Doses Of Chlordiazepoxide Research Articles

The use of chlordiazepoxide for outpatient gamma-butyrolactone (GBL) detoxification: An observational study

Background Various detoxification regimens are used for gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL), including diazepam, barbiturates, baclofen and GHB itself. However, these regimens are primarily derived from inpatient units, and literature on outpatient GBL detoxification is sparse with no previous reports on chlordiazepoxide. We describe the characteristics of outpatient GBL detoxification using chlordiazepoxide. Methods Observational study of all patients who attended a community outpatient addiction service in South London between August 2015 and November 2017 seeking detoxification from GBL. The outpatient caseload is predominantly patients with alcohol, opioid and stimulant dependence. Routine clinical data including patient demographics, GBL usage, daily chlordiazepoxide dose and Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) score were recorded. Results In the study period there were 17 attendances for GBL detoxification, 14 of which were undertaken in the outpatient setting. Twelve (86%) patients who had an outpatient detoxification were male, all of whom were men who have sex with men. Of 14 outpatient GBL detoxifications managed with chlordiazepoxide, 10 were successfully completed. One of the four patients that did not complete detoxification required inpatient treatment in an acute hospital. The average successful detoxification took 10 ± 3.1 days. For patients who completed a detoxification, the median maximum CIWA-Ar score on day one of the detoxification was 11 (range 2–17), with the mean dose of chlordiazepoxide used on day one being 140 mg (range 80–225 mg). Conclusions Chlordiazepoxide can be used for outpatient GBL detoxification in combination with a provision for crisis admission to hospital. CIWA-Ar score can be applied to GBL withdrawal to measure severity and inform a reducing regimen of chlordiazepoxide.

Assessment of Treatment Patterns in Patients with Alcohol Withdrawal Syndrome during Hospitalisation and Post-discharge: A Retrospective Cohort Study

Introduction: Alcohol dependence is an increasing and pervasive problem. Alcohol Withdrawal Syndrome (AWS) is a cluster of symptoms that occur in alcohol-dependent individuals after cessation or reduction of alcohol consumption. However, studies on the clinicoepidemiological profile of patients with AWS and treatment patterns in India are scarce. Aim: To assess the treatment patterns during hospitalisation and after discharge in Indian patients with AWS. Materials and Methods: A retrospective observational study was conducted using data from 1000 patients with AWS who were admitted to nine addiction centres across India. Data from medical charts from the previous five years were collected over six months, from January to June 2022. The study included patients of either sex, aged ≥18 years at the time of data collection, who had been hospitalised for AWS symptoms and had ≥3 months of documented follow-ups. The primary endpoints of the study were the most commonly used medications and their dose titrations in the treatment of AWS, as well as the duration of treatment in the hospital and post-discharge. Key secondary endpoints included the socio-demographic profile of patients, common comorbidities, common signs and symptoms, the association between prescription patterns of Benzodiazepines (BZDs) and liver enzyme levels, and the average duration of hospital stay. Continuous variables were summarised as mean and Standard Deviation (SD), while categorical variables were summarised as frequency and percentages. Levels of serum Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), γ-Glutamyl Transferase (GGT), and bilirubin were recorded from the source data, if available, and the association with the use of chlordiazepoxide and lorazepam was analysed using the Chi-square test. Results: The mean±SD age of the 1000 enrolled patients was 41.4±9.6 years, with the majority (n=997; 99.7%) being males. BZDs were the mainstay pharmacotherapy, with lorazepam (n=686; 68.6%) and chlordiazepoxide (n=482; 48.2%) being the two most commonly prescribed BZDs during hospitalisation. During post-discharge treatment, 57.0% (n/N=74/130) of patients received lorazepam, while 52.0% (n/N=67/130) received chlordiazepoxide. Frequently used drug regimens during hospitalisation included fixed doses of chlordiazepoxide {25 mg twice a day (BID:143/482; 29.7%), 20 mg thrice a day (TID:103/482; 21.4%), or 25mg TID (87/482; 18.0%)}, or lorazepam {2 mg TID (188/686; 27.4%), 2 mg BID (183/686; 26.7%), or 2 mg once a day (OD;175/686; 25.5%)}. Commonly observed signs and symptoms included tremors (n=567; 56.7%), irritability (n=539; 53.9%), and agitation (n=500; 50.0%). Depression (n=182; 18.2%) and anxiety (n=136; 13.6%) were the most commonly reported co-morbidities. Among the patients, only 13.4% (86/641) had an AST/ALT ratio >2, and 12.9% (44/340) had AST and GGT levels >2× Upper Limit of Normal (ULN). There was no significant difference in these patients between those receiving and not receiving chlordiazepoxide (p>0.05). The mean±SD duration of hospitalisation was 23.1±18.97 days, while the mean±SD duration of treatment during hospitalisation and post-discharge was 22.3±16.36 days and 71.6±52.3 days, respectively. Conclusion: The two most commonly prescribed drugs during hospitalisation and post-discharge were the BZDs, lorazepam and chlordiazepoxide. Fixed-dose regimens of chlordiazepoxide at 25 mg BID or TID, or 20 mg TID, and lorazepam at 2 mg TID, BID, or OD were frequently used during hospitalisation.

