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Ro 5-3335 is a new benzodiazepine highly active in vitro (IC50 = 0.1-1.0 microM [corrected]) against HIV-1 viruses of AIDS resistant or non-resistant to zidovudine (AZT). It is also active against HIV-2. Ro 5-3335 is original by its mechanism of action, acting on the trans-activation factor of transcription (TAT) and non on the reverse transcriptase. Such as, it could prevent proviral DNA to express in both evolutive and silent AIDS resistant or non-resistant to AZT or to other anti-reverse transcriptase series. In addition, in antagonizing extracellular TAT's actions, Ro 5-3335 could alleviate the syndrome commonly associated with AIDS as Kaposi's syndrome. In rodent test, Ro 5-3335 has no diazepam-like central effects and presents in comparison to AZT a more favorable therapeutic index. In dog, the elimination half-life, peak concentration and availability are 2 h, 0.8 microM and 85% respectively, after a 1 mg.kg-1 oral dose of Ro 5-3335. Theoretically, Ro 5-3335 and now its analogue Ro 24-7429 seem to possess all virtues to antagonize evolutive and latent AIDS. Its arrival is timely to cope with the ever increasing resistance phenomena, lengthy development of AIDS vaccines, exponential contamination of populations worldwide and last but not least possibly to impede evolutions of the disease. Ability to manipulate TAT-mediated activation of HIV-1 genes paves the ways to study conceivable corrections of abnormal gene expressions of neurotransmitters, hormones, oncogenes and key enzymes.

Depression is a regular accompaniment of all chronic painful conditions. A study was conducted to assess the effect of treatment of the depressive factor in patients with chronic prostatodynia. Effects were compared of psychosomatic therapy (psychotherapy, relaxation, etc.) alone in 9 patients (group I) and the same psychosomatic care plus treatment with amineptine and clobazam in 9 patients (group II). Results showed that 2 patients recovered and 3 were improved (62%) with 1 drop-out in group II, versus recovery and 2 improvements (42%) with 2 drop outs in group I. These findings are analyzed and discussed.

The authors report the case of an eleven-month old infant who was given maprotiline and clobazam. He was found in coma state and suffered from convulsions, that were treated with phenobarbital. The electrocardiogram showed a right bundle branch block and a left anterior hemiblock over 72 h. The child then recovered without sequelae.

The benzodiazepines bind to high affinity sites on neuronal membranes in the central nervous system. These sites form part of a multimolecular postsynaptic complex which also includes the GABA receptor and its ionophore. The benzodiazepine binding sites appear to present a certain heterogeneity which may correspond to a diversity of functions. A good correlation exists between the pharmacological potencies of the various benzodiazepines and their affinities for the receptor in vitro, but the relationship is less clear when binding is studied in vivo. Nevertheless, high affinity benzodiazepine binding remains an essential tool for the pharmacologist in search of more specific drugs.

Sleep and respiration studies were carried out in 12 subjects (9 males, 3 females) at an altitude of 4,800 metres, during effect of a French expedition in the Himalayas. The effect of loprazolam, a hypnotic benzodiazepine, was investigated in a double-blind, 2 parallel group, 1 mg loprazolam versus placebo trial. Sleep was evaluated by means of electroencephalographic recordings and questionnaires. The effects of altitude in each subject were intercurrent wakefulness increase, slow wave sleep and paradoxical sleep decrease and nocturnal periodic breathing. The mean duration of sleep apnea episodes was 12 seconds with a maximum of 24 seconds. These episodes occurred during stages 1 or 2 of sleep and during paradoxical sleep. Female subjects exhibited less periodic breathing than males. Acclimatization to high altitude increased total sleep time, stage 3 duration and percentage of paradoxical sleep. Loprazolam tended to decrease stage 2 latency and did not worsen slow wave sleep depression or episodes of apnea. Normal amounts of slow wave sleep and intrasleep wakefulness appeared in the loprazolam group after acclimatization.

