Serum Concentrations Of Diazepam Research Articles

On the Use of Diazepam and Pro-diazepam (2-Benzoyl-4-chloro-N-methyl-N-lysylglycin anilide), as Adjunct Antidotes in the Treatment of Organophosphorus Intoxication in the Guinea-pig

Diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide) have been used as adjunct antidotes to pyridostigmine and atropine against the organophosphate, soman, in the guinea-pig. Both added significant protection to the pyridostigmine/atropine treatment. Animals pretreated with diazepam, 60 min before soman, were "better" protected than animals given an equimolar dose of pro-diazepam therapeutically 1 min after soman. A pretreatment with diazepam for three days further increased the protection. A therapeutic dose of pro-diazepam, 1 min after soman, gave no further protection, to the three day diazepam pretreatment. The serum concentrations of diazepam (given i.p.) and desmethyldiazepam (given i.m.) were determined by GLC after diazepam (i.p.) and pro-diazepam (i.m.) were given. The protection, relative to the control, provided by the diazepam pretreatment (60 min before and for three days before soman) correlated linearly, r = 0.9898, with the serum values of diazepam achieved at these times. Our data suggest that diazepam as adjunct to pyridostigmine and atropine administered as pretreatment gives a "safer" protection, than an equimolar dose of pro-diazepam given therapeutically.

Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects

Acute administration of diazepam (2 mg/kg i.p.) to rats decreased the number of head-dips, locomotor activity and the number of rears made in the holeboard apparatus, indicating sedative effects. After daily treatment for 7 days with diazepam (2 mg/kg) tolerance developed to all these behavioural effects, despite serum concentrations of diazepam and N -desmethyldiazepam significantly higher than those following acute treatment. After 7 drug-free recovery days the rats were quite unresponsive to a probe dose of diazepam (2 mg/kg) and although there was a gradual recovery of responsiveness to diazepam, the reduction in rears still did not reach the level of the acute group even after 21 drug-free days. There was evidence for pharmacokinetic changes when probe doses of diazepam were given after 7, 14 or 21 recovery days. Lower levels of diazepam and higher levels of N -desmethyldiazepam than following an acute dose to the drug-naive group were detected, indicating that the chronic treatment had resulted in a persistently enhanced rate of N -demethylation. It is argued that these changes do not fully account for the reduced responsiveness to the probe doses, and nor can they account for the gradual return of response over the 3-week recovery period. There were no detectable serum concentrations of either compound 24 h after the end of the chronic treatment. However, no rebound increases in behavioural responses were detected at any time-point in withdrawal. Thus, the mechanism underlying this behavioural tolerance was not oppositional in nature. It is suggested that a situation-independent learned behavioural strategy is the most likely mechanism for the observed tolerance.

Value of serum diazepam and nordiazepam measurements in anxious patients

The relationship between the dose and anxiolytic effects of diazepam and the serum concentrations of diazepam and nordiazepam were examined in groups of acutely and chronically anxious patients. The results showed a significant correlation between dose and serum nordiazepam concentrations after short-term (14-day) administration, but no significant association between clinical symptoms of anxiety and serum diazepam and nordiazepam. We conclude that the main value of serum benzodiazepine measurements in anxious patients is in assessing compliance, particularly in patients suspected of taking more than the recommended dose. Serum nordiazepam is a more consistent index of dosage after chronic therapy than serum diazepam because it has a longer elimination half-life.

Absorption of diazepam in man following rectal and parenteral administration.

Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121--200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62--186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50 +/- 17 per cent (mean +/- S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.

RECOVERY AND SKILLS RELATED TO DRIVING AFTER INTRAVENOUS SEDATION: DOSE-RESPONSE RELATIONSHIP WITH DIAZEPAM

Skills related to driving, the ability to discriminate the fusion of flickering light, and hand and foot proprioception, were measured double-blind in 34 healthy volunteers before and after three doses of i.v. diazepam. The effects of diazepam were most harmful to co-ordination. With 0.15 mg/kg, 0.30 mg/kg and 0.45 mg/kg of diazepam the impairment of co-ordinative skills was statistically significant (P less than 0.05) up to 2, 6 and 8 hr respectively. No impairment of performance on any test was measurable at 6 hr after 0.15 mg/kg or at 10 hr after 0.30 or 0.45 mg/kg of diazepam. There were large interindividual variations in serum concentrations of diazepam within each dose level. The increases in serum concentrations of diazepam after the intake of food support the concept of an enterohepatic cycle for diazepam. It was concluded that patients should not drive or operate machinery for at least 6 hr after 0.15 mg/kg of i.v. diazepam and at least 10 hr after 0.30 mg/kg and 0.45 mg/kg.