Harmful Outcomes in Patients Admitted to Yeovil District Hospital in Acute Alcohol Withdrawal

AimsOur aim was to assess what proportion of patients in Acute Alcohol Withdrawal (AAW) experience harm during their admission to hospital. Our hypothesis was that patients who came to harm were likely to have had sub-optimal withdrawal management. Therefore, we also aimed to identify any underlying issues in the way AAW is currently managed which may be contributing to harmful outcomes.MethodsInclusion criteria for the audit was inpatients at Yeovil District Hospital over a three-month period from May to July 2021, clinically coded under the heading ‘alcohol abuse’, with a minimum two-day admission. Data were gathered from the patients’ medical notes. An outcome was determined as harmful if firstly, it occurred during the withdrawal period, and secondly it was clinically feasible that it had occurred at least in part, as a result of poor AAW management. Notes from 15 patients were qualitatively reviewed, guided by NICE recommendations, to assess both adherence to, and suitability of YDH AWW policy.ResultsAlcohol abuse was identified at the time of medical clerking in all 15 patients. Audit-C scores were completed in 7 patients. All 15 patients had CIWA scoring initiated within 1 hour of clerking, and chlordiazepoxide prescribed as a STAT dose and then a fixed PRN dose according to whether CIWA score was above 10 or not. 10 patients had their CIWA scores monitored for at least 24 hours. 3 out of 15 inpatients had harmful outcomes, including falls, intracerebral haemorrhage, fractured neck of femur, and cardiac arrest.ConclusionOverall, adherence to YDH guidelines was good. Despite this, a high proportion of patients admitted under our care were harmed as a result of inadequate management of alcohol withdrawal. Where issues were identified, these were arguably linked to problems with the YDH AAW policy itself. Unclear guidance over how long to monitor CIWA scores, limitation of chlordiazepoxide doses to 10 mg for even the highest CIWA scores, and omission of Audit-C score in the current hospital guidelines, are suggested as contributors to harm in the three patients identified. Going forward, it will be important to review and make appropriate changes to the YDH policy in these areas according to NICE recommendations, to protect our patients from further harm. These results may well have wider implications in terms of adjustment to AAW policy at other hospitals across the UK.

The Severity of Ethanol Withdrawal Scale in Scale-Driven Alcohol Withdrawal Treatment: A Quality Assurance Study

ABSTRACTThis quality assurance study compared two scales that drive the medicinal treatment of alcohol withdrawal syndrome (AWS): the new Severity of Ethanol Withdrawal Scale (SEWS) and the default Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar). Prospectively entered outcome data from medical intensive care (SEWS) and acute psychiatric inpatient (CIWA-Ar) units were collected and analyzed. Measures included scale administration patterns, mean lengths of time on treatment medication, and mean medication doses for the first 24 hours and for the total AWS episode. The administration patterns of the two scales were highly associated despite separate ward locations and personnel. Time-on-medication for SEWS patients shortened on average by one hospital day over the CIWA-Ar group. At the same time, however, total chlordiazepoxide doses, or the first 24 hours and over the total AWS episode, averaged twice the magnitude in the SEWS group over the CIWA-Ar. The data suggest that the SEWS shortens AWS course of treatment significantly, likely due to better assessment leading to improved medication treatment early in the course. Contributing SEWS scale factors may include item weighting, dichotomous item scoring, and ease of scale use by the nursing staff. New prospective studies should focus on these clinical metrics along with reference to biological mechanisms of an apparent improved treatment effect using the SEWS.

