Evaluation of plasma diazepam and nordiazepam concentrations following administration of diazepam intravenously or via suppository per rectum in dogs.

OBJECTIVE: To evaluate the pharmacokinetics of diazepam administered per rectum via compounded (ie, not commercially available) suppositories and determine whether a dose of 2 mg/kg in this formulation would result in plasma concentrations shown to be effective for control of status epilepticus or cluster seizures (ie, 150 to 300 ng/mL) in dogs within a clinically useful interval (10 to 15 minutes). ANIMALS: 6 healthy mixed-breed dogs. PROCEDURES: Dogs were randomly assigned to 2 groups of 3 dogs each in a crossover-design study. Diazepam (2 mg/kg) was administered IV or via suppository per rectum, and blood samples were collected at predetermined time points. Following a 6- or 7-day washout period, each group received the alternate treatment. Plasma concentrations of diazepam and nordiazepam were analyzed via reversed phase high-performance liquid chromatography. RESULTS: Plasma concentrations of diazepam and nordiazepam exceeded the targeted range ≤ 3 minutes after IV administration in all dogs. After suppository administration, targeted concentrations of diazepam were not detected in any dogs, and targeted concentrations of nordiazepam were detected after 90 minutes (n = 2 dogs) or 120 minutes (3) or were not achieved (1). CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of these results, administration of 2 mg of diazepam/kg via the compounded suppositories used in the present study cannot be recommended for emergency treatment of seizures in dogs.

Comparison by means of bispectral index score, between anxiolysis induced by diazepam and sedation induced by midazolam.

AIM: Bispectral Index Score (BIS) is an objective tool to assess sedation depth. Benzodiazepines have different pharmacological profiles and diazepam may be safer than midazolam in this setting. The aim of this study was to compare BIS values observed during anxiolysis after diazepam versus sedation after midazolam. METHODS: Thirty-six patients were randomly assigned to 3 groups: group 1 was treated with i.v. diazepam, groups 2 and 3 with iv midazolam 1 and 3 mg, respectively. Sedation was monitored clinically and by means of BIS. BIS values were evaluated as area under the curve (AUC) and compared by variance analysis. The statistical comparison of other data was performed by variance analysis or, alternatively, the χ2 according to Yates. The statistical significance was indicated by P values <0.05. RESULTS: AUC values were significantly lower after midazolam when compared to AUC values registered in diazepam treated patients; 22.6% of the group 3 patients showed BIS values <80, versus 0.4% of group 1 patients. CONCLUSION: Diazepam has a safer profile, with BIS values and clinical conditions according to the definition of minimal and/or moderate sedation. Diazepam represents the safer drug for anxiety management in dentistry, because regularly produces a state of sedation during which verbal contact with the patient is maintained and carry a margin of safety wide enough to render loss of consciousness unlikely.

Folie à deux: double case-report of shared delusions with a fatal outcome.

BACKGROUND: Treatment of shared delusional disorder (folie à deux) often involves separation and use of antipsychotic medication, with uncertain outcomes and potential risks. METHODS: We report on two highly interdependent and chronically psychotic sisters with shared systematic delusion, followed by psychiatrists over several years. RESULTS: The dominant patient was diagnosed with schizoaffective disorder and her non-dominant sister with paranoid schizophrenia. Both received antipsychotics and supportive therapy as outpatients and allowed to continue conjoint therapy with individual psychiatrists-therapists. They returned for follow-up visits for 20 months, when the dominant decided to continue treatment alone, as her sister gradually improved symptomatically and functionally. After separation, the dominant became increasingly anxious. She impulsively ingested an overdose of the non-dominant sister's medicines and died of cardiac arrest, despite her sister's efforts to seek medical assistance. The surviving non-dominant sister developed anxiety and increasing agitation requiring psychiatric hospitalization and increased pharmacotherapy. She improved gradually, but continued to be dysfunctional and required placement in a psychiatric inpatient unit for several months, eventually doing better in a community-based rehabilitative program with regular psychiatric follow-up. CONCLUSIONS: Combined treatment of patients with folie à deux may encourage continuous pathological interactions, but separation may increase risk of adverse outcomes.

Combined sedation with oral chlordemethyldiazepam and midazolam by nasal route in third molar surgery.

