RESUMEN
OBJECTIVES: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib. MATERIALS AND METHODS: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis. RESULTS: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by â¼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response. CONCLUSIONS: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
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Azepinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Factores de Edad , Anciano , Azepinas/farmacocinética , Estudios de Cohortes , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Indazoles , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias/patología , Seguridad del Paciente , Pirimidinas/farmacocinética , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Medición de Riesgo , Factores Sexuales , Sulfonamidas/farmacocinética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: There are currently no drugs clinically available to reverse general anesthesia. We previously reported that caffeine is able to accelerate emergence from anesthesia in rodents. This study was carried out to test the hypothesis that caffeine accelerates emergence from anesthesia in humans. METHODS: We conducted a single-center, randomized, double-blind crossover study with eight healthy males. Each subject was anesthetized twice with 1.2% isoflurane for 1 h. During the final 10 min of each session, participants received an IV infusion of either caffeine citrate (15 mg/kg, equivalent to 7.5 mg/kg of caffeine base) or saline placebo. The primary outcome was the average difference in time to emergence after isoflurane discontinuation between caffeine and saline sessions. Secondary outcomes included the end-tidal isoflurane concentration at emergence, vital signs, and Bispectral Index values measured throughout anesthesia and emergence. Additional endpoints related to data gathered from postanesthesia psychomotor testing. RESULTS: All randomized participants were included in the analysis. The mean time to emergence with saline was 16.5 ± 3.9 (SD) min compared to 9.6 ± 5.1 (SD) min with caffeine (P = 0.002), a difference of 6.9 min (99% CI, 1.8 to 12), a 42% reduction. Participants emerged at a higher expired isoflurane concentration, manifested more rapid return to baseline Bispectral Index values, and were able to participate in psychomotor testing sooner when receiving caffeine. There were no statistically significant differences in vital signs with caffeine administration and caffeine-related adverse events. CONCLUSIONS: Intravenous caffeine is able to accelerate emergence from isoflurane anesthesia in healthy males without any apparent adverse effects.
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Periodo de Recuperación de la Anestesia , Anestésicos por Inhalación/administración & dosificación , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Citratos/farmacología , Isoflurano/administración & dosificación , Adulto , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Factores de TiempoRESUMEN
The Forkhead box M1 (FOXM1) is a transcription factor that has been implicated in normal cell growth and proliferation through control of cell cycle transition and mitotic spindle. It is implicated in carcinogenesis of various malignancies where it is activated by either amplification, increased stability, enhanced transcription, dysfunction of regulatory pathways, or activation of PI3K/AKT, epidermal growth factor receptor, Raf/MEK/MAPK, and Hedgehog pathways. This review describes the role of FOXM1 in breast cancer. This includes how FOXM1 impacts on different subtypes of breast cancer, that is, luminal/estrogen receptor positive (ER+), expressing human epidermal growth factor receptor 2 (HER2), basal-like breast cancer (BBC), and triple negative breast cancer (TNBC). The review also describes different tested preclinical therapeutic strategies targeting FOXM1. Developing clinically applicable therapies that specifically inhibit FOXM1 activity is a logical next step in biomarker-driven approaches against breast cancer but will not be without its challenges due to the unique properties of this transcription factor.
RESUMEN
BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS), which is also known by other names, including Gorlin-Goltz syndrome and multiple basal-cell carcinoma (BCC) syndrome, is a rare multi-systemic disease inherited in a dominant autosomal manner with complete penetrance and variable expressivity. The main clinical manifestations include multiple BCCs, odontogenic keratocysts of the jaw, hyperkeratosis of the palms and soles, skeletal abnormalities, intracranial calcifications and facial deformities. PATIENTS AND METHODS: A 31-year-old male diagnosed with Gorlin-Goltz syndrome with multiple unresectable facial BCCs was treated with the Hedgehog inhibitor vismodegib. RESULTS: After one month of therapy on vismodegib, there were significant reductions in the size of multiple BCCs on the patient's face. The patient remains on this therapy. CONCLUSION: Hedgehog pathway inhibition is an effective strategy to treat unresectable BCCs from Gorlin-Goltz syndrome. Although vismodegib shows some promising clinical results in the early phase of its use, there are concerns of possible resistance developing within months. Duration of therapy, role of maintenance treatment and drug modification to reduce resistance need to be explored in future case studies.
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Anilidas/uso terapéutico , Síndrome del Nevo Basocelular/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Síndrome del Nevo Basocelular/patología , Humanos , MasculinoRESUMEN
RATIONALE: Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions. OBJECTIVE: The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine. METHODS: In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed. RESULTS: Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis. CONCLUSIONS: We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.
