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1.
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
2.
J Opioid Manag ; 15(5): 417-427, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849032

RESUMO

OBJECTIVE: To evaluate the clinical effects of naltrexone following ALO-02 administration. DESIGN: Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362). SETTING: Seventy US research centers. PATIENTS: Eight hundred and five patients with moderate-to-severe chronic noncancer pain (n = 395) or moderate-to-severe chronic low back pain (n = 410). INTERVENTIONS: Oral ALO-02 capsules (daily dose 20-160 mg oxycodone): openlabel titration followed by double-blind fixed dose ALO-02 or placebo (12 weeks) for the efficacy study; and open-label administration (≤12 months) for the safety study. MAIN OUTCOME MEASURES: Brief Pain Inventory-Short Form (BPI-sf), withdrawal-related adverse events, Clinical Opiate Withdrawal Scale (COWS), and naltrexone plasma concentrations. RESULTS: ALO-02 was received for = 30 days by 592 patients (73.5 percent), = 90 days by 348 patients (43.2 percent), and ≤361 days by 105 patients (13.0 percent). Maximum COWS scores were below the cutoff for mild withdrawal for the majority of patients: 86.6 percent of patients in the safety study, and for the efficacy study, 96.8 percent during titration and 95.0 percent during double-blind treatment. The frequency of quantifiable naltrexone plasma concentrations was similar between studies (18-23 percent of samples), and the levels were low, generally not exceeding 200 pg/mL. There was no apparent relationship between naltrexone plasma concentrations and COWS scores (total or change from baseline), or change from baseline in BPI-sf scores in the efficacy (R2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R2 = 0.0010, 0.0000, and 0.0122, respectively). CONCLUSIONS: Naltrexone plasma concentrations were low, not correlated with COWS or BPI-sf scores, and considered clinically insignificant.


Assuntos
Dor Crônica , Naltrexona , Oxicodona , Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Preparações de Ação Retardada , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Oxicodona/administração & dosagem , Medição da Dor , Resultado do Tratamento
3.
Toxicol Lett ; 316: 127-135, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539569

RESUMO

Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Pulmão/efeitos dos fármacos , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Respiração/efeitos dos fármacos , Insuficiência Respiratória/prevenção & controle , Administração por Inalação , Aerossóis , Analgésicos Opioides/farmacocinética , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Fentanila/administração & dosagem , Fentanila/farmacocinética , Fentanila/toxicidade , Humanos , Pulmão/fisiopatologia , Masculino , Camundongos , Modelos Biológicos , Pletismografia Total , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia , Medição de Risco
4.
Dermatol Online J ; 25(8)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31553867

RESUMO

Naltrexone is a competitive antagonist of µ, κ and γ opioid receptors, used for treatment of alcoholism and opioid addiction. Low-dose naltrexone (LDN) is defined as daily doses ranging from 1mg to 5mg. This is purported to have a paradoxical effect that leads to an increase in endogenous opioids, including beta-endorphins, which have anti-inflammatory properties. Theses mechanisms may also justify their possible role in the treatment of inflammatory conditions. The aim of this article is to discuss the use of LDN as an adjuvant therapeutic option in symptomatic alopecias presenting with trichodynia. Trichodynia is defined as scalp discomfort of variable intensity presenting as diffuse or localized dysesthesia and may be described by patients as pain, pruritus, or burning. These are common symptoms in patients with hair loss that negatively impacts quality of life. Scalp discomfort may be refractory to conventional therapies and does not yet have a specific therapeutic guideline. For these cases, LDN would be a possible alternative to be added to the therapeutic arsenal owing to its anti-inflammatory properties, analgesic potential, low cost, and few adverse effects described. Further studies are needed to standardize dosing, better understand its mechanism of action, and evaluate its potential therapeutic indications.


