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PubMedDate not supplied

Clinical pharmacokinetics of chlordiazepoxide.

Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biotransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (tl/2beta) of chlordiazepoxide following single doses, in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5%. Elimination of the parent compound is mirrored by formation of the first active metabolite. Clearance of chlordiazepoxide is reduced and tl/2beta is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals. A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.

Administration, Oral↗

PubMed1979

Water intake and time course of drinking after single or repeated chlordiazepoxide injections.

Chlordiazepoxide (5.0, 10.0 or 15.0 mg/kg) was given to rats either acutely or for 9 consecutive days. Its effects were examined in a 15-min drinking test in which latency to drink, volume of water consumption and the time-course of drinking were measured. Chlordiazepoxide (10.0 mg/kg) produced the strongest stimulant effect on drinking and enhanced the frequency of occurrence of drinking both at the beginning and at the end of the test period. Chlordiazepoxide (15.0 mg/kg) delayed the onset of drinking and its peak effect was observed later than for other injection conditions. Single and repeated administration of chlordiazepoxide had the same effects on the measures taken in the test. Initial sedation to the drug treatment and subsequent tolerance to this effect were not, therefore, factors influencing the drug effects observed in this experiment. Possible mechanisms underlying the stimulation of drinking by chlordiazepoxide are considered.

Animals↗

PubMed1975

Anxiety in schizophrenia. The responses to chlordiazepoxide in an intensive design study.

Six anxious schizophrenic patients who were maintained with phenothiazines participated in a double-blind intensive design study of chlordiazepoxide and placebo for 12 weeks or longer. There were substantial differences between patients in their responses to chlordiazepoxide: two patients experienced significant and conspicuous relief of distress and reduction of typical schizophrenic symptoms. In another patient the differences, although statistically significant, were clinically less striking. In the three remaining patients no differences were observed between responses to the two treatments except that one patient was more depressed with chlordiazepoxide than with placebo. The findings suggest that there are at least two kinds of anxiety in schizophrenia. A few anxious schizophrenic patients apparently benefit more from a combination of a phenothiazine with chlordiazepoxide than from a phenothiazine alone.

Adult↗

PubMed1977

Dissociation of the anti-punishment activities of chlordiazepoxide and atropine using two heterogeneous passive avoidance tasks.

The effects of chlordiazepoxide and atropine on the acquisition of passive avoidance learning in rats were compared in two superficially similar but theoretically distinct forms of the step down task in an attempt to dissociate behaviourally the disinhibiting effects of these two classes of drug. In a discrete trial procedure both chlordiazepoxide and atropine significantly retarded acquisition; on retention testing under saline treatment alone, the initial chlordiazepoxide group showed no change in behaviour while the initial atropine group showed a facilitation. In a continuous trial procedure, however, atropine but not chlordiazepoxide produced an increase in the total number of step downs; despite this, these groups showed acquisition at similar rates, though learning was not shown on retention testing under saline alone. These results enabled the two classes of drug to be distinguished. The nature of the heterogeneity between the two test paradigms is discussed, and results interpreted in terms of possible differential drug effects on punishment and escape components of the tasks.

Animals↗

PubMed1979

A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness.

In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures. Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4. The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects.

Adult↗

PubMed1979

Effects of chlordiazepoxide on maze performance of rats subjected to undernutrition in early life.

The purpose of this research was to study the isolated effects of and interactions between undernutrition and emotional reactivity upon maze performance in rats. This work compares the effects of chlordiazepoxide on learning performance in two groups of adult rats: one undernourished early in life and then rehabilitated, and the other normally nourished. Chlordiazepoxide was used at 5 mg/kg body weight administered i.p. 30 min before each test. The response was evaluated in a Hebb-Williams maze. Water was used as reinforcement. Chlordiazepoxide improved performance in the early undernourished group 197 +/- 55.9 errors to 149 +/- 33.6 (mean +/- SD). Chlordiazepoxide impaired performance of the normal group from 107 +/- 22.7 errors to 197 +/- 42.2 errors. Analysis of variance gave an F = 6.64, which is significant (P less than 0.01). This supports the hypothesis that the high emotional level of previously undernourished subjects acts negatively upon problem-solving performance.

Animals↗

PubMed1978

Effects of chlordiazepoxide, amitriptyline, imipramine, and their combinations on avoidance behaviour in mice.

Chlordiazepoxide, imipramine, and amitriptyline, given alone or in combination, were tested in mice subjected to 5 daily 100-trial avoidance sessions in the shuttle-box. When the drugs were given alone, chlordiazepoxide and the lower doses of imipramine facilitated avoidance behaviour. The higher doses of the two antidepressants impaired avoidance behaviour. Mixtures of chlordiazepoxide and imipramine produced some facilitating effects, while depressant effects prevailed in the chlordiazepoxide-amitriptyline combinations.

Amitriptyline↗

PubMed1978

Enhanced choice of familiar food in a food preference test after chlordiazepoxide administration.

