RESUMEN
This review is part of a series of annual updates that summarize the evidence base for atopic eczema (AE). The aim is to provide a succinct guide for clinicians on the key findings from 14 systematic reviews on the prevention and topical treatment of AE published or indexed in 2018. Various supplements, including long-chain polyunsaturated fatty acids, vitamin D and the probiotic Lactobacillus rhamnosus GG, given prenatally and postnatally, have not been shown to prevent AE in infants, although mixed strains of probiotics may decrease the risk of AE if given to the mother during pregnancy and to the infant for the first 6 months of life. In the postnatal period, there is no evidence that hydrolysed formula, compared with cow's milk formula (CMF), reduces the risk of AE in partially breastfed infants. However, weak evidence suggests that a specific partially hydrolysed whey formula decreases the risk of AE compared with CMF. No specific skin practices can be recommended to reduce the eczema risk in healthy term babies. There is weak evidence of a low risk of reversible hypothalamic-pituitary-adrenal axis suppression following 2-4 weeks of treatment with low-potency topical steroids, and conflicting evidence as to whether bleach bathing affects skin flora or AE severity. A single study demonstrated that the topical Janus kinase inhibitor tofacitinib at 2% significantly reduces the Eczema Area and Severity Index compared with vehicle. Topical naltrexone cream 1% improves pruritus (measured using a visual analogue scale) by 30% more than placebo. There is weak evidence that topical alternative therapies, including antioxidants, micronutrients and some herbal medicines, may improve AE.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/prevención & control , Eccema/tratamiento farmacológico , Eccema/prevención & control , Administración Tópica , Animales , Lactancia Materna/estadística & datos numéricos , Terapias Complementarias/efectos adversos , Terapias Complementarias/estadística & datos numéricos , Dermatitis Atópica/diagnóstico , Eccema/patología , Ácidos Grasos/administración & dosificación , Ácidos Grasos/uso terapéutico , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Fórmulas Infantiles/efectos adversos , Recién Nacido , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/uso terapéutico , Lacticaseibacillus rhamnosus/inmunología , Leche/efectos adversos , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Embarazo , Probióticos/uso terapéutico , Preparaciones para Aclaramiento de la Piel/efectos adversos , Esteroides/administración & dosificación , Esteroides/farmacología , Vitamina D/uso terapéutico , Proteína de Suero de Leche/administración & dosificación , Proteína de Suero de Leche/efectos adversos , Proteína de Suero de Leche/químicaRESUMEN
This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Eccema/tratamiento farmacológico , Eccema/patología , Acetatos/administración & dosificación , Acetatos/efectos adversos , Acetatos/uso terapéutico , Corticoesteroides/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Biológica/efectos adversos , Terapia Biológica/métodos , Terapia Biológica/estadística & datos numéricos , Niño , Terapias Complementarias/efectos adversos , Terapias Complementarias/métodos , Terapias Complementarias/estadística & datos numéricos , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Inductores del Citocromo P-450 CYP1A2/administración & dosificación , Inductores del Citocromo P-450 CYP1A2/efectos adversos , Inductores del Citocromo P-450 CYP1A2/uso terapéutico , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/prevención & control , Eccema/diagnóstico , Eccema/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Naltrexona/administración & dosificación , Naltrexona/efectos adversos , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/efectos adversos , Antagonistas de Narcóticos/uso terapéutico , Omalizumab/efectos adversos , Omalizumab/uso terapéutico , Efecto Placebo , Probióticos/efectos adversos , Probióticos/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Sulfuros/administración & dosificación , Sulfuros/efectos adversos , Sulfuros/uso terapéutico , Ustekinumab/efectos adversos , Ustekinumab/uso terapéuticoRESUMEN
In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M-55). This microemulsion displayed size below 200 nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8 h of contact with water following a second order kinetics. After 120 h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24 h of M-55 subcutaneous administration, and persisted locally for over 30 days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug's rewarding effects, a single dose of M-55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M-55 containing 10% of naltrexone, which was compatible with aversion. These results support M-55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.