Assuntos
Alopecia/tratamento farmacológico , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Dor/tratamento farmacológico , Parestesia/tratamento farmacológico , Prurido/tratamento farmacológico , Dermatoses do Couro Cabeludo/tratamento farmacológico , Humanos
5.
Anesthesiology ; 131(2): 381-391, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31314749

RESUMO

BACKGROUND: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between µ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific µ-opioid receptor isoforms which interact with gastrin releasing peptide receptor. METHODS: Reverse transcription polymerase chain reaction was performed on human spinal cord complimentary DNA from two human cadavers. Calcium responses to morphine (1 µM) were examined using calcium imaging microscopy on human cells (HEK293) coexpressing gastrin releasing peptide receptor and different human µ-opioid receptor isoforms. The authors assessed morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine (0.3 nmol) and a transactivator of transcription peptide designed from C-terminal sequences of 1Y isoform (0, 0.1, and 0.4 nmol). RESULTS: The authors demonstrated 1Y expression in the spinal cord dorsal horn. Morphine administration evoked a calcium response (mean ± SD) (57 ± 13 nM) in cells coexpressing both gastrin releasing peptide receptor and the 1Y isomer. This was blocked by 10 µM naltrexone (0.7 ± 0.4 nM; P < 0.0001), 1 µM gastrin-releasing peptide receptor antagonist (3 ± 2 nM; P < 0.0001), or 200 µM 1Y-peptide (2 + 2 nM; P < 0.0001). In mice, 0.4 nmol 1Y-peptide significantly attenuated morphine-induced scratching behaviors (scratching bouts, vehicle vs. 1Y-peptide) (92 ± 31 vs. 38 ± 29; P = 0.011; n = 6 to 7 mice per group), without affecting morphine antinociception in warm water tail immersion test (% of maximum possible effect) (70 ± 21 vs. 67 ± 22; P = 0.80; n = 6 mice per group). CONCLUSIONS: Human µ-opioid receptor 1Y isomer is a C-terminal splicing variant of Oprm1 gene identified in human spinal cord. Cross-talk between 1Y and gastrin releasing peptide receptor is required for mediating opioid-induced pruritus. Disrupting the cross talk may have implications for therapeutic uncoupling of desired analgesic effects from side effects of opioids.


Assuntos
Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Prurido/induzido quimicamente , Prurido/prevenção & controle , Receptores da Bombesina/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Idoso , Animais , Comportamento Animal , Cadáver , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Medula Espinal
6.
Dermatol Online J ; 25(6)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31329393

RESUMO

Gottron papules, a heliotrope rash, scalp and extremity erythema, pruritus, and fatigue are the characteristic signs and symptoms of amyopathic dermatomyositis (ADM). Amyopathic dermatomyositis is considered a distinct entity from dermatomyositis (DM) because the characteristic muscle weakness and muscle enzyme elevations of DM are absent in ADM. With respects to treatment, ADM treatments have traditionally included topical corticosteroids and/or systemic immunosuppressants and immunomodulators. Herein we present a patient with refractory ADM that was responsive to low-dose naltrexone therapy.


Assuntos
Dermatomiosite/tratamento farmacológico , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico
7.
Drug Alcohol Depend ; 200: 34-39, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082666

RESUMO

BACKGROUND AND AIMS: Despite the growing opioid overdose crisis, medication treatment for opioid use disorder remains uncommon. The comparative effectiveness of buprenorphine and naltrexone treatment in reducing overdose and the comparative risks of discontinuing treatment in the real world, remain uncertain. Our aim was to examine the effectiveness of medications for opioid use disorder in preventing opioid-related overdose. DESIGN: Retrospective cohort study SETTING: United States. PATIENTS: 46,846 commercially insured individuals diagnosed with opioid use disorder and initiating medication treatment between 2010 and 2016. MEASUREMENTS: Opioid-related overdose identified by International Classification of Diseases, Ninth and Tenth Revisions. FINDINGS: In our sample, 1386 individuals were prescribed extended-release injectable naltrexone (median filled prescriptions = 9 months), 7782 were prescribed oral naltrexone (5 months), and 40,441 were prescribed buprenorphine (19 months) at least once during follow-up. Individuals receiving buprenorphine therapy were at significantly reduced risk of opioid-related overdose compared to no treatment (adjusted hazard ratio (HR) = 0.40, 95% CI 0.35-0.46), while a significant association was not observed in extended-release injectable (HR = 0.74, 95% CI 0.42-1.31) or oral (HR = 0.93, 95% CI 0.71-1.22) naltrexone. We found no association with opioid overdose within four weeks of discontinuation of any medication. CONCLUSION: Among commercially-insured patients who initiate medications for opioid use disorder, buprenorphine, but not naltrexone, was associated with lower risk of overdose during active treatment compared to post-discontinuation. More research is needed to understand the benefits and risks unique to each treatment option to better tailor therapies to patients with opioid use disorder.