Chlordiazepoxide (5.0 and 10.0 mg/kg) increased the time spent eating familiar laboratory chow, in a food-choice test in which both familiar and novel food objects were available. Chlordiazepoxide did not affect the feeding response to the novel food. Prior handling of the rats and repeat testing affected feeding responses in the test, although in ways which were different from and independent of the effect of chlordiazepoxide. Chlordiazepoxide may facilitate feeding responses by a direct enhancement of feeding motivation, and not necessarily secondarily by either a release of suppression of feeding or as attenuation of anxiety evoked by unfamiliarity.

Animals↗

PubMed1977

Rotational behaviour and cGMP responses following manipulation of nigral mechanisms with chlordiazepoxide. Evidence for enhancement of GABA transmission by benzodiazepines.

Unilateral stereotaxic injections of 1 microgram of the soluble benzodiazepine chlordiazepoxide hydrochloride into the predominantly GABA-containing zona reticulata of the substantia nigra of amphetamine-pretreated rats induced rotational behaviour similar to that seen following unilateral elevation of nigral GABA levels and amphetamine treatment; this effect was not seen following injections into the vicinity of the predominantly dopamine-containing zona compacta. Chlordiazepoxide-induced rotations were abolished by the GABA-antagonist picrotoxin. Both chlordiazepoxide and GABA depressed production of cyclic 3',5'-guanosine monophosphate in samples of nigral tissue in vitro as estimated by radioimmunoassay. It is concluded that chlordiazepoxide may enhance GABA transmission within the substantia nigra, by some as yet unidentified mechanism, to create asymmetric activity in GABA-modulated neurones and hence induce rotation.

Aminobutyrates↗

PubMed1977

Effects of chlordiazepoxide and oxazepam administration on verbal hostility.

We compare the effects of chlordiazepoxide, oxazepam, and placebo on hostility, as both an inner motivational or potential state and verbal interpersonal behavior. This article reports the findings relevant to the latter dimension of hostility and integrates them with those findings, presented in an initial report, relevant to hostility as an inner motivational state. The verbal data again support the hypothesis that chlordiazepoxide-induced increases in verbal interpersonal hostility, following frustration, are greater than those associated with placebo. With regard to oxazepam, the verbal hostility data were consonant with the motivational data that suggested that oxazepam does not substantially disinhibit hostility but did not as consistently differentiate oxazepam and chlordiazepoxide at the level of overt hostile behavior.

Adult↗

PubMed1979

Feeding parameters with two food textures after chlordiazepoxide administration, alone or in combination with d-amphetamine or fenfluramine.

Chlordiazepoxide (5.0, 10.0 mg/kg) reduced the rate of eating and extended the duration of feeding in a 10 min feeding test. It also reduced the latency to feed. Both fenfluramine (1.0 mg/kg) and d-amphetamine (0.25 mg/kg) acted to reduce food intake, but by differing mechanisms. Fenfluramine reduced eating rate without affecting eating duration, whilst d-amphetamine reduced eating duration without reducing eating rate. The effects of chlordiazepoxide on feeding parameters were generally additive with those of either d-amphetamine or fenfluramine, whenever chlordiazepoxide was given in combination with one of the anorectic drugs. Food texture affected feeding behaviour; rats ate standard diet in pellet form faster than powdered food, although they spent longer eating the powdered food. Textural differences did not significantly interact with the changes in feeding responses induced by the 3 drugs, except that latency to eat after either d-amphetamine or fenfluramine injection, when pellets were available, was significantly prolonged. Characterising drug effects on feeding in terms of a 2-dimensional matrix of eating rate and duration is recommended, rather than relying solely on amount of food consumption as the measure of drug effects.

Animals↗

PubMed1979

Enhancement by chlordiazepoxide of the anticholinergic-induced locomotor stimulation in mice.

Spontaneous locomotor activity has been studied in mice treated with chlordiazepoxide, atropine, and scopolamine, given alone or in combination. Chlordiazepoxide alone increased activity for a short time, while the two anticholinergic drugs produced longer lasting stimulatory effects. Locomotor stimulation was stronger when chlordiazepoxide and anticholinergics were given in combination.

Animals↗

PubMed1977

Effects of chlordiazepoxide, oxazepam, chlorpromazine, and d-amphetamine on sexual responses in male and female hamsters.

The acute effects on sexual behavior of oxazepam (16--64 mg/kg), chlordiazepoxide (8--64 mg/kg), chlorpromazine (2--8 mg/kg), and d-amphetamine (0.8--3.2 mg/kg) were examined in intact male and female golden hamsters (Mesocricetus auratus). Intraperitoneal injections were given 45 min before the first behavioral test. In 10-min tests, lordosis was observed in estrous females both before and after copulation, and mounts, intromissions, and ejaculations were observed in males. Dose-response related decrements in male sexual behavior were observed following chlorpromazine and chlordiazepoxide. All dose levels of oxazepam depressed male sexual behavior. The highest dose of chlordiazepoxide and oxazepam attenuated the onset of female sexual behavior, and all dose levels reduced postcopulatory lordosis durations. Amphetamine did not interrupt either male or female sexual behavior, and chlorpromazine disrupted male but not female behavior.