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Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/antagonistas & inhibidores , Voluntarios Sanos/psicología , Morfina/administración & dosificación , Morfina/antagonistas & inhibidores , Naltrexona/análogos & derivados , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Infusiones Intravenosas , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Pupila/efectos de los fármacos , Pupila/fisiología , Compuestos de Amonio Cuaternario/farmacología , Receptores Opioides mu/agonistas , Resultado del Tratamiento , Adulto JovenRESUMEN
Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
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Analgésicos , Dolor/tratamiento farmacológico , Dolor/epidemiología , Mal Uso de Medicamentos de Venta con Receta/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto , Determinación de Punto Final , Humanos , Dimensión del Dolor , Población , Mal Uso de Medicamentos de Venta con Receta/psicología , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Estudios Retrospectivos , Riesgo , Factores de Riesgo , Factores Socioeconómicos , Detección de Abuso de Sustancias , Terminología como AsuntoRESUMEN
Two prominent and important risk factors for nonmedical use of prescription opioids (NMUPO) identified in epidemiological studies are smoking status and sex (i.e., there is a greater likelihood of NMUPO in smokers and in men, relative to nonsmokers and women). Interestingly, nonsmokers and women are at greater risk for the aversive effects of postoperative nausea and vomiting. We have conducted six studies examining the subjective effects of oral oxycodone (0, 10, 20 mg) in samples that included both men and women and nonsmokers and light smokers (fewer than six cigarettes per day). Four groups were comprised of 115 volunteers: male smokers (n = 20), male nonsmokers (n = 38), female smokers (n = 15), and female nonsmokers (n = 42). We hypothesized that there would be an additive effect between smoking status and sex such that male smokers would experience less nausea and disliking, and greater overall liking, and that female nonsmokers would respond in the opposite fashion. As predicted, nausea and disliking ratings were lowest, and overall liking ratings the highest, in male smokers after oxycodone administration, whereas nausea and disliking ratings were highest, and overall liking ratings the lowest, in female nonsmokers. Thus, our hypotheses were generally supported, and suggest a possible biobehavioral mechanism for the epidemiological links between smoking status and sex and increased risk of NMUPO.
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Motivación , Náusea/inducido químicamente , Oxicodona/efectos adversos , Factores Sexuales , Fumar , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Oxicodona/administración & dosificación , Adulto JovenRESUMEN
A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.
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Analgésicos Opioides/efectos adversos , Ensayos Clínicos como Asunto/normas , Neurología/normas , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/etiología , Evaluación de Resultado en la Atención de Salud/normas , Guías de Práctica Clínica como Asunto , Humanos , Internacionalidad , Medición de RiesgoRESUMEN
Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.
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Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Descubrimiento de Drogas , Trastornos Relacionados con Opioides/prevención & control , Dolor/prevención & control , Guías de Práctica Clínica como Asunto/normas , Proyectos de Investigación/normas , Humanos , Estados UnidosRESUMEN
BACKGROUND: There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. METHODS: Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5mg alprazolam, 10mg oxycodone, and 0.5mg alprazolam combined with 10 mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. RESULTS: Oxycodone by itself increased drug liking and "take again" ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. CONCLUSIONS: In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint.
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Alprazolam/farmacología , Moduladores del GABA/farmacología , Memoria/efectos de los fármacos , Narcóticos/farmacología , Oxicodona/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Tiempo de Reacción/efectos de los fármacos , Pensamiento/efectos de los fármacosRESUMEN
BACKGROUND: Some chronic pain patients on long-term opioid therapy also take centrally active skeletal muscle relaxants. One of those muscle relaxants is carisoprodol, a drug that is abused and capable of producing impairment. It would be of relevance to characterize the effects of an opioid and carisoprodol when taken together to determine if abuse liability-related measures and psychomotor impairment are increased compared to when the drugs are taken alone. METHODS: As part of a larger crossover, randomized, double-blind study, we examined the subjective and psychomotor responses of 15 healthy volunteers to four experimental conditions: placebo, 350 mg carisoprodol, 10mg oxycodone, and 350 mg carisoprodol followed 60 min later by 10mg oxycodone (intended to test the interaction of the two drugs when they were producing their maximal effects). RESULTS: Preliminary data analyses indicated that some of carisoprodol's effects were declining when we tested for drug interactions. Despite this, on some outcome measures in which the drugs alone did not differ from placebo, when tested together subjective effects were increased, including those that were abuse liability-related, and psychomotor performance decreased, relative to placebo. CONCLUSIONS: This is the first study that we are aware of that has shown that carisoprodol and oxycodone, two drugs that are sometimes co-prescribed for relief of pain, produce effects when administered "together" (i.e., separated by 60 min) that are of greater magnitude than when they are administered alone. Some of the effects were not benign, and are of concern from both abuse liability and public safety standpoints.