Assuntos
Buprenorfina/administração & dosagem , Seguro Saúde , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adulto , Buprenorfina/efeitos adversos , Estudos de Coortes , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Overdose de Drogas/diagnóstico , Overdose de Drogas/epidemiologia , Overdose de Drogas/prevenção & controle , Feminino , Seguimentos , Humanos , Seguro Saúde/tendências , Masculino , Pessoa de Meia-Idade , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Tratamento de Substituição de Opiáceos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
8.
Acta Neurobiol Exp (Wars) ; 79(1): 73-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038486

RESUMO

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co­preconditioning effect of toll­like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co­preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty­eight hours after LPS and twenty­four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5­triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co­preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co­preconditioning with LPS and NTX resulted in a synergistic protective effect.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Precondicionamento Isquêmico/métodos , Lipopolissacarídeos/administração & dosagem , Naltrexona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Hipocampo/irrigação sanguínea , Injeções Intraventriculares , /prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estimulação Luminosa/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Resultado do Tratamento
10.
Life Sci ; 224: 232-240, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930116

RESUMO

AIMS: Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice. MAIN METHODS: We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses. KEY FINDINGS: Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group. SIGNIFICANCE: Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.


Assuntos
Densidade Óssea/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Osteoblastos/citologia , Receptores Opioides/química , Animais , Proliferação de Células , Células Cultivadas , Encefalina Metionina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurotransmissores/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
11.
Pharmacol Biochem Behav ; 181: 28-36, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991059

RESUMO

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bupropiona/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Etanol/administração & dosagem , Feminino , Técnicas de Inativação de Genes , Hipotálamo/metabolismo , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naltrexona/administração & dosagem , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Fotoperíodo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Sacarina/farmacologia , Fatores Sexuais , Sacarose/farmacologia
13.
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 de Medicamentos/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
15.
J Drugs Dermatol ; 18(3): 235-238, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909326

RESUMO

Low-dose naltrexone (LDN) has been successfully studied as an immunomodulatory and anti-inflammatory therapy in a wide range of conditions including Crohn's disease, fibromyalgia, major depressive disorder, cancer, chronic regional pain syndrome, Charcot-Marie-Tooth, and multiple sclerosis.1-5 Recently, off label LDN has been shown to improve dermatologic conditions such as systemic sclerosis, Hailey-Hailey Disease, lichen planopilaris, and guttate psoriasis.6-9 In this article, we examine the existing evidence for use of LDN in skin disease and discuss its potential application in the treatment of atopic dermatitis (AD). J Drugs Dermatol. 2019;18(3):235-238.


Assuntos
Dermatite Atópica/tratamento farmacológico , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Uso Off-Label , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ensaios Clínicos como Assunto , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Relação Dose-Resposta a Droga , Humanos , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Receptores Opioides/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
Drug Alcohol Depend ; 197: 220-227, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30852374

