Oral repeated-dose toxicity studies of BIA 10–2474 in cynomolgus monkeys

Publication date: Available online 6 December 2019Source: Regulatory Toxicology and PharmacologyAuthor(s): Klaus Weber, Rüdiger Häcker, Jerold F. Hardisty, Stephen B. Harris, A. Wallace HayesAbstractBIA 10–2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys.Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10–2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards.Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanised d...
Source: Regulatory Toxicology and Pharmacology - Category: Toxicology Source Type: research

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AW Abstract BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys. Maximum Tolera...
Source: Regulatory Toxicology and Pharmacology : RTP - Category: Toxicology Authors: Tags: Regul Toxicol Pharmacol Source Type: research
Conclusions: Magnesium sulfate is an important adjuvant drug in the practice of anesthesia, with several clinical effects and a low incidence of adverse events when used at recommended doses. Introduction Magnesium is the fourth most common ion in the body, and it participates in several cellular processes, including protein synthesis, neuromuscular function and stability of nucleic acid, as well as regulating other electrolytes such as calcium and sodium. Magnesium acts as a cofactor in protein synthesis, neuromuscular function and stability and the function of nucleic acids. It is a component of adenosine 5-triph...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
On my birthday last April, it was another sunny spring day in Seattle. I was turning 62, feeling 22, and anxious to ride my electric bike, the EZ Sprint. I'd been riding 10 miles to work and back almost every day for the past year. The ride took me through some congested areas downtown, but put me on a wondrous trail along the Puget Sound. When I rode, I felt on top of the world. I purchased the electric bike in June of 2015, and it was a beast. It was really heavy, checking in at almost 60 pounds. But it was very comfortable with its upright styling. Its weight added to its stability and added to my sense of invincibili...
Source: Healthy Living - The Huffington Post - Category: Consumer Health News Source Type: news
Conclusions PB block combined with GA improved significantly operating conditions and lower incidence of OCR. Patients in the block group also had better postoperative analgesia.
Source: Egyptian Journal of Anaesthesia - Category: Anesthesiology Source Type: research
Time limit: 0 Quiz-summary 0 of 30 questions completed Questions: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ...
Source: Cardiophile MD - Category: Cardiology Authors: Tags: Cardiology MCQ DM / DNB Cardiology Entrance Featured Source Type: blogs
BACKGROUND CONTEXT: Scoliosis is common in Duchenne muscular dystrophy (DMD). It leads to impaired respiratory function, poor sitting balance and pain. Surgical correction of scoliosis improves sitting balance and prevents deterioration of respiratory function. However, conventional surgery in these patients is associated with significant intraoperative bleeding and risk of infection; percutaneous surgical techniques have the advantage of reducing this.
Source: The Spine Journal - Category: Orthopaedics Authors: Source Type: research
ConclusionHS is a condition associated with one‐sided sympathetic denervation of the face that can occur after intrathecal pump implantation. An understanding of the pathophysiology of this condition and reassurance are vital factors for successful management of this condition.
Source: Neuromodulation - Category: Neurology Authors: Tags: Case Series Source Type: research
Abstract Bleeding or rupture of the ovary often accompanies ovarian cysts and causes severe pain and autonomic responses such as hypotension. It would be expected that ovarian afferents contribute to cardiovascular responses induced by ovarian failure. The present study examined cardiovascular responses to noxious chemical stimulation of the ovary by bradykinin, an algesic substance released by tissue damage, and explored the role of ovarian afferents in the ovarian-cardiovascular responses in anesthetized rats. Non-pregnant adult rats were anesthetized with pentobarbital and artificially ventilated. The carotid a...
Source: Autonomic Neuroscience - Category: Neuroscience Authors: Tags: Auton Neurosci Source Type: research
Conclusions: Many unnecessary tests are obtained to evaluate syncope. Selecting tests based on history and examination and prioritizing less expensive and higher yield tests would ensure a more informed and cost-effective approach to evaluating older patients with syncope._____________________________________________________________________________4)    Reed MJ.  The ROSE (Risk Stratification of syncope in the emergency department) Study.  J Am Coll Cardiol, 2010; 55:713-721, doi:10.1016/j.jacc.2009.09.049  Objectives: The aim of this study was to develop and validate a clinical deci...
Source: Dr. Smith's ECG Blog - Category: Cardiology Authors: Source Type: blogs
Conclusions: Many unnecessary tests are obtained to evaluate syncope. Selecting tests based on history and examination and prioritizing less expensive and higher yield tests would ensure a more informed and cost-effective approach to evaluating older patients with syncope._____________________________________________________________________________4)    Reed MJ.  The ROSE (Risk Stratification of syncope in the emergency department) Study.  J Am Coll Cardiol, 2010; 55:713-721, doi:10.1016/j.jacc.2009.09.049  Objectives: The aim of this study was to develop and validate a clinical deci...
Source: Dr. Smith's ECG Blog - Category: Cardiology Authors: Source Type: blogs
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