Different effects of light food on pharmacokinetics and pharmacodynamics of three benzodiazepines, quazepam, nitrazepam and diazepam.

OBJECTIVE: Quazepam, nitrazepam and diazepam are administered under fed or fasted conditions for insomnia or anxiety disorder. Light bedtime food may have clinically relevant effects on the plasma levels of those drugs and hence on psychomotor performance. This study assessed the effect of light food on the pharmacokinetics and pharmacodynamics of these drugs. METHOD: Twenty-one eligible subjects were randomized to one of three groups of seven subjects: quazepam 20 mg, diazepam 5 mg or nitrazepam 5 mg. Each healthy subject took a single oral dose of the assigned drug after overnight fasting and after light food, on a separate occasion. Blood samples were collected until 72 h after dosing. The plasma samples were assayed using high-pressure liquid chromatography with spectrophotometric detection. Reaction time, critical flicker fusion test and visual analogue scales were conducted. RESULTS: The peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) of quazepam with light food were 1.2-fold [90% confidence interval (CI): 1.1-1.5; P < 0.05] and 1.5-fold (90% CI: 1.3-1.9; P < 0.05) higher than that without light food, respectively. For nitrazepam and diazepam, the time to peak was delayed about 1 h in fed condition (P > 0.05). However it had no effect on their C(max) and AUC. Reaction time of quazepam with light food was prolonged at 4 and 6 h after dosing and its area under the effect-time curve from 0 to 10 h was increased (P < 0.05). CONCLUSION: Light food increased the bioavailability of quazepam and affected psychomotor performance. Light food delayed T(max) of nitrazepam and diazepam but had no effect on C(max) and AUC.

Cross-sensitivity in a child with anticonvulsant hypersensitivity syndrome.

We describe a fulminant picture of anticonvulsant hypersensitivity syndrome (AHS) and the possible role of nitrazepam. A 5-month-old boy developed fever and rash after the use of phenobarbitone. Allergy to phenobarbitone was suspected. Nitrazepam was substituted for seizure control. Over the next few days he progressively collapsed with fever, facial oedema and multi-organ involvement. The diagnosis of AHS was delayed because nitrazepam has not been implicated in the development of cross-sensitivity. AHS is a severe multi-organ reaction to aromatic anti-epileptic drugs. It has been thought to occur as a consequence of pre-existing pharmacogenetic and immunologic abnormalities. Careful selection of anti-epileptic drugs is essential as cross-sensitivity is common. Intermittent benzodiazepines have been recommended in managing breakthrough seizures in AHS. However, the structure of benzodiazepines contains aromatic rings and potential cross-reactivity cannot be totally ignored. Although we do not have direct proof, we believe that nitrazepam prolonged the clinical course.

Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats.

The encephalographic (EEG) properties of zaleplon were investigated in comparison with those of other sedative hypnotics in conscious rats with chronically implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg), triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25 mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose-dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in particular, increased the slow wave deep sleep (SWDS), whereas triazolam, brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose-dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused no influence on fast wave sleep (FWS) at doses tested. The appearance of the sleep-inducing activity of zaleplon was more rapid than those of any compounds tested, and zaleplon significantly increased the relative EEG power density in the delta frequency band over that of triazolam at 20 and 30 min after the administration in the spectral analysis. Therefore, the present findings suggest that the non-benzodiazepine zaleplon can be expected to exhibit high practical potential as a hypnotic and is characterized by an increase in SWDS with rapid onset of hypnotic action.

Tissue distribution of nitrazepam and 7-aminonitrazepam in a case of nitrazepam intoxication.