In a double-blind cross over randomized study for the first two nights efficacy and safety of triazolam 0.25 mg and loprazolam 1 mg have been compared in 67 out-patients complaining of common insomnia and treated by general practitioners. After the second night patients had to choose one of the two treatments and were continuing a 3-week treatment period with the preferred one. In case of no preference they received one of the 2 drugs according to a new randomization. Cross over administration of the two drugs for the first two nights shows that with triazolam global help to get in sleep is greater (p = 0.016) and sleep latency is shorter (p = 0.07) than with loprazolam, and number of night awakenings is decreased (p = 0.02) compared to loprazolam. Patients felt more rested under triazolam (p = 0.015) than loprazolam. Triazolam (N = 31) is more frequently preferred than loprazolam (N = 19) p = 0.09. Preferred treatment continued to be effective during the following three weeks and quality of sleep improved drastically for all items compared to baseline data (p = 0.01). Both treatments are well tolerated (4 drop-outs for side-effects: 2 under each treatment). The one-week tapering period allows progressive withdrawal with rare reappearance of minimum sleep disorders (5 cases: 2 under triazolam, 3 under loprazolam).

A method has been developed for gas-chromatographic determination of clobazam in human plasma using a nitrogen-selective detector. The unchanged drug was extracted from the plasma at pH 9 by benzene. The method used methyl-1-clonazepam as internal standard. Calibration graphs were linear in the range of 20 to 10,000 ng/ml. The recovery of the compound was 102.29%. The sensitivity of the method was adequate for determination of the drug at toxic concentrations and at therapeutic doses. It was a simple, rapid, reproductible method for determination of clobazam and most of the commercialized benzodiazepines. The method has been tested in a few number of clinicals cases. No interferences occurred in plasma from patients treated with various drugs.

A method is developed for direct gas-chromatographic determination of clonazepam (Rivotril) and its main metabolite, 7-amino clonazepam, in plasma, using desmethylflunitrazepam as internal standard. Following selective extraction, the benzodiazepines are analyzed by gas-chromatography, with a glass column filled with 3% OV17 on Gas Chrom Q and 63Ni electron capture detector. The procedure, which requires neither hydrolysis nor derivatisation, has a good selectivity. The sensitivity is 5 ng/ml of plasma for a valid quantitative determination. We have to improve this limit for fine pharmacokinetic studies, but the method is already available for therapeutic and pharmacovigilance controls. It is also suitable for diagnostic of eventual overdosing or poisoning, based on plasma or urine analysis.

Twenty-five epileptic children were treated with clobazam alone for periods of 10 days to 36 months (mean = 9 months and 16 months for children who responded well). Satisfactory results were obtained in 11 patients and marked improvement with a 75% decrease in the initial frequency of seizures in 6 patients. The seizures recurred after a few weeks in 3 other patients. This preliminary study shows that clobazam is well tolerated and remarkably effective, especially in benign partial epilepsy, even in carbamazepine-resistant cases.

Polygraphic sleep recordings were performed in two patients with nocturnal myoclonus. The beneficial effect of Clonazepam has been confirmed in the two cases.

The effects of the acute or chronic administration of clobazam (20 mg/kg per os) on the plasma levels of the main anterior pituitary hormones (prolactin, FSH and LH) were studied in the male rat. This 1,5 benzodiazepine did not induce any modification of the hormones levels either after acute or chronic administration. These negative data are discussed as compared to the effects of other benzodiazepines or GABA and GABAmimetic drugs on the pituitary hormones levels according to particular experimental conditions.

The acute administration of the 1,5 benzodiazepine clobazam (20 and 100 mg/kg orally) reduces the sulpiride-induced release of prolactin in the male rat. The decrease in prolactin plasma level is respectively of 66 and 75% for the two doses, whereas it has minimal effects on the gonadotropins (FSH and LH). The clobazam induced prolactin lowering effect is compared to the one observed after diazepam administration. Finally, we have shown that the two benzodiazepines have no effect either on prolactin or on gonadotropins, when administered alone.

The activity of some schistosomicidal drugs have been studied by electron microscopy on the tegument of Schistosoma mansoni. Results are different and depend of the compound which is tested. Two new compounds: RO 11 3128 and RO 13 3978 are specially active and act in different ways on the tegument. On of them, a benzodiazepine, have been tested in association with an "antibenzodiazepine" compound in order to avoid the sedative action without decrease of the schistosomicidal activity.

