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1.
Alcohol Alcohol ; 55(3): 338, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32166325
2.
Nihon Yakurigaku Zasshi ; 155(2): 113-119, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115477

RESUMO

Nalmefene (Selincro®), an opioid receptor modulator, is approved in Japan, the European Union, and other countries for reducing alcohol consumption in patients with alcohol dependence. This article reviews the efficacy and safety of as-needed use of nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. Ethanol increases the release of endogenous opioids, such as ß-endorphin, a µ-opioid receptor agonist; and dynorphin, a κ-opioid receptor agonist. Preclinical data suggest that nalmefene acts as an antagonist at the µ-opioid receptor and a partial agonist at the κ-opioid receptor, and reduces ethanol self-administration in ethanol-dependent and ethanol-non-dependent rats. Nalmefene counters alcohol-induced dysregulation of the ß-endorphin/µ-opioid receptor and the dynorphin/κ-opioid receptor systems. In a multicenter, randomized, double-blind, phase 3 study of as-needed use of nalmefene combined with psychosocial support in alcohol-dependent Japanese patients with at least high drinking risk level, compared with placebo, nalmefene 10 mg and 20 mg significantly reduced the number of heavy drinking days and total alcohol consumption at week 12. In the 24-week treatment period, treatment-emergent adverse events occurred in ≥5% of patients in either the nalmefene 10 mg or 20 mg group and at least twice as often as in the placebo group were nausea, dizziness, somnolence, vomiting, insomnia, decreased appetite, constipation, malaise, and palpitations. Most adverse events were mild or moderate in severity. In conclusion, as-needed use of nalmefene provides a new concept for the treatment of alcohol dependence: namely, "reduction of alcohol intake".


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Animais , Ensaios Clínicos Fase III como Assunto , Humanos , Japão , Estudos Multicêntricos como Assunto , Naltrexona/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Receptores Opioides kappa/agonistas , Receptores Opioides mu/antagonistas & inibidores
3.
Expert Opin Drug Saf ; 19(1): 9-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31868031

RESUMO

Introduction: Reduced drinking has been debated as a treatment goal for heavy drinking alcohol-dependent patients, in whom treatment based on abstinence is not always an option. Nalmefene was the first drug approved by the European Medicines Agency (2013) with the indication of reduced drinking in high drinking risk level alcohol-dependent patients. Six years after its introduction in Europe, data from clinical experience can be compared with those from preclinical studies and pivotal registration studies to evaluate what nalmefene has added to the treatment of AUD.Areas covered: Systematic review of efficacy and safety data of nalmefene use in humans from preclinical, phase III and phase IV studies, including systematic reviews, meta-analyses, cost-effectiveness analyses, and other secondary analyses.Expert opinion: Nalmefene introduces a paradigm change in the treatment of AUD that makes it appealing to patients that are reluctant to embrace abstinence, and facilitate patient-centered care in heavy users. However, information regarding safety data in special populations (e.g., patients with alcohol-related diseases, pregnancy, psychiatric disease), and direct comparisons with other potential drugs for alcohol reduction are further needed. Despite the promising role of nalmefene, there are still some factors that limit its wide prescription further than in specialized settings.


Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Consumo de Bebidas Alcoólicas/prevenção & controle , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Aprovação de Drogas , Humanos , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos
5.
BMC Med ; 17(1): 174, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526369

RESUMO

BACKGROUND: Different methodological choices such as inclusion/exclusion criteria and analytical models can yield different results and inferences when meta-analyses are performed. We explored the range of such differences, using several methodological choices for indirect comparison meta-analyses to compare nalmefene and naltrexone in the reduction of alcohol consumption as a case study. METHODS: All double-blind randomized controlled trials (RCTs) comparing nalmefene to naltrexone or one of these compounds to a placebo in the treatment of alcohol dependence or alcohol use disorders were considered. Two reviewers searched for published and unpublished studies in MEDLINE (August 2017), the Cochrane Library, Embase, and ClinicalTrials.gov and contacted pharmaceutical companies, the European Medicines Agency, and the Food and Drug Administration. The indirect comparison meta-analyses were performed according to different inclusion/exclusion criteria (based on medical condition, abstinence of patients before inclusion, gender, somatic and psychiatric comorbidity, psychological support, treatment administered and dose, treatment duration, outcome reported, publication status, and risk of bias) and different analytical models (fixed and random effects). The primary outcome was the vibration of effects (VoE), i.e. the range of different results of the indirect comparison between nalmefene and naltrexone. The presence of a "Janus effect" was investigated, i.e. whether the 1st and 99th percentiles in the distribution of effect sizes were in opposite directions. RESULTS: Nine nalmefene and 51 naltrexone RCTs were included. No study provided a direct comparison between the drugs. We performed 9216 meta-analyses for the indirect comparison with a median of 16 RCTs (interquartile range = 12-21) included in each meta-analysis. The standardized effect size was negative at the 1st percentile (- 0.29, favouring nalmefene) and positive at the 99th percentile (0.29, favouring naltrexone). A total of 7.1% (425/5961) of the meta-analyses with a negative effect size and 18.9% (616/3255) of those with a positive effect size were statistically significant (p < 0.05). CONCLUSIONS: The choice of inclusion/exclusion criteria and analytical models for meta-analysis can result in entirely opposite results. VoE evaluations could be performed when overlapping meta-analyses on the same topic yield contradictory result. TRIAL REGISTRATION: This study was registered on October 19, 2016, in the Open Science Framework (OSF, protocol available at https://osf.io/7bq4y/ ).


