Influence of age and previous use of diazepam dosage required for endoscopy.

In 19 patients (10 men and 9 women) a 22-fold variation was observed in the intravenous dose of diazepam necessary as preparation for endoscopy (median dose, 20 mg; range, 5 to 110 mg). Analysis of plasma samples for diazepam and N-desmethyldiazepam revealed that the clinical response did not relate to the rate or character of initial drug distribution. There was a high correlation (r = 0.96) between the dose and the plasma concentration 10 minutes after administration. Users of diazepam displayed tolerance to its pharmacologic effects, requiring a significantly larger (P less than 0.05) dose than nonusers (median doses, 35.0 mg and 14.5 mg respectively). Older patients required less than younger patients (r = -0.54, P less than 0.05). The variation between individuals in the dose of diazepam required as preparation for endoscopy cannot be explained by variation in drug disposition but instead reflects previous diazepam use, age and probably differences in sensitivity at the site or sites of drug action.     

Adrenaline potentiates antiepileptic but not sedative action of diazepam in rats

Intramuscular (i.m.) administration ofdiazepam in a dose of 10 mg/kg and adrenaline in a dose of 0.2 mg/kg prevents generalized clonic-tonic pentylenetetrazol (PTZ) seizures in 75-80 % of rats, but only in 35-40 % of rats it prevents local clonic PTZ seizures. In the above mentioned dose, diazepam causes a strong sedation, but adrenaline does not cause a sedative effects. The combined administration of diazepam and adrenaline in threshold independently ineffective doses prevents both clonic-tonic and clonic PTZ seizures in 80 % of rats without a sedation development. The basis for mechanism of potentiation of anticonvulsant action of diazepam is the stimulation of gastric mucosa afferents by adrenaline.     

Interdisciplinary Study of Diazepam Sedation for Outpatient Dentistry

Patients unable to submit themselves to routine dental treatment under local anaesthesia were studied during treatment under diazepam sedation accompanied by local anaesthesia, and compared with a matched control group for psychiatric assessment. Physiological responses, operating conditions, amnesia, pain threshold, and recovery were all assessed by various tests.Some of the patients had an anxiety neurosis, and several had been referred because of previous failure to complete dental treatment. Satisfactory conditions were obtained in all but two instances, and no adverse physiological responses occurred with diazepam in an intravenous dose of 0·2 mg./kg. Patients were clinically safe to leave accompanied by a responsible adult within one hour of administration of the drug. Some patients showed an improvement in attitude towards dentistry following treatment.     

Biochemical Evidence of Anxiety in Dental Patients

Urinary metabolites before dental treatment were compared in a group of patients with dental phobia and in a matched control group. Plasma adrenaline, noradrenaline, and free fatty acids were estimated before treatment, immediately after sedation with diazapam 0·2 mg/kg body weight in the phobic patients, during induction of oral anaesthesia, and during and after surgery. Patients with dental phobia had significantly higher levels of adrenaline, which were only temporarily lowered by sedation, and which during treatment remained consistently higher than those of control patients.     

Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.

Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.     

Gabamimetic properties of anxiolytic drugs

Diazepam (5 mg/kg, ip) and tracazolate (40 mg/kg, ip), a nonbenzodiazepine anxiolytic, blocked electrically-induced head-turning without producing sedation. Bicuculline and picrotoxin, GABA antagonists, at doses not affecting head-turning (2 mg/kg, ip) antagonized the effects of diazepam and tracazolate on head-turning. However, at the same dose, bicuculline was more effective as an antagonist of diazepam whereas picrotoxin was more effective as an antagonist of tracazolate. These results suggest that benzodiazepine as well as nonbenzodiazepine anxiolytics possess GABAmimetic activity. The difference in potency between bicuculline and picrotoxin as antagonists of diazepam and tracazolate may be related to their reported differences as GABA antagonists (e.g., site of receptor interaction).     