RESUMO

AIM: To determine whether extended-release injectable naltrexone (XR-NTX), incentives for opiate abstinence, and their combination reduce opiate use compared to a usual care control and whether the combination reduces opiate use compared to either treatment alone. DESIGN: Randomized 2 × 2 single-site controlled trial conducted from November 2012 through May 2016. After a detoxification and oral naltrexone induction, participants were assigned to a Usual Care, Abstinence Incentives, XR-NTX, or XR-NTX plus Abstinence Incentives group for a six-month intervention period. SETTING: A model therapeutic workplace where participants could work on automated computer programs that targeted job-skills training for 4 h every weekday for 24 weeks and earn about $10 per hour. PARTICIPANTS: 84 heroin-dependent adults who were unemployed and medically approved for naltrexone. Most participants were male (71.4%), African American (80.1%), and cocaine dependent (71.4%). MEASUREMENTS: The primary outcome measure was the percentage of urine samples negative for opiates that were collected at once weekly assessments (24 per participant) that were not part of the intervention and for which participants were paid $10 for completing. INTERVENTION: Participants who attended the workplace provided thrice-weekly urine samples. Abstinence Incentives participants had to provide opiate-free urine samples to maintain maximum pay. XR-NTX participants received one injection every 4 weeks and were required to take injections in order to work and to maintain maximum pay. Usual Care participants were not offered XR-NTX and opiate urinalysis results did not affect pay. FINDINGS: A large percentage (65 of 149; 43.6%) of individuals failed the induction protocol required for randomization and to be eligible to receive XR-NTX. When missing urine samples were considered positive, there was no significant interaction between XR-NTX and Abstinence Incentives. XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (81.3%, SD 39.0%) than XR-NTX participants (64.5%, SD 47.9%; aOR 10.4, 95% CI 1.3-85.5; P = .030). When urine samples were not replaced, there was a significant interaction between XR-NTX and Abstinence Incentives (aOR 77.0, 95% CI 1.3-4432;P = 0.036); XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (99.6%, SD 0.1%) than XR-NTX participants (85.0%, SD 35.7%; aOR 147.6, 95% CI 6.3-3472; P = 0.002), Abstinence Incentives participants (91.9%, SD 27.3%; aOR 121.7, 95% CI 4.8-3067; P =0.004), and Usual Care participants (78.7%, SD 41.0%; aOR 233.4, 95% CI 9.4-5814; P <.001). No other group differences were significant. CONCLUSION: XR-NTX plus incentives for opiate abstinence increased opiate abstinence, but XR-NTX alone did not. XR-NTX can promote opiate abstinence when it is combined with incentives for opiate abstinence in a model therapeutic workplace.


Assuntos
Cocaína/urina , Heroína/urina , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adulto , Afro-Americanos/psicologia , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Motivação , Transtornos Relacionados ao Uso de Opioides/etnologia , Transtornos Relacionados ao Uso de Opioides/psicologia , Detecção do Abuso de Substâncias , Local de Trabalho
17.
Am J Hosp Palliat Care ; 36(10): 907-912, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30917675

RESUMO

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. Naltrexone is a reversible competitive antagonist at µ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.


Assuntos
Analgésicos não Entorpecentes/uso terapêutico , Dor Crônica/tratamento farmacológico , Naltrexona/uso terapêutico , Analgésicos não Entorpecentes/administração & dosagem , Dor do Câncer/tratamento farmacológico , Síndromes da Dor Regional Complexa/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Relação Dose-Resposta a Droga , Fibromialgia/tratamento farmacológico , Humanos , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Manejo da Dor/métodos , Cuidados Paliativos/métodos , Qualidade de Vida
18.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(3): 140-149, mar. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-182613

RESUMO

La prevalencia de la obesidad se ha incrementado mundialmente en las últimas décadas. La obesidad se asocia a múltiples comorbilidades, como la diabetes tipo 2, que generan un gran impacto en la salud y en la economía. La pérdida de peso en este colectivo favorece el control glucémico, por lo que es uno objetivo a lograr. Los cambios en el estilo de vida son poco efectivos por sí solos, y en los últimos años se han desarrollado otras opciones terapéuticas como la cirugía bariátrica/metabólica, así como fármacos para la diabetes tipo 2 y fármacos para reducir peso en la obesidad. El objetivo de la revisión es la comparación de los resultados en reducción de peso y control glucémico de los distintos tipos de fármacos con los resultados de la cirugía bariátrica/metabólica en diabetes tipo 2