Assuntos
Metanálise como Assunto , Projetos de Pesquisa , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Humanos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico
6.
Drugs R D ; 19(3): 277-287, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31463821

RESUMO

BACKGROUND AND OBJECTIVES: Samidorphan (SAM) is a novel µ-opioid receptor antagonist. We report clinical pharmacokinetic (PK) properties of SAM following different routes of administration, and the effects of food and age on the PK of SAM following oral administration in healthy volunteers. METHODS: An open-label, fixed-sequence study (study 1, N = 10) examined the PK parameters following intravenous, sublingual, and oral exposure to SAM to determine absolute bioavailability. A double-blind, placebo-controlled study (study 2, N = 45) compared the PK in participants aged 18-40 years (cohort 1, n = 30) and ≥ 65 years (cohort 2, n = 15) who received a single oral dose of SAM 10 mg under fed (cohort 1 only) or fasted conditions. RESULTS: In study 1, intravenous SAM had a plasma clearance of 33.7 L/h, volume of distribution of 341 L, and elimination half-life of 7-8 h. SAM was well-absorbed following sublingual or oral administration and reached peak concentrations (Cmax) within 2 h, with absolute bioavailability of 71% (sublingual) and 69% (oral). In study 2, concentration-time profiles were similar under fed and fasted conditions (cohort 1) and for young and elderly participants from both cohorts; 90% confidence intervals for the geometric least squares mean ratios for Cmax and area under the concentration-time curve from time zero extrapolated to infinity indicated equivalence. CONCLUSIONS: SAM has high bioavailability that is comparable following sublingual and oral administration and is not subject to extensive first-pass metabolism. The PK of orally administered SAM are not affected by food or age.


Assuntos
Interações Alimento-Droga/fisiologia , Alimentos/efeitos adversos , Naltrexona/análogos & derivados , Administração Oral , Administração Sublingual , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Jejum/fisiologia , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/farmacocinética
7.
Drugs ; 79(11): 1241-1247, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267482

RESUMO

Naldemedine [Symproic® (Japan; USA); Rizmoic® (EU)], an orally available peripherally acting µ-opioid receptor antagonist (PAMORA), is approved in several countries for the treatment of opioid-induced constipation. In phase III trials, naldemedine was more effective than placebo at increasing the frequency of bowel movements in patients with constipation induced by opioid treatment for cancer pain or chronic non-cancer pain. Naldemedine was also associated with improvements in patient-rated constipation-related symptoms and quality of life. Naldemedine was generally well tolerated, including over the longer term. Because naldemedine specifically targets opioid receptors in the gastrointestinal (GI) tract and does not cross the blood-brain barrier, it does not cause opioid withdrawal symptoms or interfere with centrally mediated opioid analgesia. Consistent with its mechanism of action, the most commonly reported adverse events were GI in nature. In conclusion, current data indicate that naldemedine is an effective and generally well-tolerated treatment option for opioid-induced constipation in patients with cancer pain or chronic non-cancer pain, with the convenience of once-daily oral dosing.


Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor Crônica/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Constipação Intestinal/induzido quimicamente , Humanos , Naltrexona/uso terapêutico , Qualidade de Vida
8.
Eur J Pharmacol ; 852: 265-273, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959048

RESUMO

Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation.


