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1.
Clin Ter ; 171(5): e412-e413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901784

RESUMO

Fentanyl is a full synthetic opioid acting as a strong µ-opioids receptor agonist. As other opioids, it exerts effects on central nervous systems like euphoria, sedation, anesthesia and respiratory depression at high dosage. It is the parent compound of the high potent opioids class, characterized by a potency up to 10,000 fold higher than mor- phine, currently prescribed as anesthetic and pain killers. Anyway, the diversion of fentanyl analogues has been reported since their appear- ance on the market, rising until alarming rate. Every year, new synthetic alternatives to the controlled fentanyl are proposed on the black market causing an increasing number of fatalities all over the World. Due to the high potency of this class of substances, it may be difficult to ana- lytically detect the molecules in biological matrices and find the actual cause of the deaths. Moreover, an additional analytical challenge is represented by the emergence of newly synthesized derivatives. In this concern, the harmonization of international guidelines, the adoption of common legal responses and the enforcement of international collaboration is desirable to face this alarming public health threat.


Assuntos
Analgésicos Opioides/química , Fentanila/análogos & derivados , Anestesia , Humanos , Saúde Pública
2.
Anesthesiology ; 133(4): 740-749, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773684

RESUMO

The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.


Assuntos
Comitês Consultivos/normas , Analgésicos Opioides/química , Analgésicos/química , Anestésicos/química , Aprovação de Drogas/métodos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anestésicos/efeitos adversos , Congressos como Assunto/normas , Tomada de Decisões , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Humanos , Oximorfona/efeitos adversos , Oximorfona/química , Compostos de Espiro/efeitos adversos , Compostos de Espiro/química , Tiofenos/efeitos adversos , Tiofenos/química , Estados Unidos
3.
Mol Pharmacol ; 98(4): 386-388, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788221

RESUMO

In the past 50 years, scientists have made considerable strides toward understanding how opioids act. This special issue of Molecular Pharmacology celebrates these 50 years of opioid research and the role that the International Narcotics Research Conference has played in driving this research, by bringing together review and original research articles that present historical highlights, the current state of the art, and perspectives on the future of opioid research. SIGNIFICANCE STATEMENT: Opioids have been used for thousands of years to manage pain and cause euphoria, but their use has been highly limited due to serious side effects. Deciphering the mechanisms of how opioids mediate beneficial and adverse physiological outcomes is essential for developing better treatments for pain and for opioid addiction.


Assuntos
Analgésicos Opioides/síntese química , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Dor/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/química , Pesquisa Biomédica , Congressos como Assunto , Desenho de Fármacos , Humanos
4.
AAPS PharmSciTech ; 21(7): 244, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856114

RESUMO

Ethylmorphine hydrochloride (EtM) is a derivative of morphine used as analgesic to treat severe pain in case of cancer and bone injury. This study aimed to formulate and evaluate core in cup tablets containing 2 doses of EtM, the cup was formulated as lyophilized oro-dispersible tablet (ODT) for immediate release (IR), and the core was formulated as directly compressed tablet for sustained release (SR). Factorial design was adopted for the optimization of tablets prepared via lyophilized form and direct compression techniques: a 41.22 design was used for the former, while a 32 one was used for the latter. All prepared tablets showed acceptable physical properties which were in accordance with pharmacopeial standards. Two lyophilized ODTs (F9 and F10) formulae were selected as the cup for instant release. While one directly compressed tablet formula (S6) was selected based on the in vitro release profile to represent the sustained core, the outcome was 2 core in cup tablets, namely B1 and B2 which were evaluated for their in vivo absorption and showed a maximum plasma concentration (Cpmax) of 354.12 ± 17.55 ng/mL and 350.82 ± 12.15 ng/mL respectively attained after 3.0 h which were twofolds significantly higher in comparison to the market tablet with Cpmax of only 172.05 ± 12.53 ng/mL attained after 2.20 ± 0.24 h.


Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Etilmorfina/química , Etilmorfina/farmacocinética , Dor/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Composição de Medicamentos , Etilmorfina/uso terapêutico , Liofilização , Masculino , Ratos , Comprimidos
5.
Anesth Analg ; 131(3): 935-942, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32701545

RESUMO

BACKGROUND: The misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication. METHODS: We determined the binding affinity of butorphanol to KOR with a naltrexone competition study. Recombinant KORs expressed in mammalian cell membranes (Chem-1) were used for G-protein activation studies, and a human embryonic kidney-293 (HEK-293) cell line stably transfected with the human KOR was used for ß-arrestin study as previously described in the literature. The effects of butorphanol on KOR internalization were investigated using mouse neuroblastoma Neuro2A cells stably transfected with mKOR-tdTomato fusion protein (N2A-mKOR-tdT) cells overexpressing KOR. The active-state KOR crystal structure was used for docking calculation of butorphanol to characterize the ligand binding site. Salvinorin A, a full KOR agonist, was used as a control for comparison. RESULTS: The affinity of KOR for butorphanol is characterized by Kd of 0.1 ± 0.02 nM, about 20-fold higher compared with that of the µ-opioid receptor (MOR; 2.4 ± 1.2 nM). Our data indicate that butorphanol is more potent on KOR than on MOR. In addition, butorphanol acts as a partial agonist of KOR in the G-protein activation pathway and is a full agonist on the ß-arrestin recruitment pathway, similar to that of salvinorin A. The activation of the ß-arrestin pathway is further confirmed by KOR internalization. The in silico docking model indicates that both salvinorin A and butorphanol share the same binding cavity with the KOR full agonist MP1104. This cavity plays an important role in determining either agonist or antagonist effects of the ligand. CONCLUSIONS: In conclusion, butorphanol is a partial KOR agonist in the G-protein activation pathway and a potent KOR full agonist in the ß-arrestin recruitment pathway. The structure analysis offers insights into the molecular mechanism of KOR interaction and activation by butorphanol.


Assuntos
Analgésicos Opioides/farmacologia , Butorfanol/farmacologia , Neurônios/efeitos dos fármacos , Receptores Opioides kappa/agonistas , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/toxicidade , Animais , Butorfanol/química , Butorfanol/metabolismo , Butorfanol/toxicidade , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Células HEK293 , Humanos , Camundongos , Simulação de Acoplamento Molecular , Neurônios/metabolismo , Ligação Proteica , Conformação Proteica , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , beta-Arrestinas/metabolismo
6.
Nat Commun ; 11(1): 3337, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620756

RESUMO

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L-1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.


Assuntos
Alcaloides/biossíntese , Benzilisoquinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Alcaloides/química , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Benzilisoquinolinas/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Engenharia Genética , Modelos Químicos , Estrutura Molecular , Saccharomyces cerevisiae/genética , Tetra-Hidroisoquinolinas/química
7.
Mol Pharmacol ; 98(4): 475-486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32680919

RESUMO

Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classic opioids-in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of ß-arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classic opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes are unknown. Here, we report the results of submillisecond adaptive sampling molecular dynamics simulations of a predicted methadone-bound MOR complex and compare them with analogous data obtained for the classic opioid morphine and the G protein-biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov state models and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR. SIGNIFICANCE STATEMENT: Opioid addiction has reached epidemic proportions in both industrialized and developing countries. Although methadone maintenance treatment represents an effective therapeutic approach for opioid addiction, it is not as widely used as needed. In this study, we contribute an atomic-level understanding of how methadone exerts its unique function in pursuit of more accessible treatments for opioid addiction. In particular, we present details of a methadone-specific active conformation of the µ-opioid receptor that has thus far eluded experimental structural characterization.


Assuntos
Analgésicos Opioides/farmacologia , Metadona/farmacologia , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Analgésicos Opioides/química , Animais , Sítios de Ligação , Entropia , Humanos , Cadeias de Markov , Metadona/química , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Compostos de Espiro/química , Tiofenos/química
8.
J Chromatogr A ; 1624: 461241, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32540079

RESUMO

Synthetic opioids are responsible for numerous overdoses and fatalities worldwide. Currently, fentanyl and its analogs are also mixed with heroin, cocaine and methamphetamine, or sold as oxycodone, hydrocodone and alprazolam in counterfeit medications. Microextraction techniques became more frequent in analytical toxicology over the last decade. A method to simultaneously quantify nine synthetic opioids, fentanyl, sufentanil, alfentanil, acrylfentanyl, thiofentanyl, valerylfentanyl, furanylfentanyl, acetyl fentanyl and carfentanil, and two metabolites, norfentanyl and acetyl norfentanyl, in urine samples by microextraction with packed sorbent (MEPS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. A multivariate optimization was performed to establish the number and speed (stroke) of draw-eject sample cycles and the extraction solvent. The best extraction condition was eight draw-eject sample cycles, with a velocity of 3.6 µL/sec and acetonitrile as elution solvent. Linearity was achieved between 1 to 100 ng/mL, with a limit of detection (LOD) of 0.1 ng/mL and limit of quantification (LOQ) of 1 ng/mL. Imprecision (% relative standard deviation) and bias (%) were less than 12.8% and 5.7%, respectively. The method had good specificity and selectivity when challenged with 10 different matrix sources and 36 pharmaceuticals and drugs of abuse at concentrations of 100 or 500 ng/mL. The method was successfully applied to authentic urine samples. MEPS was an efficient semi-automatic extraction technique, requiring small volumes of organic solvents (640 µL) and sample (200 µL). The cartridges can be cleaned and reused (average of 150 sample extractions/barrel inside and needle).


