Delving into the Latest Updates on Alfaxalone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Alfaxalone (INN), Phaxan

+ [3]

Target

GABAA receptor

Mechanism

GABAA receptor positive allosteric modulators(Gamma-aminobutyric acid A receptor positive allosteric modulators)

Therapeutic Areas

Other Diseases

Active Indication

AnesthesiaSedation

Inactive Indication-

Originator Organization

Drawbridge Pharmaceuticals

Active Organization

Cali Biosciences Co. Ltd.

Inactive Organization

Drawbridge Pharmaceuticals

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC21H32O3

InChIKeyDUHUCHOQIDJXAT-OLVMNOGESA-N

CAS Registry23930-19-0

PIM-1 kinase, a member of the Serine/Threonine kinase family, has emerged as a promising therapeutic target in various cancers due to its role in promoting tumor growth and resistance to conventional therapies. In this study, we employed a structure-based approach to screen 3800 FDA-approved drugs to discover potential inhibitors of PIM-1. After an initial selection of 50 candidates based on high docking scores, four drugs, stanozolol, alfaxalone, rifaximin, and telmisartan, were identified as strong PIM-1 binders, interacting with key residues in the ATP-binding pocket of the kinase. To assess the stability of these interactions, we conducted all-atom molecular dynamic simulations, confirming favorable dynamics. Experimental validation via a kinase inhibition assay on recombinant PIM-1 showed that rifaximin significantly inhibited PIM-1 activity, with an IC₅₀ of ∼26 μM. Fluorescence binding assays further demonstrated a strong binding affinity for rifaximin, with a binding constant, corroborated by isothermal titration calorimetry studies. Our findings suggest that rifaximin may serve as a potential repurposed drug for targeting PIM-1 in cancer treatment. However, further validations are required in a clinical setting before the final therapeutic implications.

01 Feb 2025·Research in Veterinary Science

Efficacy of transdermal ketoprofen on surgical inflammation in dogs

Article

Author: Sadowski, P ; Satake, N ; Mills, P C ; Ravuri, H G

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation in dogs. Despite having effective analgesic efficacy, prolonged oral administration has been associated with adverse effects. Transdermal delivery of ketoprofen has reduced the incidence of adverse effects in humans and could potentially be used in veterinary clinical medicine. A transdermal (TD) ketoprofen formulation was recently developed for use in dogs and this study aimed to determine the pharmacodynamic activity of this formulation using surgical castration as an acute inflammatory model. Twelve dogs were randomly assigned to either a Control group (n = 6) or a TD group (n = 6). All dogs were castrated using standard surgical protocols, administered with pre-medication, consisting of acepromazine (0.055 mg/kg) and methadone (0.5 mg/kg) intramuscularly (IM) 30 min prior to induction of general anaesthesia. All dogs were then anaesthetised by injecting alfaxalone (2 mg/kg IV) via a 20 G 3 cm catheter in the left cephalic vein and subsequently maintained using isoflurane. Along with that TD group dogs also received TD ketoprofen (10 mg/kg) 1 h before pre-medication. Bloods were collected at 0 - hour (pre-surgery), and 1 and 2-h post-surgery and analysed for circulating eicosanoids using liquid chromatography mass spectrometry (LCMS) methods. Measured levels of Thromboxane B₂ (TXB₂) at both 1 and 2 h and Prostaglandin E₂ (PGE₂) at 2 h post-surgery were higher in the Control group compared to the TD group, suggesting pre-operative application of TD ketoprofen has a possible inhibitory effect on systemic inflammation and could be used to treat pain and inflammation in dogs.

01 Jan 2025·Veterinary Anaesthesia and Analgesia

Effects of hydromorphone alone and combined with medetomidine-vatinoxan or dexmedetomidine on alfaxalone induction dose and mean arterial pressure in dogs anesthetized with sevoflurane

Article

Author: Bussières, Genevieve ; Hampton, Chiara E ; Kleine, Stephanie A ; Seddighi, Reza ; Davis, Lily V ; Smith, Christopher K ; Zhu, Xiaojuan

OBJECTIVETo evaluate the dose of alfaxalone needed for induction of anesthesia following sedation with medetomidine-vatinoxan plus hydromorphone (MVH), dexmedetomidine plus hydromorphone (DH), or hydromorphone (H) alone. A secondary objective included evaluating selected cardiopulmonary variables before, during, and after sedation and general anesthesia with sevoflurane in healthy dogs.STUDY DESIGNProspective, randomized, masked, crossover.ANIMALSEight healthy Beagle dogs, 3-4 years old.METHODSAll dogs received three intramuscular (IM) treatments: H (0.1 mg kg^-1), DH (0.005 mg kg^-1 + 0.1 mg kg^-1, respectively), or MVH (0.01 mg kg^-1 + 0.2 mg kg^-1 + 0.1 mg kg^-1, respectively) at least 6 days apart. General anesthesia was induced with alfaxalone 20 minutes after treatment administration and maintained for 60 minutes with 2.8% sevoflurane (expired). Sedation scores, selected cardiopulmonary variables, and recovery scores were measured before, during, and after anesthesia at selected timepoints. Mixed-effects ANOVA and ANOVA on ranks were used to evaluate differences between treatments, time, and their interaction, and Tukey-Kramer method was used for post hoc analysis (p < 0.05). Data are presented as mean ± SD or median (range).RESULTSDogs given MVH required a lower dose of alfaxalone for induction of anesthesia (0.77 ± 0.4 mg kg^-1) compared to DH and H (1.16 ± 0.34 mg kg^-1; p = 0.02, 1.13 ± 0.18 mg kg^-1; p = 0.02), and had a higher incidence (50%; p = 0.038) and longer duration [median; 10 (0-35) minutes] of hypotension during sevoflurane anesthesia compared to H [0%; 0 (0-0) minutes; p = 0.040] but not DH (p = 0.272).CONCLUSIONS AND CLINICAL RELEVANCEPremedication with MVH provided the greatest alfaxalone-sparing effect. However, this treatment was associated with lower arterial pressures and clinically relevant hypotension. Off-label use of medetomidine-vatinoxan before sevoflurane-based anesthesia should be used with caution due to a high incidence of hypotension.

100 Deals associated with Alfaxalone

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