Effects of adinazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects on psychomotor and cognitive performance of adinazolam (15 or 30 mg), alone and in combination with ethanol (0.8 g/kg), were studied in healthy male volunteers and compared to effects of 10 mg diazepam.Adinazolam 30 mg produced relatively long-lasting impairments on tests of tracking, attention, verbal and nonverbal information processing, and memory. Adinazolam 15 mg resulted in descreased visual information processing. Adinazolam decreased supine mean arterial pressure, but only the 15 mg resulted in a tendency for decreased plasma norepinephrine concentrations.After standing for 5 min, 30 mg adinazolam was associated with increased heart rate.Although ethanol consumption produced additive decrements on a continuous performance task, there was little evidence to support a synergistic effect.Adinazolam 30 mg was accompanied by increased self-reports of side effects, especially drowsiness.     

Oral bromazepam in premedication. A comparison with diazepam

Bromazepam, a relatively newly benzodiazepine with marked anxiolytic effects, was compared in a randomised, double-blind manner with diazepam for its effectiveness as an oral premedicant drug. A scoring system was used to assess sedation, relief of anxiety, nausea, and cardiovascular effects in two groups of women having gynaecological operations. No difference was demonstrated between the effectiveness of the two drugs.     

Rectal Diazepam Compared to Intramuscular Pethidine/Promethazine/Chlorpromazine with Regard to Gastric Contents in Paediatric Anaesthesia

Sixty children, aged 1—12 years, were investigated with regard to gastric pH and volume before general anaesthesia. Thirty children (group D) received diazepam 0.75 mg/kg b.w. rectally 1 h before anaesthesia. Thirty children (group L) received a "lytic cocktail" (pethidine 28 mg, promethazine 7 mg, chlorpromazine 7 mg per ml) 0.05 ml/kg b.w. intramuscularly 1 h before anaesthesia. The pH values were significantly higher and the amount of gastric juice was significantly lower in group L compared to group D. The number of children in group L with gastric juice volume exceeding 0.4 ml/kg and the number of children with pH less than 2.5 was significantly smaller compared to group D. The number of children with both gastric pH less than 2.5 and gastric juice volume greater than 0.4 ml/kg was significantly smaller in the group receiving "lytic cocktail" intramuscularly compared to the group receiving diazepam rectally. Bile-stained gastric contents was not related to the gastric pH.     

Lorazepam as night sedation and premedication: a comparison with diazepam

Fifty healthy female patients scheduled for surgery were randonly allocated into two groups in a double-blind study. One group received lorazepam 2.5 mg orally at 2200 h on the evening before surgery as night sedation, and again at 0800 h on the morning before surgery as premedication. The second group received diazepam 10 mg orally at the samte times. The quality of sleep the night before surgery was superior in the lorazepam group (p less than 0.02). The frequency of effective sedation produced pre-operatively was similar in both groups. Although the incidence of amnesia for visual stimuli following lorazapam was higher (p less than 0.05) than with diazepam, there was no difference in the recall of auditory and painful stimuli. The overall incidence of side effects was similar for each drug and at the dosage used no difference was found in the time to awaken from anaesthesia.     

Dental treatment in young handicapped patients

A trial was undertaken to assess the suitability of oxygen/nitrous oxide sedation (relative analgesia) for dental treatment in unmanageable handicapped young patients. Fifty patients with chronological ages 5-22 years and mental ages 1 1/2-14 years participated in the double blind trial to see if premedication with diazepam 0.2 mg/kg would be a useful adjunct. After the trial, previous dental histories and behaviour at regular recall visits over the next 12-18 months were studied. Seventeen of 19 patients previously treated with general anaesthesia and 27 of 31 formerly untreated patients accepted treatment in the trial; of the 50 patients, 33 are continuing treatment with oxygen/nitrous oxide sedation, seven need general anaesthesia and 10 have moved from the district. It appears that the use of diazepam premedication improves patient demeanour and operating conditions although this improved effect is not carried over to recall visits. The results obtained indicate that routine dental procedures can be safely carried out by an experienced operator-sedationist in young handicapped patients using oxygen/nitrous oxide sedation. The frequency with which potentially hazardous techniques need to be used can be reduced, as can hospital admissions.     

Diazepam effects on striatal met-enkephalin levels following long-term pharmacological manipulations

As measured by highly specific radioimmunoassay, long-term treatment of rats for 28 days with benzodiazepines resulted in a significant increase in the striatal met-enkephalin content, which was opposite to the decrease in this area observed after acute administration. Other areas investigated i.e. the hypothalamus, the medulla oblongata/pons and the midbrain, were unchanged after chronic benzodiazepine treatment. Acute diazapam challenge of these animals revealed a considerable degree of tolerance towards the acute drug effect. In rats chronically treated with morphine for 28 days, acute diazepam administration no longer decreased striatal met-enkephalin, in contrast to rats receiving ethanol for the same time, in which the diazepam-induced decrease was potentiated.     