AIM: This study was performed to evaluate the effects on the cardiocirculatory system, on perioperative anxiety and compliance of sedation with 2 benzodiazepines, chlordemethyldiazepam (CDDZ) a long acting oral drug for presedation and midazolam, a short acting drug, administered by nasal route to induce intraoperative sedation. METHODS: Fifty randomized patients undergoing third molar extraction at the Dental Clinic, University of Padua, were preoperatively evaluated. Anxiety was evaluated through a visual, analogue, scale (VAS) of 10 cm, a questionnaire of adjectives called interval scale of anxiety response (ISAR) and the Newman test was applied to evaluate the changes in psychomotor functions. All patients were treated with 1 ml of oral CDDZ for presedation and midazolam by the nasal route for intraoperative sedation at doses of 1 mg in Group 1 (25 patients) and 2 mg in Group 2 (25 patients). In all patients preoperative cardiocirculatory parameters were evaluated and in the first 20 min after the beginning of intervention. At the end of intervention the Newman test was reapplied, anxiety and postoperative cardiocirculatory data were reevaluated and the quality of the intervention judged in an interview made 1 week after the intervention (quality of the sedation technique, perioperative pain intensity, assumption of analgesic drugs, swelling, amnesia etc. after intervention). RESULTS: The treatment with 1 mg CDDZ + 2 mg midazolam by nasal route is the best association to slightly attenuate intra- and postoperative cardiocirculatory response, anxiety and to improve the quality of the treatment without interfering on the psychomotor response of patients at the time of the discharge. CONCLUSION: To conclude, the sedative technique employed is easily applied by the dentist, and is safe, efficacious and well tolerated by patients.

The effect of chronic benzodiazepines exposure on body weight in rats.

Changes in body weight (BW) in female rats treated for 5 weeks (wk) with weekly subcutaneous implantation of silastic capsules containing different benzodiazepines (BZs): diazepam (DZ) 90, 180, 360 and 540 mg wk-1; nordiazepam (ND) 600 mg wk-1; oxazepam (OX) 600 mg wk-1 and flunitrazepam (FN) 540 mg wk-1 and in male rats exposed to DZ (540 mg wk-1) were evaluated herein. Rats (female and male) implanted with empty capsules served as controls. The BW gain was significantly higher in male than in female rats (both DZ-treated and controls). The BW gain increased with increasing doses of DZ but slowed with time of exposure. In comparison to control rats, the BW gain was significantly higher in DZ-(540 mg wk-1) and OX- but not in ND- and FN-treated female rats. However, the differences between BZs were not of statistical significance. In rats exposed to empty capsules (male, female); DZ (male); ND and OX (female) the BW gain increased with time (1-4 wk) while in rats exposed to DZ and FN (female) the BW stabilised within 2 wk. Acute injection of the central BZ receptor antagonist, flumazenil (40 mg kg-1, i.v., 5th wk of chronic exposure), tended to inhibit the time-related BW gain in rats exposed to empty capsules (male, female), DZ (male), ND and OX (female) but did not affect the BW in DZ- (540 mg wk-1) and FN-exposed rats (female) where BW stabilised prior to FLU injection. Repeated administration of flumazenil (30 mg kg-1 wk-1, i.p.) did not affect the BW gain in DZ- and ND-treated female rats. The present data indicate that different BZs have different effects on BW gain in the rat suggesting that different subtypes of BZ receptors are involved.

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

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

Lymphatic bioavailability of diazepam and desmethyldiazepam in the rat.

The lymphatic bioavailability (FL) of diazepam (DZ) and its major metabolite desmethyldiazepam (DDZ) was studied. DZ was administered in intravenous and intraduodenal boluses, and in intravenous infusion in three groups of rats with different total lipid (TL) content in the central lymph. The effect of a) different lipophilicity of DZ and DDZ, b) lymphatic TL content, and c) route of DZ administration on FL was determined. It was found that a) FL values of DZ exceeded the FL values of DDZ and b) FL values of DZ increased with increasing TL content in the lymph (an opposite relation was found in DDZ), and c) the highest FL value of DZ + DDZ sum after intravenous bolus administration was attained contrary to the lowest one after intraduodenal bolus administration.

[Comparison of the effectiveness of orally administered clorazepate dipotassium and nordiazepam on preoperative anxiety]. / Vergleich der Wirkung von oral appliziertem Dikaliumclorazepat und Nordiazepam auf die präoperative Angst.