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Carisoprodol/farmacología , Relajantes Musculares Centrales/farmacología , Narcóticos/farmacología , Oxicodona/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Afecto/efectos de los fármacos , Carisoprodol/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Relajantes Musculares Centrales/administración & dosificación , Narcóticos/administración & dosificación , Oxicodona/administración & dosificación , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75 mg pregabalin, 150 mg pregabalin, 10 mg oxycodone, and 75 mg pregabalin combined with 10 mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75 mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75 mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.
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Analgésicos Opioides/efectos adversos , Analgésicos/efectos adversos , Anticonvulsivantes/efectos adversos , Síndromes de Neurotoxicidad/fisiopatología , Oxicodona/efectos adversos , Ácido gamma-Aminobutírico/análogos & derivados , Adulto , Analgésicos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Síndromes de Neurotoxicidad/psicología , Trastornos Relacionados con Opioides/psicología , Pregabalina , Desempeño Psicomotor/efectos de los fármacos , Frecuencia Respiratoria/efectos de los fármacos , Trastornos Relacionados con Sustancias/psicología , Pruebas de Toxicidad Aguda , Adulto Joven , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/efectos adversosRESUMEN
Carisoprodol is a centrally acting drug used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. There is evidence from different sources that this oral muscle relaxant is abused and that it is associated with impairment leading to arrests for "driving under the influence" as well as increased risk of automobile accidents. Its subjective and psychomotor effects in healthy volunteers at therapeutic and supratherapeutic doses have not been well-characterized, and form the basis of this report. Fifteen healthy volunteers (8 males, 7 females) were administered 0, 350, and 700 mg of carisoprodol in separate sessions and for 6h afterwards they completed a battery of tests at fixed time intervals so as to assess the subjective and psychomotor effects of the drug. The supratherapeutic dose, 700 mg, increased visual analog scale ratings of terms that were more reflective of sedation (e.g., "sleepy," "heavy, sluggish feeling") than those of abuse liability, and produced impaired performance on several psychomotor tests. The therapeutic dose, 350 mg, while producing few and mild subjective effects, still produced psychomotor impairment. The fact that the therapeutic dose of carisoprodol produced minimal subjective effects while adversely affecting performance is of concern in that patients prescribed this drug may feel relatively normal and engage in tasks (driving) that could put themselves and others at risk.
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Carisoprodol/farmacología , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Adulto , Cognición/fisiología , Método Doble Ciego , Emociones/fisiología , Femenino , Humanos , Masculino , Relajantes Musculares Centrales/farmacología , Desempeño Psicomotor/fisiología , Adulto JovenRESUMEN
RATIONALE: Nonmedical use of prescription opioids is sometimes accompanied by the ingestion of ethanol. Whether ethanol increases the abuse liability-related effects of prescription opioids has not been determined. OBJECTIVE: The purpose of this study was to characterize the subjective, psychomotor, and physiological effects of oxycodone, a widely prescribed and abused opioid, and ethanol, alone and in combination. METHODS: Fourteen volunteers participated in a randomized, crossover trial in which they were exposed to placebo, oxycodone (10 mg), two doses of ethanol (0.3 and 0.6 g/kg), and oxycodone combined with the lower dose and the higher dose of ethanol on separate sessions. RESULTS: Several abuse liability-related subjective effects (drug liking, take again, pleasant bodily sensations) were not increased by the low dose of ethanol or oxycodone alone relative to placebo, but were when the two were combined. Self-reported liking of the higher dose of ethanol was higher than that of placebo, but oxycodone neither increased nor decreased this effect. Psychomotor and cognitive performance was not affected by any of the active drug conditions. Absorption of ethanol was decreased by oxycodone. CONCLUSIONS: In this study, 10 mg of oral oxycodone combined with a low dose of ethanol generated abuse liability-related effects, but when tested separately, they did not. Further psychopharmacological investigations of this combination are warranted in light of these findings and the fact that nonmedical use of prescription opioids is sometimes accompanied by use of ethanol.