Comparative study of the teratogenic effects of chlordiazepoxide and diazepam in the fetal hamster

A single, intraperitoneal injection of either chlordiazepoxide (280–3100 mg/kg) or diazepam (120–980 mg/kg) was administered to pregnant hamsters on day 8 of gestation. These dosages produced a dose-dependent sedation of pregnant animals lasting up to 36 hours, and a combined maternal mortality rate of 21% (chlordiazepoxide) and 5% (diazepam). Animals were sacrificed on gestation day 12 and the fetuses were examined for gross malformations. Although there was a dose-related increase in the frequency of malformed fetuses (3.4%–54.7% for chlordiazepoxide, and 0–58.7% for diazepam), the lowest teratogenic dose was noted to be 280 mg/kg, i.e., almost 500 times and 1000 times the average daily recommended therapeutic doses for chlordiazepoxide and diazepam, respectively. The majority of fetal malformations observed with both compounds were either exencephaly or cranioschisis. The results of this study should be interpreted with caution in so far as their relevance to humans is concerned. The terata were observed at exceedingly high doses (700–7000 times the average human use dose), and the malformations noted by us have not been associated with the use of minor tranquilizers in human pregnancy. Also, although we found no gross anomalies in the litters of dams deprived of food and water for up to 72 hours, the confounding role of prolonged periods of sedation and resulting inactivity, and possible hypoxia and hypothermia needs to be explored further.     

Coenzyme Q, Vitamin E and Apo-E alleles in Alzheimer Disease

Neurodegenerative Diseases represent the most common cause of Dementia, about 5-10% of the population aged above 65 years and about 30% above 80 years. A study about Apo-E alleles, Coenzyme Q and Vitamins E as biological indicators was performed in plasma samples of patients aged from 30 to 85 years, affected by Neurodegenerative Diseases. The results were compared with control subjects of approximately the same ages as the reference group. A frequency of 21.7% of epsilon4 allele in control group was estimated, against 15.8% observed in patients. The frequency of epsilon2 and epsilon3 alleles was 13.0% and 65.2% in the control group against 10.5% and 73.7% in patients. No significant differences were observed between the frequency of epsilon3/epsilon3 genotype and epsilon3/epsilon4 genotype in the control group compared to patients' group. The frequencies observed in epsilon2/epsilon3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The epsilon2/epsilon2 and epsilon4/epsilon4 genotypes were not identified in any groups. Plasma CoQ10 concentrations were similar in patient and control groups and no differences were found even taking into account the distribution of male and female subjects in the two groups. Also, vitamin E did not provide evidence of any differences between groups and the analysis among sexes revealed that again vitamin E concentrations were similar in between subgroups.     

Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination

Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.     

Influence of cimetidine on pharmacokinetics of propranolol.

Whole-blood propranolol concentrations were estimated for 12 hours after a single 80 mg oral dose was given in six patients taking cimetidine and two weeks after they had stopped the drug. Mean blood propranolol concentrations were higher throughout the sampling period when the patients were taking cimetidine than when they were not, and the difference was statistically significant between one and four hours (p less than 0.05). The mean relative bioavailability of propranolol, measured as the area under the concentration time curve, was significantly higher when the patients were taking cimetidine (p less than 0.025). The mean increase in bioavailability was 136.5 +/- 57.6%, and the results were consistent in each subject. It is concluded from these results that cimetidine reduces the hepatic first-pass extraction of propranolol.     

Sedation for stereotactic headframe application: a randomized comparison of two techniques

A prospective, randomized study was performed in 87 patients to compare the safety, efficacy and dose requirements of two sedation techniques for stereotactic headframe application. Sedation administration and headframe application averaged 30 min. Fifty patients weighing 76 +/- 13 kg (mean +/- SD) received mean doses of 154 micrograms fentanyl plus 5.5 mg droperidol i.v. (FD group). An additional 37 patients weighing 76 +/- 19 kg received mean doses of 127 micrograms fentanyl plus 6.7 mg Valium (diazepam; FV group). Both treatments provided excellent hemodynamic stability and a low incidence of adverse side effects while providing adequate analgesia and sedation. The incidence of anesthetist-assessed patient anxiety and discomfort was more favorable in the FD group.     