Clorazepate dipotassium (Tranxilium) is one of the benzodiazepines which is widely used for oral premedication. After oral administration it is decarboxylated to its active metabolite nordiazepam (desmethyldiazepam). Nordiazepam is also commercially available in the form of drops (Tranxilium N). The aim of the present study was to compare the effect of these drugs on preoperative anxiety. One hundred and eight patients scheduled for orthopaedic surgery (ASA I-II) were studied. Medication was administered at 10 p.m. the evening before surgery (E) and at 7 a.m. on the morning of surgery (M). There were four groups: 1) E no medication; M clorazepate dipotassium; 2) E no medication; M nordiazepam; 3) E clorazepate dipotassium; M clorazepate dipotassium, 4) E clorazepate dipotassium; M nordiazepam. Dosages were: clorazepate dipotassium: body weight < 55 kg: 10 mg; body weight > 55 kg: 20 mg; nordiazepam: 1 gtt/kg; 5 mg = 24 gtt). Anxiety was measured by using the self-evaluating Erlangen anxiety scales, which measure both background and situational anxiety. Background anxiety (EAS-H) was evaluated during the evening before surgery; situational anxiety (EAS-S) was evaluated at the same time and also on the day of surgery before premedication and immediately before surgery. Pulse rate was measured each time the test was administered. There were no differences between the groups in sex, age, weight or the intervals between premedication and anaesthesia induction (p > 0.05). There were no statistically significant differences between the groups with respect to background anxiety. Situational anxiety did not significantly increase or decrease at any of the testing times, nor were there any differences between the groups (p > 0.05). Heart rate did not vary between the groups or with time (p > 0.05). In this group of patients undergoing elective orthopaedic procedures, clorazepate prevented a rise in anxiety in the immediate preoperative period. Since clorazepate is rapidly metabolized to nordiazepam when administered orally it might be predicted that the two drugs have similar properties. This hypothesis is confirmed by the results of the present study. We conclude that orally administered clorazepate dipotassium and nordiazepam have a similar effect on preoperative anxiety.

[Monitoring of diazepam treatment: comparison of the results of gas chromatography and radioreceptor methods]. / Monitorowane leczenie diazepamem: porównanie wyników uzyskanych metoda chromatografii gazowej i radioreceptorowa.

26 patients with generalized anxiety disorder have been treated with diazepam (20 mg/24h) for 3 weeks. Blood samples were taken on the days of clinical assessment (before treatment and on the 7th, 14th, 21st day). Determination of drug level was performed parallelly by RRA and GC. The results obtained by both methods agreed well. The intra- and interindividual variations were high. We conclude that diazepam can adequately be measured by both techniques.

Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis.

The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients. After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l.kg-1) and a reduced clearance (5.0 vs. 10.5 ml.min-1.kg-1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.

Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam.

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P less than .01) and with percent ideal body weight (r = .91, P less than .001). Eleven of the same subjects also received 5- to 15-mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P less than .02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.

Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans.

Six healthy, fasting volunteers were given single doses of chlordesmethyldiazepam by 1 mg i.v., or as drops or tablets. Chlordesmethyldiazepam and its metabolite, lorazepam, in multiple plasma samples and in urine collected for 120 h after each dose were determined by electron-capture GLC. Mean kinetic variables for intravenous chlordesmethyldiazepam were: volume of distribution, 1.71 l.kg-1; elimination half-life, 113 h; total clearance, 0.21 ml.min-1.kg-1; cumulative excretion of lorazepam glucuronide 24.2% of the dose. Following a lag time of 15.5 min (tablets) and 4.2 min (drops), which were significantly different, the absorption of oral chlordesmethyldiazepam was a first order process, with apparent absorption half-life values averaging 1.5 h (tablets) and 1.1 h (drops). Bioavailability was 77% for tablets and 79% for drops.

Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans.

The pharmacokinetics of chlordemethyldiazepam--a pharmacologically very active new 1,4-benzodiazepine derivative--in healthy subjects after administration of a single oral dose of 2 mg, was studied. Peak concentrations were reached in 1.2 +/- 0.2 hours. Plasma levels declined with a biphasic pattern, and the elimination phase had a half-life of 82.9 +/- 14.1 hours. The concentrations of the main metabolite of chlordemethyldiazepam, lorazepam, were about 7% of those of the parent compound. In urine only conjugated lorazepam could be found its 96 hour excretion reaching about 15% of the administered dose of parent drug.