Asunto(s)
Disuasivos de Alcohol/administración & dosificación , Alcoholismo/tratamiento farmacológico , Desarrollo de Medicamentos/métodos , Etanol/administración & dosificación , Naltrexona/administración & dosificación , Nanoestructuras/administración & dosificación , Disuasivos de Alcohol/sangre , Disuasivos de Alcohol/síntesis química , Alcoholismo/sangre , Animales , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos C57BL , Naltrexona/sangre , Naltrexona/síntesis química , Nanoestructuras/químicaRESUMEN
Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/-12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.
Asunto(s)
Acamprosato/uso terapéutico , Disuasivos de Alcohol/uso terapéutico , Alcoholismo/tratamiento farmacológico , Utilización de Medicamentos/estadística & datos numéricos , Naltrexona/uso terapéutico , Acamprosato/administración & dosificación , Adulto , Anciano , Disuasivos de Alcohol/administración & dosificación , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/administración & dosificación , Pautas de la Práctica en Medicina/estadística & datos numéricos , Especialización/estadística & datos numéricosRESUMEN
BACKGROUND: Although opioid agonist treatments (OAT) with methadone or buprenorphine are available to treat opioid use disorders (OUD) in Ukraine, OAT acceptability and coverage remains low. Extended-release naltrexone (XR-NTX) that recently became available as another treatment option provides new opportunities for treating OUDs in this region and we aimed to test its feasibility. METHODS: Patients with OUD (N=135) and interested in treatment with XR-NTX were initiated on monthly XR-NTX injections and monitored for three months. Correlates of 3-month retention on XR-NTX and drug use at each time-point using self-reports and urine drug testing (UDT) were assessed. RESULTS: Of the 134 participants initiated XR-NTX, 101 (75%) completed three months, defined as 4 consecutive XR-NTX injections. Independent factors negatively associated with retention in XR-NTX treatment included previous maintenance with OAT (aOR=0.3; 95%CI=0.1-0.9) and extrinsic help-seeking treatment motivation (aOR=0.7; 95%CI=0.5-0.9). Of these 101 participants completing three months of treatment, opioid use markedly reduced using self-report (67%% to 22%; p>0.001) and UDT (77% to 24%; p<0.001) outcomes over time. Alcohol, marijuana and stimulant use, however, remained unchanged. Craving for opioids and symptoms of depression also significantly decreased, while health-related quality of life scores improved over time. No adverse side effects were reported during the period of observation. CONCLUSION: The first introduction of XR-NTX in Ukraine among persons with OUD resulted in high levels of retention, marked reductions in opioid use and improved quality of life. These descriptive results suggest that XR-NTX treatment is feasible and well-tolerated over a 3-month period in Ukraine.
Asunto(s)
Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Cooperación del Paciente , Calidad de Vida , Adulto , Preparaciones de Acción Retardada , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , UcraniaRESUMEN
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.
Asunto(s)
Dermatomiositis/tratamiento farmacológico , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéuticoRESUMEN
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 BPPâ¯+â¯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 BPPâ¯+â¯NTX. A single administration of BPPâ¯+â¯NTX (10â¯mg/kgâ¯+â¯1â¯mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPPâ¯+â¯NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPPâ¯+â¯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 BPPâ¯+â¯NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPPâ¯+â¯NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPPâ¯+â¯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 BPPâ¯+â¯NTX effects on alcohol drinking in male mice.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Alcoholismo/tratamiento farmacológico , Bupropión/farmacología , Bupropión/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Naltrexona/farmacología , Naltrexona/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Bupropión/administración & dosificación , Combinación de Medicamentos , Sinergismo Farmacológico , Etanol/administración & dosificación , Femenino , Técnicas de Inactivación de Genes , Hipotálamo/metabolismo , Inyecciones Intraperitoneales , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Naltrexona/administración & dosificación , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Fotoperiodo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , Sacarina/farmacología , Factores Sexuales , Sacarosa/farmacologíaRESUMEN
BACKGROUND: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: After systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 µg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.