Prevention of alcohol withdrawal seizures with oral diazepam loading

Twenty patients withdrawing from alcohol who had reliable histories of previous alcohol-withdrawal seizures and thus were at high risk for a subsequent seizure were treated in hospital with oral diazepam loading: 20 mg of the drug was given every hour to a minimum total of 60 mg. None of the patients had a seizure during the stay in hospital. We believe that phenytoin prophylaxis is not necessary in these circumstances. However, if the patient is already taking phenytoin, this drug should not be abruptly discontinued in the withdrawal period in favour of diazepam loading.     

Effect of butorphanol,midazolam or ketamine on romifidine based sedation in horses during standing cheek tooth removal

Background

Standing surgery, especially dental procedures, are commonly performed in horses. This leads to an increasing demand for reliable sedation protocols. Therefore, it was the purpose of this study to investigate the influence of butorphanol, midazolam or ketamine on romifidine based sedation in horses during cheek tooth removal.

Methods

Forty horses presented for tooth extraction were divided in four groups using matched pair randomization. Group R was sedated with romifidine (bolus 0.03 mg/kg, followed by a constant rate infusion (CRI) 0.05 mg/kg/h) and group RB with romifidine (same dose) and butorphanol (0.02 mg/kg; CRI 0.04 mg/kg/h). Group RM received romifidine (same dose) and midazolam (0.02 mg/kg; CRI 0.06 mg/kg/h) whereas group RK was administered romifidine (same dose) and ketamine (0.5 mg/kg; CRI 1.2 mg/kg/h). If sedation was not adequate a top up bolus of romifidine (0.01 mg/kg) was administered. The quality of sedation and the conditions for tooth extraction, the level of ataxia, chewing, head and tongue movement were evaluated by using a scoring system. The investigator was blinded to the applied sedation protocol. Furthermore, serum cortisol concentrations before, during and after the procedure were analyzed to gain more information about the stress level of the horses.

Results

Horses in group RM showed significantly less chewing and tongue activity compared to horses sedated with romifidine alone or with butorphanol additionally, but also significantly higher levels of ataxia. The quality of sedation was significantly better if romifidine was administered in combination with ketamine compared to romifidine alone. Furthermore, horses of group RK needed less additional romifidine boli compared to all other groups. Blood cortisol concentrations during surgery in groups RB and RM remained unchanged. Horses of group R showed higher cortisol concentrations during sedation compared to horses of groups RB and RM.

Conclusion

Romifidine alone at an initial bolus dose of 0.03 mg/kg followed by a constant rate infusion of 0.05 mg/kg/h was insufficient to obtain an adequate level of sedation and led to increased stress levels, whereas the addition of butorphanol inhibited the stress response. The combination of romifidine with either midazolam or ketamine improved sedation quality and surgical conditions.

     

The effect of regular alcohol use on the management of non-insulin diabetes mellitus.

This is a retrospective study, in which we investigated the impact of regular alcohol use on the clinical management of non-insulin dependent diabetes mellitus (NIDDM) patients from the outpatient clinic of the VA Medical Center in New Orleans, Louisiana. The study population included randomly selected NIDDM patients of which 40% used alcohol regularly. The fasting blood sugar (FBS) in non-users of alcohol stayed in the "normal" (< or = 140 mg/dl) and "acceptable " (< or = 175 mg/dl) range and that of regular users of alcohol remained at the "fair" (< or = 235 mg/dl) and "poor" (> 235 mg/dl) range. NIDDM patients who were regular users of alcohol had a higher frequency of dose adjustments than that of non-users of alcohol (96% vs 4%, respectively). The treatment failure was significantly higher among patients who regularly used alcohol than among those who abstained (90 vs 10%, respectively). On the basis of our findings, it was recommended that attending physician should routinely identify the regular alcohol users and monitor blood alcohol levels of ambulatory NIDDM patients during their follow-up visits. Also, complete cessation of alcohol consumption should be established prior to making dosage adjustment in situations where the oral hypoglycemic agent fails.     