Assuntos
Analgésicos Opioides/urina , Cromatografia Líquida/métodos , Miniaturização/métodos , Microextração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Analgésicos Opioides/química , Cromatografia Líquida de Alta Pressão/métodos , Fentanila/urina , Humanos , Limite de Detecção , Solventes/química
9.
Nat Commun ; 11(1): 3033, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561830

RESUMO

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.


Assuntos
Peptídeos Opioides/química , Receptores CXCR/metabolismo , Analgésicos Opioides/química , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Ligantes , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Relação Estrutura-Atividade , beta-Arrestina 1/metabolismo
10.
J Pharmacol Exp Ther ; 374(1): 52-61, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32327529

RESUMO

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the angiopep-2 peptide (An2) that crosses the blood-brain barrier (BBB) by low-density lipoprotein receptor-related protein 1 receptor-mediated transcytosis with either morphine or M6G. We demonstrated improvement of BBB permeability of these new entities compared with that of unconjugated M6G and morphine. Intravenous or subcutaneous administration of the An2-M6G conjugate exerted greater and more sustained analgesic activity than equivalent doses of either morphine or M6G. Likewise, subcutaneous An2-morphine induced a delayed but prolonged antinociceptive effect. The effects of these conjugates on the gastrointestinal tract motility were also evaluated. An2-morphine significantly reduced the intestinal transit time, whereas An2-M6G exhibited a reduced constipation profile, as compared with an equimolar dose of morphine. In summary, we have developed new brain-penetrant opioid conjugates exhibiting improved analgesia to side effect ratios. These results thus support the use of An2-carrier peptides as an innovative BBB-targeting technology to deliver effective drugs, such as M6G, for pain management. SIGNIFICANCE STATEMENT: The metabolite morphine-6-glucuronide (M6G) does not efficiently cross the blood-brain barrier. The low-density lipoprotein receptor-related protein 1 peptide ligand angiopep-2 may serve as an effective drug delivery system to the brain. Here, we demonstrated that the coupling of M6G to angiopep-2 peptide (An2) improves its brain penetration and significantly increases its analgesic potency. The An2-M6G conjugate has a favorable side effect profile that includes reduction of developing constipation. An2-M6G exhibits a unique pharmacodynamic profile with a better therapeutic window than morphine.


Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Barreira Hematoencefálica/metabolismo , Derivados da Morfina/química , Derivados da Morfina/metabolismo , Peptídeos/química , Administração Intravenosa , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Transporte Biológico , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Derivados da Morfina/administração & dosagem , Derivados da Morfina/farmacologia , Nociceptividade/efeitos dos fármacos
11.
J Opioid Manag ; 16(2): 127-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329888

RESUMO

Opioids can be an effective treatment option for appropriate patients with chronic pain for whom nonpharmacological or nonopioid treatment does not provide adequate pain relief. However, extended-release (ER) opioid formulations, because of their high drug content, are attractive options for nonmedical use and abuse. Xtampza® ER (oxycodone DETERx®) capsules, an ER abuse-deterrent formulation (ADF), contain microspheres that combine oxycodone with inactive ingredients to increase the difficulty of tampering with the ER mechanism. The aim of this article is to review five previously published studies highlighting the impact of physical manipula-tion (ie, crushing and chewing) on the pharmacokinetic (PK) properties of orally administered Xtampza ER compared with immedi-ate-release (IR) oxycodone and/or reformulated OxyContin® (the first approved oxycodone ER ADF). Across five studies, manipulated (crushed or chewed) Xtampza ER retained an ER PK profile similar to that of intact Xtampza ER, with respect to maximum plasma con-centration (Cmax) and time to Cmax. Additionally, bioequivalence was established between manipulated and intact Xtampza ER, based on Cmax and area under the concentration-time curve values in healthy volunteers and nondependent recreational opioid users. In contrast, crushed OxyContin failed to retain the ER PK profile of intact OxyContin and was bioequivalent to IR oxycodone, based on Cmax in healthy volunteers. The retention of ER PK properties when capsule contents are physically manipulated before oral administra-tion suggests Xtampza ER has lower potential to be manipulated for oral abuse when compared with IR oxycodone or OxyContin.


