An alternative to detoxification by oral therapy with the narcotic antagonist naltrexone is the subcutaneous implantation of naltrexone pellets. From detoxified patients with naltrexone implants (1g) 26 blood samples were collected up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol in plasma was developed using automated mixed-mode solid-phase extraction, catalysed trimethylsilylation and gas chromatography-mass spectrometry in single ion monitoring mode with naloxone as internal standard. The analytical method was very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60 ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy 1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6 each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and 10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0 ng/ml, respectively. The simple analytical procedure described provided good sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone pellet implantation.

15 Jun 2001·Journal of NeurochemistryQ2 · MEDICINE

Inverse agonists and neutral antagonists at µ opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence

Q2 · MEDICINE

Article

Author: Danxin Wang ; Wolfgang Sadée ; Kirsten M. Raehal ; Edward J. Bilsky

The µ opioid receptor, MOR, displays spontaneous agonist‐independent (basal) G protein coupling in vitro. To determine whether basal MOR signaling contributes to narcotic dependence, antagonists were tested for intrinsic effects on basal MOR signaling in vitro and in vivo, before and after morphine pretreatment. Intrinsic effects of MOR ligands were tested by measuring GTPγS binding to cell membranes and cAMP levels in intact cells. β‐CNA, C‐CAM, BNTX, and nalmefene were identified as inverse agonists (suppressing basal MOR signaling). Naloxone and naltrexone were neutral antagonists (not affecting basal signaling) in untreated cells, whereas inverse agonistic effects became apparent only after morphine pretreatment. In contrast, 6α‐ and 6β‐naltrexol and ‐naloxol, and 6β‐naltrexamine were neutral antagonists regardless of morphine pretreatment. In an acute and chronic mouse model of morphine‐induced dependence, 6β‐naltrexol caused significantly reduced withdrawal jumping compared to naloxone and naltrexone, at doses effective in blocking morphine antinociception. This supports the hypothesis that naloxone‐induced withdrawal symptoms result at least in part from suppression of basal signaling activity of MOR in morphine‐dependent animals. Neutral antagonists have promise in treatment of narcotic addiction.

01 Nov 2000·British Journal of Clinical PharmacologyQ2 · MEDICINE

Kinetics and inhibition of the formation of 6β‐naltrexol from naltrexone in human liver cytosol

Q2 · MEDICINE

Article

Author: Susan J. Porter ; Andrew A. Somogyi ; Jason M. White

Aims To determine the kinetics of the formation of 6β‐naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors.Methods The kinetics of the formation of 6β‐naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6β‐naltrexol and, the extent of inhibition of 6β‐naltrexol formation was determined using chemical inhibitors. The formation of 6β‐naltrexol and the back reaction of 6β‐naltrexol to naltrexone were also examined in a microsomal preparation.Results The Vmax, Km and CLint values for the formation of 6β‐naltrexol from naltrexone were in the ranges of 16–45 nmol mg−1 protein h−1, 17–53 µm and 0.3–2.2 ml h−1 mg−1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 ± 0.1 µm) and dihydrotestosterone (Ki = 0.7 ± 0.4 µm) were the most potent competitive inhibitors of 6β‐naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 µm. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 µm. In the microsomal preparation, there was no formation of naltrexone from 6β‐naltrexol nor any formation of 6β‐naltrexol from naltrexone.Conclusions The intersubject variability in the kinetic parameters of 6β‐naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6β‐naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.

100 Deals associated with LD-6ßN

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neonatal Abstinence Syndrome	IND Application	US	Aether Therapeutics, Inc.	06 Mar 2024
Pain	Preclinical	US	Aether Therapeutics, Inc.	06 Mar 2024
Substance Withdrawal Syndrome	Preclinical	US	Aether Therapeutics, Inc.	06 Mar 2024

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

LD-6ßN

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation