Delayed-onset MRI findings in acute chorea related to anoxic brain injury.

Anoxic brain injury can manifest with various abnormal movements. We describe acute chorea in a young patient with anoxic brain injury due to chlordiazepoxide toxicity who had delayed radiographic lesions in bilateral globus pallidus. Although brain MRI 8days after the anoxic event was unremarkable, repeat brain MRI 15days after the event showed T2 hyperintensities and enhancement within the bilateral globus pallidi. It is possible that MRI brain findings of bilateral basal ganglia lesions may appear later than onset of chorea in anoxic brain injury. However, given the normal brain MRI in between, other etiologies cannot be excluded entirely.

Baclofen for alcohol withdrawal.

BACKGROUND: Baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review published in 2015, Issue 4. OBJECTIVES: To assess the efficacy and safety of baclofen for people with AWS. SEARCH METHODS: We updated our searches of the following databases to March 2017: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language. SELECTION CRITERIA: We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included three RCTs with 141 randomised participants. We did not perform meta-analyses due to the different control interventions. For the comparison of baclofen and placebo (1 study, 31 participants), there was no significant difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores (very low quality evidence). For the comparison of baclofen and diazepam (1 study, 37 participants), there was no significant difference in CIWA-Ar scores (very low quality evidence), adverse events (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no significant difference in CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low quality evidence), adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence). AUTHORS' CONCLUSIONS: No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low quality evidence.

A randomized, open-label, standard controlled, parallel group study of efficacy and safety of baclofen, and chlordiazepoxide in uncomplicated alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is a distressing condition, generally controlled by benzodiazepines (BZD's). Baclofen, a gamma-aminobutyric acid-B (GABAB) agonist, has also shown promising results in controlling AWS. As there are few studies comparing the efficacy and tolerability of chlordiazepoxide with baclofen, the present study was taken up. The objective of this study was to compare efficacy and tolerability of baclofen with chlordiazepoxide in uncomplicated AWS. METHODS: Sixty subjects with uncomplicated AWS were randomized into two groups of 30 each, to receive baclofen (30 mg) or chlordiazepoxide (75 mg) in decremented fixed dose regime for 9 days. Clinical efficacy was assessed by Clinical Institute Withdrawal Assessment for Alcohol-Revised Scale (CIWA-Ar) and tolerability by the nature and severity of adverse events. Lorazepam was used as rescue medication. Secondary efficacy parameters were Clinical Global Impression scores, symptom-free days, and subject satisfaction as assessed by visual analog scale. This study was registered with Clinical Trial Registry-India (CTRI/2013/04/003588), also subsequently registered with WHO's ICTRP clinical trial portal. RESULTS: Both baclofen and chlordiazepoxide showed a consistent reduction in the total CIWA-Ar scores. However, chlordiazepoxide showed a faster and a more effective control of anxiety and agitation requiring lesser lorazepam supplementation, and also showed a better subject satisfaction compared to baclofen. Both the drugs showed good tolerability with mild self-limiting adverse events. CONCLUSION: The present study demonstrates that baclofen is not as good as chlordiazepoxide in the treatment of uncomplicated AWS. However, baclofen might be considered as an alternative.

Is long-term use of benzodiazepine a risk for cancer?

The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression.The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92-1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92-1.04), medazepam (HR, 1.01; 95%CI, 0.84-1.21), nitrazepam (HR, 1.06; 95%CI, 0.98-1.14), oxazepam (HR, 1.05; 95%CI, 0.94-1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09-1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use.Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research.

Capgras delusion with violent behavior in Alzheimer dementia: case analysis with literature review.

BACKGROUND: Capgras delusion (CD) has multiple etiologies including neurodegenerative disorders and can be associated with violent behavior. CD is a common complication of Alzheimer dementia (AD); however, CD with violent behavior is uncommon in AD. We report escalating violent behavior by a patient with advanced AD and CD who presented to the emergency department (ED) and required admission to an academic medical center. METHODS: Case analysis with PubMed literature review. RESULTS: A 75-year-old male with a 13-year history of progressive AD, asymptomatic bipolar disorder, chronic kidney disease, hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with recurrent/escalating violence toward his wife, whom he considered an impostor. His psychotropic regimen included potentially inappropriate medications (PIMs) for geriatric/AD patients-topiramate/amitriptyline/chlordiazepoxide/olanzapine-that are associated with delirium, cognitive decline, dementia, and mortality. Renal dosing for topiramate, reduction in PIMs/anticholinergic burden, and substituting haloperidol for olanzapine resolved his violent behavior and CD. CONCLUSIONS: CD in AD is a risk factor for violent behavior. As the geriatric population in the United States grows, CD in patients with AD may present more frequently in the ED, requiring proper treatment. Pharmacovigilance is necessary to minimize PIMs in geriatric/AD patients. Clinicians and other caregivers require further education to appropriately address CD in AD.

