Congruence modularity implies cyclic terms for finite algebras

An n-ary operation f : A(n) -> A is called cyclic if it is idempotent and f(a(1), a(2), a(3), ... , a(n)) = f(a(2), a(3), ... , a(n), a(1)) for every a(1), ... , a(n) is an element of A. We prove that every finite algebra A in a congruence modular variety has a p-ary cyclic term operation for any prime p greater than vertical bar A vertical bar

AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study

Background Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs. Methods This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days. Results 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%). Conclusions AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH

Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD

Abstract The Biopharmaceutics Classification System (BCS), developed in the 1990s for oral immediate release drugs, is utilized by R&D scientists and regulators to streamline product development and regulatory approval timelines. This elegant, science-based approach is based on three in vitro parameters representing a combination of drug substance physicochemical and physiological properties with respect to oral administration; specifically a dose number, dissolution number, and absorption number. Interest in applying similar principles to pulmonary drug products is increasing. To date the focus has been on dissolution of drugs in the lung. A workshop co-sponsored by the AAPS, FDA, and USP was held in March 2015 in Baltimore to evaluate if a systematic framework to classify pulmonary drugs could be established, and the scope and relevance of such a classification scheme. The focus of the workshop was to address factors influencing drug delivery and action in the lungs rather than the development of a specific model or system. Presentations included: the history and evolution of the oral BCS (described as the “giBCS” by Gordon Amidon), lung physiology and the fate of inhaled drugs, regional aerosol deposition and dose, macroscopic clearance mechanisms, particle dissolution, drug permeability, absorption and their interplay with pharmacokinetics and pharmacodynamics. Background discussions were followed by three separate breakout sessions each focused on the BCS concepts of dose, dissolution, and absorption numbers as they would apply to pulmonary drug delivery. The workshop concluded that a classification system, if fully developed, would be a useful tool for formulators and discovery chemists. The scope of such a system, at this point in time, would not include aspects relevant to regulatory relief. The goals of the workshop were met by identifying an opportunity to develop a model to classify pulmonary drugs based on physicochemical attributes specific to lung physiology and drug delivery