A review of the pharmacology and clinical application of alfaxalone in cats

AbstractAlfaxalone-2-hydroxpropyl-β-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats

G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

‘Globesity’ is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable ‘unimolecular poly-incretin-agonist’ therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity

Influence of two administration rates of alfaxalone at induction on its relative potency in cats: a pilot study

Objectives: The aim of the study was to evaluate, in a controlled, randomised, masked clinical trial, the influence of administration rate of alfaxalone at induction on its relative potency in cats and to report the incidence of cardiorespiratory adverse effects. Methods: Twelve healthy female domestic cats admitted for ovariohysterectomy were premedicated with buprenorphine 20 µg/kg intramuscularly and alfaxalone 3.0 mg/kg subcutaneously. Sedation scores were established (using a published scale ranging from 1 [no sedation] to 5 [profound sedation]) prior to anaesthesia induction with alfaxalone intravenously at 2 mg/kg/min (group A2; n = 6) or 0.5 mg/kg/min (group A0.5; n = 6) to effect until orotracheal intubation was achieved. Sedation scores and alfaxalone induction doses were compared between the groups, using a Mann–Whitney exact test. Results are reported as median and range. Presence of apnoea (no breathing for more than 30 s) or hypotension (mean arterial blood pressure <60 mmHg) within 5 mins postintubation was also reported. Results: Although sedation scores (1.5 [range 1.0–3.0] and 2.5 [range 1.0–3.0] for A2 and A0.5, respectively) were not significantly different (P = 0.32), cats in group A2 required significantly more alfaxalone (4.3 mg/kg [range 3.4–7.0 mg/kg]) than group A0.5 (2.1 mg/kg [range 1.5–2.5 mg/kg]) (P = 0.002). Two cats in each group presented postinduction apnoea, and two cats in group A2 and three cats in group A0.5 presented postinduction hypotension. Conclusions and relevance: The use of a slower induction infusion rate resulted in an increase in the alfaxalone relative potency without obvious cardiorespiratory benefit

Evaluation of the influence of atipamezole on the postoperative analgesic effect of buprenorphine in cats undergoing a surgical ovariohysterectomy

Ojective: To evaluate the influence of atipamezole on postoperative pain scores in cats. Study design: Controlled, randomized, masked clinical trial. Animals: Twelve healthy female domestic cats. Methods: Cats admitted for ovariohysterectomy (OVH) surgery were randomly allocated to group atipamezole (n = 6) or group saline (n = 6) and were premedicated with buprenorphine 20 μg kg−1 intramuscularly (IM) and alfaxalone 3.0 mg kg−1 subcutaneously (SC). Anaesthesia was induced with alfaxalone intravenously (IV) to effect and maintained with isoflurane in oxygen. Ten minutes after extubation, cats from group atipamezole received IM atipamezole (0.0375 mg kg−1) whereas group saline received an equivalent volume [0.0075 mL kg−1 (0.003 mL kg−1 IM)] of 0.9% saline. A validated multidimensional composite scale was used to assess pain prior to premedication and postoperatively (20 minutes after extubation). If postoperative pain scores dictated, rescue analgesia consisting of buprenorphine and meloxicam were administered. Pain score comparisons were made between the two groups using a Mann–Whitney exact test. Results are reported as the median and range. Results: Preoperatively, all cats scored 0. At the postoperative pain evaluation, the pain scores from group atipamezole [16 (range, 12–20)] were not significantly different from group saline [18 (range, 15–23)] (p = 0.28). All cats required rescue analgesia post-operatively. Conclusions and clinical relevance: Atipamezole (0.0375 mg kg−1 IM) administration did not significantly affect the postoperative pain scores in cats after OVH. Preoperative administration of buprenorphine (20 μg kg−1 IM) did not provide adequate postoperative analgesia for feline OVH

Accidental alfaxalone overdose in a mature cat undergoing anaesthesia for magnetic resonance imaging

Case summary This case report describes the clinical signs and treatment of an alfaxalone 10 times overdose in a 12-year-old cat undergoing anaesthesia for MRI. The cat was discharged from hospital following a prolonged recovery including obtunded mentation and cardiorespiratory depression for several hours following cessation of anaesthesia. The cat received supportive therapy that included supplemental oxygen via a face mask, intravenous crystalloid fluids and active rewarming. The benefits of using alfaxalone for maintenance of anaesthesia, its pharmacokinetics and previously reported lethal doses are discussed. Strategies for reducing the incidence of medication errors are presented. Relevance and novel information An unintentional overdose of alfaxalone by continuous rate infusion has not been reported previously in a cat. Treatment is supportive and directed towards maintenance of the cardiorespiratory systems. Whenever possible, smart pumps that have been designed to reduce human error should be used to help prevent medication errors associated with continuous rate infusions

Dataset for manuscript 'Health-related quality of life in patients accessing medicinal cannabis in Australia: The QUEST Initiative results of a 3-month follow-up observational study.'

