Effects of clorazepate, diazepam, lorazepam, and placebo on human memory

Healthy adults (N = 10) were given oral doses of lorazepam (1 and 2 mg), diazepam (5 and 10 mg), clorazepate (7.5 and 15 mg), or placebo and tested 30, 60, 90, and 120 minutes later on a word-recall memory task. All subjects received each drug dose once and placebo twice in randomized order at weekly intervals. Testing was double-blind. Lorazepam was found to have a significantly greater effect on memory than placebo. Diazepam and clorazepate did not differ significantly from placebo in their effect on word recall. High doses of lorazepam produced more pronounced memory effects than did low doses; neither diazepam nor clorazepate was found to exert a dose-related effect on memory.     

Effects of single doses of diazepam, chlorpromazine, imipramine and trihexyphenidyl on visual-evoked potentials

There is increasing evidence that the P 100 peak of the pattern-reversal visual-evoked potential (VEP-PR) is delayed by drug-induced dopamine antagonism and in Parkinson's disease. Recent studies have reported that components of the flash-VEP (VEP-F) are delayed by an anticholinergic which does not affect the VEP-PR. The present study found that a single dose of chlorpromazine increased the latencies of the VEP-PR and of the VEP-F and increased the VEP-F P2 amplitude. Trihexyphenidyl increased the VEP-PR amplitude but had only minor effects on the VEP-F. There was a tendency for imipramine to increase VEP-F latencies, especially the N3 peak, but had no effect on the VEP-PR. Both VEPs were unaffected by diazepam. These VEP findings add further support to the role of dopamine in the human visual system. Possible reasons are advanced for the failure of trihexyphenidyl to cause previously reported VEP changes associated with hyoscine hydrobromide. Several important issues need to be addressed by future research.     

Efficient serum concentrations after single doses of antiepileptic drugs: concept of loading-dose

Single doses of phenytoin (500 and 1.000 mg), carbamazepine 400 and 1.00 mg) and sodium valproate (600 mg) were given orally to 5 healthy young volunteers and serum concentrations determined between 1-8h after administration. The design was double-blind and placebo-controlled. Serum concentrations considered "therapeutic" were obtained after sodium valproate and the 100 mg dose of carbamazepine. The results suggest the loading-doses of phenytoin (1500-2000 mg) and carbamazepine (800 mg) are useful in the subacute control of frequent epileptic seizures on an out-patient basis, and that carbamazepine may be used for lasting control of seizures of status epilepticus treated initially with diazepam or other rapidly-acting preparation.     

Comparison of anticonvulsant effects of clorazepate dipotassium and diazepam. Four week anticonvulsant study in Rhesus monkeys

Clorazepate dipotassium and diazepam were administered daily for the first 5 days of each week to Rhesus monkeys at equimolar doses and challanged once a week with a convulsant dose of pentylenetetrazol. Clorazepate exhibited sustained anticonvulsant activity throughout the second, third, and fourth weeks while diazepam was effective only during the second and third weeks.     

A comparison of prazepam, diazepam, lorazepam and placebo in anxious outpatients in non-psychiatric private practices

A double-blind, random design, parallel group, four-week study of prazepam, diazepam, lorazepam, and placebo was conducted in diverse private outpatient practices (surgeon, internist, and obstetrician-gynecologist) using a common protocol, in order to evaluate their comparative efficacy in these settings. In addition, the effects of these anxiolytics on depressive symptoms in patients with anxiety were studied. Results showed that the non-psychiatric practitioners used lower dosages than psychiatrists in previous reports, and perception of anxiety levels of their patients were lower than the psychiatric raters. When patients were divided into two groups (1. predominantly depressed with anxiety, and 2. predominantly anxious with depression), differences between the benzodiazepines were shown. In the high depression-low anxiety group, all four treatment methods were effective in alleviating both anxiety and depression. In the high anxiety-low depression group, only prazepam and placebo were effective in alleviating both anxiety and depression, while diazepam and lorazepam decreased anxiety levels, but not depression.     

Effects of single oral doses of bromazepam, buspirone and clobazam on performance tasks and memory

Three anxiolytic drugs (bromazepam 3 mg, buspirone 10 mg, and clobazam 10 mg p.o.) were evaluated for their effects on memory, psychomotor performance and subjective response in a double-blind, placebo-controlled, crossover study in 20 healthy volunteers. At each session, measurements were made before and 2 and 6 h after drug administration. The psychometric tests used were the images test, digit/symbol substitution test (DSST), choice reaction time (CRT), and critical fusion frequency (CFF). Free recall after 30 s in the 2-hour session was altered for all 3 drugs as compared to placebo (p less than 0.01), but in the 6-hour session only bromazepam showed a significant difference (p less than 0.05). The number of symbols reproduced by subjects during DSST was significantly decreased by bromazepam and buspirone as compared to placebo (p less than 0.05), whereas clobazam showed no differences with placebo. Analysis of variance for all four treatments (the 3 drugs and the placebo) showed no differences at recognition time or for motor response in CRT, except between bromazepam and clobazam after 6 h (p less than 0.05). None of the drugs altered performance during CFF (except bromazepam), and clobazam actually improved performance. All the drugs studied disturbed acquisition phenomena or restitution of memory; however, only bromazepam and buspirone significantly modified performance during DSST and disturbed the recognition and processing of sensory data.     