Clearance of diazepam can be impaired by its major metabolite desmethyldiazepam

Summary The pharmacokinetics of a single intravenous dose of diazepam 0.1 mg/kg was studied in 6 healthy volunteers, in random order under controlled conditions and following pretreatment with its major metabolite, desmethyldiazepam (20 mg/day) for one week. In the two subjects with the highest plasma concentration of desmethyldiazepam (990 and 1100 ng/ml, respectively), total plasma clearance (Cl) of diazepam was reduced after desmethyldiazepam, by 31% and 54%, respectively. In three individuals there was a moderate decrease of 14% to 21%, and no effect was seen in one volunteer. Cl was significantly reduced (11.5±1.8 vs. 9.1±3.3 ml/min;p=0.015) and elimination half-life tended to be prolonged (38.5±10.4 vs. 65.8±67.1 h;p=0.15). It is concluded that high concentrations of desmethyldiazepam can influence the elimination of its parent drug diazepam by product inhibition.     

Coffee consumption,cigarette smoking and reporting of drowsiness in anxious patients treated with benzodiazepines or placebo

Data obtained from anxious outpatients treated with either chlordiazepoxide or diazepam (n= 533) or placebo (n= 285) were used to explore the impact of coffee/tea and cigarette consumption upon the frequency of reporting of drowsiness after 2 weeks of treatment. Strong evidence was provided that both cigarette smoking and coffee drinking afiect the frequency with which drowsiness is reported by patients receiving the two benzodiazepines. However, not only the magnitude but also the direction of the impact of coffee consumption upon drowsiness depends upon the level of cigarette smoking and vice versa. For patients smoking ≦ 1 pack of cigarettes/day, drowsiness is reported less frequently by heavy coffee users while for patients smoking > 1 pack of cigarettes/day, drowsiness is reported more frequently by heavy coffee users. Similarly, for patients drinking ≦ 2 cups of coflee/day, drowsiness occurs less frequently among heavier smokers while for patients drinking > 2 cups of coffee/day, drowsiness occurs more frequently among heavier smokers. These results are consistent with reports that particular substances contained in coffee and tea and in cigarette smoke stimulate the synthesis of hepatic enzymes which metabolize both the benzodiazepines here studied and the substances which have stimulated enzyme synthesis.     

Midazolam and diazepam for gastroscopy

Midazolam 0.1 mg/kg was compared with diazepam 0.15 mg/kg intravenously in patients undergoing gastroscopy. The patients receiving midazolam were more sedated at the end of the procedure. The mean discharge times from the clinic for diazepam and midazolam patients were 85 and 102 minutes, respectively. The principal differences between the two drugs were that midazolam had a faster rate of onset, was virtually free from venous complications, provided much better amnesia (90% compared with 50%), and although the recovery time was longer with midazolam, the rate of recovery during the period of observation was faster. Neither drug caused any significant cardiorespiratory depression.     

Effects of different rates of absorption of two benzodiazepins on subjective and objective parameters

Summary Two benzodiazepins with different rates of absorption have been compared in a double-blind cross over study in six healthy subjects using single doses of diazepam (Valium) 2, 5 and 10 mg and oxazepam (Sobril) 15, 25 and 50 mg. Further, oxazepam formulations with different rates of absorption have been compared in 8 healthy subjects. Lastly, the diurnal variation in serum levels during long-term therapy with the benzodiazepins has been followed up in a pilot study in hospital. Drug influence was assessed at intervals and showed that the quantitative and qualitative subjective effects as well as the alteration of reaction time and hand steadiness were more pronounced during the rising phase than in the constant plateau or falling phase of serum drug concentrations. Rapidity of increase in concentration appeared more important than the absolute level. Diazepam has the faster rate of absorption and had a significantly (p<0.05–0.001) greater influence at 30 min, and usually at 90 min, too, than oxazepam or the placebo. Oxazepam, even when administered as a formulation with near-maximal absorption rate, still had not high enough a rate of absorption to produce the distinctly identifiable onset of reactions characteristic of diazepam and did not give noticeable prolongation of reaction time or increased hand unsteadiness even at its maximal serum concentrations. The separate pilot study showed that relatively large diurnal variations in serum concentrations might occur during continuous treatment for more than four weeks and that a preparation with a high rate of absorption (diazepam) could still produce a subjectively apparent experience after each individual dose. It seems reasonable to assume that the risk of abuse, and equally also one of the factors increasing the risk of habituation to psycho-pharmaceutical drugs, is related to subjectively experienced effects, which, as shown above, depend to a large extent on the rate of absorption. For maintenance treatment a steady serum level adapted to the individual is probably to be preferred, while in acute treatment, for example, of attacks of anxiety, a compound with rapid absorption is required, and the therapeutic advantages must then be weighed against the greater risk of abuse.