ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02381.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

Oxazepam is the final metabolic product in vitro and in vivo of a large number of pharmacologically active benzodiazepines. Oxazepam shows antimetrazol activity varying in intensity and duration according to the animal species considered.This difference is in part related to different “sensitivity and in part due to different disposition of oxazepam. Particularly relevant is the difference in biliary excretion by various animal species. Oxazepam is currently available as a racemate but two optical isomers can be separated as succinate half esters. The (+) form appears to bc more active than the (‐) form, probably because more oxazepam is released from the (+) than the (‐) isomerin vivo. In vitro studies confirm that the liver hydrolyzes the (+) oxazcpam succinate half ester more than the (‐) form.Other work has aimed at analyzing the effects of oxazepam on brain chemical mediators, with particular reference to the cholinergic system. Finally it is shown that oxazeparn, similarly to other benzodiazepines. increased aggressiveness in male mice during chronic tr

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02382.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

Benzodiazepines influence on a number of neurotransmitters such as acetylcholine, catecholamines, serotonin, glycine and gamma‐aminobutyric acid (GABA), but during recent years the major interest has been focused on the inhibitory transmitter GABA. This paper reviews the hypothesis that benzodiazepines actviaGABA‐ergic mechanisms in the central nervous system.At NIMH in Washington D. C. a novel method to measure the turnover rate of GABA in rat brain nuclei has been developed(Bertilsson et al., J. Pharmacol. Exp. Therap.200:277, 1977). The incorporation of13C from glucose into glutamic acid and GABA was quantitated in stereomicroscopically isolated nuclei. Using this technique it was shown that the GABA agonist muscimol and diazepam have a similar action. Both drugs decreased the turnover rate of GABA in N. caudatus and accumbens, but not in globus pallidus(Mao et al., Biol. Psychiatry12:395, 1977). This gives further support to the theory that diazepam acts as a GABA‐mimetic

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02383.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02384.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

The effects of 25 mg of oxazepam, a benzodiazepine with a short half‐life and no active metabolites, were compared with placebo in two healthy volunteers in a single‐blind polygraphically recorded sleep study.The experiment lasted for 24 nights and recordings were made for 11 nights. It was found that 25 mg oxazepam induced sleep faster than placebo, and that the subjects awoke less often during the treatment period. The total amount of REM‐sleep was not affected. However, REM‐sleep was shortened during the first part of the night and extended during the latter part of the night. Slow‐wave sleep diminished differently in the two subjects, possibly due to interindividual differences in the rate of elimination of oxazepam. The effect on blood pressure was small, and the normal physiological difference between bedtime and morning blood pressure was

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02385.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02386.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

Oxazepam has the shortest half life of the benzodiazepines and does not form any active metabolites. Its pharmacokinetic properties in healthy volunteers, uremic patients and dogs are reviewed. In normal man half lives between 6 and 25 hours are obtained. The drug is completely absorbed and steady state concentrations develop after multiple doses. In uremic patients the terminal half life of oxazepam in plasma was prolonged to 24–91 hours. However the clearance of oxazepam was not significantly decreased in this patient group and similar doses as in normal subjects are recommended. There was a marked retention of the water soluble oxazepam conjugate in the uremic patients but no pharmacological effect could be detected. In the uremic patients, as in dogs, secondary plasma concentration peaks were seen after single doses. In uremic patients, fecal excretion of oxazepam was increased. In the dog one third of a single intravenous dose was recovered in the bile. Thus enterohepatic cycling may occur in the dog and in uremic patient

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02387.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

The benzodiazepines constitute a class of drugs of considerable disparity in a number of potentially clinically important ways. They are also used so widely that the characteristics of the patient population important in overall drug responsiveness vary considerably, also. The possibility, therefore, exists that one drug may have more desirable qualities than another related benzodiazepine when used in a particular group of patients. A clinical response has both pharmacokinetic and pharmacodynamic components, and as an initial exploration of the latter hypothesis the disposition of a number of benzodiazepines has been investigated with respect to the effects of aging and liver disease on the involved processes.Considerable differences exist between the drugs when studied in a group of young and old individuals aged usually below 30 and above 60 years. With diazepam and chlordiazepoxide aging leads to a 3‐ to 6‐fold prolongation in the elimination half‐life from about 20–30 hours to 60–80 hours and 6–8 hours to 30–36 hours, respectively. In both cases this involves an age‐related increase in the distribution volume, but in addition the plasma clearance of chlordiazepoxide decreases about 3‐fold. In contrast, the removal of both oxazepam and lorazepam from the body, appears to be unaffected by aging, whether expressed by the half‐life or plasma clearance.Similar differences between these drugs also exist with respect to the effects of liver disease on their disposition. Cirrhosis produces a 2‐ to 3‐fold increase in the half‐life of both diazepam and chlordiazepoxide relative to age‐matched controls. The predominant cause of this is a significant reduction in plasma clearance but the distribution of the drugs is slightly increased due to a reduction in plasma binding. Acute viral hepatitis has a similar but slightly smaller effect upon plasma clearance, which is reversible upon clinical recovery. Neither of these diseases has a significant effect on the disposition of oxazepam and lorazepam.The aging process and liver disease, therefore, affect the disposition of these closely related benzodiazepines quite differently. The fact that the pharmacokinetics of benzodiazepines which are eliminated by glucuroni‐dation are relatively unaffected by the investigated disease processes suggests that they may be more clinically advantageous than perhaps similar drugs which are oxidatively metabolized. However, well designed clinical studies including assessment of any pharmacodynamic alterations will be required to test w

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02388.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

摘要:

The transfer across the placenta and the maternal and neonatal kinetics of oxazepam and its conjugate was studied in 12 patients and their newborns.Oxazepam was readily absorbed and peak plasma concentrations were similar to those in healthy non‐pregnant volunteers. When meperidine was given within one hour of the dose of oxazepam the absorption was delayed but the bioavailability did not decrease.In the newborns the umbilical vein plasma concentration of oxazepam usually exceeded that of the conjugate. The reverse was true for all subsequent plasma samples from the newborn. The half‐life of oxazepam in the newborn averaged 22 hours as compared to 6.5 hours in the mothers. A significant rise of the plasma concentration of oxazepam conjugate was noted in three newborns during the first 6–10 hours of extrauterine life. This shows that the newborn is able to conjugate oxazepam. The Apgar score values were n

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02389.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1978.tb02390.x

出版商:Blackwell Publishing Ltd    

年代:1978

数据来源: WILEY