Assuntos
Constipação Intestinal/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/efeitos adversos , Receptores Opioides delta/antagonistas & inibidores , Analgésicos/efeitos adversos , Animais , Constipação Intestinal/induzido quimicamente , Tolerância a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/etiologia , Insuficiência Respiratória/complicações
9.
Clin Drug Investig ; 39(5): 477-484, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888624

RESUMO

BACKGROUND: A combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4. OBJECTIVE: The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects. METHODS: In this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUC∞) for olanzapine and samidorphan in the presence and absence of rifampin, along with its two-sided 90% confidence interval, were derived from a linear mixed-effects model. Safety was monitored throughout the study. RESULTS: Compared with OLZ/SAM alone, coadministration of OLZ/SAM with rifampin decreased the Cmax and AUC∞ of olanzapine by 11% and 48%, and that of samidorphan by 44% and 73%, respectively. OLZ/SAM 10/10 was generally well tolerated in this study. CONCLUSION: Coadministration with rifampin decreased total systemic exposure (based on AUC∞) of olanzapine and samidorphan by 48% and 73%, respectively.


Assuntos
Antipsicóticos/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacocinética , Olanzapina/farmacocinética , Rifampina/farmacocinética , Adulto , Antipsicóticos/administração & dosagem , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/administração & dosagem , Olanzapina/administração & dosagem , Rifampina/administração & dosagem , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia , Adulto Jovem
11.
J Gastrointestin Liver Dis ; 28(1): 41-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851171

RESUMO

BACKGROUND AND AIM: Opioid induced constipation (OIC) is the most common side effect of opioid therapy. It can lead to a decreased quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonist that has been recently studied in randomized controlled trials (RCTs) for the management of OIC. The aim of this study is to perform a meta-analysis of existing clinical trials to estimate the efficacy and safety of naldemedine in opioid-induced constipation. METHODS: A systematic search of PubMed, CINAHL, Scopus, Cochrane database of systematic reviews, and ClinicalTrials.gov registry was performed in March 2018. Two independent reviewers systematically identified prospective RCTs published in the English language that compared the effect of oral naldemedine versus placebo in adults with OIC. Meta-analysis was performed using a random effects model to assess the primary outcome: spontaneous bowel movement (SBM) responder rates. Assessed secondary outcomes were: a change in SBM frequency per week from baseline during the treatment period, change from baseline in the frequency of complete SBM and incidence of treatment-emergent adverse events. Review Manager 5.3 software program was utilized for statistical analysis. RESULTS: Six RCTs met the inclusion criteria. A total of 2,762 patients were included in the meta-analysis. The proportion of SBM responders was significantly higher in the naldemedine group compared to the placebo group (56.4%, vs. 34.7%, p<0.00001). There was no statistically significant difference in treatment-emergent adverse events between naldemedine group and placebo group (mean odds ratio=1.18, p = 0.25, 95% CI: 0.89-1.55). Change in SBM frequency was higher in the naldemedine group versus placebo group (p<0.00001), as well as the change in complete SBM frequency. CONCLUSIONS: Naldemedine 0.2 mg daily significantly improved symptoms in patients with opioid-induced constipation and was generally well tolerated. These results support the use of naldemedine for the treatment of opioid-induced constipation.


Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/tratamento farmacológico , Defecação/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/diagnóstico , Constipação Intestinal/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/efeitos adversos , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/efeitos adversos , Recuperação de Função Fisiológica , Resultado do Tratamento
12.
Am J Psychiatry ; 176(6): 457-467, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30845818

RESUMO

OBJECTIVE: Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia. METHODS: This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan. RESULTS: Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group. CONCLUSIONS: The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.


Assuntos
Antipsicóticos/uso terapêutico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Olanzapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Ganho de Peso , Adulto , Constipação Intestinal/induzido quimicamente , Tontura/induzido quimicamente , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Naltrexona/uso terapêutico , Sonolência
13.
BMC Palliat Care ; 18(1): 31, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922276

RESUMO

BACKGROUND: Opioids are prescribed in over 40% of patients with advanced cancer, but side effects occur frequently. In this study we evaluated the development and treatment of opioid induced constipation (OIC), and OIC resolving effect of methylnaltrexone for different opioid subtypes in daily clinical practice. METHODS: Patients with cancer using opioids were included in a retrospective chart analysis. Baseline characteristics, data on opioid use, laxative use, and OIC were collected. Patients with OIC who were prescribed methylnaltrexone, were included in a prospective observational trial (NCT01955213). RESULTS: Thirty-nine of 327 patients (pts) with cancer who were treated with opioids suffered from OIC (overall prevalence 12%; 95%-CI: 8-15%). The prevalence of OIC was similar in patients treated with oxycodone or fentanyl (12 of 81 pts. vs. 18 of 110 pts., RR 0.9; 95%CI 0.4-2.0). The morphine equivalent daily dose did not significantly differ between opioid subtypes (fentanyl 89 mg (IQR 60-180) vs. oxycodone 40 mg (40-80), P = 0.231). Twenty-two individual patients (7%) were admitted for OIC. Most effective laxatives in admitted patients were enemas, methylnaltrexone, or 4-l polyethylene-glycol solution. In the prospective observational study, the effect of methylnaltrexone could be evaluated in 23 patients. Eleven patients achieved the primary endpoint of ≥2 laxation responses out of the first four doses methylnaltrexone, independent of opioid subtype. CONCLUSIONS: OIC is a burdensome clinical problem independent of opioid subtype. Timely intensification of prophylactic laxative treatment, especially when opioid doses increase, may help to prevent OIC. Clinically overt OIC requires a more intensive laxative regimen with for example methylnaltrexone. TRIAL REGISTRATION: NCT01955213 .


Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/tratamento farmacológico , Idoso , Analgésicos Opioides/uso terapêutico , Constipação Intestinal/etiologia , Feminino , Fentanila/efeitos adversos , Fentanila/uso terapêutico , Humanos , Laxantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Oxicodona/efeitos adversos , Oxicodona/uso terapêutico , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Estudos Prospectivos , Compostos de Amônio Quaternário/uso terapêutico , Estudos Retrospectivos , Inquéritos e Questionários
14.
Lipids Health Dis ; 18(1): 52, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764838

RESUMO

BACKGROUND: This study was designed to test the hypothesis that κ-opioid receptor (κ-OR) stimulation reduces palmitate-induced HUVECs apoptosis and to investigate its mechanisms. METHODS: HUVECs were subjected to sodium palmitate, apoptosis and cell viability were determined, HUVECs were treated with specific inhibitors to PI3K, Akt, eNOS and siRNAs targeting κ-OR and Akt. Groups were divided as follows: the control group, the sodium palmitate group, the sodium palmitate+U50,488H (a selective κ-OR agonist) group and the sodium palmitate+U50,488H + nor-BNI (a selective κ-OR antagonist) group. RESULTS: Treatment with sodium palmitate significantly reduced cell viability and increased apoptosis rate which were significantly alleviated by pretreatment with U50,488H, the effect of U50,488H was abolished by nor-BNI. Phosphorylation of Akt and eNOS, as well as NO production were attenuated and accompanied by an increased expression of caspase 3 when HUVECs were subjected to sodium palmitate, and all these changes were restored by pretreatment with U50,488H, the effects of U50,488H were abolished by nor-BNI, and specific inhibitors to PI3K, Akt, eNOS, respectively. SiRNAs targeting κ-OR or Akt abolished the effects of U50,488H on phosphorylation of Akt and eNOS as well as the expressions of caspase 3, Bax and Bcl-2. SiRNAs targeting Akt elicited no effect on the expression of κ-OR. CONCLUSION: This study provides the evidence for the first time that κ-OR stimulation possesses anti-palmitate-induced apoptosis effect, which is mediated by PI3K/Akt/eNOS signaling pathway.


Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Opioides kappa/genética , Analgésicos Opioides/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Drug Metab Pharmacokinet ; 34(2): 126-133, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30770183

RESUMO

Naldemedine tosylate, a peripherally acting µ-opioid receptor antagonist, is indicated for treatment of opioid induced constipation in both Japan and US. Naldemedine has limited ability to affect the central analgesic effect of opioid analgesics. In this study, we investigated the contribution of P-glycoprotein (P-gp) on the brain distribution of naldemedine. Naldemedine tosylate showed acceptable oral absorption in rats. Following a single oral administration of [14C]-naldemedine tosylate to rats and ferrets, little radioactivity was detected in the region protected by the blood-brain barrier (BBB). In the assessment using Caco-2 cells, it was determined that naldemedine is a substrate for P-gp. The contribution of P-gp to the brain distribution of naldemedine was assessed using multidrug resistance 1a/b (mdr1a/b) knockout mice. While the brain-to-plasma concentration ratio (brain Kp) of naldemedine in the mdr1a/b knockout mice was 4-fold of that in the wild-type mice, the brain Kp in the mdr1a/b knockout mice was quite low (brain Kp < 0.1). These results suggest that the low brain distribution of naldemedine was due to the limited ability to cross the BBB rather than efflux by P-gp and therefore brain distribution of naldemedine would not be affected by concomitant administration of P-gp inhibitors or functional disorder of P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Naltrexona/análogos & derivados , Receptores Opioides mu/antagonistas & inibidores , Animais , Células CACO-2 , Humanos , Masculino , Camundongos , Camundongos Knockout , Estrutura Molecular , Naltrexona/química , Naltrexona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo , Distribuição Tecidual
16.
Anesth Analg ; 128(5): 1013-1021, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801358

RESUMO

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with µ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by µ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.