We report a case of nitrazepam poisoning in which the distribution of nitrazepam and 7-aminonitrazepam was determined in body fluids and tissues. A 52-year-old woman was found dead in a shallow ditch (approximately 5 cm in depth), in the winter. Ambient temperature was 2-8 degrees C. The postmortem interval was estimated to be approximately 1 day and no putrefaction was observed. The cause of death was thought to be drowning due to nitrazepam overdose and cold exposure. Blood concentrations of nitrazepam and 7-aminonitrazepam were very site dependent (0.400-0.973 microg/ml and 0.418-1.82 microg/ml). In addition, the concentration of the same analytes in the bile were 4.08 and 1.67 microg/ml, respectively, and in the urine: 0.580 and 1.09 microg/ml, respectively. A high accumulation of both substances was observed in various types of brain tissue (2.17-6.22 microg/g and 2.49-5.11 microg/g). Only small amounts of nitrazepam and 7-aminonitrazepam were detected in the liver (0.059 and 0.113 microg/g, respectively). Large differences in the observed concentrations of nitrazepam and 7-aminonitrazepam among arterial and venous blood samples were thought to be mainly due to dilution of arterial blood by water entering the circulation through lungs at the time of death. Bacterial metabolism of nitrazepam may also have contributed to the observed differences.

Pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam in healthy volunteers: an interethnic comparative study between Japanese and European volunteers.

Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double-blind, placebo-controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age- and sex-matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 +/- 0.165 mL/min/kg and 1.17 +/- 0.492 mL/min/kg, and half-life (t1/2) was 22.1 +/- 4.96 hours and 21.5 +/- 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time-effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration-effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs. Such studies can form a rational basis for comparative clinical trials.

Interaction between erythromycin and nitrazepam in healthy volunteers.

Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mg x 3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P < 0.05) and the peak concentration by 30% (P < 0.05). The concentration peak time of nitrazepam was shortened by over 50% (P < 0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.

Nitrazepam clearance unimpaired in patients with renal insufficiency.

Eight patients with mild to moderate renal insufficiency (mean serum creatinine: 2.4 mg/100 ml) and 9 matched control subjects with normal renal function received a single 5-mg oral dose of nitrazepam, cleared mainly by hepatic nitroreduction. Serum nitrazepam levels were determined by gas chromatography during the 72 hours after dosage. Renal patients and controls were well-matched for age (74 vs. 63 years), height (165 vs. 164 cm), and weight (68 vs. 64 kg). Patients and control subjects did not differ significantly in nitrazepam elimination half-life (32 vs. 24 hour) or volume of distribution (4.2 vs. 3.6 liters/kg). Clearance was higher in patients than in controls (4.2 vs. 1.7 ml/min/kg), but the difference was not significant. Nitrazepam free fraction in serum was increased in renal patients (16.8 vs. 15.0% unbound, p = 0.08). After correction for individual values of free fraction, the two groups still did not differ in kinetic variables for nitrazepam. Thus, mild to moderate renal insufficiency does not alter the kinetics of nitrazepam.

Detection of benzodiazepine intake in therapeutic doses by immunoanalysis of urine: two techniques evaluated and modified for improved performance.

We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake.

Efecto de un derivado de la 1,5 benzodiazepina sobre el sueño / Effect of a derivative of 1,5 benzodiazepine upon the sleep cycle

El propósito de este trabajo fue analizar el efecto de un derivado de la benzodiazepina sobre el ciclo vigilia-sueño, que no había sido estudiado. Para este propósito, se le administraron a ratas Wistar 0.9 mg/kg de un derivado clorado de la beta lactama de 1,5 benzodiazepina por vía intraperitoneal, analizando su acción mediante diez horas de registro poligráfico contínuo. Los resultados muestran que esta substancia disminuye el estado de vigilia e incrementan ligeramente el sueño lento y, de manera estadísticamente significativa (p<0.05), el sueño paradójico. Asimismo, la latencia de la primera fase de sueño paradójico se reduce de manera importante. Estos hallazgos indican que la substancia, analizada bajo las condiciones experimentales descritas, facilita la inducción y el mantenimiento del sueño

Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam.

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.

[Screening and detection of nimetazepam and its chief metabolites]. / Screening und Nachweis von Nimetazepam und seinen Hauptmetaboliten.

The article describes analytical data for the screening and detection of nimetazepam and its major metabolites. The methods comprise thin-layer chromatography, gas chromatography, UV-spectrophotometry, infrared- and mass spectrometry.