Randomized clinical trial of magnesium,diazepam, or both after out-of-hospital cardiac arrest

OBJECTIVE: To evaluate the feasibility, safety, and efficacy of interventions aimed at improving neurologic outcome after cardiac arrest. METHODS: The authors conducted a double-blind, placebo-controlled, randomized clinical trial with factorial design to see if magnesium, diazepam, or both, when given immediately following resuscitation from out-of-hospital cardiac arrest, would increase the proportion of patients awakening, defined as following commands or having comprehensible speech. If the patient regained a systolic blood pressure of at least 90 mm Hg and had not awakened, paramedics injected IV two syringes stored in a sealed kit. The first always contained either 2 g magnesium sulfate (M) or placebo (P); the second contained either 10 mg diazepam (D) or P. Awakening at any time by 3 months was determined by record review, and independence at 3 months was determined by telephone calls. Over 30 months, 300 patients were randomized in balanced blocks of 4, 75 each to MD, MP, PD, or PP. The study was conducted under waiver of consent. RESULTS: Despite the design, the four treatment groups differed on baseline variables collected before randomization. Percent awake by 3 months for each group were: MD, 29.3%; MP, 46.7%; PD, 30.7%; PP, 37.3%. Percent independent at 3 months were: MD, 17.3%; MP, 34.7%; PD, 17.3%; PP, 25.3%. Significant interactions were lacking. After adjusting for baseline imbalances, none of these differences was significant, and no adverse effects were identified. CONCLUSIONS: Neither magnesium nor diazepam significantly improved neurologic outcome from cardiac arrest.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

Plasma hypercoagulability after termination of oral anticoagulants

The effect of discontinuation of a long term oral anticoagulant therapy with phenprocoumon on blood clotting parameters has been evaluated in patients in a controlled prospective trial. After termination of phenprocoumon the prothrómbin time normalized within 15 days and the thrombotest coagulation value within 57 days. Fibrinopeptide A (FPA) increased significantly during the observation period. FPA release in vitro also rose after discontinuation of anticoagulants. In control patients on a phenprocoumon maintenance therapy no alterations of the above mentioned parameters occured within the same period. The data indicate that plasma hypercoagulability is found in many patients, orally anticoagulated because of myocardial infarction, when the anticoagulant therapy is discontinued.     

A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients.

The clinical anticonvulsant efficacy of single dose rectal and oral administration of diazepam 20 mg was examined in two double-blind placebo-controlled trials in adult epileptic patients. All subjects suffered from drug resistant epilepsy and frequently experienced serial seizures. Diazepam was administered rectally as a new experimental suppository formulation immediately after a seizure and was highly effective in preventing recurrent fits within a 24 h observation period (p less than 0.001). Pharmacokinetic studies revealed a wide range of serum diazepam concentrations 60 min after administration of the suppository (mean serum diazepam level 190 +/- 73 (SD ng/ml). In a similar study oral administration of diazepam 20 mg significantly reduced the incidence of serial seizures compared with a placebo (p less than 0.01) and the mean 60 min serum diazepam level was 273 +/- 190 (SD) ng/ml.     

Plasma concentrations of sodium valproate: their clinical value

Plasma valproate concentrations were monitored prospectively in 54 previously untreated adult patients with epilepsy. Dose and plasma concentration were highly correlated. Adverse effects were common in association with plasma levels above 100 micrograms/ml. In patients suffering tonic-clonic seizures without focal symptoms, no seizures occurred when plasma levels were higher than 50 micrograms/ml. In patients with partial seizures, it was difficult to define a lower limit to a therapeutic range.     

Plasma concentrations of phensuximide, methsuximide, and their metabolites in relation to clinical efficacy.

The clinical efficacy of phensuximide and methsuximide was studied in relation to plasma concentrations of these compounds and their desmethyl metabolites. Single- and chronic-dose studies of each drug were carried out in five patients with intractable seizures. Patients were evaluated before and during treatment by 6-hour simultaneous video and telemetered electroencephalographic recordings to characterize the seizure type and by daily determinations of plasma antiepileptic drug concentrations. Phensuximide had a mean half-life of 7.8 hours and accumulated to an average fasting level of only 5.7 micrograms per milliliter. Desmethylphensuximide averaged only 1.7 micrograms per milliliter with a similar half-life. Methsuximide had an even shorter half-life, averaging 1.4 hours, but its desmethyl metabolite had a mean half-life of 38 hours and therefore accumulated to levels in excess of 40 micrograms per milliliter. The addition of phensuximide to their regimens benefited none of the patients, but two had an excellent response to methsuximide. The failure of phensuximide and its desmethyl metabolite to accumulate to reasonable levels is the likely explanation for the relatively weak antiepileptic effect of phensuximide as compared with methsuximide.     

Comparison of sublingual and oral prazepam in normal subjects. I. Clinical data

Five normal volunteers received at a 2-week interval a single dose of sublingual or oral prazepam in double-blind and cross-over conditions. All subjects completed a battery of 15 visual analogue scales before drug intake and 7.5, 15, 22.5, 30, 45, 60, 90 min, 2, 3, 5, 6, 7, 8, 9, 10 and 24 h following intake whereas a computerized assessment of vigilance (reaction time) was performed before intake, 15, 30, 60 min, 2, 3, 6, 8, 10 h following intake. Subjects rated themselves significantly more feeble, clumsy, lethargic, and incompetent following sublingual as compared to oral prazepam while a trend in the same direction was noted for the adjectives muzzy and mentally slow. In contrast, reaction time did not exhibit significantly different changes over time between the two forms. These results suggest a subjectively more rapid onset of activity following sublingual compared to oral prazepam.