Assuntos
Analgésicos Opioides , Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Oxicodona , Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Preparações de Ação Retardada , Humanos , Oxicodona/química , Oxicodona/farmacocinética
12.
PLoS Comput Biol ; 16(4): e1007394, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32275713

RESUMO

The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or ß-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent ß-arrestin biased agonist, binds the µ-opioid receptor (µOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce ß-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates µOR ß-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated ß-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.


Assuntos
Fentanila/farmacologia , beta-Arrestinas/metabolismo , beta-Arrestinas/ultraestrutura , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Fentanila/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Simulação de Dinâmica Molecular , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , beta-Arrestinas/agonistas
13.
Eur J Med Chem ; 191: 112145, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092588

RESUMO

Morphine and its derivatives play inevitably important role in the µ-opioid receptor (MOR) targeted antinociception. A structure-activity relationship study is presented for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and 20-alkyl substitutions starting from agonists, antagonists and partial agonists. In vitro competition binding experiments with [3H]DAMGO showed low subnanomolar affinity to MOR. Generally, 6-O-demethylation increased the affinity toward MOR and decreased the efficacy changing the pharmacological profile in some cases. In vivo tests in osteoarthritis inflammation model showed significant antiallodynic effects of thevinol derivatives while orvinol derivatives did not. The pharmacological character was modelled by computational docking to both active and inactive state models of MOR. Docking energy difference for the two states separates agonists and antagonists well while partial agonists overlapped with them. An interaction pattern of the ligands, involving the interacting receptor atoms, showed more efficient separation of the pharmacological profiles. In rats, thevinol derivatives showed antiallodynic effect in vivo. The orvinol derivatives, except for 6-O-desmethyl-dihydroetorfin (2c), did not show antiallodynic effect.


Assuntos
Analgésicos Opioides/farmacologia , Inflamação/tratamento farmacológico , Morfinanos/farmacologia , Osteoartrite/tratamento farmacológico , Receptores Opioides mu/agonistas , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Cobaias , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfinanos/administração & dosagem , Morfinanos/química , Ratos Wistar , Receptores Opioides mu/antagonistas & inibidores , Relação Estrutura-Atividade
14.
Forensic Sci Int ; 308: 110175, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032869

RESUMO

Recently, there has been an increase in overdose deaths due to novel synthetic opioids (NSO). Due to backlogs experienced by many forensic laboratories, it is important to understand drug stability in a variety of storage conditions. The objective of this study was to investigate the stability of AH-7921, U-47700, U-49900, U-50488, MT-45, W-15, and W-18 in blood at various temperatures over a 36-week period. NSO were generally stable over the 36-week period (66%-118%) at low and high concentrations when blood samples were stored in the refrigerator or freezer. Most analytes were stable for at least 2 weeks at room temperature (77%-120%). At the elevated temperature (35°C), analytes were generally stable for at least 14 days (75%-109%). This study has determined the stability of several NSO at various temperatures over a 36-week period. These results reflect the forensic significance of keeping samples stored at proper temperatures. Blood samples suspected to contain synthetic opioids should be stored refrigerated or frozen, when possible, in order to preserve analyte stability, especially at low concentrations.


Assuntos
Analgésicos Opioides/sangue , Analgésicos Opioides/química , Estabilidade de Medicamentos , Manejo de Espécimes , Medicamentos Sintéticos , Temperatura , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/sangue , Animais , Benzamidas/sangue , Bovinos , Toxicologia Forense , Piperazinas/sangue
15.
Anesthesiology ; 132(5): 1229-1234, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32028373

RESUMO

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.


Assuntos
Analgésicos Opioides/química , Pesquisa Biomédica/métodos , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Remifentanil/química , Analgésicos Opioides/uso terapêutico , Animais , Humanos , Dor/tratamento farmacológico , Remifentanil/uso terapêutico
17.
Psychopharmacology (Berl) ; 237(4): 1195-1208, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912192

