The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.
The means for rating dependence to narcotic drugs and determining the severity of physical dependence is examined, using the administration at 0
During disulfiram therapy erythrocyte aldehyde dehydrogenase (ALDH) was fully inhibited. The time for total loss of erythrocyte ALDH activity ranged from 36 to 120 hr. In contrast to the 85% recovery of in vitro disulfiram-inhibited ALDH activity, this in vivo disulfiram-ALDH inhibition could not be reversed by mercaptoethanol. It is proposed that the in vivo and in vitro mechanisms of ALDH inhibition by disulfiram differ. Erythrocyte ALDH activity can be readily monitored to determine patient compliance and is an accessible model for investigations of in vivo mechanisms of drug inhibition. Because the disulfiram-inhibited erythrocyte ALDH is not regenerated until new erythrocytes are made (120 days), a significant portion of the extrahepatic acetaldehyde metabolic capacity remains inhibited for long periods after disulfiram is discontinued. Thus, the recidivistic patient who discontinues disulfiram and waits several days (to regenerate liver ALDH activity) before drinking will be exposed to even higher ethanol-derived blood acetaldehyde levels than usual, which may induce further alcohol-associated organ damage and alcohol dependence.
Naloxone and naltrexone are antagonists to the narcotic analgesics. Our interest in the metabolism of these two compounds has been stimulated by our observation of species differences in metabolic disposition. For naloxone ( Fig. 1, I) we have that in man (1) and the rabbit (2), one metabolite formed is naloxone-3-glucuronide. In the chicken (2), the major metabolite is N-allyl-14-hydroxy-7,8 -dihydronormorphine -3 -glucuronide where the 6-keto group of naloxone has been reduced. More recently, Cone et al. ( 3 , 4) and we (5) have found that naltrexone ( Fig. 1, 11) is reduced in man to give N-cyclopropylmethyl -14 -hydroxy -7,8 -dihydronorisomorphine. The reduction of the 6-keto group yielded a product with a 6P-OH configuration. In the chicken, the reduction gave the 6a-OH product(5). Since all of the commercially available 6-OH morphine type compounds are of the CY epimer form, the formation of the 6P-OH epimer as a metabolite is of particular interest in view of the possible pharmacologic activity that such products may possess.The purpose of this paper is to present a method for enzymatically producing limited quantities of the 6P-OH epimers. The result of testing these compounds in morphine dependent mice for narcotic antagonist action is also described.Methods. Biosynthesis of N-allyl-14-hydroxy-7,8-dihydronorisomorphine (111) and N-cyclopropylmethyl-14-hydroxy-7,8-dihydronorisomorphine (IV) . The partial characterization of an enzyme system from the liver cytosol of rabbits has been described by Pollock and Fujimoto (6). This enzyme system used to reduce naloxone and naltrexone consisted of the following in each of lThis study was supported by USPHS Grant Nos. DA 00451 and SAODAP, DA 00458.four flasks : 290 pmole glucose-6-phosphate, 0.5 pmole NADP; 5 units glucose-6-phosphate dehydrogenase; 0.8 ml 0.05 M KH2P04/NaOH buffer, pH 7.4; 40 pmole naltrexone or naloxone; 0.5 ml rabbit enzyme preparation; final volume 3 ml. The rabbit enzyme preparation was made by homogenizing 57 g of liver in 114 mlO.05 M phosphate buffer, pH 7.9, taking all of the 100,OOOg supernatant and performing an ammonium sulfate fractionation. The protein fraction precipitating between 45 to 65 % saturation with ammonium sulfate was isolated as a pellet; this pellet was suspended in 5 ml of 0.005 M phosphate buffer, pH 7, and used as stated above. After incubation of the flasks at 37" for 3 to 5 hr in a Dubnoff shaker, the mixture was adjusted to pH 8.5 (by adding sodium hydroxide solution until basic and dissolving about 1 g of NaHCOJ and the alkaloids were extracted with ethyl acetate. The subsequent procedures for isolating the 6P-OH epimers were like those described for isolation of the 6a-OH epimers from an in vitro hepatic enzyme preparation of the chicken (5). About 6 mg each of I11 and IV were obtained as the hydrochloride salt.Nuclear magnetic resonance spectra and gas chromatographic analysis. The NMR procedure and instrument used were those described previously ( 5 ) for characterizing the human and chicken metabolites.Fo...
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