Projeto Bambuí: percepção do uso de benzodiazepínicos pela população idosa da cidade de Bambuí

O presente volume constitui requisito parcial para a obtenção do grau de Doutor pelo Curso de Pós-Graduação em Ciências de Saúde, área de concentração Saúde Coletiva, do Centro de Pesquisa René Rachou da Fundação Oswaldo Cruz(FIOCRUZ). Ele é constituído por dois artigos que apresentam resultados relativos a dois estudos qualitativos sobre a percepção de idosos sobre os benzodiazepínicos.Os dois artigos inserem-se em um estudo mais amplo sobre envelhecimento e saúde, o Projeto Bambuí, desenvolvido na cidade de mesmo nome, no sudoeste de Minas Gerais. Os dados analisados para produção dos dois artigos foram coletados,por meio de entrevistas não estruturadas, junto a 22 idosos não institucionalizados,residentes na cidade. O primeiro artigo, intitulado, “Uso crônico de benzodizepínicos entre idosos: nervoso controlado, alívio garantido”, analisa as motivações apontadas pelos idosos para a utilização desta medicação,considerando questões ligadas ao processo de obtenção dessa medicação e o vínculo dos usuários com o medicamento. No segundo artigo, que intitula-se, “Uso de benzodiazepínicos entre idosos: o alívio de poder ‘jogar água no fogo’, não pensar e dormir”, o foco da investigação é a percepção do usuário quanto ao uso de benzodiazepínico, considerando questões ligadas ao risco de desenvolvimento de dependência física e psicológica, em um cenário de uso crônico.

Projeto Bambuí: percepção do uso de benzodiazepínicos pela população idosa da cidade de Bambuí / Bambuí Project: perception of benzodiazepine use by the elderly population of the study area

O presente volume constitui requisito parcial para a obtenção do grau de Doutor pelo Curso de Pós-Graduação em Ciências de Saúde, área de concentração Saúde Coletiva, do Centro de Pesquisa René Rachou da Fundação Oswaldo Cruz(FIOCRUZ). Ele é constituído por dois artigos que apresentam resultados relativos a dois estudos qualitativos sobre a percepção de idosos sobre os benzodiazepínicos.Os dois artigos inserem-se em um estudo mais amplo sobre envelhecimento e saúde, o Projeto Bambuí, desenvolvido na cidade de mesmo nome, no sudoeste de Minas Gerais. Os dados analisados para produção dos dois artigos foram coletados,por meio de entrevistas não estruturadas, junto a 22 idosos não institucionalizados,residentes na cidade. O primeiro artigo, intitulado, “Uso crônico de benzodizepínicos entre idosos: nervoso controlado, alívio garantido”, analisa as motivações apontadas pelos idosos para a utilização desta medicação,considerando questões ligadas ao processo de obtenção dessa medicação e o vínculo dos usuários com o medicamento. No segundo artigo, que intitula-se, “Uso de benzodiazepínicos entre idosos: o alívio de poder ‘jogar água no fogo’, não pensar e dormir”, o foco da investigação é a percepção do usuário quanto ao uso de benzodiazepínico, considerando questões ligadas ao risco de desenvolvimento de dependência física e psicológica, em um cenário de uso crônico...

Assessing the cumulative effects of exposure to selected benzodiazepines on the risk of fall-related injuries in the elderly.

BACKGROUND: The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated. METHODS: We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall. RESULTS: For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of flurazepam in the past months was associated with a highly significant increase in the risk of fall-related injuries (HR = 2.83, 95% CI: 1.45-4.34). The cumulative effect of a 30-day exposure to alprazolam was 1.27 (1.13-1.42). For temazepam, the results suggested a potential withdrawal effect. CONCLUSIONS: Mechanisms affecting the risk of falls differ across benzodiazepines, and may include cumulative effects of use in the previous few weeks. Thus, benzodiazepine-specific analyses that account for individual patterns of use should be preferred over simpler analyses that group different benzodiazepines together and limit exposure to current use or current dose.

[Diagnostics and therapy of alcohol withdrawal syndrome: focus on delirium tremens and withdrawal seizure]. / Diagnostik und Therapie des Alkoholentzugssyndroms: Fokus auf Delirium tremens und Entzugskrampfanfall.

INTRODUCTION: Delirium tremens and withdrawal seizures are serious complications of an alcohol withdrawal syndrome. This review presents the diagnostic procedures required in case of the occurrence of a withdrawal seizure and delirium tremens as well as possible treatment options including prophylactic medication regimen for alcohol withdrawal syndrome. Furthermore non-pharmacological procedures accompanying delirium tremens and a potential integration of viewing videotapes of delirium tremens in the course of alcohol-specific therapy are discussed. METHODS: A systematic literature research using Pubmed has been carried out to find recent studies and review articles dealing with alcohol withdrawal syndrome. RESULTS AND DISCUSSION: Regarding the diagnostic algorithm in case of the occurrence of a withdrawal seizure or a delirium tremens basic diagnostic procedures and special diagnostics including neuro-imaging or cerebrospinal fluid puncture depending on patients' clinical condition have to be considered. Sedatives are important in treatment of alcohol withdrawal seizures and delirium tremens as well as in the prophylaxis of alcohol withdrawal syndrome. A long-lasting prescription of anticonvulsant medication in patients suffering from withdrawal seizure should be considered critically and can be carried out only under certain conditions.

Septal co-infusions of glucose with the benzodiazepine agonist chlordiazepoxide impair memory, but co-infusions of glucose with the opiate morphine do not.

We have found repeatedly that medial septal (MS) infusions of glucose impair memory when co-infused with the gamma-amino butyric acid (GABA) agonist muscimol. The present experiments sought to determine whether the memory-impairing effects of this concentration of glucose would generalize to another GABA(A) receptor agonist and to an agonist from another neurotransmitter system that is known to impair memory. Specifically, we determined whether the dose of glucose that produces memory deficits when combined with muscimol in the MS would also impair memory when co-infused with the GABA(A) receptor modulator chlordiazepoxide (CDP) or the opiate morphine. Male Sprague-Dawley rats were given MS co-infusions and then 15 min later tested for spontaneous alternation or given shock avoidance training (retention tested 48 h later). The results showed that MS infusions of the higher dose of glucose with morphine did not produce memory deficits, whereas, the performance of rats given MS co-infusions of CDP with glucose was impaired. These findings suggest that the memory-impairing effects of brain glucose administration may involve an interaction with the GABA(A) receptor.

A novel operant conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogenic effects of drugs.

There is a need for novel anxiolytics, which are effective, but do not cause sedation, tolerance, and rebound anxiety on discontinuation. To investigate a procedure that can be used to assess these characteristics preclinically, rats were initially trained to press a lever at a high rate to obtain food. Once trained, periods of punishment were introduced in which electric shocks were superimposed. The intensity of these electric shocks was increased every 90 s from very low (0.01 mA) to sufficiently high to stop most subjects responding (0.4 mA), so that a complete rate/intensity function was obtained during each punishment period. The benzodiazepine, chlordiazepoxide, and two novel subtype-selective gamma-aminobutyric acid-A agonists, TP003 and TPA023, significantly increased response rates mildly suppressed by intermediate levels of electric shock without any effect on unpunished response rate. Two clinically anxiogenic agents, yohimbine and flumazenil, reduced the rate of punished responding. Aripiprazole and amphetamine reduced both punished and unpunished responding. Repeated treatment with diazepam 2.5 mg/kg daily for 15 days, initially markedly reduced unpunished response rates, but also increased punished response rates, an effect which became greater with repeated treatment. Abrupt cessation of diazepam treatment produced a reduction in punished responding. Diazepam (5 mg/kg daily) produced a greater reduction in unpunished responding, a smaller increase in punished responding, and a larger and longer lasting reduction in punished rates on withdrawal. In conclusion, the procedure detected anxiolytic and anxiogenic effects of drugs, and the sedative side effects, development of tolerance, and rebound-anxiety on discontinuation of a benzodiazepine. This procedure should have utility in the characterization of novel treatments of anxiety.

A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal.

OBJECTIVE: For important reasons, lorazepam (Ativan) and chlordiazepoxide (Librium) are both popular treatments for alcohol-withdrawal syndrome. Nevertheless, there is little literature directly comparing the two drugs. A formal comparison is desirable because of pharmacokinetic and other differences that could affect safety and efficacy considerations relevant to practice in developing countries. METHOD: One hundred consecutive consenting male inpatients in a state of moderately severe, uncomplicated alcohol withdrawal at screening were randomized to receive either lorazepam (8 mg/day) or chlordiazepoxide (80 mg/day) with dosing down-titrated to zero in a fixed-dose schedule across 8 treatment days. Double-blind assessments of withdrawal-symptom severity and impairing adverse events were obtained during treatment and for 4 days afterward. RESULTS: One chlordiazepoxide patient developed withdrawal delirium. Lorazepam and chlordiazepoxide showed similar efficacy in reducing symptoms of alcohol withdrawal as assessed using the revised Clinical Institute Withdrawal Assessment for Alcohol scale. During withdrawal, irritability and dizziness were more common with lorazepam, and palpitations were more common with chlordiazepoxide. No difficulties in drug discontinuation or differences in impairing adverse events were observed with either drug. CONCLUSIONS: With the treatment schedule used in this study, lorazepam is as effective as the more traditional drug chlordiazepoxide in attenuating uncomplicated alcohol withdrawal. Lorazepam, therefore, could be used with confidence when liver disease or the inability to determine liver function status renders chlordiazepoxide therapy problematic. The absence of clinically significant withdrawal complications with lorazepam in this large study contrasts with findings from previously published studies and suggests that higher doses of lorazepam than those formerly used may be necessary during alcohol withdrawal.