PTH-159 Alcohol Detoxification Drug Chart Audit

Introduction Alcohol misuse is a rising problem and alcohol related admissions are common. Alcohol detoxification (DETOX) regimes vary and frequently confuse the prescribers and nurses leading to administration errors, compromising the patient’s care and possibly contributing to early readmissions, by not achieving maximum detoxification. In order to improve that, we have developed and trialled a chlordiazepoxide prescription drug chart in our emergency assessment unit. Following the introduction of the chart there was a significant reduction in prescription and administration errors. The chart is now the standard means of prescribing alcohol detoxification regimes in our hospital. Methods We reviewed 43 patient’s notes with respect to chlordiazepoxide prescription and identified errors in the prescribed DETOX schedule, timing and missed doses. We then developed a drug chart, which was intended to guide the clinician to assess the severity of alcohol dependence using the severity of alcohol dependency questionnaire (SADQ) and then prescribing the correct chlordiazepoxide schedule, bypassing possible prescription errors. We then reviewed 56 medical notes following the introduction of the drug chart and statistically compared the prescription errors (2 population proportion test). We also compared the median total chlordiazepoxide dose given in milligrams and the duration of regimes in days (t test for 2 independent means) in order to identify a possible impact of those elements to alcohol related early ( Results The chart has led to significant (p Conclusion Our experience suggests that DETOX regimes can be cumbersome to prescribe leading to prescription errors, thus compromising patient’s care. The idea of introducing a chlordiazepoxide drug chart was to achieve better care for these patients, by simplifying the prescription process. Our results imply that this was achieved with a suggestion that early readmissions were reduced. The chart is now established as part of alcohol DETOX management at Ipswich Hospital. References 1 Alcohol Misuse Management Guideline Version 1.0 – 2014, Ipswich Hospital 2 Emergency Medicine Journal, 2014. 3 Alcohol use disorders: sample chlordiazepoxide dosing regimens for use in managing alcohol withdrawal, NICE Feb. 2010. 4 Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence, NICE 2011. Disclosure of Interest None Declared

Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice

Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains.

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.

EXPERIENCE IN A DISTRICT GENERAL HOSPITAL OF ALCOHOL WITHDRAWAL MANAGEMENT COMPARING SYMPTOM TRIGGERED WITH FIXED DOSE REGIMEN IN ACUTE MEDICAL WARD

IntroductionHarmful drinking is endemic in the UK and is a worrying health hazard. It is estimated that up to 24% of the UK adults drink in a hazardous/harmful way.1 Recent...

Unplanned alcohol withdrawal: a survey of consecutive admissions to an acute medical unit in 2010 and 2011

Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group. Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied. There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period. A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients.

OC-030 Benefits of introduction of a symptom triggered regimen for management of alcohol withdrawal in a large teaching hospital trust: reduced admission duration and cost savings

IntroductionAcute alcohol withdrawal (AAW) is an increasingly frequent cause for hospital admission in the UK. NICE guidance (2010) recommends the use of a symptom triggered regimen (STR) rather than a...

Symptom triggered pharmacotherapy for acute unplanned alcohol withdrawal can be both clinically and cost-effective in a hospital setting: experience from a specialist hepatology unit

