Orvinol-based opioid receptor antagonist fluorinated at C(20)-pharmacophore.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the antagonist activity of the N-allyl substituted orvinol derivative fluorinated within the pharmacophore associated with C(20) and its surrounding.

Effects of Opioid Withdrawal on Psychobiology in People Living with HIV.

Objective: Many persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood.

Method And Participants: Study participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation.

C(21)-fluorinated thevinol scaffold for opioid ligands. 21,21,21-Trifluoro-6-O-nororvinols: Design, synthesis and analgesic activity.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the OR activity of orvinols fluorinated within the pharmocophore associated with C(20) and its surrounding along with a dependence of the activity profile on the substituent at N(17).

The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions.

Slow-release naltrexone implant versus oral naltrexone for improving treatment outcomes in people with HIV who are addicted to opioids: a double-blind, placebo-controlled, randomised trial.

Background: Untreated opioid addiction in people with HIV is associated with poor HIV treatment outcomes. Slow-release, long-acting, implantable naltrexone might improve these outcomes. Here, we present results of a study aimed to test this hypothesis.

Opening up new horizons for psychiatric genetics in the Russian Federation: moving toward a national consortium.

We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations.

[Anhedonia, depression, anxiety, and craving in opioid dependent patients stabilized on oral naltrexone or naltrexone implant].

Aim: To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals.

Material And Methods: Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales.

Efficacy and side effects of baclofen and the novel GABA receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction.

Rationale: Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABA receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained?

Objective: To test efficacy and adverse effects of baclofen and the novel GABA positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM.

mGlu1 receptor as a drug target for treatment of substance use disorders: time to gather stones together?

Modulation of the mGlu1 receptor was repeatedly shown to inhibit various phenomena associated with exposure to abused drugs. Efficacy in preclinical models was observed with both positive and negative allosteric modulators (PAMs and NAMs, respectively) using essentially non-overlapping sets of experimental methods. Taken together, these data indicate that the mGlu1 receptor certainly plays a significant role in the plasticity triggered by the exposure to abused drugs and is involved in the maintenance of drug-seeking and drug-taking behaviors.

Psychiatric symptoms, quality of life, and HIV status among people using opioids in Saint Petersburg, Russia.

Background: The Russian Federation is experiencing a very high rate of HIV infection among people who inject drugs (PWID). However, few studies have explored characteristics of people with co-occurring opioid use disorders and HIV, including psychiatric symptom presentations and how these symptoms might relate to quality of life. The current study therefore explored a.

Morphine-induced Straub tail reaction in mice treated with serotonergic compounds.

Constitutively active 5-HT receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program.

Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant.

Background: Naltrexone is a μ-opioid receptor antagonist that blocks opioid effects. Craving, depression, anxiety, and anhedonia are common among opioid dependent individuals and concerns have been raised that naltrexone increases them due to blocking endogenous opioids. Here, we present data that address these concerns.

Antagonist Models for Relapse Prevention and Reducing HIV Risk.

Naltrexone is an antagonist that binds tightly to μ-opioid receptors and blocks the subjective and analgesic effects of opioids. It does not produce physiologic dependence and precipitates withdrawal if administered to an opioid dependent person, thus starting it must begin with detoxification. It was first available in the mid-1970s as a 50 mg tablet that blocked opioids for 24-36 h if taken daily, or every 2-3 days at higher doses - for example: 100 mg Monday and Wednesday, 150 mg on Friday.

Preclinical models of muscle spasticity: valuable tools in the development of novel treatment for neurological diseases and conditions.

Poor validity of preclinical animal models is one of the most commonly discussed explanations for the failures to develop novel drugs in general and in neuroscience in particular. However, there are several areas of neuroscience such as injury-induced spasticity where etiological factor can be adequately recreated and models can focus on specific pathophysiological mechanisms that likely contribute to spasticity syndrome in humans (such as motoneuron hyperexcitability and spinal hyperreflexia). Methods used to study spasticity in preclinical models are expected to have a high translational value (e.

[A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine].

Aim: To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial.

Material And Methods: Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

Objective: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts.

Material And Methods: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment.

[Morphine-induced Straub tail reaction as a model of spasticity in mice: effects of serotonergic compounds].

Aim: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds.

Material And Methods: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al.

[Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach].

Aim: To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone.

Material And Methods: Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups.

Heroin Use and HIV Disease Progression: Results from a Pilot Study of a Russian Cohort.

Opioids have immunosuppressive properties, yet their impact on HIV disease progression remains unclear. Using longitudinal data from HIV-infected antiretroviral therapy-naïve Russian individuals (n = 77), we conducted a pilot study to estimate the effect of heroin use on HIV disease progression. Heroin use was categorized based on past 30 days self-reported use at baseline, 6 and 12 months as none, intermittent or persistent.

Depression, substance use, viral load, and CD4+ count among patients who continued or left antiretroviral therapy for HIV in St. Petersburg, Russian Federation.

Antiretroviral therapy (ART) became more widely available in the Russian Federation in 2006 when the Global Fund made a contribution to purchase ART with a mandate to increase numbers of patients receiving it. Funds were distributed to AIDS Centers and selected hospitals, and numbers quickly increased. Though ART is highly effective for adherent patients, dropout has been a problem; thus understanding characteristics of patients who remain on ART vs.

HERMITAGE--a randomized controlled trial to reduce sexually transmitted infections and HIV risk behaviors among HIV-infected Russian drinkers.

Aims: This study assessed the effectiveness of HERMITAGE (HIV's Evolution in Russia-Mitigating Infection Transmission and Alcoholism in a Growing Epidemic), an adapted secondary HIV prevention intervention, compared with an attention control condition in decreasing sexually transmitted infections (STIs) and sex and drug risk behaviors among Russian HIV-infected heavy drinkers.

Design: We conducted a single-blinded, two-armed, randomized controlled trial with 12-month follow-up.

Setting: The study was conducted in St Petersburg, Russia.

[Naltrexone implant treatment of polydrug dependence].

Objective. Recent studies indicate that naltrexone implant may be one of the effective pharmacological treatments for opiate dependence. However, nowadays many of addicts are polydrug dependent.

Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia.

Background: Stress is a key precipitant to discontinuing naltrexone and relapsing to opiate abuse. Alpha-2 adrenergic agonists like guanfacine may reduce stress induced craving and have reduced opiate relapse in small clinical trials.

Methods: This randomized, double blind double dummy placebo-controlled 6-month trial tested oral naltrexone with or without guanfacine for reducing stress and preventing opiate relapse.