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Molecules (Basel, Switzerland) Dec 2022The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and...
The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).
Topics: Crystallography, X-Ray; Oxides; Morphinans; Isomerism; Receptors, Opioid, mu
PubMed: 36557961
DOI: 10.3390/molecules27248808 -
The International Journal of... Dec 2023There is a strong link between chronic stress and vulnerability to drug abuse and addiction. Corticotropin releasing factor (CRF) is central to the stress response that...
BACKGROUND
There is a strong link between chronic stress and vulnerability to drug abuse and addiction. Corticotropin releasing factor (CRF) is central to the stress response that contributes to continuation and relapse to heroin abuse. Chronic heroin exposure can exacerbate CRF production, leading to dysregulation of the midbrain CRF-dopamine-glutamate interaction.
METHODS
Here we investigated the role of midbrain CRF1 receptors in heroin self-administration and assessed neuroplasticity in CRF1 receptor expression in key opioid addiction brain regions.
RESULTS
Infusions of antalarmin (a CRF1 receptor antagonist) into the ventral tegmental area (VTA) dose dependently reduced heroin self-administration in rats but had no impact on food reinforcement or locomotor activity in rats. Using RNAscope in situ hybridization, we found that heroin, but not saline, self-administration upregulated CRF1 receptor mRNA in the VTA, particularly on dopamine neurons. AMPA GluR1 and dopamine reuptake transporter mRNA in VTA neurons were not affected by heroin. The western-blot assay showed that CRF1 receptors were upregulated in the VTA and nucleus accumbens. No significant changes in CRF1 protein expression were detected in the prefrontal cortex, insula, dorsal hippocampus, and substantia nigra. In addition, we found that 15 days of environmental enrichment implemented after heroin self-administration does not reverse upregulation of VTA CRF1 receptor mRNA but it downregulates dopamine transporter mRNA.
CONCLUSIONS
Overall, these data suggest that heroin self-administration requires stimulation of VTA CRF1 receptors and upregulates their expression in brain regions involved in reinforcement. Such long-lasting neuroadaptations may contribute to continuation of drug use and relapse due to stress exposure and are not easily reversed by EE exposure.
Topics: Rats; Animals; Corticotropin-Releasing Hormone; Heroin; Dopamine; Ventral Tegmental Area; Self Administration; Recurrence; RNA, Messenger
PubMed: 37864842
DOI: 10.1093/ijnp/pyad060 -
The Primary Care Companion For CNS... Feb 2022
Topics: Buprenorphine; Humans; Male; Middle Aged; Naloxone
PubMed: 35213940
DOI: 10.4088/PCC.21cr03007 -
Therapeutic Drug Monitoring Apr 2020In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug...
BACKGROUND
In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation.
METHODS
Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays.
RESULTS
In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum.
CONCLUSIONS
The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.
Topics: Adult; Buprenorphine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Glucuronosyltransferase; Humans; Longitudinal Studies; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Postpartum Period; Pregnancy; Pregnancy Trimesters; Young Adult
PubMed: 31929398
DOI: 10.1097/FTD.0000000000000724 -
Veterinaria Italiana Dec 2022This study describes the selected pharmacodynamics and pharmacokinetics of nalbuphine (NAL) in xylazine (XYL)‑sedated horses. Five adult healthy horses were randomly...
This study describes the selected pharmacodynamics and pharmacokinetics of nalbuphine (NAL) in xylazine (XYL)‑sedated horses. Five adult healthy horses were randomly received 2 treatments at a 1‑week interval; XYL treatment (0.55 mg/kg IV) and XYL/NAL treatment (XYL, 0.55 mg/kg IV; NAL, 0.3 mg/kg IV). The measured pharmacodynamic variables were sedative and analgesic effects and the effect on ataxia and some physiological parameters. for the pharmacokinetics of NAL, its plasma concentrations were measured using HPLC and a 2‑compartment analysis was performed. Greater and prolonged sedation was evident after XYL/NAL treatment compared with XYL treatment. Slightly improved and prolonged analgesia was demonstrated after XYL/NAL treatment. Significant changes in blood pressure and respiratory rate lasted for a shorter duration with XYL/NAL treatment than with XYL treatment. After XYL treatment, rectal temperature was significantly different from baseline and XYL/NAL treatment. Elimination half‑life of NAL was 3.47 ± 1.39 hours and total body clearance was 2.88 ± 0.73 L/kg/hour. In conclusion, addition of NAL to XYL resulted in remarkable advantages on the measured parameters. The obtained pharmacokinetics of NAL could be useful in determining the effective NAL infusion rate, which could be further evaluated as an adjunctive agent to XYL for prolonged sedation in horses.