Asunto(s)
Analgésicos Opioides/efectos adversos , Isoquinolinas/efectos adversos , Naltrexona/análogos & derivados , Fenilpropionatos/efectos adversos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Tolerancia a Medicamentos , Hiperalgesia/tratamiento farmacológico , Inyecciones Espinales , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Macaca mulatta , Masculino , Naltrexona/administración & dosificación , Naltrexona/efectos adversos , Naltrexona/farmacología , Nocicepción/efectos de los fármacos , Trastornos Relacionados con Opioides/etiología , Umbral del Dolor/efectos de los fármacos , Fenilpropionatos/administración & dosificación , Fenilpropionatos/farmacologíaRESUMEN
BACKGROUND: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. METHODS: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. RESULTS: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. CONCLUSION: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.
Asunto(s)
Disuasivos de Alcohol/administración & dosificación , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Trastornos Relacionados con Alcohol/tratamiento farmacológico , Morfinanos/uso terapéutico , Naltrexona/administración & dosificación , Compuestos de Espiro/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Tolerancia a Medicamentos , Femenino , Masculino , Ratones Endogámicos C57BL , Morfinanos/farmacología , Naltrexona/análogos & derivados , Receptores Opioides kappa/agonistas , Sacarina/administración & dosificación , Compuestos de Espiro/farmacología , Sacarosa/administración & dosificaciónRESUMEN
BACKGROUND: There are no FDA-approved pharmacotherapies for cannabis use disorders (CUD), despite the evaluation of numerous medications. Notably, chronic dosing of oral naltrexone decreases self-administration of cannabis in human laboratory studies. OBJECTIVES: To test the feasibility of long-acting injectable naltrexone for the treatment of CUD, while obtaining preliminary safety and efficacy data. METHODS: Twelve adult participants (seven male) meeting DSM-IV-TR criteria for cannabis dependence enrolled into an 8-week, open-label pilot study conducted at an academic treatment research clinic. They received 380 mg intramuscular injections of long-acting naltrexone on study day 1 and at the start of study week 5. Outcome measures included percentages of study completers and participants who received the second injection, frequency of adverse events (AEs), and cannabis consumption measured by average daily grams, dollars, and using days per week as measured by timeline follow-back and urine oral delta-9-tetrahydrocannabinol (THC) concentrations. RESULTS: Of the 12 participants enrolled in the study, 9 completed the study and 6 received the second injection. There were no severe AEs but an unexpected AE led to the addition of supportive medications to the protocol. Number of cannabis use days per week significantly decreased over the course of the study (p = .001). Creatinine-corrected urine THC concentrations and average daily cannabis use per study week in grams and in dollars did not decrease over the course of the study. CONCLUSIONS: Long-acting injectable naltrexone is a feasible intervention for CUD worthy of further study in a placebo-controlled, double-blinded randomized clinical trial.
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Abuso de Marihuana/tratamiento farmacológico , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Adulto , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Proyectos Piloto , Resultado del TratamientoRESUMEN
Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.
Asunto(s)
Conducta de Elección/efectos de los fármacos , Ritmo Circadiano , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Etanol/administración & dosificación , Inmunidad Innata , Naltrexona/administración & dosificación , Receptor Toll-Like 4/antagonistas & inhibidores , Animales , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones Endogámicos BALB C , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fotoperiodo , Recompensa , Receptor Toll-Like 4/metabolismoRESUMEN
In this case report, we describe the treatment of a 64-year-old male patient diagnosed with metastatic renal cell carcinoma (RCC) in June of 2008. In spite of a left nephrectomy and the standard oncological protocols, the patient developed a solitary left lung metastasis that continued to grow. He was informed that given his diagnosis and poor response to conventional therapy, any further treatment would, at best, be palliative. The patient arrived at the Integrative Medical Center of New Mexico in August of 2010. He was in very poor health, weak, and cachectic. An integrative program-developed by one of the authors using intravenous (IV) α-lipoic acid, IV vitamin C, low-dose naltrexone, and hydroxycitrate, and a healthy life style program-was initiated. From August 2010 to August 2015, the patient's RCC with left lung metastasis was followed closely using computed tomography and positron emission tomography/computed tomography imaging. His most recent positron emission tomography scan demonstrated no residual increased glucose uptake in his left lung. After only a few treatments of IV α-lipoic acid and IV vitamin C, his symptoms began to improve, and the patient regained his baseline weight. His energy and outlook improved, and he returned to work. The patient had stable disease with disappearance of the signs and symptoms of stage IV RCC, a full 9 years following diagnosis, with a gentle integrative program, which is essentially free of side effects. As of November 2017 the patient feels well and is working at his full-time job.