Introduction In recent guidance, NICE (2010) recommend a symptom-triggered (STW) pharmacological dosing regimen to treat AAW as both clinically and cost effective.1 Supporting evidence is from a small number of studies largely undertaken in specialised addiction units and a paucity of published evidence from other settings remains. With this in mind our liver unit formulated and piloted a STW regimen using chlordiazepoxide (CDP). Our aim was to evaluate STW and explore potential cost savings. Methods The STW regimen allowed a maximum daily dose of 240 mg CDP without specialist review. Pharmacotherapy was tailored to the patient9s requirements as determined by the severity of their withdrawal signs and symptoms using a designated questionnaire (modified CIWA-AD2). Patients were scored hourly or 4 hourly according to protocol score. Data was collected prospectively over a 10-month period (Nov 09 – Aug 10) and case note review undertaken in those previously admitted with AAW (all managed on a fixed dose regimen). Results 135 individuals had STW, each consuming a mean of 28 units of alcohol/day. Most (n= 78, 58%) were admitted with uncomplicated AAW, although over a third had significant liver disease (n=51, 38%). 6 (4%) had no significant liver disease but other serious co-morbidity requiring admission. 41 (30.4%) were previously admitted with AAW. The mean total dose of CDP prescribed during STW was 70.6 mg c.f. 541.6 mg on a fixed dose regimen. A significant number (n= 53, 39%) of STW patients did not require CDP at all, allowing early discharge. Patients on STW required CPD on average for shorter duration (3.11 days vs 7.52 days for fixed dose regimen). In the group admitted with uncomplicated AAW, we estimate within one ward cost savings of at least £220k per annum in bed days alone. Nursing staff welcomed the STW protocol, citing improved patient care and a reduction in violence and aggressive behaviour on the ward. Conclusion Our results support the recommendations made by NICE (2010) that symptom-triggered regimens are associated with lower doses of benzodiazepines, shorter treatment duration and cost-savings, especially in those with uncomplicated AAW. Designated questionnaires (such as CIWR-AD) are a useful adjunct to clinical experience.

Effects of chlordiazepoxide on predator odor-induced reductions of playfulness in juvenile rats

The extent to which a non-sedative dose of chlordiazepoxide (CDP) is able to modify the behavioral responses toward a predator odor was assessed in juvenile rats. Play behavior was suppressed and defensive behaviors were enhanced in the presence of a collar previously worn by a cat, when tested 24h later in the same context as that where the exposure occurred, and when tested in a context different than that in which the exposure occurred for up to 3h after exposure. CDP had no effect on the ability of cat odor to suppress play when rats were tested in the presence of the odor or when tested 24h later in the same context where that exposure occurred. When rats were exposed to a worn cat collar in their home cage and tested in a different context CDP attenuated the ability of cat odor to reduce one measure of play (nape contacts) but not another measure (pins). Rats had an opportunity to hide during testing and CDP either decreased hiding or increased risk assessment from within the hide box in all of the testing scenarios. These data suggest that CDP can alter the defensive strategy used by juvenile rats that are confronted with a predatory threat and can also lead to an earlier return to pre-threat levels of playfulness when that threat becomes less immediate.

Antidepressants, thiazide diuretics and alcoholism: central pontine myelinolysis waiting to happen?

A 50-year-old man, with a known weekly alcohol intake of almost 100 units, presented to his GP feeling drowsy. Routine blood tests revealed a profound hyponatraemia of 100 mmol/litre, and he was referred to hospital for investigations. On admission he was drowsy, but had a Glasgow Coma Scale score of 15, an abbreviated mental test score of 10/10 and an entirely normal neurological examination. Liver function tests were consistent with excessive alcohol consumption. He had been prescribed bendroflumethazide and clomipramine (a tricyclic antidepressant) by his GP. In view of their potential tocause hyponatraemia these were subsequently withheld and he was fluid restricted to 1.5 litres per day. His sodium level rose gradually and on day 5 of admission it had increased to 122 mmol/litre. He was discharged on day 8 having been advised to stop drinking. Less than a week after discharge he represented to his GP with symptoms of excessive sweating, shaking, constipation, disorientation and dysarthria. He was febrile at 38.6°C , and had a blood pressure of 180/90 mmHg. Electrolytes were normal (Na+ 135 mmol/litre). Although he denied consuming any alcohol since his initial admission, his symptoms were consistent with acute alcohol withdrawal and he was treated accordingly. He failed to improve on two attempts at reducing doses of chlordiazepoxide. His dysarthria progressed until his speech was difficult to understand and his swallow became unsafe. He continued to spike temperatures throughout the admission and although a catheter specimen of urine was positive for enterococcus, treatment with a prolonged course of antibiotics had not resolved his fever. A computed tomography scan of his head and a lumbar puncture were performed. Other than cortical atrophy in keeping with alcohol abuse, neither investigation provided any answers. It was considered that his symptoms could be explained by autonomic dysfunction. In view of his corrected hyponatraemia, central pontine myelinolysis was suggested and a magnetic resonance imaging head scan was performed (Figure 1). This confirmed the presence of central hyperintensity on the water sensitive sequences within the central pons, in keeping with an osmotic demyelination syndrome. Additionally these changes were identified within the caudate nuclei, possibly accounting for the patient's inability to fully control voluntary movement. The ongoing temperatures without sepsis suggested hypothalamic involvement. Following diagnosis this patient failed to improve. Treatment became supportive, and he died 7 weeks later.