Topics: Animals; Horses; Xylazine; Nalbuphine
PubMed: 37219832
DOI: 10.12834/VetIt.2408.16506.1 -
Molecules (Basel, Switzerland) Aug 2022The abuse of buprenorphine and methadone has grown into a rising worldwide issue. After their consumption, buprenorphine, methadone and their metabolites can be found in... (Review)
Review
The abuse of buprenorphine and methadone has grown into a rising worldwide issue. After their consumption, buprenorphine, methadone and their metabolites can be found in the human organism. Due to the difficulty in the assessment of these compounds by routine drug screening, the importance of developing highly sensitive analytical approaches is undeniable. Liquid chromatography tandem mass spectrometry is the preferable technique for the determination of buprenorphine, methadone and their metabolites in biological matrices including urine, plasma, nails or oral fluids. This research aims to review a critical discussion of the latest trends for the monitoring of buprenorphine, methadone and their metabolites in various biological specimens.
Topics: Buprenorphine; Chromatography, Liquid; Humans; Methadone; Tandem Mass Spectrometry
PubMed: 36014451
DOI: 10.3390/molecules27165211 -
Journal of Substance Use and Addiction... Jun 2023Conflictual evidence exists regarding the effects of cannabis use on the outcomes of opioid agonist therapy (OAT). In this exploratory analysis, we examined the effect... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Conflictual evidence exists regarding the effects of cannabis use on the outcomes of opioid agonist therapy (OAT). In this exploratory analysis, we examined the effect of recent cannabis use on opioid use, craving, and withdrawal symptoms, in individuals participating in a trial comparing flexible buprenorphine/naloxone (BUP/NX) take-home dosing model to witnessed ingestion of methadone.
METHODS
We analyzed data from a multi-centric, pragmatic, 24-week, open label, randomized controlled trial in individuals with prescription-type opioid use disorder (n = 272), randomly assigned to BUP/NX (n = 138) or methadone (n = 134). The study measured last week cannabis and opioid use via timeline-follow back, recorded at baseline and every two weeks during the study. Craving symptoms were measured using the Brief Substance Craving Scale at baseline, and weeks 2, 6, 10, 14, 18 and 22. The study measured opioid withdrawal symptoms via Clinical Opiate Withdrawal Scale at treatment initiation and weeks 2, 4, and 6.
RESULTS
The mean maximum dose taken during the study was 17.3 mg/day (range = 0.5-32 mg/day) for BUP/NX group and 67.7 mg/day (range = 10-170 mg/day) in the methadone group. Repeated measures generalized linear mixed models demonstrated that cannabis use in the last week (mean of 2.3 days) was not significantly associated with last week opioid use (aβ ± standard error (SE) = -0.06 ± 0.04; p = 0.15), craving (aβ ± SE = -0.05 ± 0.08, p = 0.49), or withdrawal symptoms (aβ ± SE = 0.09 ± 0.1, p = 0.36). Bayes factor (BF) for each of the tested models supported the null hypothesis (BF < 0.3).
CONCLUSIONS
The current study did not demonstrate a statistically significant effect of cannabis use on outcomes of interest in the context of a pragmatic randomized-controlled trial. These findings replicated previous results reporting no effect of cannabis use on opioid-related outcomes.
Topics: Humans; Analgesics, Opioid; Cannabis; Narcotic Antagonists; Bayes Theorem; Opiate Substitution Treatment; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Opioid-Related Disorders; Methadone; Substance Withdrawal Syndrome
PubMed: 37003540
DOI: 10.1016/j.josat.2023.209031 -
Harm Reduction Journal Jul 2022Syringe services programs (SSPs) hold promise for providing buprenorphine treatment access to people with opioid use disorder (OUD) who are reluctant to seek care...