Modification of the anticonvulsant efficacy of diazepam by Ro-15-1788 in the kindled amygdaloid seizure model

The effects of various doses of diazepam and the new central benzodiazepine antagonist Ro-15-1788 were investigated in fully amygdaloid kindled rats. Diazepam had a pronounced dose-dependent anticonvulsant effect in this model. Ro-15-1788 dose-dependently reduced the behavioral ranks of the elicited kindled seizures to a maximum of 60% of control without consistently modifying the afterdischarge duration. No prestimulation convulsant effects were seen with Ro-15-1788. When 2 mg/kg i.p. of Ro-15-1788 was given after various doses of diazepam, the prestimulation sedation and ataxia anticonvulsant effects of diazepam (0.5-2.0 mg/kg) were attenuated by treatment with 2 mg/kg dose of Ro-15-1788. At the low dose of diazepam (0.25 mg/kg), increased reduction of behavioral rank and after discharge duration was seen after the 2 mg/kg dose of Ro-15-1788. Thus, Ro-15-1788 appears not to have proconvulsant properties in the kindled amygdaloid seizure model. Further, Ro-15-1788 appears to have some anticonvulsant properties of its own. Mixed agonist and antagonist effects were seen with Ro-15-1788 when given after various doses of diazepam in this model.     

Comparison of midazolam and diazepam for sedation during plastic surgery

A randomized double-blind study was designed to compare midazolam, a rapid-acting water-soluble benzodiazepine, with diazepam for sedation when administered as an adjuvant to ketamine during local anesthesia. In the preliminary dose-ranging study, midazolam (0.05 to 0.15 mg/kg IV) was found to produce a spectrum of central nervous system activity (e.g., sedation, amnesia) that was similar to diazepam (0.1 to 0.3 mg/kg IV). However, the slope of midazolam's dose-response curve for sedation appeared to be steeper (i.e., a narrower therapeutic dosage range). In a comparative evaluation of their relative sedative-amnestic properties and recovery characteristics, the median effective doses of the two benzodiazepines were compared. Midazolam (0.1 mg/kg IV) was found to produce more profound sedation and amnesia than diazepam (0.2 mg/kg IV). Midazolam was associated with significantly less pain on injection and a lower incidence of postoperative venoirritation. Overall patient acceptance was higher with midazolam compared to diazepam. Finally, recovery characteristics were similar for the two benzodiazepines in our outpatient setting.     

RESPONSE OF ANTARCTIC FUR SEALS TO IMMOBILIZATION WITH KETAMINE, A KETAMINE-DIAZEPAM OR KETAMINE-XYLAZINE MIXTURE, AND ZOLETIL®

Adult Antarctic fur seals (Arctocephalus gazella) were immobilized with Zoletil^® ( n = 172), ketamine ( n = 30), ketamine mixed with diazepam ( n = 23) and with ketamine mixed with xylazine ( n = 45). Response to all drugs was highly variable. There was a relationship between dose rate and level of immobilization in females given Zoletil^®. Males were slightly more sensitive to Zoletil^® than females but this could have been due to the greater body mass and lower mass-specific metabolic rate of males. The dose required to achieve a level of immobilization declined with greater body mass for Zoletil^® and ketamine but not for ketamine-diatepam. Ketamine and ketamine-sedative mixtures commonly caused mild tremoring and occasionally caused convulsions. Neither reaction was seen with Zoletil^®. Mean doses were, Zoletil^® 1.5 mg/ kg, ketamine 6.9 mg/kg, ketamine-diazepam 6.3 mg/kg ketamine and 6.3 μg/kg diazepam, and ketamine-xylazine 7.3 mg/kg ketamine and 0.62 mg/ kg xylazine. Zoletil^® performs at least as well on Antarctic fur seals as ketamine but it may cause respiratory depression. The dose of ketamine required for Antarctic fur seals was greater than for most other species of seals.     