37 patients with endoscopically confirmed gastric ulcers received either cimetidine (19 patients) or pirenzepine (18 patients) in a double-blind trial. At 4 weeks, 53% of the patients treated with cimetidine and 44% of those treated with pirenzepine had endoscopically healed ulcers. At 8 weeks, complete healing had occurred in 83% of the patients taking cimetidine and 71% of those taking pirenzepine. These differences are not statistically significant.

Fifty practitioners treated 224 patients with clobazam for 4 weeks. The anxiolytic action, the tolerability, the degree of satisfaction and the dosage of clobazam were evaluated by means of a modified "Rating Scale for Anxiety" by Hamilton and self-evaluation scales. Clobazam proved to have an important anxiolytic activity together with good tolerability. The ability to concentrate was remarkably improved, which seems to confirm the specificity of the molecule (benzodiazepine-1,5). The reduction of anxiety and of anxious equivalents and the good tolerability of the product were confirmed by the judgement of satisfaction of the doctors as well as of their patients.

A 20 year old woman with complex partial seizures from childhood developed a stuporous state when her anticonvulsant therapy was substituted by VPA. She recovered when treated orally with clonazepam. This case was compared with others in the literature for which the origin of the stuporous state have been hypothesized.

The authors administered clobazam (CLB) to treat status epilepticus in 16 patients from 3 to 62 years old. Status epilepticus was of absence type (6 cases), myoclonic-absence type (1 case), myoclonic type (1 case), tonic (1 case) and elementary or complex partial (7 cases). In all patients consciousness was sufficiently retained to allow ingestion of the drug. CLB administration was performed under EEG monitoring, in a single oral dose averaging 1.0 mg/kg. In 15 patients, the status was stopped after a period ranging from 19 to 31 min without significant sedation or other side effects. In one patient a somatomotor status epilepticus, lasting 8 days, terminated 6 h after drug administration. It is well known that the efficacy of a drug on status epilepticus depends on the clinical context and semiological form of the status. Nevertheless, the authors conclude that the pharmacokinetic properties of CLB, its mild sedative effects and ease of administration, make this a useful drug in the management of some forms of status epilepticus.

The authors describe the case of a 12 years old boy suffering from an epilepsy with complex partial seizures evolving to a syndrome of epilepsy with continuous spikes-waves during sleep. A dramatic improvement follows clobazam introduction in the treatment. The originality of this case report and the possible mechanism of action of clobazam are discussed.

Some clinical studies are available showing that benzodiazepine drugs are essentially devoid of major neuroendocrine effects, at least at anxiolytic doses. Moreover, sedative doses are necessary to evidence in laboratory animals an increased secretion of corticosteroids, a reduced activation of the adrenocortical axis by stress and an inhibition of prolactin secretion. In fact, the neuroendocrinology of anxiety and the neuroendocrine effects of benzodiazepines in the anxious subject are hardly known.

Abundance of beta activity in epileptic patients under clonazepam (Rivotril) treatment shows a significant correlation with the suppression of epileptic seizures and/or of epileptic EEG activity such as spikes and spike/wave complexes. In a longitudinal two-year study in 21 children with severe epilepsy treated with clonazepam, relative spectral peak power (RSPP) of beta activity was correlated with daily dose and serum concentration as well as with its effect on seizures and on epileptic EEG activity. Eight cases showed significant correlation of beta RSPP to daily dose, but only 4 to serum concentration. A significant (inverse) correlation was found between beta RSPP and the relative occurrence of epileptic EEG activity. Most illustrative were the individual follow-ups, with beta RSPP as an interesting additional parameter regarding the course of the epileptic condition. Quantitative measurement of beta activity by means of spectral analysis during long-term antiepileptic treatment promises important additional information on specific aspects in the individual case.

Diazepam and clonazepam when given by intra- veinous or rectal route are the first-choice treatment of epileptic status. They are active in 80 per cent of cases whatever is the form of the status with a better efficacy in generalized seizures. Clonazepam, chlorazepate, nitrazepam and clobazam are also prescribed as chronic treatment of various forms of epilepsy. However tolerance and side-effects on higher nervous functions are frequent. In the state of the art benzodiazepine utilisation is limited as add-on therapy in severe epilepsies. They may have broader indications in monotherapy.