Assuntos
Analgésicos Opioides/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/administração & dosagem , Anestesia , Buprenorfina/administração & dosagem , D-Penicilina (2,5)-Encefalina/administração & dosagem , Fentanila/administração & dosagem , Fluoresceínas/administração & dosagem , Humanos , Imunossupressão , Células K562 , Loperamida/administração & dosagem , Metadona/administração & dosagem , Morfinanos/administração & dosagem , Morfina/administração & dosagem , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Succinimidas/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Tramadol/administração & dosagem , Tramadol/análogos & derivados
17.
Bioorg Med Chem ; 27(4): 630-643, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626554

RESUMO

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Peptidomiméticos/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/uso terapêutico , Animais , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Trânsito Gastrointestinal/efeitos dos fármacos , Células HEK293 , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/uso terapêutico , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo
18.
Expert Rev Clin Pharmacol ; 12(2): 121-128, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30652502

RESUMO

INTRODUCTION: Opioid-induced constipation (OIC) is a common adverse effect in patients under long-term opioid therapy. Naldemedine is a novel peripherally acting µ-opioid receptor antagonists being developed for the treatment of OIC without affecting central analgesia. This meta-analysis is to assess the current evidence for efficacy and safety of naldemedine for the treatment of OIC. Areas covered: We searched through MEDLINE, EMBASE, Web of Science and Cochrane Library, 'ISRCTN Register' and'ClinicalTrials.gov' (up to Aug 2018). Our final review included five randomized clinical trials (1751 participants in total), three trials observed naldemedine for the treatment of OIC in non-cancer patients and two trials in cancer patients. A Random Effects model was used for all comparisons. Subgroup analyses for the following subgroups were carried out: naldemedine 0.1 mg; 0.2 mg; 0.4 mg; cancer patients; non-cancer patients. Expert opinion: Naldemedine improved the proportion of responders and spontaneous bowel movements frequency. The incidence of serious adverse effects (AEs) in naldemedine group was higher than placebo, especially in cancer patient subgroup. The AEs occurred in participants with naldemedine were mild to moderate and well tolerated during treatment. The results of this network meta-analysis will guide the future researchers in evaluating naldemedine for the treatment of OIC.


Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Analgésicos Opioides/administração & dosagem , Constipação Intestinal/induzido quimicamente , Relação Dose-Resposta a Droga , Humanos , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Opioides mu/antagonistas & inibidores
19.
Pain ; 160(4): 824-832, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681985

RESUMO

Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.


Assuntos
Núcleo Central da Amígdala/metabolismo , Inibição Neural/efeitos dos fármacos , Neuralgia/prevenção & controle , Neuralgia/terapia , Receptores Opioides kappa/metabolismo , Transdução de Sinais/fisiologia , Animais , Núcleo Central da Amígdala/patologia , Dor Crônica/terapia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
20.
Neurosci Lett ; 699: 103-108, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30690119

RESUMO

Sinomenine, an alkaloid originally isolated from the roots and the rhizome of Sinomenium acutum is used as a traditional Chinese herbal medicines for rheumatoid arthritis and neuralgia. The aims of this study were to investigate the effects of oral administration of shinomenine on formalin-induced nociceptive behavior in mice and the opioid receptor subtypes involved in the antinociceptive effects of sinomenine. Our findings showed that a single dose of oral-administrated sinomenine inhibited the formalin induced licking and biting responses in a dose-dependent manner. Intraperitoneal pretreatment with naloxone hydrochloride, an opioid receptor antagonist, and ß-funaltrexamine hydrochloride (ß-FNA), a selective µ-opioid receptor antagonist, significantly attenuated sinomenine induced antinociception, but not by naltrindole, a nonselective δ-opioid receptor antagonist and nor-binaltorphimine, a selective κ-opioid receptor antagonist. Furthermore, in western blot analysis, oral administration of sinomenine resulted in a significant blockage of spinal extracellular signal-regulated protein kinase (ERK1/2) activation induced by formalin. Naloxone hydrochloride and ß-FNA significantly reversed the blockage of spinal ERK1/2 activation induced by sinomenine. These results suggest that sinomenine-induced anti nociceptive effect and blockage of spinal ERK1/2 activation may be triggered by activation of µ-opioid receptors.


Assuntos
Formaldeído , Morfinanos/farmacologia , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Administração Oral , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Morfinanos/administração & dosagem , Morfinanos/antagonistas & inibidores , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Medula Espinal/metabolismo
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