Asunto(s)
Supervivientes de Cáncer , Carcinoma de Células Renales/terapia , Oncología Integrativa/métodos , Neoplasias Renales/terapia , Naltrexona/administración & dosificación , Ácido Tióctico/administración & dosificación , Administración Intravenosa , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/rehabilitación , Terapia Combinada , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Renales/patología , Neoplasias Renales/rehabilitación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de TiempoRESUMEN
Importance: Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare and debilitating genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. Despite the reported therapeutic modalities, such as topical and systemic corticosteroids, systemic immunomodulators, topical and systemic retinoids, and laser, HHD can still be markedly difficult to control. Objective: To assess low-dose naltrexone hydrochloride in the treatment of recalcitrant HHD. Design, Setting, and Participants: In this case series, 3 patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic. Each patient was treated with low-dose naltrexone hydrochloride at a dosage of 1.5 to 3.0 mg per day. No laboratory monitoring was necessary. Clinical response (healing of erosions, improvement in erythema, and alleviation of pain), adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017. Main Outcomes and Measures: Objective clinical response as assessed by the treating dermatologist, subjective quality of life as reported by the patient, and recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. Results: The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded. Conclusions and Relevance: Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD.
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Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Pénfigo Familiar Benigno/tratamiento farmacológico , Calidad de Vida , Adulto , Biopsia , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/administración & dosificación , Naltrexona/efectos adversos , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/efectos adversos , Pénfigo Familiar Benigno/diagnóstico , Pénfigo Familiar Benigno/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: Explore the efficacy of extended-release injectable naltrexone (XR-NTX) for preventing relapse to amphetamine use. METHOD: Clinical trial of 100 amphetamine-dependent, treatment-seeking patients who were randomized to 6 monthly 380âmg doses of XR-NTX or matching placebo before entering intensive outpatient after varying lengths of inpatient treatment in Reykjavik, Iceland. Weekly urine drug tests, retention, and standardized instruments assessed efficacy. RESULTS: Of 169 approached, 100 were randomized. Although amphetamine dependence was the main reason for seeking treatment, three-quarters or more of participants had 1 or more other substance dependencies. Of 51 randomized to XR-NTX, 20 received 4 or more injections; of 49 assigned to placebo, 26 received 4 or more injections. Of the planned 2400 weekly urine drug tests, 1247 were collected (52%); 4% of these were positive for amphetamine, 8% for benzodiazepine, 7% for marijuana, 1% for cocaine, and 1% for opioid. XR-NTX had no effect on amphetamine-positive tests, retention, or other outcomes. Those providing half or more of their tests attended more weeks of treatment than those providing less than half of their tests (mâ=â10.76 vs 3.31; t (92)â=â5.91, Pâ<â0.0001), and 92 participants provided at least 1 test. CONCLUSIONS: Adding XR-NTX to the usual combination of inpatient and intensive outpatient treatment did not reduce amphetamine use. The low prevalence of substance use among collected urine samples, and the association between collected samples and weeks in treatment, was consistent with other studies showing that staying in treatment is associated with better outcomes.