RESUMO

RATIONALE AND OBJECTIVES: The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration). RESULTS: BBI-11008 had a 78-fold greater affinity for the delta opioid receptor than the mu receptor, and there was no binding to the kappa opioid receptor. BBI-11008 (3.2-100; 10-32 mg kg-1, i.v.) and morphine (1-10; 1-3.2 mg kg-1, i.v.) produced antinociceptive and anti-allodynic effects in assays of acute thermal nociception and complete Freund's adjuvant (CFA)-induced inflammatory pain, with BBI-11008 being less potent than morphine in both assays. BBI-11008 (1-18 mg kg-1, i.v.) had similar efficacy to gabapentin (10-56 mg kg-1, i.v.) in a spinal nerve ligation (SNL) model of neuropathic pain. In the respiration assay, with increasing %CO2 exposure, BBI-11008 produced an initial increase (32 mg kg-1, s.c.) and then decrease (56 mg kg-1, s.c.) in minute volume (MV) whereas morphine (3.2-32 mg kg-1, s.c.) produced dose-dependent decreases in MV. In the drug self-administration procedure, BBI-11008 did not maintain self-administration at any dose tested. CONCLUSIONS: These results suggest that the glycopeptide drug candidate possesses broad-spectrum antinociceptive and anti-allodynic activity across a range of pain-like conditions. Relative to morphine or fentanyl, the profile for BBI-11008 in the respiration and drug self-administration assays suggests that BBI-11008 may have less pronounced deleterious side effects. Continued assessment of this compound is warranted.


Assuntos
Analgésicos Opioides/administração & dosagem , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Mecânica Respiratória/efeitos dos fármacos , Analgésicos Opioides/química , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/psicologia , Masculino , Camundongos , Morfina/administração & dosagem , Neuralgia/metabolismo , Neuralgia/psicologia , Medição da Dor/psicologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Mecânica Respiratória/fisiologia , Autoadministração
18.
Int J Pharm ; 577: 119042, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953084

RESUMO

Prescription opioids have widely been abused as an epidemic. In this research, we developed a drug composition based on the crosslinked carboxymethylcellulose (XCMC) and a drug model that can effectively deter abuse by injection via multiple mechanisms. The anionic nature of the XCMC is responsible for complexing the cationic opioids in aqueous solutions, minimizing the free drug amount accessible for extraction. The crosslinked nature of the polymer is responsible for its swelling and partial containment of the drug solution within the swollen polymer's network, thus minimizing the available volume for subsequent injection. We have shown that XCMC can efficiently interact with cationic drugs in the form of physical blends and chemical complexes in different aqueous solvents, forming abuse-deterrent complexes. The complexation efficiency was affected by the solution pH and ionic strength, as well as the drug to polymer ratio in the formulation. The in vitro dissolution studies were conducted in two stages, the stage I in 0.1 M HCl and the stage II in water and pH 7.5 phosphate buffer. These studies confirmed the proper drug release under the legitimate conditions of use. Therefore, the XCMC polymers have a great potential to be used as deterring agents in developing opioid medications with abuse-deterrent properties.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Carboximetilcelulose Sódica/química , Analgésicos Opioides/química , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Concentração Osmolar , Solventes/química , Abuso de Substâncias por Via Intravenosa/prevenção & controle
19.
J Am Soc Mass Spectrom ; 31(2): 277-291, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31939667

RESUMO

The global drug market is characterized by the fast development of new psychoactive substances such as fentanyl analogues and novel synthetic opioids, the detection of which is complicated by the lack of appropriate quality control procedures and references. Herein, we analyze the fragmentation pathways and characteristic ions of 25 novel fentanyl analogues and 5 novel synthetic opioids by electron ionization (EI) and electrospray ionization (ESI) high-resolution mass spectrometry to provide a reference for the identification of these species. In the ESI mode, fentanyl analogues mainly undergo piperidine ring degradation, phenethyl and piperidine ring dissociation, and piperidine ring and amide moiety cleavage, while piperidine ring degradation and phenethyl and piperidine ring dissociation are the major pathways in the EI mode. The five novel synthetic opioids largely undergo amide group dissociation and N-cyclohexyl bond cleavage in the ESI mode. Thus, this work facilitates the detection and quantitation of fentanyl analogues and novel synthetic opioids or other substances with similar structures in forensic laboratories.


Assuntos
Analgésicos Opioides/química , Fentanila/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Medicamentos Sintéticos/química , Analgésicos Opioides/análise , Fentanila/análise , Modelos Moleculares , Medicamentos Sintéticos/análise , Espectrometria de Massas em Tandem
20.
Drugs ; 80(3): 263-283, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919755

RESUMO

Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a 'drug of concern', and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2-49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24-10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.


Assuntos
Analgésicos Opioides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Colestase/induzido quimicamente , Mitragyna/química , Alcaloides de Triptamina e Secologanina/efeitos adversos , Analgésicos Opioides/química , Analgésicos Opioides/isolamento & purificação , Humanos , Folhas de Planta/química , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação
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