The comparative effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol seizure threshold in the rabbit.

The anticonvulsant effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol (PTZ) seizure threshold were studied and compared in the rabbit. The PTZ seizure threshold determined in various rabbit groups during the control phase of conducted experiments, was found to be in the range of 10.1 +/- 2.0 to 13.5 +/- 3.7 mg/kg. Intravenous administration of comparable doses of propofol, thiopental, and diazepam resulted in marked and significant increases in PTZ seizure threshold. At all administered doses (1.25-10.0 mg/kg), propofol was found to be more effective than thiopental in increasing the PTZ threshold dose. However, the anticonvulsant effects of diazepam were more marked than those of propofol, except at a dose of 10 mg/kg where both agents exhibited equipotent activities. These data demonstrate that propofol enjoys a considerable degree of anticonvulsant activity in the rabbit. This anticonvulsant action is greater than that of thiopental at doses ranging from 2.5 to 10 mg/kg and equipotent with diazepam at the 10 mg/kg dose.     

Gender-related differences in diazepam effects on performance

In order to investigate the possible differences of diazepam effects in the two sexes, two placebo-controlled double-blind studies were conducted on healthy volunteer students. In one study the subjects received diazepam 10 mg alone or combined with 0.5 g/kg of alcohol in a parallel group design; in the other 0.2 mg/kg of diazepam or placebo were given in a cross-over manner. In both trials diazepam impaired the psychomotor skills of women more than men. The difference was similar in tasks measuring cognitive (digit symbol substitution), motor (balance of extraocular muscles) and sensory (critical flicker fusion) performances. Tapping speed was affected to a similar degree in both genders. Diazepam 10 mg did not cause impairment of body balance, a parameter sensitive to alcohol. The combined effect of diazepam and alcohol was of similar magnitude in both sexes in all objective tests. Subjectively the women felt themselves clumsier than did the men. The calming effect was similar in both groups. The results suggest that while the performance of women may be more vulnerable than men to impairment by diazepam they also are aware of it. The difference of effects is of such magnitude that it may cause bias in experiments unless carefully balanced groups are used.     

地西泮和戊巴比妥钠对两种小鼠镇静催眠作用强度的观察

目的：观察地西泮和戊巴比妥纳对不同种属小鼠自主活动和睡眠效应的影响,为筛选影响中枢神经系统功能的药物提供可参考的选择动物的依据。方法：分别取昆明种和ICR小鼠各40只,设对照组和地西泮给药组,每组20只,给药组ig地西泮4mg／kg,对照组给生理盐水,连续3天,末次给药后45分钟测定小鼠自主活动。另取两种小鼠各20只,分别ip戊巴比妥钠50mg／kg,观察两种小鼠的睡眠情况,记录潜伏期和睡眠时间。结果：ICR小鼠ig地西泮后,表现明显的镇静作用,自主活动的次数和对照组比较明显减少,P〈0．01;而昆明种小鼠给相同剂量的地西泮,小鼠自主活动的次数减少不明显,P〉0．05。昆明种和ICR小鼠同样ip阈上剂量的戊巴比妥钠,两者在睡眠潜伏期上无明显差异,但在睡眠时间上,则ICR小鼠的睡眠时间明显长于昆明种小鼠,P〈0．01。结论：ICR小鼠对中枢抑制药的反应性更好,适合于这类药物的筛选,尤其对作用相对较弱的中药制剂,可能提高筛选的阳性率。