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Trastornos Relacionados con Anfetaminas/prevención & control , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Psicoterapia , Prevención Secundaria/métodos , Adulto , Atención Ambulatoria/métodos , Trastornos Relacionados con Anfetaminas/diagnóstico , Trastornos Relacionados con Anfetaminas/rehabilitación , Terapia Combinada , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Estudios de Seguimiento , Hospitalización , Humanos , Inyecciones Intramusculares , Masculino , Modelos Estadísticos , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Recurrencia , Centros de Tratamiento de Abuso de Sustancias , Resultado del TratamientoRESUMEN
BACKGROUND: The laparoscopic adjustable gastric band (AGB) has been effective in reducing excess weight by approximately 50% for at least 16 years. However, as with all weight loss approaches, reduction in weight resulting from bariatric surgery is associated with a compensatory reduction in energy expenditure, which may confound and limit weight loss. Adjuvant therapies that reduce food intake and increase energy expenditure may be used to improve weight loss outcomes by ameliorating, or even reversing, this reduction in energy expenditure. METHODS: Rats were either fitted with an AGB or were sham operated and received one of 2 adjunctive pharmacologic treatments, (1) thyroxine or (2) bupropion/naltrexone (Contrave), at a range of doses and matched with vehicle controls (n = 6-8/group) over a 4-week period of combined treatments. Metabolic parameters including food intake, weight, fat mass, and energy expenditure in brown adipose tissue (BAT), whole body calorimetry, and physical activity were assessed. RESULTS: Inflation of the AGB caused a reduction in weight gain that was further enhanced by cotreatment with either thyroxine or Contrave (P<.05). Thyroxine completely ameliorated the reduction in AGB-induced BAT thermogenesis and significantly improved weight loss, particularly in fat mass. Contrave also augmented the loss of weight and fat mass associated with the AGB and increased BAT thermogenesis in banded rats even at doses below that required to change food intake. CONCLUSION: Adjuvant therapies can improve the efficacy of the AGB, at least in part by negating the compensatory reduction in energy expenditure, but also via a combined effect on food intake.
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Gastroplastia/instrumentación , Laparoscopía/instrumentación , Tejido Adiposo Pardo/anatomía & histología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiología , Animales , Fármacos Antiobesidad/farmacología , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Composición Corporal/fisiología , Distribución de la Grasa Corporal , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Bupropión/administración & dosificación , Bupropión/farmacología , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Intolerancia a la Glucosa/fisiopatología , Inyecciones Subcutáneas , Resistencia a la Insulina/fisiología , Masculino , Naltrexona/administración & dosificación , Naltrexona/farmacología , Obesidad/fisiopatología , Obesidad/cirugía , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Termogénesis/efectos de los fármacos , Termogénesis/fisiología , Tiroxina/administración & dosificación , Tiroxina/farmacología , Pérdida de Peso/efectos de los fármacos , Pérdida de Peso/fisiologíaRESUMEN
INTRODUCTION: Chronic low back pain (CLBP) is a common and difficult illness to manage. Some individuals with CLBP have pain processing disorders and are also at risk for opioid abuse, misuse; addiction and diversion. Guidelines have been published to guide management; neuromodulation, exercise, mindfulness-based stress reduction and cognitive behavior therapies among other non-pharmacological reduce the pain of CLBP with minimal toxicity. Pharmacological management includes acetaminophen, NSAIDs and antidepressants, mainly duloxetine. Abuse-deterrent opioids have been developed which have been shown to reduce pain and opioid abuse risk. ALO-02 is a tamper-resistant sustained release opioid consisting of extended release oxycodone and sequestered naltrexone. Pivotal studies of ALO-02 have centered on patients with CLBP. AREAS COVERED: This manuscript will review CLBP, the pivotal analgesic and clinical abuse potential studies of ALO-02. The opinion will cover whether opioids should be used for CLBP, when they should be used and opioid choices. EXPERT OPINION: ALO-02 is one of several opioids which can be considered in the management of CLBP. The outcome to a trial of opioids should be function rather than analgesia. Most analgesic trials for CLBP have had analgesia as the primary outcome and function has not been vigorously studied as an outcome. Opioids should be considered as a trial only when other non-opioid analgesics have failed to improve analgesia and function. Universal precautions should be routinely part of phase III analgesic trial particularly for chronic non-malignant pain.