Deidentified patient-reported outcome dataset and data dictionary.Raw data and scores for EQ-5D, DASS, and QLQ-C30 measures calculated using IBM SPSS Statistics 28.0.0.0. Fatigue and sleep PROMIS measures scored via the online HealthMeasures scoring platform

Health-related quality of life in patients accessing medicinal cannabis in Australia: The QUEST initiative results of a 3-month follow-up observational study.

AimsPatients with chronic health conditions not responding to conventional treatment can access medicinal cannabis (MC) prescriptions from clinicians in Australia. We aimed to assess overall health-related quality of life (HRQL), pain, fatigue, sleep, anxiety, and depression in a large real-world sample of patients accessing prescribed medicinal cannabis. We hypothesized that all patient-reported outcomes (PROs) would improve from baseline to 3-months.MethodsThe QUEST Initiative is a large prospective multicenter study of patients with any chronic health condition newly prescribed medicinal cannabis between November 2020 and December 2021. Eligible patients were identified by 120 clinicians at medical centers across six Australian states. Consenting participants completed the EuroQol Group EQ-5D-5L health status questionnaire; European Organization for Research & Treatment of Cancer Quality of Life questionnaire (QLQ-C30); Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms in Fatigue and Sleep Disturbance, and the Depression Anxiety Stress Scale (DASS-21) before starting therapy, at 2-weeks titration, then monthly for 3-months.ResultsOf the 2762 consenting participants, 2327 completed baseline and at least one follow-up questionnaire. Ages ranged between 18-97 years (mean 51y; SD = 15.4), 62.8% were female. The most commonly treated conditions were chronic pain (n = 1598/2327; 68.7%), insomnia (n = 534/2327; 22.9%), generalized anxiety (n = 508/2327; 21.5%), and mixed anxiety and depression (n = 259/2327; 11%). Across the whole cohort both EQ-5D-5L utility scores and QLQ-C30 summary scores showed clinically meaningful improvement in HRQL from baseline to mean follow-up with d = 0.54 (95%CI:0.47 to 0.59) and d = 0.64 (95%CI:0.58 to 0.70) respectively; and clinically meaningful improvement in fatigue (d = 0.54; 95%CI:0.48 to 0.59). There was clinically meaningful reduction of pain for those with chronic pain (d = 0.65; 95%CI:0.57 to 0.72); significant improvements for those with moderate to extremely severe anxiety (X2 = 383; df = 4; pConclusionsWe observed statistically significant, clinically meaningful improvements in overall HRQL and fatigue over the first 3-months in patients with chronic health conditions accessing prescribed medical cannabis. Anxiety, depression, and pain also improved over time, particularly for those with corresponding health conditions. The study continues to follow-up patients until 12-months to determine whether improvements in PROs are maintained long-term.Trail registrationStudy registration - Australian New Zealand Clinical Trials Registry: ACTRN12621000063819. https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000063819

Domestication through clandestine cultivation constrained genetic diversity in magic mushrooms relative to naturalized populations

Summary Fungi that are edible or fermentative were domesticated through selective cultivation of their desired traits. Domestication is often associated with inbreeding or selfing, which may fix traits other than those under selection, and causes an overall decrease in heterozygosity. A hallucinogenic mushroom, Psilocybe cubensis, was domesticated from its niche in livestock dung for production of psilocybin. It has caused accidental poisonings since the 1940s in Australia, which is a population hypothesized to be introduced from an unknown center of origin. We sequenced genomes of 38 isolates from Australia and compared them with 86 genomes of commercially available cultivars to determine (1) whether P. cubensis was introduced to Australia, and (2) how domestication has impacted commercial cultivars. Our analyses of genome-wide SNPs and single-copy orthologs showed that the Australian population is naturalized, having recovered its effective population size after a bottleneck when it was introduced, and it has maintained relatively high genetic diversity based on measures of nucleotide and allelic diversity. In contrast, domesticated cultivars generally have low effective population sizes and hallmarks of selfing and clonal propagation, including low genetic diversity, low heterozygosity, high linkage disequilibrium, and low allelic diversity of mating-compatibility genes. Analyses of kinship show that most cultivars are founded from related populations. Alleles in the psilocybin gene cluster are identical across most cultivars of P. cubensis with low diversity across coding sequence; however, unique allelic diversity in Australia and some cultivars may translate to differences in biosynthesis of psilocybin and its analogs