Animals↗

PubMed1978

Residual effects of ethanol and chlordiazepoxide treatments for alcohol withdrawal.

Eighteen male alcoholics were randomly assigned to one of two alcohol detoxification treatments. One group received a low dose ethanol treatment while the other group received a chlordiazepoxide treatment. This study compares recovery of sleep EEG and clinical symptomatology following these two detoxification treatments. Sleep EEG and clinical measures were obtained for the final medication day and during a 6-day postmedication "recovery" period. The chlordiazepoxide treatment produced suppression of rapid eye movement (REM) sleep lasting for about 4 days and virtually eliminated delta sleep (stages III and IV) during the recovery period. The low dose ethanol treatment regimen produced less disruption of REM and delta sleep during the recovery period. These findings suggest that under some circumstances an ethanol treatment regimen may prove more beneficial to the healthy alcoholic patient than current regimens which employ other psychoactive medication. In particular, the long lasting suppression of delta sleep during the recovery period in subjects treated with chlordiazepoxide suggests a vulnerability of the slow wave sleep mechanisms during early alcohol abstinence and raises the possibility that this regimen prolongs functional tolerance to alcohol effects. Continued clinical evaluation of low dose ethanol detoxification treatment is suggested.

Adult↗

PubMed1979

Effects on learning and memory of 2-week treatments with chlordiazepoxide lactam, N-desmethyldiazepam, oxazepam and methyloxazepam, alone or in combination with alcohol.

A double-blind study with 40 healthy students was done in order to measure the effects of a 2-week treatment with chloridiazepoxide lactam (5 mg), nordiazepam (10 mg), oxazepam (15 mg) and methyloxazepam (20 mg) on immediate memory and associative learning. The drugs were administered t.i.d. and the tests were done after the very last capsule was given. It was ingested with a placebo drink and 0.5 g alcohol/kg body weight. Oxazepam and methyloxazepam alone behaved similar to the placebo. Immediate memory was significantly impaired following the treatment with nordiazepam, chlordiazepoxide lactam, alcohol, and after the simultaneous administration of nordiazepam and chlordiazepoxide lactam with alcohol. Chlordiazepoxide lactam was the only drug which alone impaired associative learning. Also alcohol alone, and all the drugs in combination with alcohol retarded learning acquisition.

Adult↗

PubMed1979

Treatment of ovine annual ryegrass toxicity with chlordiazepoxide.

The results of pen trials indicate that sheep affected by annual ryegrass toxicity can be treated successfully with chlordiazepoxide. In the first experiment, 87% of chlordiazepoxide-treated animals survived a lethal dose of toxic ryegrass. In the second experiment, 90% of chlordiazepoxide treated animals survived compared with a 10% recovery of control animals.

Animals↗

PubMed1979

Chlordiazepoxide and oxazepam disposition in cirrhosis.

When disease impairs clearance of drugs, multiple-dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy-proven cirrhosis. In the normal subjects, mean (+/- SE) kinetic parameters were: t 1/2 beta, 10.0 (+/- 0.9) hr; Vd, 0.38 (+/- 0.04) l/kg; clearance, 0.54 (+/- 0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = -0.63). Values in cirrhotic patients were: t 1/2 beta, 34.9 (+/- 8.7) hr; Vd, 0.34 (+/- 0.024) 1/kg; and clearance, 0.185 (+/- 0.34) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean t 1/2 beta for oxazepam (7.1 +/- 1.0 hr) was 27% longer than in control subjects (5.6 +/- 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.

Adult↗

PubMed1976

Kinetics and mechanisms of hydrolysis of 1,4-benzodiazepines I: chlordiazepoxide and demoxepam.

Differential absorbance spectroscopy was successfully used to follow the hydrolysis kinetics of chlordiazepoxide and demoxepam from pH 1 to 11. Loss of the methylamino group from chlordiazepoxide produced demoxepam. Demoxepam degraded by a parallel consecutive reaction to 2-amino-5-chlorobenzophenone and a glycine derivative. Two intermediates were observed by TLC for demoxepam hydrolysis. One was assigned the open-ring structure resulting from amide hydrolysis, which kinetically appears to be the major mechanistic route leading to the benzophenone product. The other intermediate, representing an alternative but minor pathway, presumably results from initial scission of the azomethine linkage. Protonation of the N-oxide slightly alters the importance of these two pathways. Recyclization of the carboxylic acid intermediate was facile at pH values below the pKa of this intermediate. The stability parameters involving buffer catalysis, ionic strength effects, and temperature dependence of rate constants are reported.

Benzodiazepines↗