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Dolor Crónico/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Naltrexona/administración & dosificación , Oxicodona/administración & dosificación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacocinética , Animales , Preparaciones de Acción Retardada , Combinación de Medicamentos , Humanos , Naltrexona/efectos adversos , Naltrexona/farmacocinética , Trastornos Relacionados con Opioides/prevención & control , Oxicodona/efectos adversos , Oxicodona/farmacocinética , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). METHODS: Opioid dependent participants were randomized to receive dronabinol 30mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. RESULTS: The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. CONCLUSION: Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment.
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Preparaciones de Acción Retardada/uso terapéutico , Dronabinol/uso terapéutico , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Adulto , Cannabinoides/uso terapéutico , Método Doble Ciego , Dronabinol/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Masculino , Antagonistas de Narcóticos/uso terapéutico , Cooperación del Paciente , Adulto JovenRESUMEN
Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as 'delayed ADE'. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be triggered by acetaldehyde after ethanol consumption. Hence, we conjecture that the combination of NTX and DP, due to their distinct but complementary mechanisms to impede OR activation, may be more efficacious in the prevention of the ADE and, specifically, the 'delayed ADE'. Herein, we compare the effects of the combination NTX/DP (NTX: 2×5 mg/kg SC injection daily/DP: SC infusion (0.25 mg/h)) versus NTX on the ADE in long-term ethanol-experienced rats. As expected, NTX-treated animals displayed a delayed ADE. However, NTX/DP treatment prevented this delayed effect. Our present data indicate that this combination therapy shows an adequate anti-relapse preclinical efficacy being able to overcome the preclinical limitations of NTX alone.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/prevención & control , Naltrexona/uso terapéutico , Penicilamina/uso terapéutico , Prevención Secundaria , Disuasivos de Alcohol/administración & dosificación , Disuasivos de Alcohol/uso terapéutico , Animales , Quimioterapia Combinada , Infusiones Subcutáneas , Inyecciones Subcutáneas , Masculino , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Penicilamina/administración & dosificación , RatasRESUMEN
OBJECTIVE: The significant weight loss observed with combination naltrexone-sustained release (SR) 32 mg and bupropion SR 360 mg (NB32) therapy is thought to be due, in part, to bupropion stimulation of hypothalamic pro-opiomelanocortin (POMC) neurons, and naltrexone blockade of opioid receptor-mediated POMC autoinhibition, but the neurobiological mechanisms are not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment. METHODS: Forty women (31.1±8.1 years; body mass index: 32.5±3.9) received 4 weeks of NB32 or placebo, and were instructed to maintain their dietary and exercise habits. Functional magnetic resonance imaging responses (analyzed using SPM2 and clusters (>100 pixels)) to a 5-min food video (preparation of the subject's favorite food) and a 5-min neutral video (manipulation of neutral objects) under conditions of mild food deprivation (â¼14 h) were assessed before and after treatment. RESULTS: The food cues video induced positive brain activation in visual and prefrontal cortices, insula and subcortical brain regions. The group-by-treatment interaction on regional brain activation was significant and showed that whereas NB32 attenuated the activation in the hypothalamus in response to food cues (P<0.01), it enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal) regions (whole-brain analysis; P<0.05). CONCLUSIONS: Blunting the hypothalamic reactivity to food cues while enhancing the activation of regions involved with self-control and internal awareness by NB32 might underlie its therapeutic benefits in obesity.
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Apetito/efectos de los fármacos , Bupropión/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Hipotálamo/efectos de los fármacos , Comidas/psicología , Naltrexona/administración & dosificación , Obesidad/tratamiento farmacológico , Adolescente , Adulto , Señales (Psicología) , Dieta , Quimioterapia Combinada , Femenino , Ghrelina , Humanos , Leptina , Imagen por Resonancia Magnética , Obesidad/prevención & control , Péptido YY , Resultado del Tratamiento , Pérdida de PesoRESUMEN
Earlier research has demonstrated that hyperbaric oxygen (HBO2) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO2 can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO2 treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO2-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO2 at 3.5 atm absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO2 treatment, another group of rats was implanted with Alzet(®) osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO2-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO2 significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO2 was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO2.