In the present article, we review the pharmacological properties of KDS-4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS-4103 inhibits FAAH activity with median inhibitory concentrations (IC 50 ) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS-4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID 50 ) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid-related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS-4103 elicits significant, anxiolytic-like, antidepressant-like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS-4103 does not evoke classical cannabinoid-like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Ä 9 -tetrahydrocannabinol (Ä 9 -THC). These findings suggest that KDS-4103 acts by enhancing the tonic actions of anandamide on a subset of CB 1 receptors, which may Address correspondence and reprint requests to: Daniele Piomelli, PhD, Department of Pharmacology, 360 MSR II, University of California, Irvine, CA 92697-4625, USA; Tel.: +1 (949) 824-6180, Fax: +1 (949) 824-6305, E-mail: piomelli@uci.edu normally be engaged in controlling emotions and pain. KDS-4103 is orally available in rats and cynomolgus monkeys. Sub-chronic repeated dose studies (1500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS-4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1500 mg/kg. The results suggest that KDS-4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.
Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3, 0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.
Summary:Purpose: Studies were conducted to establish the safety, tolerability, and pharmacokinetics of the antiepileptic drug (AED) ganaxolone. Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the y-aminobutyric acid type A (GABA,) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals.Methods: Ninety-six healthy male and female volunteers received ganaxolone in a variety of formulations, doses, and dosing regimens. The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented.Results: Ganaxolone was well tolerated after single doses (S1,500 mg) and after multiple doses (C300 mg b i d . for 10 days). Steady-state plasma levels (trough) occurred after -7 days of dosing, with mean steady-state plasma concentrationsin multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or lifethreatening adverse events attributed to the drug were observed. The majority of adverse events reported were mild (82%) to moderate (14%) and were limited to headache, dizziness, somnolence, gastrointestinal disturbances, and malaise.Conclusions: Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg. Pharmacokinetic analysis revealed a linear and proportional increase in the area under the curve (AUC) and C, , , values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable. Key Words: Ganaxolone-Neurosteroid-Antiepileptic-Epalon-GABA agonist.Ganaxolone is a member of a novel class of neuroactive steroids called epalons, which allosterically modulate the y-aminobutyric acid (GABAA) receptor complex (GRC) in the brain through a unique recognition site. The compound was developed after endogenously occurring metabolites of progesterone, such as 3a-hydroxy-5a-pregnan-20-one (3a,5a-P), were observed to have prominent anticonvulsant effects in animal models of epilepsy (1-3).Ganaxolone (3a-hydroxy-3P-methyl-5a-pregnan-20-one) is the 3P-methylated, synthetic analog of 3a,5aU-P. 3a,5a-P is formed endogenously with its 5p-isomer when progesterone undergoes 5a-reduction of the 4-5 double bond to form 5a(b)-pregnan-3,20-dione followed by the reduction of the 3-ketone to a 3a-hydroxyl. This Accepted May 1, 1997. Address correspondence and reprint requests to Dr. E. P. Monaghan at CoCensys, Inc., 213 Technology Drive, Irvine, CA 92618, U.S.A. reduction of progesterone to 3a,5a-P results in the loss of progestational activity (i.e., loss of hormonal activity) (3,4).Endogenously occurring epalons were initially characterized as potent allosteric modulators of the GABA, receptor by using in vitro binding (5,6). In radioligandbinding stu...
Summary:Purpose: A double-blind, randomized, placebocontrolled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.Methods: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner.Results: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. KaplanMeier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc x' probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group.Conclusions: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity. Key Words: Ganaxolone-Epilepsy-Presurgical trial-Partial seizures-y-Aminobutyric acid A modulator.Ganaxolone is a member of a novel class of neuroactive steroids called epalons, which allosterically modulate the y-aminobutyric acid type A receptor complex via a unique recognition site (1). The compound was developed after it was observed that endogenously occurring metabolites of progesterone and deoxycorticosterone, such as 3a-hydroxy-501-pregnan-2O-one and 501-tetrahydrodeoxycorticosterone, had substantial anticonvulsant effects in animal models of epilepsy (24). Ganaxolone (3au-hydroxy-3~-methyl-5a-pregnan-20-one) is the 3P-methylated, synthetic analog of 301-hydroxy-501-pregnan-20-one and possesses no detectable hormonal acAccepted May 12, 2000. Dr. Morrell is now with The Neurological Institute, Columbia Presbyterian Medical Center, New York, NY.Address correspondence to Dr. Edward P. Monaghan at Serono, Inc., 700 Longwater Dr, Norwell, MA 02061. E-mail: edward.monaghan. us-bos0 1 @ serono.com tivity (5). In vivo pharmacology studies demonstrated that ganaxolone provides protection in a wide variety of animal models, including pentylenetetrazol-, bicuculline-, aminophylline-, t-butylbicyclophosphorothionate-, and corneal kindling-induced seizure models, suggesting that it may have utility in the treatment of a broad range of seizure types (6-8).Traditionally, early clinical trials in epilep...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.