Discriminative-stimulus and time-course effects of kava-kava ( Piper methysticum) in rats

Kava is a widely available and used herbal medicine that is not regulated in many countries. There are many questions concerning kava's stimulus properties, potential for therapeutic use, and potential for abuse. Although there is evidence that kava may possess some anxiolytic properties, kava's mechanism of action and the extent to which it may serve as an alternative to pharmaceutical anxiolytics are not fully known. The current study was designed to evaluate whether kava shares discriminative-stimulus properties with the anxiolytic chlordiazepoxide (CDP). Effects of different doses of kava extract were evaluated in two groups of rats trained to discriminate either a high or low training dose of CDP (i.p.). In order to assess time-course effects, two tests were conducted/session at 60 (Test One) and 90 (Test Two) min following oral administration of kava, CDP, or d-amphetamine. Dose-dependent substitution of CDP was found in both training groups in both tests. Kava (560 mg/kg, p.o.) occasioned responding indicative of partial substitution in both groups during Test One and only the low-dose group during Test Two. Partial substitution of kava extract for CDP suggests that the herbal compound may share a mechanism of action similar to CDP, but is less potent.

Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam

Although cross tolerance can develop among positive gamma-aminobutyric acidA (GABAA) modulators acting at the same modulatory site, cross tolerance does not always develop to drugs acting at sites that are different from the site of action of the drug administered chronically. To examine the relationship between cross tolerance and site of action, four rhesus monkeys discriminated midazolam and, on separate occasions, received 32 mg/kg of chlordiazepoxide 24 h before dose-effect determinations for drugs acting at different sites. Midazolam, pentobarbital, and pregnanolone produced >80% midazolam-lever responding. Although monkeys responded on the midazolam lever 2-4 h after 32 mg/kg of chlordiazepoxide, they responded on the saline lever 24 h later. Twenty-four hours after an acute injection of 32 mg/kg of chlordiazepoxide, midazolam dose-effect curves were shifted 4.6-fold to the right, whereas pregnanolone dose-effect curves were shifted three-fold to the left. Sensitivity to pentobarbital increased in one monkey and decreased in others 24 h after chlordiazepoxide administration. Decreased sensitivity to midazolam shows that acute cross tolerance develops after chlordiazepoxide administration, although it does not develop to drugs acting at other sites on GABAA receptors. These differences among positive GABAA modulators suggest that even short-term benzodiazepine administration changes GABAA receptors, and those changes impact modulatory sites differently.

A study of the teratogenic and fetotoxic effects of large doses of chlordiazepoxide used for self-poisoning by 35 pregnant women