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Analgésicos Opioides/farmacología , Etanol/farmacología , Oxicodona/farmacología , Desempeño Psicomotor/efectos de los fármacos , Administración Oral , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Cognición/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Etanol/administración & dosificación , Etanol/efectos adversos , Femenino , Humanos , Masculino , Trastornos Relacionados con Opioides/psicología , Oxicodona/administración & dosificación , Oxicodona/efectos adversos , Adulto JovenRESUMEN
A number of studies have documented a relationship between anxiety disorders and opioid misuse and abuse, and there is some data to suggest that some people use opioids in an attempt to reduce their anxiety. We tested the hypothesis that volunteers with an anxiety disorder would report a more positive spectrum of subjective effects (i.e., greater ratings of drug liking and wanting to take the drug again) from oxycodone, a mu opioid agonist, than would volunteers without the disorder, and that oxycodone would have greater reinforcing efficacy in volunteers with the anxiety disorder. In addition to subjective and reinforcing effects, the psychomotor and physiological effects of oxycodone also were assessed. Individuals with generalized anxiety disorder (GAD, n = 8) and nonanxious controls (CTL, n = 8) were administered 0, 10, and 20 mg oxycodone (per os) in 3 separate sessions. Oxycodone produced a number of effects in a dose-related fashion in both groups. However, on several subjective effects measures, only CTL participants reported effects of oxycodone (e.g., high, lightheaded). Neither group had statistically significant increases in peak liking or "take drug again" ratings in the oxycodone conditions relative to the placebo condition, and in neither group did the drug function as a reinforcer, as measured by the Multiple-Choice Procedure (Griffiths, Troisi, Silverman, & Mumford, 1993). Anxiety ratings were low in the GAD group (in the absence of drug), and this may have lessened the possibility of detecting a more positive spectrum of oxycodone effects in this group than in the CTL group.
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Analgésicos Opioides/efectos adversos , Ansiedad/psicología , Oxicodona/efectos adversos , Adulto , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , PlacebosRESUMEN
BACKGROUND: Although numerous studies have assessed subjective effects of nitrous oxide, few studies have analyzed for sex differences. Since sex differences have been reported in subjective effects of several drugs such as opioids, nicotine and alcohol, we sought to determine if sex modulates the subjective effects of the inhalant, nitrous oxide, in healthy volunteers. METHODS: Thirty-eight females and seventy-two males from nine studies that were conducted in our laboratory were included in this retrospective analysis. All experimental studies utilized randomized, placebo-controlled, repeated measures designs in which subjects inhaled 30% nitrous oxide in oxygen and 100% oxygen (placebo). Dependent measures in this analysis were subjective effects measured at baseline and 15 min into the inhalation period. RESULTS: Nitrous oxide produced a number of subjective effects, including those that could be considered abuse liability-related ("elated," "having pleasant thoughts," drug liking), but sex did not modulate these effects. CONCLUSIONS: Females and males showed similar subjective responses to 30% nitrous oxide. Future prospective studies might assess other concentrations, other measures (choice, analgesic response), and other inhaled general anesthetics to more comprehensively characterize the role of sex in response to inhalants.
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Afecto/efectos de los fármacos , Anestésicos por Inhalación/farmacología , Euforia/efectos de los fármacos , Óxido Nitroso/farmacología , Caracteres Sexuales , Adulto , Femenino , Humanos , Masculino , Óxido Nitroso/administración & dosificación , Adulto JovenRESUMEN
Sensation-seeking is a personality trait that is linked to use and abuse of drugs. Laboratory studies have established that high sensation seekers, as measured by different instruments, are more likely to report abuse liability-related subjective effects from drugs such as nicotine, alcohol, and d-amphetamine than low sensation seekers. One class of drugs that has not been studied to date in this fashion is opioids. Accordingly, a retrospective analysis encompassing five studies that examined oxycodone effects, including its abuse liability-related effects, was conducted in subjects categorized as high or low sensation seekers. In addition, because there appear to be sex differences in how males and females respond to opioids, this factor was taken into account in the analysis. Seventy one subjects who scored on the lower end (15 and 19 low sensation-seeking males and females, respectively) or the higher end (23 and 14 high sensation-seeking males and females) of the Disinhibition subscale of the Sensation-Seeking Scale-Form V were studied for their responses to 0, 10, and 20mg of oral oxycodone. Ratings of "pleasant bodily sensations" were significantly higher after oxycodone administration than placebo only in male and female high sensation seekers. Ratings of "take again," "drug liking," "carefree," and "elated (very happy)" also tended to differentiate high from low sensation seekers although Group x Dose interactions were only marginally significant with the latter three ratings. Male and female low sensation seekers and female high sensation seekers reported dysphoric effects (e.g., ratings of nauseated) particularly after administration of the 20mg oxycodone dose. The results of this analysis provide suggestive evidence that high sensation seekers are more likely to experience greater positive subjective effects from oxycodone than low sensation seekers, but likelihood of experiencing negative effects is more complex (involving both sensation-seeking status and sex).
