RESUMEN
Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.
Asunto(s)
Fumar Marihuana/tratamiento farmacológico , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Adulto , Afecto/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Cannabis , Método Doble Ciego , Ingestión de Alimentos/efectos de los fármacos , Femenino , Humanos , Masculino , Fumar Marihuana/fisiopatología , Fumar Marihuana/psicología , Persona de Mediana Edad , Naltrexona/efectos adversos , Naltrexona/sangre , Antagonistas de Narcóticos/efectos adversos , Antagonistas de Narcóticos/sangre , Cooperación del Paciente , Distribución Aleatoria , Riboflavina/orina , Autoadministración , Adulto JovenRESUMEN
2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a â¼ 20-fold reduced affinity for human µ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 µM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.
Asunto(s)
Compuestos de Bifenilo/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Receptores Opioides kappa/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Conducta Adictiva/tratamiento farmacológico , Biomarcadores Farmacológicos/sangre , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/metabolismo , Condicionamiento Psicológico , Depresión/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Extinción Psicológica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Terapia Molecular Dirigida , Actividad Motora/efectos de los fármacos , Antagonistas de Narcóticos/sangre , Antagonistas de Narcóticos/metabolismo , Narcóticos/sangre , Piperazinas/metabolismo , Prolactina/sangre , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Sulfonamidas/sangre , Sulfonamidas/metabolismoRESUMEN
This research is based on the recognized need for an in vitro release method for drug implants that better simulate physiological conditions at the site of implantation ('biorelevance'). In this paper, we describe the evaluation of a 'biorelevant' approach for in vitro drug release testing of a biodegradable implant of naltrexone in a pre-clinical stage of development. A miniature, capillary cell culture device was modified and tested as a biorelevant alternative for a standard commercially available flow-through cell. The real-time data generated through 90 days indicated a 48% lower rate of release for the capillary system. The profiles using both systems followed zero-order kinetics after an initial period of burst release. In vitro release data from the capillary device resulted in a 1-to-1 correlation with dog plasma pharmacokinetic data, and furthermore, the capillary device potentially simulated the lag-time in absorption more effectively than the flow-through cell. Scanning electron micrographs revealed that the sheath was continuous with no signs of cracks at the end of in vitro and in vivo studies. However, at the interface of the sheath and the core, intercalating, "finger-like" projections were observed consistent with penetration of the medium. No macroscopic or clinical toxicity signs were observed during the in vivo implantation study.
Asunto(s)
Reactores Biológicos , Evaluación Preclínica de Medicamentos/instrumentación , Implantes de Medicamentos , Naltrexona/química , Antagonistas de Narcóticos/química , Tecnología Farmacéutica/instrumentación , Animales , Química Farmacéutica , Difusión , Perros , Composición de Medicamentos , Implantes de Medicamentos/efectos adversos , Implantes de Medicamentos/química , Diseño de Equipo , Reacción a Cuerpo Extraño/etiología , Reacción a Cuerpo Extraño/patología , Cinética , Modelos Biológicos , Naltrexona/efectos adversos , Naltrexona/sangre , Naltrexona/farmacocinética , Antagonistas de Narcóticos/efectos adversos , Antagonistas de Narcóticos/sangre , Antagonistas de Narcóticos/farmacocinética , Reproducibilidad de los Resultados , Solubilidad , Tejido Subcutáneo/ultraestructura , Propiedades de SuperficieRESUMEN
A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t(1/2) of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.