The human teratogenic potential of chlordiazepoxide is debated. To study the effects on the fetal development of very large doses of chlordiazepoxide that were used for a suicide attempt during pregnancy, self-poisoned pregnant women were identified from patients in a toxicological inpatient clinic in Budapest, Hungary. Comparisons were made between congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status of the exposed children born to mothers who attempted suicide with chlordiazepoxide alone or in combination with other drugs during pregnancy and their sib controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 88 (8.4%) used chlordiazepoxide with or without other drugs for suicide attempt; 35 of these women delivered live-born infants. Doses of chlordiazepoxide taken ranged between 20 and 300 mg, with a mean of 117 +/- 86 mg. Of 35 exposed children, six (17.1 %) were affected with congenital abnormalities compared with three (13.6%) of their 22 sibs (OR with 95% CI: 1.3 (0.3-4.4). Of 18 pregnant women who attempted suicide between the 4th and 12th postconceptional week, the period most sensitive to congenital malformation, four delivered live-born children affected with a congenital abnormality (atrial septal defect type II, complex defect of respiratory system, mild pyelectasis because of the stenosis of ureteropelvic junction, congenital inguinal hernia). Two other children had fetal alcohol syndrome and unrecognized multiple congenital abnormality including talipes equinovarus, deformation type, and four minor anomalies. The pregnancy age-specific mean birth weight indicated intrauterine fetal growth retardation, which was confirmed by a dose-response relationship and by the higher rate of low birth-weight newborns. Cognitive status and behavioral scale of exposed children did not indicate neurotoxic effects. Very large doses of chlordiazepoxide used for suicide attempts during pregnancy did not induce a higher rate of congenital abnormalities but were associated with dose-dependent intrauterine growth retardation.

Development of tolerance to nitrous oxide (N2O)‐induced anxiolysis and cross‐tolerance to chlordiazepoxide (CP) in mice

Our laboratory has long studied the pharmacology of the anesthetic gas N2O, and we have implicated brain benzodiazepine receptors in N2O-induced anxiolytic effects (Li and Quock, Pharmacol. Biochem. Behav. 68:789-796, 2001). This study was conducted to determine the extent to which tolerance develops to the anxiolytic effect of N2O and whether there is cross-tolerance to the anxiolytic effects of the benzodiazepine CP. Male NIH Swiss mice, 18–30 g, were exposed to 70% N2O in oxygen (O2) for 1½ to 24 hr, removed to 100% O2 (to reduce diffusion hypoxia) and placed in a room air environment to complete the washout of N2O. Thirty minutes following removal from N2O, mice were individually tested in the light/dark exploration test to determine behavioral responsiveness to 70% N2O in O2. Results show that it required a continuous exposure of 9 hr or longer of 70% N2O to induce tolerance to the anxiolytic-like effects of a subsequent exposure to 70% N2O in the light/dark box paradigm. Preliminary results suggest that N2O-tolerant mice also exhibited reduced responsiveness to the anxiolytic-like effects of some doses of CP when compared to control mice that were exposed for an equal period of time to compressed air. These results provide evidence for development of tolerance of mice to the anxiolytic effects of N2O and possible cross-tolerance to the effects of benzodiazepines. (Supported in part by NIH Grant DA-10343.)

Pharmacological evaluation of the stress-induced social avoidance model of anxiety

We have shown earlier that mild electric shocks induce a lasting social avoidance in male rats. Here we investigated whether shock-induced social avoidance can be developed into a laboratory model of stress-induced anxiety. The putative new model would assess sub-chronic, stress-induced anxiety (as opposed to tests based on natural fear) in a heterologous context (as opposed to classical fear conditioning). A single exposure to mild electric shocks induced a robust social avoidance that lasted more than 5 days. Low doses of chlordiazepoxide (0.5, 1 mg/kg), diazepam (0.5, 1, 5 mg/kg), buspirone (0.3, 1 mg/kg), and fluoxetine (1, 3, 5 mg/kg) abolished this effect, whereas the anxiogenic compound m-chlorophenylpiperazine (0.5–3 mg/kg) induced social avoidance in unshocked rats. These effects were produced at doses that did not affect locomotion in the open field. Haloperidol (0.05, 0.1, 1, 5 mg/kg) influenced social avoidance at sedative doses only. The sensitivity of the model to anxiolytic agents was compromised at high (sedating) doses. Taken conjointly, these data show that shock-induced social avoidance can be used to assess the anxiolytic potential of compounds. In addition to predictive validity, the model appears to show construct and face validity as well: stress is among the etiological factors of, whereas social avoidance simulates the social deficits seen in, a variety of anxiety disorders. The model may be used to study the effects of anxiolytics on sub-chronic states of stress-induced anxiety.

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.

Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour

Several recent studies have shown that reducing γ-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838,417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.