Deuterium labeled methadone and deuterium labeled metabolites were synthesized to use in gas chromatography mass spectrometry (GCMS) studies of the metabolic pathways of metha-done in rats. These compounds were also useful to develop sensitive and selective analytical methods to study the pharmacokinetics and disposition of methadone. Synthesis of the deuterium labeled compounds was mainly achieved by using known procedures with special treatments required to provide label enrichment. Using the labeled and unlabeled derivatives, mass fragmentation processes that are common to methadone and its metabolites were defined. Aryl ring migration was observed in a fragmentation process for 2-ethylidene-l,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP). This aryl ring migration was not a favorable process for ring substituted EDDP analogs. Various aspects regarding the optimization of the selected ion monitoring (SIM) analysis of methadone and its metabolites in biological fluids are described. The SIM analysis using deuterium labeled compounds as internal standards generally proved to be selective but not as sensitive as expected using electron impact ionization (EI) conditions of GCMS. One advantage of using SIM over GC analysis was described in terms of ratio analysis. Quantitation of methadone in human plasma and saliva using SIM gave a lower limit of sensitivity of 20 ng/0.5 ml of sample by monitoring the base peak, m/e 72. The mean methadone ratios of saliva to plasma for two patients were 0.55 ± 0.15 (standard deviation) and 0.48 ± 0.10 (standard deviation). Methadone metabolism studies emphasized the detection of minor metabolites using special extraction methods for rat bile and using labeled and unlabeled compounds. Comparison of the mass spectra from total ion current (TIC) profiles of metabolites from unlabeled compounds with those from labeled compounds run as separate experiments gave GCMS evidence for methadone nitrone (N-methylene-l-methyl-3,3-diphenyl-4-oxo-hexanamine-oxide). Possibilities for the metabolic formation of N-hydroxynormethadone and the pharmacological significance of the detection of methadone nitrone were described. A proposal for metabolic studies to examine the potential formation of other methadone metabolites resulting from metabolic oxidation of nitrogen was presented. Structural evidence for the methadone nitrone molecule was obtained indirectly by chemical oxidation studies of metha done metabolites. m-Chloroperbenzoic acid treatment of EDDP perchlorate gave three products: methadone nitrone, 4,4-diphen yl-2,5-heptanedione (diketone), and 2-acetyl-5-methyl-3,3-di-phenyl-l-pyrroline. These compounds were identified from their IR, NMR and mass spectral data. Mass fragmentation processes were defined for the methadone nitrone. Possible mechanisms for the formation of methadone nitrone and diketone from chemical oxidation of EDDP are proposed. Since diazepam is a drug widely abused by methadone maintenance patients, methadone-diazepam interaction studies were designed to analyze metabolites using deuterium labeled authentic compounds as internal standards. Metabolites in the conjugated fraction of rat bile were analyzed using deuterium labeled biosynthetic internal standards. Diazepam (5 mg/kg) was given to rats through a cannulated jugular vein and a subcutaneous dose of methadone (10 mg/kg) was given. Bile was collected through the cannulated bile duct over a period of 24 hours. The deuterium label was found to be stable even under severe conditions of incubation temperature and time. SIM analysis of bile sample extracts showed that concomitant administration of diazepam with methadone did not affect biliary excretion of EDDP nor the conjugated metabolites. This indicates that diazepam does not interact with methadone at the hepatic metabolism level and with transport of the metabo-: lites by the biliary excretion route. Application of the use of a biosynthetic internal standard to drug metabolism and pharmacokinetic studies by means of ratio analysis was described with examples. / Pharmaceutical Sciences, Faculty of / Graduate

by Yiu-kuen Kam. / Bibliography: leaves 108-118 / Thesis (M.Phil.) -- Chinese University of Hong Kong, 1983