BACKGROUND
Syringe services programs (SSPs) hold promise for providing buprenorphine treatment access to people with opioid use disorder (OUD) who are reluctant to seek care elsewhere. In 2017, the New York City Department of Health and Mental Hygiene (DOHMH) provided funding and technical assistance to nine SSPs to develop "low-threshold" buprenorphine services as part of a multipronged initiative to lower opioid-related overdose rates. The aim of this study was to identify barriers to and facilitators of implementing SSP-based buprenorphine services.
METHODS
We conducted 26 semi-structured qualitative interviews from April 2019 to November 2019 at eight SSPs in NYC that received funding and technical assistance from DOHMH. Interviews were conducted with three categories of staff: leadership (i.e., buprenorphine program management or leadership, eight interviews), staff (i.e., buprenorphine coordinators or other staff, eleven interviews), and buprenorphine providers (six interviews). We identified themes related to barriers and facilitators to program implementation using thematic analysis. We make recommendations for implementation based on our findings.
RESULTS
Programs differed in their stage of development, location of services provided, and provider type, availability, and practices. Barriers to providing buprenorphine services at SSPs included gaps in staff knowledge and comfort communicating with participants about buprenorphine, difficulty hiring buprenorphine providers, managing tension between harm reduction and traditional OUD treatment philosophies, and financial constraints. Challenges also arose from serving a population with unmet psychosocial needs. Implementation facilitators included technical assistance from DOHMH, designated buprenorphine coordinators, offering other supportive services to participants, and telehealth to bridge gaps in provider availability. Key recommendations include: (1) health departments should provide support for SSPs in training staff, building health service infrastructure and developing policies and procedures, (2) SSPs should designate a buprenorphine coordinator and ensure regular training on buprenorphine for frontline staff, and (3) buprenorphine providers should be selected or supported to use a harm reduction approach to buprenorphine treatment.
CONCLUSIONS
Despite encountering challenges, SSPs implemented buprenorphine services outside of conventional OUD treatment settings. Our findings have implications for health departments, SSPs, and other community organizations implementing buprenorphine services. Expansion of low-threshold buprenorphine services is a promising strategy to address the opioid overdose epidemic.
Topics: Buprenorphine; Harm Reduction; Humans; New York City; Opiate Substitution Treatment; Opioid-Related Disorders; Syringes
PubMed: 35818071
DOI: 10.1186/s12954-022-00654-0 -
Biomedical Chromatography : BMC Jul 2023The purpose of this review study was to sum up the main recent advances reported in the scientific literature about the detection of common drugs of abuse in biological... (Review)
Review
The purpose of this review study was to sum up the main recent advances reported in the scientific literature about the detection of common drugs of abuse in biological samples upon their collection by dried blood spot devices. The most recent, innovative and fully validated methods for the qualitative and/or quantitative detection of common drugs of abuse are reported, including alprazolam, clonazepam, diazepam, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methyl-enedioxyethylamphetamine, amphetamine, methamphetamine, cocaine, tetrahydrocannabinol, 6-monoacetylmorphine, morphine, codeine, hydromorphone, hydrocodone, oxycodone, noroxycodone, tramadol, methadone, buprenorphine, fentanyl, ketamine and their respective metabolites and γ-hydroxybutyric acid. Dried blood spot proved to be extremely promising for routine analysis of forensic cases, although large-scale experiments on real samples need to be performed to confirm the emerging advantages of the technique and remove the potential limitations still affecting its widespread application.
Topics: Tandem Mass Spectrometry; Substance Abuse Detection; Codeine; Methamphetamine; Amphetamine
PubMed: 36417316
DOI: 10.1002/bmc.5555 -
Pharmacology Research & Perspectives Apr 2021Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of... (Review)
Review
Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were C 4.31 µg/L (1.93-15.5), AUC 2.89 h*µg/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t½ 1.75 h (1.07-31.0), V 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.
Topics: Animals; Buprenorphine; Disease Models, Animal; Female; Humans; Injections, Intravenous; Metabolic Clearance Rate; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Sheep
PubMed: 33619904
DOI: 10.1002/prp2.726