Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate

Summary Clorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. Total nordiazepam, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.     

Delusional misidentification of the Capgras and intermetamorphosis types responding to clorazepate. A case report

A patient with chronic psychosis and intermittent psychotic misidentification of the Capgras and intermetamorphosis types refractory to neuroleptic treatment was given a trial of clorazepate. Complete remission of psychotic symptoms was achieved for the first time in 19 years, but these recurred when the patient discontinued her clorazepate. It is concluded that clorazepate may be a useful treatment for some cases of chronic psychosis and psychotic misidentification. A possible mechanism for this is discussed.     

Transfer in vitro of three benzodiazepines across the human placenta

Summary A comparative study of the placental transfer to the foetus of three benzodiazepines was performed using a dual perfusion system of the human placental lobule. A transport fraction was calculated for each benzodiazepine and was compared with reference substances. Relative to antipyrine, the transport fraction of diazepam was 85%, and that of nordiazepam was 84%. The transport fraction of clorazepate represented only 20% of that of tritiated water. The relatively high transfer of diazepam and nordiazepam can be attributed to their high lipid solubility, and the lower transfer of clorazepate is due to its polar nature. It is suggested that in certain instances this benzodiazepine may be of especial value to obstetricians.Michèle Guerre-Millo is an M.S. aided by D.G.R.S.T.     

Pharmacokinetics of clorazepate in pregnant and non-pregnant women

Summary A single dose of clorazepate 20 mg was injected i.m. in 7 pregnant and 7 non-pregnant women. Blood samples were collected for one week, and urine was collected for 24 h after the dose. The concentrations of clorazepate and its metabolite nordiazepam were determined by electron capture gas liquid chromatography. There was no difference between the two groups on physical examinations. Clorazepate was rapidly absorbed and the peak concentration was reached within 2h. Mean pharmacokinetic parameters for clorazepate were absorption half life 0.77h in pregnant women and 0.56h in non-pregnant women; elimination half life 1.3h in pregnant women and 2.0h in non-pregnant women; volume of distribution: 0.43 l · kg^–1 in the pregnant women and 0.33 l · kg^–1 in non-pregnant women. Nordiazepam reached its peak concentration within 12h after dosing; its mean half life of elimination was 180h in pregnant women and 60h in non-pregnant women. Within 24h, 1.3% of the clorazepate was recovered in urine from pregnant women and 7% in urine from the non-pregnant women.     

Effect of clorazepate in spasticity and rigidity: a quantitative study of reflexes and plasma concentrations

The effect on increased myotatic reflexes of desmethyldiazepam, formed from its precursor clorazepate, was assessed in a double-blind cross-over study of 27 days duration. Eight patients with spasticity or rigidity were given placebo or active substance; first in loading doses for 2 days, then 5 mg every 12 h for a total of 10 days. A wash-out period of 7 days was interposed between the 2 10-day periods. Desmethyldiazepam had a normalizing effect on the increased phasic ankle reflexes seen in spasticity, but not on the increased tonic reflex seen in rigidity. The mean concentration of desmethyldiazepam in the steady state was 1227 nmol/l (range 600-1990 nmol/l). The plasma concentration of desmethyldiazepam tended to correlate with the percent decrease in phasic reflex activity (P = 0.08, 2-tailed). A slight drowsiness in 2 patients was the only side-effect seen. In conclusion, desmethyldiazepam given as clorazepate seems to be a suitable medicament in the treatment of spasticity.     

Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: The effect of smoking

Summary The pharmacokinetics of N-desmethyl-diazepam was evaluated after oral administration of clorazepate 20 mg to 12 healthy male volunteers (6 smokers; 6 non-smokers), aged 23–29 years. Plasma levels of desmethyldiazepam were measured by gas liquid chromatography. The half life of elimination (t_1/2) was significantly longer in the non-smoking volunteers than in the smokers: 54.7±17.7 versus 29.8±9.9 h (p<0.05). Peak plasma concentrations (C_max) were higher in non-smokers than in smokers, 413±106 µg/l and 245±50 µg/l, respectively (p<0.05). The sedative effect of clorazepate was less severe in smokers than in non-smokers.     

Patient acceptance as a factor in the effectiveness of treatment: an open assessment of potassium clorazepate (‘Tranxene’) and lorazepam in anxiety

Summary

Two new benzodiazepines, potassium clorazepate (15?mg. at night), and lorazepam (1?mg. t.d.s.) were compared in 50 patients presenting with anxiety in general practice. The response to treatment was assessed clinically and for patient acceptance. The single-dose regime of potassium clorazepate was significantly better, both for clinical effectiveness and patient acceptance.

In the potassium clorazepate treated group there were significantly fewer side-effects. In particular, sedation was a problem with lorazepam, 6 patients stopping treatment and 8 voluntarily reducing the dose. Only 2 patients stopped treatment because of the sedative effect of potassium clorazepate. The sedative effects also show qualitative differences: in patients who completed the assessment lorazepam caused mainly daylong sedation and potassium clorazepate mid-day sedation, and when asked for their opinion on the value of sedation, only the potassium clorazepate group considered it to be beneficial.     

Anticonvulsant effects of dipotassium clorazepate on hippocampal kindled seizures in rats

We examined the anticonvulsant properties of dipotassium clorazepate (DC) against hippocampal kindled seizures in rats. Adult male Wistar rats were subjected to kindling 1 week after the implantation of electrodes. After five stage 5 seizures were induced, the generalized convulsion triggering threshold (GST) was determined. Dipotassium clorazepate was administered intraperitoneally in rats that showed two stable stage 5 seizures induced at the GST current intensity. Dipotassium clorazepate at doses of 1 mg/kg or more produced an anticonvulsant effect, but did not readily suppress limbic seizures. Dipotassium clorazepate did not completely suppress after-discharges (AD) even at the highest dose, which was 5 mg/kg. Moreover, raised stimulus intensity failed to affect its efficacy as an anticonvulsant. The results of the present study suggest that DC has a modest anticonvulsant potency. It is reasonable to assume that its anticonvulsant efficacy is primarily due to attenuation of AD propagation rather than the raising of the seizure triggering threshold at the kindling focus.     

Benzodiazepines in epilepsy: pharmacology and pharmacokinetics

Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.