Maternal drug use, fertility problems, and infant craniostenosis.

OBJECTIVE: To test the hypothesis that maternal drug use or treatment for infertility is related to the occurrence of infant craniostenosis. DESIGN AND MATERIAL: Maternal drug use and infertility treatment were studied in 398 cases of craniostenosis, identified from various Swedish health registers. Exposure information was ascertained in early pregnancy, and comparisons after adjustment for some confounders were made with all infants born. In order to validate some findings, data from the Central-East France Registry were studied for first trimester drug exposure in 235 infants, and use of ovarian stimulation in 315 infants with craniostenosis. RESULTS: A statistically significant association between maternal use of anticonvulsants and infant craniostenosis was found (risk ratio [Swedish data], 6.9; 95% confidence interval, 1.10 to 7.94). With the Swedish data, an association was found with three nitrosatable drugs (risk ratio, 3.4; 95% confidence interval, 1.10 to 7.94), previously associated with the occurrence of craniostenosis, but this was based on only five exposures, and no such exposure occurred in the French data set. No association with subfertility (odds ratio, 0.72; 95% confidence interval, 0.60 to 1.86) or infertility treatment (odds ratio, 1.06; 95% confidence interval, 0.60 to 1.87) was found in the Swedish data and no statistically significant increase in the use of ovulation stimulation in the French data. CONCLUSIONS: A strong association was found between the maternal use of anticonvulsants and infant craniostenosis, and a tentative association was found with the use of nitrofurantoin and two other nitrosatable drugs. There was no association with maternal subfertility or infertility treatment.

Chlordiazepoxide-induced Stevens-Johnson syndrome.

The causes of Stevens-Johnson syndrome (SJS) can be categorized as iatrogenic, infectious or idiopathic. Drug-induced SJS is associated with various antibiotics, anticonvulsants, and other drugs. However, no previous reports have mentioned an association between chlordiazepoxide, a benzodiazepine sedative, and SJS. Here, we present a case of SJS induced by chlordiazepoxide overdose. This case reminds us that SJS may be an adverse effect of chlordiazepoxide. Further, overdosage with benzodiazepine sedatives should be added to the list of potential causes of SJS.

Evidence for PTZ-like cues as a function of time following treatment with chlordiazepoxide: implications for understanding tolerance and withdrawal.

The present study used a two-lever, drug-discrimination procedure to train rats to discriminate between the cues associated with 5 mg/kg of the anxiolytic, chlordiazepoxide (CDP) and 15 mg/kg of the anxiogenic, pentylenetetrazol (PTZ), to investigate the relationship between withdrawal and acute tolerance. Training doses of the two drugs were chosen so that rats responded about equally on both levers when tested on saline (SAL). Following acquisition of the discrimination, rats were injected with 10 mg/kg CDP and tested for lever choice at various intervals from 6 h to 192 h. These tests revealed that cues associated with CDP withdrawal lasted approximately three times longer than the cues associated with the drug's primary effects. At the shortest retest interval (6 h) after treatment with 10 mg/kg CDP, rats responded primarily on the CDP lever, followed by a shift to predominant responding on the PTZ lever at the 16 h and 24 h intervals before returning to predrug, baseline levels at the longer intervals (48-192 h). In order to investigate the relationship between tolerance and withdrawal to the cue properties of CDP, CDP dose-response curves were determined 24 h following treatment with SAL or 10 mg/kg CDP. Acute tolerance, as defined by a rightward, parallel shift in the dose-response function, was observed in the rats pretreated with CDP. Furthermore, it was evident that the baseline shift associated with CDP withdrawal, rather than a weaker drug cue, accounted for acute tolerance. The results from this study are relevant to evaluating the role positive and negative reinforcement play in motivating compulsive drug use.

Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests.

RATIONALE: Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF(1) receptor antagonists are being developed as potential novel anxiolytics, but while CRF(1) receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF(1) receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF(1) receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function. OBJECTIVE: The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF(1) receptor antagonists in these tests. RESULTS: The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF(1) receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects. CONCLUSIONS: The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF(1) receptor antagonists seem to have a wider therapeutic index than benzodiazepines.