:1:1 to receive solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg + mirabegron 50 mg, (combination 5 + 50 mg), solifenacin 5 mg, mirabegron 25 mg, mirabegron 50 mg or placebo for 12 weeks, followed by a 2-week washout period. At each visit, PROs related to quality of life, symptom bother, and treatment satisfaction were assessed, including OAB-q Symptom Bother score, health-related quality of life (HRQOL) Total score, treatment satisfaction-visual analogue scale (TS-VAS), and patient perception of bladder condition (PPBC) questionnaires.

Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study).

Objective: To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with urinary incontinence (UI).

Patients And Methods: After a 4-week placebo run-in, patients aged ≥18 years with wet OAB (urgency, urinary frequency and UI) for ≥3 months who recorded on average ≥8 micturitions/24 h, ≥1 urgency episode/24 h, and ≥3 UI episodes over the 7-day micturition diary, were eligible for randomisation to double-blind treatment [2:2:1:1:1:1 ratio, solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25 group); solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50 group); solifenacin 5 mg; mirabegron 25 mg; mirabegron 50 mg; or placebo for 12 weeks], and 2-weeks' single-blind, placebo run-out. Co-primary efficacy variables were change from baseline to end of treatment (EoT) in the mean number of UI episodes/24 h and micturitions/24 h, assessed using a 7-day electronic micturition diary.

Electronic bladder diaries of differing duration versus a paper diary for data collection in overactive bladder.

Aims: This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations.

Methods: Subjects ≥18 years with overactive bladder (OAB) on stable antimuscarinic treatment for ≥12 weeks were assigned to one of five, 15-week diary schedules in this randomized, parallel-group observational study. Sample size was sufficient to assess reliability and consistency of diary data with adequate precision.

Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony).

Background: Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects.

Objective: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy.

Bioequivalence of zonisamide orally dispersible tablet and immediate-release capsule formulations: results from two open-label, randomized-sequence, single-dose, two-period, two-treatment crossover studies in healthy male volunteers.

Background: To make it easier for patients who are prescribed zonisamide to administer their medicine, a rapidly disintegrating oral tablet formulation has been developed.

Objective: These 2 trials assessed the bioequiva-lence of a new orally dispersible tablet formulation of zonisamide (test) versus an immediate-release reference capsule.

Methods: Study 1 assessed the bioequivalence of a 100-mg orally dispersible tablet versus a 100-mg reference capsule.