Asunto(s)
Analgésicos Opioides/administración & dosificación , Oxicodona/administración & dosificación , Analgésicos Opioides/farmacología , Femenino , Humanos , Masculino , Oxicodona/farmacología , Valores de Referencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Studies have shown that alcohol-drinking status modulates psychopharmacological effects of several drugs. We sought to determine if drinking status modulates the effects of a prescription opioid, oxycodone, in healthy volunteers. We included sex of the volunteer in the statistical analyses since this is a factor that is known to alter several pharmacodynamic effects of opioids in nonhumans and humans. METHODS: Fifteen light drinkers (eight males) and 14 moderate drinkers (eight males) participated in a crossover, randomized, double-blind study in which they received 0, 10, and 20mg of oxycodone (p.o.). Dependent measures were subjective, psychomotor/cognitive, reinforcing, and physiological effects. RESULTS: Self-reported alcohol-drinking status did not modulate the effects of oxycodone. However, there were a number of Sex x Dose interactions with females reporting more and larger unpleasant effects than males (e.g., visual analog scale ratings of "nauseated" greater in females than in males). CONCLUSIONS: Studies have established that moderate drinkers report a greater degree of abuse liability-related effects than do light drinkers with several different drugs, including diazepam, amphetamine, and nitrous oxide, but we were unable to establish this with the prescription opioid, oxycodone. However, we did observe sex differences in several subjective effects of oxycodone, a finding that is consistent with the extant literature showing sex differences in pharmacodynamic effects of opioids.
Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Analgésicos Opioides/farmacología , Etanol/farmacología , Oxicodona/farmacología , Desempeño Psicomotor/efectos de los fármacos , Caracteres Sexuales , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Náusea/inducido químicamente , Oxicodona/administración & dosificación , Oxicodona/efectos adversos , Psicofarmacología , Refuerzo en Psicología , Factores Sexuales , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
This study examined the effects of oral oxycodone, a prescription opioid, on several measures of impulsive behavior in healthy volunteers. Volunteers (n=12) participated in a four-session, double-blind, randomized design in which they received capsules containing oxycodone (5, 10, and 20 mg) or placebo. From 70 min to approximately 120 min after ingesting the capsules, subjects completed five impulsivity tasks: delay and probability discounting task, balloon analogue risk task (BART), go/no-go task, stop task, and simple reaction time test. Mood questionnaires were also completed at fixed time points in the sessions. Oxycodone produced prototypic changes in mood in a dose-related manner, but did not affect performance on any of the impulsivity tasks. Lack of effect on impulsivity stands in contrast to other studies in which other psychoactive drugs including ethanol, delta-9-tetrahydrocannabinol, and amphetamine altered behavior on one or more behavioral measures of impulsivity.
Asunto(s)
Analgésicos Opioides/efectos adversos , Conducta Impulsiva , Oxicodona/efectos adversos , Adulto , Afecto/efectos de los fármacos , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Conducta Impulsiva/diagnóstico , Masculino , Oxicodona/administración & dosificación , Pruebas Psicológicas , Recompensa , Valores Sociales , Detección de Abuso de Sustancias , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Non-medical use and abuse of prescription opioids is a significant problem in the United States. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. The purpose of this study was to directly compare the psychopharmacological profile of two widely prescribed and abused oral opioid combination products within the same subject. METHODS: Twenty non-drug-abusing volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o.: placebo; 975 mg acetaminophen (ACET); 10mg oxycodone (OXY)/487 mg ACET; 20mg OXY/975 mg ACET; 15 mg hydrocodone (HYD)/487 mg ACET; and 30mg HYD/975 mg ACET. OXY and HYD doses were chosen to equate the drugs on an objective measure of opiate effects: miosis. Dependent measures were subjective, psychomotor/cognitive, reinforcing, and physiological effects, and relative potency estimates. RESULTS: In general, the two opioid combination products at equi-miotic doses produced similar prototypic opiate-like effects and psychomotor impairment, and of similar magnitude. The higher dose of OXY/ACET produced slightly more abuse liability-related subjective effects than the higher dose of HYD/OXY, but also produced slightly more negative effects. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated that OXY/ACET was approximately 1.5 times more potent than HYD/ACET. CONCLUSIONS: Consistent with a recent study published in this journal using identical doses of HYD and OXY (without ACET) in prescription opioid abusers (Walsh, S.L., Nuzzo, P.A., Lofwall, M.R., Holtman Jr., J.R., 2008. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription drug abusers. Drug Alcohol Depend. 198, 191-202), we found little difference in the pharmacodynamic effects of HYD/ACET and OXY/ACET in non-drug-abusing volunteers.