Fatal and non-fatal opioid overdoses resulting from opioid induced respiratory depression are a significant problem throughout the world. Whilst the opioid receptor antagonist, naloxone hydrochloride, can effectively reverse opioid overdoses, its use is limited because of the adverse effects it produces. These include severe withdrawal and the reversal of analgesia produced by opioid receptor agonists. In this project, the peripherally acting opioid receptor antagonist, naloxone methiodide, was investigated for its potential to reverse opioid induced respiratory depression without altering centrally mediated effects, such as withdrawal. In the publications presented in this thesis, naloxone hydrochloride and naloxone methiodide were shown to effectively reverse the decreases in respiratory rate produced by the administration of morphine, methadone and heroin in mice. Naloxone hydrochloride and naloxone methiodide also reversed the analgesia produced by these opioid receptor agonist treatments, but only naloxone hydrochloride induced significant withdrawal. The doses of naloxone methiodide required to produce the effects described above were higher than the naloxone hydrochloride doses required. Radioligand binding techniques indicated that this was due to a difference in the affinity of naloxone hydrochloride and naloxone methiodide for µ, δ and κ opioid receptor binding sites. Radioligand binding techniques were also used to confirm that naloxone methiodide, or its metabolites, could not readily cross the blood brain barrier. Therefore, the effects of naloxone methiodide appear to be mediated outside the central nervous system. The final publication aimed to extend our knowledge of opioid induced respiratory depression by utilising new radiotelemetry technology to test the efficacy of naloxone methiodide in rats subjected to a chronic opioid administration regime. This experiment showed that circadian rhythm plays a role in the development of tolerance to the cardiorespiratory effects of continuous and chronic methadone administration, and that naloxone hydrochloride and naloxone methiodide treatment can increase respiratory rate and heart rate after this methadone administration. Therefore, naloxone methiodide can effectively antagonise the peripheral effects produced by opioid receptor agonists. Peripherally acting opioid receptor antagonists should be developed in the future to prevent or treat the adverse effects of opioid receptor agonists. / Thesis (Ph.D.)--Department of Clinical and Experimental Pharmacology, 2004.

Methadone treatment continues to be the most widely used treatment modality for heroin addiction despite continued controversy. The efficacy of methadone treatment has been determined primarily by statistical research of program outcomes. This study explored heroin addicts' perceptions of methadone treatment.

Tho present thesis represents a summary or research done by the author (and others) that was conducted with heroin addicts and drug abusers undergoing behavioral and pharmacological therapy at Stockton State Hospital, Stockton, California. From June 1970 to December 1970 the Research Department of Stockton State Hospital, in conjunction with the Drug Abuse Program at Stockton State Hospital, conducted research investigating a number of difference facets relating to inpatient programs for heroin addicts undergoing methadone maintenance and drug abusers. These facets included the investigation and evaluation of (a) motivational factors; affecting the voluntary participation of inpatient heroin addicts and drug abusers in behavioral and pharmacological therapy, (b) the effectiveness of the synthetic narcotic methadone hydrocloride as a primary reinforcing technique for appropriate behavior, (c) the effectiveness of various therapeutic approaches used in conjunction with behavioral modification techniques, and (d) the effect of methadone on perceptual and motor functioning in the heroin addict under-going methadone maintenance. The present thesis is a compilation cf these research projects.

Submitted by Maria Eneide de Souza Araujo (mearaujo@ipen.br) on 2017-03-10T16:49:56Z No. of bitstreams: 0 / Made available in DSpace on 2017-03-10T16:49:56Z (GMT). No. of bitstreams: 0 / A saúde do meio ambiente vem sendo comprometida devido ao descarte incorreto de produtos e seus subprodutos. Dentre os contaminantes emergentes encontram-se os fármacos, causadores de problemas ambientais por serem descartados no meio ambiente através dos efluentes. As técnicas convencionais de tratamento são insuficientes na remoção de diversos fármacos, por apresentarem resíduos resistentes e baixa biodegradabilidade. Sendo assim os processos oxidativos avançados vêm sendo estudados como alternativa para o tratamento de diferentes tipos de efluentes. O objetivo desse trabalho foi aplicar o processo de irradiação com feixe de elétrons para reduzir os efeitos tóxicos do propranolol, e de sua mistura com cloridrato de fluoxetina, em solução aquosa. Foram realizados ensaios ecotoxicológicos com o fármaco propranolol, e de sua mistura com o cloridrato de fluoxetina, utilizando como organismos-teste o microcrustáceo Daphnia similis, e a bactéria Vibrio fischeri. Observamos que o organismo D. similis mostrou-se mais sensível as amostras de fármacos quando comparado à bactéria V.fischeri. Após serem submetidas ao tratamento com radiação ionizante, todas as doses aplicadas para o propranolol e a mistura, mostraram significativa redução de toxicidade, tendo como organismo-teste D. similis. Para a bactéria V. fischeri apenas na dose de 5,0 kGy foi verificada a redução da toxicidade para o fármaco propranolol. Quanto à mistura dos fármacos, apenas as doses de 2,5 e 5,0 kGy apresentaram eficiência de remoção da toxicidade. A dose 5,0 kGy mostrou-se a melhor, apresentando redução de 79,94% para D. similis, e 15,64% para V. fischeri, quando expostas ao fármaco propranolol. Quanto à mistura, apresentou 81,59% e 26,93%, para D.similis e V.fischeri, respectivamente. / Dissertação (Mestrado em Tecnologia Nuclear) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP