Chlordiazepoxide Treatment Research Articles

Gabapentin Versus Chlordiazepoxide for Outpatient Alcohol Detoxification Treatment

Benzodiazepines are used to treat alcohol withdrawal (AW) but cause cognitive impairment, sedation, and ataxia, and interact with alcohol. Nonbenzodiazepine anticonvulsants are promising and possibly safer alternatives for the treatment of AW. To compare follow-up measures of Epworth Sleepiness Scale (ESS), Penn Alcohol Craving Scale (PACS), ataxia rating, and Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) symptoms between alcohol-dependent individuals randomized to treatment with gabapentin or chlordiazepoxide. A randomized, double-blind study was conducted in US veterans with alcohol withdrawal (DSM-IV criteria). Subjects requiring hospitalization or taking benzodiazepines or nonbenzodiazepine anticonvulsants were excluded. Twenty-six participants were randomized: 17 received gabapentin and 9 received chlordiazepoxide. Gabapentin doses were 1200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each. Chlordiazepoxide doses were 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each. CIWA-Ar, ESS, PACS scales and evaluation for ataxia were administered daily. Follow-up mean ESS and PACS scores did not differ significantly between treatment groups in the early treatment period (days 1-4) but were lower (mean difference -3.70; 95% CI -7.21 to -0.19; p = 0.04) and (mean difference -6.05; 95% CI -12.82 to 0.72; p = 0.08), respectively, at the end of the treatment period (days 5-7) in gabapentin-treated subjects. CIWA-Ar scores were reduced similarly in both groups. Ataxia was not observed. No significant adverse events were noted. Limitations include our small sample size and 35% loss to follow-up at the end of the treatment period. In ambulatory veterans with symptoms of alcohol withdrawal, gabapentin treatment resulted in significantly greater reduction in sedation (ESS) and a trend to reduced alcohol craving (PACS) by the end of treatment compared to chlordiazepoxide treatment. Although limited by the small sample size, the suggestion of reduction in sleepiness and less craving warrants replication of the study with a larger sample.

Effect of Restraint Stress Duration on Humoral Immune Response in Albino Rats: Modulation by Chlordiazepoxide

We evaluated the effect of restraint stress (1hr/day) for 6, 10, 14 and 21 days on antibody response against sheep RBC (SRBC) and modulation by chlordiazepoxide (CDP) pretreatment (10 mg/kg/day) in albino rats. Anti-SRBC titer was significantly decreased with increase in number of days of restraint stress exposure. CDP pretreatment significantly reversed the effects of 6, 10 and 14 (but not of 21) days of restraint stress. CDP treatment for 21 days per se suppressed immune response, but no additive effect was observed. CDP was not effective in chronic stress (i.e., 21 days of stress). Hence, the rationale behind benzodiazepines therapy in chronic stress needs to be evaluated.

Prevention by L-Arginine/Nitric Oxide of Chlordiazepoxide-Induced Toxic Reactions in the Rat Salivary Gland

The effects of chlordiazepoxide, L-Arginine (nitric oxide precursor), L-NAME (nitric oxide synthesis inhibitor), and concurrent treatment of these drugs on concentration of salivary total protein, calcium, sodium, potassium concentrations, amylase activity, and flow rate in rats were studied. Total saliva was collected 2 hours postintraperitoneal administration of chlordiazepoxide (5 mg/kg), L-Arginine (250 mg/kg), and L-NAME (10 mg/kg) intraorally by polyethylene cannula from anaesthetized rats for 30 min using pilocarpine (6 mg/kg) as secretagogue. Chlordiazepoxide reduced flow rate to 43%, total protein concentration to 30%, calcium concentration to 33%, and amylase activity to 33% of control. Potassium and sodium levels were not affected by chlordiazepoxide. L-Arginine increased flow rate to 10%, total protein to 65%, and calcium to 17%, while L-NAME decreased flow rate to 9%, total protein to 55%, and calcium to 25%. Concurrent treatment of rats by chlordiazepoxide plus L-Arginine or L-NAME influenced chlordiazepoxide-induced alterations in saliva composition. The inhibitory effects of chlordiazepoxide on salivary flow rate, amylase activity, and concentrations of total protein and calcium were blocked by L-Arginine while potentiated by L-NAME coadministrations.It is concluded that benzodiazepines induce toxicity in salivary gland function by disturbing the homeostasis of inositol triphosphate and Ca homeostasis in the cells. Administration of L-Arginine prevents benzodiazepine-induced toxicity most probably through its vasoregulatory action and balancing intracellular Ca homeostasis.

A population-based case–control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities

The objective of the study was to check the human teratogenic potential of oral chlordiazepoxide treatment during pregnancy at the analysis of pairs of 22,865 cases with congenital abnormalities (CAs) and 38,151 matched healthy controls in the population-based data set of the Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA) between 1980 and 1996. Two hundred and one (0.9%) case mothers and 268 (0.7%) control mothers had chlordiazepoxide treatment during pregnancy, respectively. Our analysis showed higher odds ratio (OR) with 95% confidence interval (CI; 2.5, 1.0–6.0) for chlordiazepoxide use during the 2nd–3rd month of gestation in the group of congenital cardiovascular malformations. However, this association was found when exposure data were based mainly on maternal self-reported chlordiazepoxide treatments (80% in cases and 71% in controls). There was no increase in the rate of any specific congenital cardiovascular malformation type. In conclusion, therapeutic doses of chlordiazepoxide during pregnancy are unlikely to pose a substantial teratogenic risk to the human fetus, although a somewhat higher rate of congenital cardiovascular malformations cannot be excluded.

State-dependent behavioural sensitization: evidence from a chlordiazepoxide state.

The present study investigated the hypothesis that behavioural sensitization to psychomotor stimulants is expressed only if the internal state of the animal is the same as it was at the time of sensitization development. This state-dependency hypothesis has previously been put forward to explain the apparent blockade of sensitization by N-methyl-D-aspartate (NMDA) receptor antagonists. The present study used amphetamine (0.375 mg/kg) as the stimulant and chlordiazepoxide (CDP) as a secondary stimulus. Mice were given double injections of either amphetamine + CDP, amphetamine + saline, CDP + saline, or saline + saline daily over 8 days. On the ninth and tenth days, all mice were challenged with amphetamine + saline and with CDP + saline, in a counterbalanced design. CDP does not show evidence of locomotor sensitization and does not act at NMDA receptors, but in other studies it has been shown to give rise to state-dependent-like effects. Thus any progressive augmentation of the response to repeated amphetamine + CDP treatment would be attributable to amphetamine sensitization, and any blockade of sensitization would not be due to NMDA receptor antagonism. Both groups receiving amphetamine became sensitized over the first 8 days (shown by progressive increases in locomotion). When challenged with amphetamine alone, the amphetamine + CDP group failed to show a sensitized response. This observation supports the state-dependency hypothesis and emphasizes the importance of considering the context provided by drug-induced internal states in studies of sensitization.

Repeated administration of flumazenil does not alter its potency in modifying schedule-controlled behavior in chlordiazepoxide-treated rhesus monkeys.

Previous reports have suggested that the effects of the benzodiazepine antagonist flumazenil diminish over repeated exposure in subjects treated chronically with a benzodiazepine agonist. The current study examined whether the frequency of exposure to flumazenil altered its potency in decreasing rates of responding in monkeys treated with chlordiazepoxide (CDP). Three monkeys responded under a multiple fixed ratio (FR10:FR10) schedule of food presentation and stimulus-shock termination (SST). In untreated monkeys, flumazenil (0.1-3.2 mg/kg) had no effect in either component. After 2 weeks of treatment with 32.0 mg/kg per day of CDP, flumazenil decreased response rates in the food component, with a dose of 3.2 mg/kg decreasing rates to 10% of control; rates in the SST component were not altered by flumazenil. When flumazenil dose-effect curves were redetermined at 28-, 14-, 7-, 4-, 2- or 1-day intervals, there was no further change in the potency of flumazenil in decreasing food-maintained responding. When CDP treatment was terminated, the potency of flumazenil recovered to pre-CDP values within 23 days. These results suggest that dependence develops to CDP, since changes in the potency of flumazenil co-varied with CDP treatment. Moreover, it does not appear as though results from previous reports, that showed a diminished response to frequently-administered flumazenil, can be generalized to all conditions.

Discriminative Stimulus Effects of Flumazenil in Rhesus Monkeys Treated Chronically With Chlordiazepoxide

Discriminative stimulus effects of the benzodiazepine antagonist flumazenil were studied in two rhesus monkeys receiving 3.2 mg/kg/12 h of chlordiazepoxide while discriminating between vehicle and 0.056 mg/kg of flumazenil. In a drug discrimination component responding was maintained under a FR 10 schedule of stimulus-shock termination; in a non-discrimination component responding was maintained under a FR 10 schedule of food presentation. Flumazenil and Ro 15-4513 occasioned >80% flumazenil-lever responding at doses larger than 0.032 and 0.056 mg/kg, respectively. Pentylenetetrazole, ethyl-β-carboline-3-carboxylate (βCCE), ketamine and spiradoline failed to substitute for flumazenil although >80% drug-lever responding was observed for two of the compounds in one monkey. Flumazenil, Ro 15-4513, pentylenetetrazole, βCCE but not ketamine or spiradoline decreased rates of responding in the food component at doses that had little effect on rates in the stimulus-shock termination component. When chlordiazepoxide injections were discontinued and saline was administered before the session, monkeys did not respond on the flumazenil lever; when flumazenil was administered under the same conditions, monkeys responded on the flumazenil lever despite not having received chlordiazepoxide for nine days. Drug stimulus control was established with flumazenil in monkeys receiving chlordiazepoxide and substitution studies suggest that this effect of flumazenil might result from antagonist actions at benzodiazepine receptors; however, lack of withdrawal-related effects after termination of chlordiazepoxide treatment precludes validation of this procedure for studying benzodiazepine dependence.

Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA receptors.

Repeated administration of benzodiazepines has been reported to produce tolerance in animals and humans. Using an elevated plus-maze test and an autoradiographic technique, we investigated whether repeated administration of chlordiazepoxide produced tolerance to its anxiolytic effects, and whether such repeated administration altered benzodiazepine and GABAA receptors. Tolerance to the anxiolytic effect of chlordiazepoxide was produced when it was administered at a dose of 30 mg/kg (i.p.) once a day for 10 and 14 days. In the quantitative autoradiographical study, although repeated chlordiazepoxide treatment had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, such treatment reduced [3H]muscimol binding to GABAA receptors in the cortex, caudate putamen, and hippocampus. These results suggest firstly, the production of tolerance to the anxiolytic effects of chlordiazepoxide, and, secondly, that this tolerance may be due to the down-regulation of GABAA receptors, but not of benzodiazepine receptors.

Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats.

This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal--so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT3 antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at doses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT3 antagonist ondansetron (0.01-0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT3 antagonists may have relatively limited utility in treating some signs of BZ dependence.

Evaluation of the dependence potential of the selective 5-H1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal

Two initial studies investigated: i) the effects of withdrawal from ipsapirone [a putative non-benzodiazepine (BZ) anxiolytic] and chlordiazepoxide (CDP); and ii) effects of ipsapirone in animals withdrawn from CDP. Rats were injected b.i.d. for 21 days with saline, ipsapirone or CDP at doses up to 40 mg/kg/injection. Subsequently, controls received the treatment administered previously, other subjects received saline during withdrawal from ipsapirone or CDP. Further subjects received ipsapirone (3, 10 or 30 mg/kg b.i.d.) during CDP withdrawal. Withdrawal indices recorded were body weight and food intake. Withdrawal signs were absent after ipsapirone treatment but present after CDP treatment, when food intake and bodyweight measures fell and then recovered. At the high dose of 30 mg/kg (b.i.d.) ipsapirone potentiated CDP withdrawal signs. Potentiation of withdrawal was not seen in animals treated with ipsapirone at lower doses (3 and 10 mg/kg, b.i.d.). In a subsequent study we found that ipsapirone conditioned a taste aversion, a possible index of drug-induced "malaise", at doses as low as 7.5 mg/kg. Therefore a possible explanation for the potentiation of BZ withdrawal in subjects treated with high doses of ipsapirone was that drug-induced "malaise" reduced food intake and body weight, rather than ipsapirone causing true potentiation of BZ withdrawal. However, in a further study we showed that the ipsapirone treatment regime which potentiated BZ withdrawal did not significantly reduce food intake or body weight, suggesting that high doses of ipsapirone potentiate BZ withdrawal by a mechanism that does not simply involve "malaise".(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of buspirone and chlordiazepoxide on plasma catecholamine and corticosterone levels in stressed and nonstressed rats

The effects of intragastric administration of the prototypical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. Acute dosing of CDP (1–27 mg/kg) produced dose-related increases in basal CS secretion but was without effect on basal NA levels. The high dose of CDP caused a slight short-term A increase. Dose-dependent increases in plasma A, NA and CS contents were observed after acute treatment with BUSP (2 and 20 mg/kg). A medium dose of CDP (9 mg/kg) attenuated the stress-induced CS and A elevations. High doses of CDP that elevated basal CS release prevented a further increase of CS by stress and inhibited the NA and A response to stress. BUSP (2 and 20 mg/kg) was not effective in decreasing the stress-elicited rise of CS, NA or A. Conversely, the 20 mg/kg dose of BUSP enhanced the stress-induced A response. Repeated administration of CDP (9 mg/kg/day for six days) produced tolerance to the elevation of basal CS triggered by acute CDP treatment, but increased the efficacy of the drug's CS and A attenuating action in stressed rats. Repeated administration of BUSP (2 mg/kg/day for six days) also produced tolerance to the acute BUSP-induced effect on basal CS release, but did not affect the stress-induced CS, NA and A responses. It is concluded that the clinically effective anxiolytic BUSP does not have the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the present data support other evidence that activation of 5-HT 1A receptor mechanisms increases plasma catecholamine and corticosterone concentrations.

Chronic treatment with ethanol or chlordiazepoxide alters the metabolism of chlordiazepoxide

Although chronic ethanol administration in C57BL/6J mice did not cause an induction of ethanol metabolism, it altered the metabolism of chlordiazepoxide (CDP). Significantly lower blood levels of CDP, but higher levels of N-desmethyl CDP (NDCDP), were observed in ethanol-dependent mice compared to pair-fed controls during the first hour after CDP injection. Mice treated chronically with CDP showed significantly lower blood levels of CDP and NDCDP than pair-fed controls after a test dose of CDP. In response to an injection of ethanol, the CDP-dependent mice had lower blood alcohol levels (BAL) than the pair-fed controls, but the rate of fall of BAL was not different in the two groups. Thus, chronic CDP treatment affected the absorption and distribution of ethanol. These results provide a metabolic basis for the manifestations of CDP tolerance and ethanol cross-tolerance that have been reported in CDP-dependent mice.

Interaction of Psychoactive Drugs with Exposure to Electromagnetic Fields

Evidence has previously been presented to show that the dopamine (DA) and opiate systems of the brain, in part, mediate the effects of exposure to electromagnetic (EM) fields. The hypothesis was broadened to predict that low-intensity EM energy exposure would interact with naloxone, chlor-diazepoxide and haloperidol treatment in tests using analgesia and stereotypic behavior. In the set of experiments reported here, the data obtained indicated there were such interactions.One implication of the dopamine-opiate hypothesis is that EM energy exposure would likely affect the hypothalamic set-point for body temperature regulation. Substantial evidence for this view now exits. This theory and data indicate that body temperature rise with exposure is likely to be a consequence of the energy affecting the dopamine-opiate systems of the brain.

Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity

Rats displayed a reduction in the percentage of time spent on the open arms of the elevated plus-maze 24–30 hours after withdrawal from chronic chlordiazepoxide treatment (10 mg/kg/day IP for 4 weeks). This indicated an anxiogenic response in this test. This anxiogenic response was not significantly reversed by DL-propranolol (5 and 10 mg/kg IP) or clonidine (0.02 and 0.04 mg/kg IP). These results provide no evidence to suggest that the anxiogenic effects of chlordiazepoxide withdrawal are mediated by an increase in noradrenergic activity. The possible involvement of multiple transmitter systems in benzodiazepine withdrawal symptomology is discussed.

Pentylenetetrazole‐like stimulus is produced in rats during withdrawal from ingested chlordiazepoxide

AbstractThe present study was undertaken to determine whether withdrawal from chlordiazepoxide administered via a liquid diet would produce a pentylenetetrazole (PTZ)‐like stimulus. Rats were trained with food reward in a two‐lever operant task. Presses on one lever were reinforced after injections of PTZ (20 mg/kg, i.p.) and on the other lever after saline (1 ml/kg, i.p.). After rats had acquired the PTZ discrimination, training was halted, and chlordiazepoxide (240 mg/kg/day) was administered via a nutritionally balanced liquid diet to three groups of rats for 3, 4, or 6 days. Upon termination of chronic administration, withdrawal was precipitated with the benzodiazepine receptor blocker flumazenil (Ro 15‐1788) given intraperitoneally. During precipitated withdrawal, the rats selected the PTZ‐appropriate lever, indicating the presence of a PTZ‐like stimulus, and this stimulus was blocked by phenobarbital (80 mg/kg, i.p.). The percentage of rats selecting the PTZ‐appropriate lever depended on the duration of chlordiazepoxide treatment and dose of flumazenil. At 10 days after the last chlordiazepoxide dose, the rats had recovered baseline discrimination, as indicated by their selection of the saline appropriate lever following saline injections and the PTZ‐appropriate lever following PTZ. These data indicate that a subjective effect of withdrawal similar to that produced by the anxiogenic drug PTZ is present during withdrawal from oral chlordiazepoxide.

Plasma opioids in alcoholics after acute alcohol consumption and withdrawal.

Beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) plasma concentrations were examined in ten chronic alcohol abusers, eight men and two women aged 25-56 years with histories of continuously elevated ethanol consumption dating from 5-30 years. Plasma levels of the two peptides were measured after acute alcohol consumption and then after 3, 6 and 9 days of forced abstinence, during chlordiazepoxide treatment. Beta-EP and beta-LPH concentrations were normal on all four occasions. A reduced sensitivity of opioid receptors to acute alcohol administration due to chronic alcohol consumption is suggested.

Maternal aggression towards different sized male opponents: Effect of chlordiazepoxide treatment of the mothers and d-amphetamine treatment of the intruders

Lactating female rats vigorously attack equally sized conspecific males introduced into their home cage. Under conditions of such high aggression, the previously reported pro-aggressive action of a low (5 mg/kg) dosage of chlordiazepoxide (CDP) is hardly detectable. When opponents are large, the intensity of the aggression is less than what is seen with small ones. In this situation treatment of the females with CDP increases aggression levels substantially. The importance of intruders evoking aggression was further investigated by treating different sized opponents with d-amphetamine. d-Amphetamine treatment did not lead to major changes in the defensive capacities of either types of intruder. The data demonstrate that drug effects, such as pro-aggressive actions, may be observed using larger sized opponents that are not so easily defeated and show more adequate defense than small ones. The subtleness of the dyadic interactions in maternal aggression indicates that drug effects should considered carefully before extrapolation to other conditions.

Effects of chlordiazepoxide on competition for a preferred food in the rat

In rats with previous experience of chocolate this is a food that is rapidly taken and eaten and for which rats will compete. Female rats preferred white and milk chocolate to dark chocolate, but male rats displayed no preferences among the different types, regardless of whether it was offered in a novel environment or in the home-cage. Chronic (5 days) administration of chlordiazepoxide (5 mg/kg) to dominant animals, as judged in a previous competition for chocolate, led to a fall in success, whether the animals had been previously housed together for 1, 2 or 6 months. There were no significant effects of chlordiazepoxide treatment on the behaviour of subordinate rats. The potential usefulness of serial chocolate competition as a test of dominance is discussed.

Monoamines and effects of chlordiazepoxide on the corticosterone response to stress

Administration of chlordiazepoxide (CDP) (5 mg/kg) decreased plasma corticosterone (CS) levels of mice exposed to noise stress and increased CS levels in nonstressed mice (20 and 40 mg/kg). The increase in CS may be related to an observed decrease in locomotor activity. Quipazine (0.5 mg/kg), a serotonergic agonist, failed to alter CS levels in animals without prior drug treatment and attenuated the rise in CS of nonstressed mice. These results contradicted a possible serotonergic facilitatory effect on CS regulation. Administration of apomorphine (0.5 mg/kg) or clonidine (0.1 mg/kg) prevented the significant reduction of CS levels in stressed mice treated with low doses of CDP. Apomorphine, alone, increased CS of nonstressed mice to levels approximating those of vehicle-treated stressed mice. Thus, a norepinephrine inhibitory effect was not evident and possible dopaminergic involvement in CS response regulation was suggested. It seemed likely that the effect of CDP on the hypothalamic-pituitary-adrenal system was dependent upon the endocrine state of the animal. Mice exposed to stress and exhibiting higher levels of CS were affected differently by CDP treatment than their nonstressed counterparts.

Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide

The acute administration of ethanol, pentobarbital and chlordiazepoxide impaired, in a dose-dependent manner, the performance of rats on the moving-belt and two-way shuttle-box avoidance tests. Administration of these drugs for three weeks resulted in tolerance to their motor-impairing effects. Tolerance to ethanol or pentobarbital was characterized by a parallel shift of the dose-response curve to the right. Tolerance to chlordiazepoxide, however, was of greater extent and was accompanied by an apparent flattening of the dose-response curve. Symmetrical cross-tolerance developed between ethanol and pentobarbital. On the other hand, while chlordiazepoxide treatment conferred full cross-tolerance to ethanol and pentobarbital, only partial cross-tolerance to chlordiazepoxide was observed following treatment with ethanol or pentobarbital. These results suggest that at least part of the tolerance to chlordiazepoxide depends on changes in specific benzodiazepine receptors and is independent of the tolerance associated with non-specific changes in the cell membrane.