The prevalence of obesity has increased worldwide over the past decades. Obesity is associated with multiple comorbidities, such as type 2 diabetes, that generates a great impact on health and economy. Weight loss in these patients leads to glycemic control so it is a target to achieve. Lifestyle changes are not effective enough and recently other treatments have been developed such as bariatric/metabolic surgery, as well as drugs for type 2 diabetes and antiobesity drugs. The aim of this review is to compare the results in weight reduction and glycemic control of the different kinds of drugs with bariatric / metabolic surgery's results in type 2 diabetes


Assuntos
Humanos , Diabetes Mellitus Tipo 2/terapia , Obesidade/epidemiologia , Perda de Peso , Índice Glicêmico , Terapia Combinada/tendências , Cirurgia Bariátrica , Obesidade/tratamento farmacológico , Simportadores/administração & dosagem , Orlistate/administração & dosagem , Liraglutida/administração & dosagem , Naltrexona/administração & dosagem , Obesidade/fisiopatologia
19.
Psychopharmacology (Berl) ; 236(6): 1887-1900, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30758525

RESUMO

RATIONALE AND OBJECTIVES: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. METHODS: Animals were randomly assigned to one of four drinking conditions of 24-h access to a three-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during four consecutive days. RESULTS: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. DISCUSSION: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/administração & dosagem , Naltrexona/administração & dosagem , Nicotina/administração & dosagem , Tabagismo/tratamento farmacológico , Vareniclina/administração & dosagem , Dissuasores de Álcool/administração & dosagem , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Animais , Feminino , Injeções Subcutâneas , Distribuição Aleatória , Ratos , Autoadministração , Agentes de Cessação do Hábito de Fumar/administração & dosagem , Tabagismo/genética , Tabagismo/psicologia
20.
Am J Addict ; 28(2): 77-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30701613

RESUMO

BACKGROUND AND OBJECTIVES: It is presently unclear whether extended-release naltrexone hydrochloride treatment induces pain or aggravates existing pain among individuals with opioid use disorders. We assessed changes in pain among individuals receiving treatment with either extended-release naltrexone hydrochloride or buprenorphine-naloxone hydrochloride. METHODS: This randomized prospective open-label clinical study included 143 participants (aged 18-60 years) with opioid dependencies, recruited from outpatient addiction clinics at five urban hospitals in Norway. After in-patient detoxification from opioids, patients were randomized to 12-week treatment with either long-acting naltrexone (380 mg intramuscularly injected every four weeks) or buprenorphine-naloxone (flexible 4-16 mg sublingual doses daily). This phase was followed by a 9-month open-treatment study with the participant's choice of either naltrexone or buprenorphine-naloxone. Changes in pain were assessed every 4 weeks using the Norwegian Short-Form of McGill Pain Questionnaire. RESULTS: Throughout the study period, we found no increase in mean sensory pain, affective pain, or present pain intensity on the McGill Pain Questionnaire, in either treatment group, including the subgroups of participants with chronic pain. Participants who switched from buprenorphine-naloxone to extended-release naltrexone treatment after week 12 reported no increase in pain intensity during longer-term treatment. Women experienced significantly more affective pain symptoms than men (p = .01). DISCUSSION AND CONCLUSIONS: Among individuals with opioid use disorder, switching from daily opioid use to long-acting naltrexone did not induce pain, or aggravate mild-to-moderate chronic pain. SCIENTIFIC SIGNIFICANCE: In opioid-dependent individuals, mild-to-moderate chronic pain was not influenced by opioid agonist or antagonist treatment. TRIAL REGISTRATION: Clinicaltrials.gov #NCT01717963, first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012. (Am J Addict 2018;XX:1-9).


Assuntos
Combinação Buprenorfina e Naloxona , Dor Crônica/diagnóstico , Naltrexona , Adulto , Combinação Buprenorfina e Naloxona/administração & dosagem , Combinação Buprenorfina e Naloxona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/uso terapêutico , Noruega , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Medição da Dor
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