Substitution of deuterium for the N-methyl hydrogens of morphine produced a significant reduction in the potency and lethality of morphine in mice regardless of the route of administration. There was no effect on the time of onset, maximal effect, or duration of action. N-demethylation by rat liver microsomal enzymes was characterized by a smaller reaction rate constant, a higher energy of activation, and a larger Michaelis constant with respect to the deuterated morphine. These findings indicated that deuteration of the N-methyl group of morphine not only caused reduction in potency, but also a reduction in the rate of oxidative N-demethylation, and a distinct weakening of the binding to the enzyme active centers.

No abstract

No abstract

The benzodiazepine derivatives exert many actions on the central nervous and cardiovascular systems that are characteristic of the sedative-hypnotics. 7 The compound lorazepam [7-chloro-5-( o-chlorophenyl) -1,3,dihyro-3-hydroxy-2H-l,4-benzodiazepin-2-one], which differs from oxazepam only in that it has CI in the ortho position on the 5-phenyl ring, has shown in experimental animals pharmacologic properties comparable to those of others in the benzodiazepine series (Formula 1), e.g., as an antianxiety agent, it is 20 times as potent and as an anticonvulsant it is 10 to 50 times as active as chlordiazepoxide.1I

The metabolism of lorazepam by man and four other species is reviewed. Lorazepam and its metabolites in blood, urine and faeces were identified by thin-layer and gas chromatography and by mass spectrometry. The principal metabolite in man, dog, pig and cat is the glucuronide, but the rat produces other metabolites after small doses of lorazepam, and significant amounts of the glucuronide only after high doses. Since all metabolites, except the glucuronide, occur in small quantities only in man, most studies in man have been confined to an estimation of gree and conjugated lorazepam. Blood concentrations of unconjugated lorazepam peak at 1-4 h, significant concentrations persisting for 24 h and decreasing slowly over the next 24 h. About 95% of a dose of lorazepam was accounted for in urine and faeces over a period of 5 days; 74.5% was excreted in the urine as lorazepam glucuronide and 13.5% as minor metabolites. The excretory half-life was 12 h. The blood concentrations and excretion rates are compatible with the clinical effects of lorazepam.

The effects of heroin given to human subjects by continuous intravenous infusion are described. Progressive CNS depression eventually required reversal with levallorphan. There was no indication of development of acute tolerance to the depressant effects of heroin. Blood and urine specimens were collected for analysis of metabolites and analyzed for morphine, 6‐monoacetylmorphine, and heroin by gas‐liquid chromatography. Blood concentrations were too low to identify any heroin or metabolites, but about fifty per cent of the dose was recovered in the urine mostly as bound morphine with small amounts of 6‐monoacetylmorphine and heroin present in some specimens. Rate of excretion of total morphine indicated that man can metabolize about 6 mg. per 93 Kg. per hour of heroin.

Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.

Fate and Relationship of N-Methyl to Activity of Morphine 237 This material gelled in most organic solvents, but was recrystallized from about 5 1. of dioxane 3 times and once from 3.5 1. of chloroform to obtain white waxy crystals, m.p. 120-122°. Other close analogs showed the same tendency to gel in most organic solvents at conventional concentrations.Acknowledgments.-We are grateful to Dr. D. B. Seeley for the fermentative preparation of the epoxy-succinic acid, to Dr. S. Y. P'an for measuring hypnotic activities, to Joseph Kaiser for toxicity determinations, to Dr. Arthur English for the antifungal tests, and to Charles Scott for technical assistance. Insecticide tests were done at the Wisconsin Alumni Research Foundation.