Withdrawal reactions to diazepam in combined imipramine/diazepam treatment of primary nonagitated depressed outpatients

Twenty-seven outpatients who had primary nonagitated depression that had been treated for 3.5 months with imipramine were included in the study. Of these, 14 patients were given additional diazepam treatment (10 mg/day) and 13 patients got placebo. The additional medication was stopped, and withdrawal reactions were observed after two weeks. The depression scores (both global evaluation and CPRS) increased significantly in the diazepam group, without any changes in the placebo group. Eleven patients in the diazepam group and four in the placebo group reported their condition as impaired after discontinuing their additional medication. Four patients in the placebo group and none in the diazepam group reported improvement. The level of working activity decreased significantly in the diazepam group and increased in the placebo group. The serum level of imipramine decreased in the placebo group (P = 0.07), but not in the diazepam group. Serum levels of desipramine decreased significantly in both groups (P less than 0.05). Our study indicates that the discontinuation of diazepam, even when given in moderate dosage over a relatively short period of time, may cause withdrawal reactions in combined antidepressant/diazepam treatment. This may be caused by a possible tendency for the depression to become chronic. Such chronicity may be the reason for secondary dependency to diazepam.     

安定对人工流产手术扩宫效果的观察─—附208例分析

本文通过安定10mg宫颈注射对108例人工流产孕妇进行观察，结果用药后宫颈口扩张有显著性意义（P＜0．01），且不影响于它收缩，不增加出血量（P＞0．05），人工流产综合征发生率明显减少（P＜0．01），提示安定宫颈注射可起到扩宫，减少人工流产综合征发生的作用。     

Flumazenil oral absorption in dogs

Flumazenil is rapidly absorbed after oral or gastric fistula administration to the dog reaching peak plasma concentrations in about an hour. Plasma level decrease rapidly thereafter reaching barely detectable levels by four hours. The onset of signs of flumazenil precipitated abstinence in diazepam-dependent dogs is well correlated with the rise of flumazenil plasma levels, however, precipitated abstinence seizures occur when plasma levels have markedly decreased. Oral dosing is a more efficient way of administering flumazenil than gastric fistula dosing.     

ACUTE TOLERANCE TO DIAZEPAM IN MICE: PHARMACOKINETIC CONSIDERATIONS

The tolerance to the hypnotic effect of diazepam developed after a single exposure to diazepam in the presence or absence of cycloheximide, which blocks liver enzyme induction, was studied. At the high dose (30-35 mg/kg) used in this study, diazepam was found to be metabolized very rapidly in mice, consistent with previous findings using a much smaller dose (5 mg/kg). There was no significant difference in the pharmacokinetics of diazepam in control and tolerant mice as observed by monitoring the plasma and brain concentrations of diazepam and N-desmethyldiazepam. It is concluded that acute tolerance to diazepam in mice may not be attributed to changes in pharmacokinetic factors.     

The effects of diazepam on anxiety-related cognition

It has generally been assumed that the therapeutic action of benzodiazepines results from the effect of these drugs on mood. We suggest, however, that in reducing anxiety, benzodiazepines may have a direct effect on anxiety-related cognitions. The investigation was designed to examine the question of whether anxiety-related cognitive bias is reduced by diazepam in subjects selected according to DSM-III(R) criteria for generalized anxiety disorder (American Psychiatric Association, 1987). A modification of the Stroop color-naming task was used to measure bias toward the processing of threatening material. The results demonstrate that the reduction in anxiety shown by anxious patients after diazepam is not accompanied by a reduction in cognitive bias toward the processing of threatening material. This suggests that diazepam fails to reduce anxiety-related cognitive bias in clinically anxious subjects. It would seem, therefore, that diazepam alleviates anxious mood rather than cognitive manifestations of anxiety.We would like to thank Malcolm Lader and Andrew Mathews for their help in developing this research. We would also like to thank the Medical Research Council for supporting the investigation.     

Role of GABA during the multiple consolidation of memory

Alzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients is the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA-A and GABA-B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA-A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of thee drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose- and time-related, and cannot be explained by state-dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long-term potentiation (LTP); (7) GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo-hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the “multiple consolidation” process of memory storage. © 1993 Wiley-Liss, Inc. © 1993 Wiley-Liss, Inc.     

静注安定亚微乳的制备及其特征

应用泊洛沙姆108与精制豆磷脂为乳化剂,制成静注安定亚微乳剂。用单纯形优化法来优化处方中乳化剂的用量(最优化值分别为4%和0.3%)。粗乳经两步高压乳匀机处理后,得很细的单分散乳剂。乳剂用透射电子显微镜检查,粒径均小于364nm。亚微乳不溶血,毒性低,小鼠 LD_(50)是市售安定注射液的2.5倍。药时曲线与市售安定注射液相似。     

Adenosine in the inhibition of diazepam sedationby aminophylline

Aminophylline in a low dose has been shown to reverse diazepam sedation. The present investigation was performed as a double-blind study to compare the effects of aminophylline and enprofylline on deep diazepam sedation after surgery. Enprofylline is a xanthine derivative with anti-asthmatic effect but, in contrast to aminophylline, enprofylline has very weak adenosine antagonistic properties. A comparison should make it possible to evaluate if adenosine is involved in the observed effects. Twenty male patients undergoing transurethral surgery in spinal anaesthesia were given diazepam during surgery to maintain a state of deep sedation. Postoperatively aminophylline or enprofylline was given from coded ampoules in equipotent anti-asthmatic doses (4.5 or 1.5 mg/kg). The degree of sedation was assessed prior to and after the injections. A difference between the groups was obvious. Patients given aminophylline showed rapid reversal of sedation, persisting throughout the 2-h observation period. Following enprofylline, a markedly slower reversal of sedation was observed. It is likely that aminophylline antagonises diazepam sedation by blocking adenosine receptors. Some clinical implications are outlined.     

Intermittent prophylaxis in febrile convulsions: diazepam or valproic acid?

In an open, prospective, randomized, and hospital-based study, comprising 219 consecutive children, 169 were given intermittent prophylaxis for one year, receiving either diazepam or valproic acid after their first febrile convulsion. Children admitted on odd dates (n = 89) were given rectal diazepam in solution every 12 h, whenever the temperature was 38.5 degrees C or more. Children admitted on even dates (n = 80) were given valproic acid as suppositories at times of fever. Twenty-three children in the diazepam group had a recurrence within 1 year versus 14 in the valproic acid group. On an intention-to-treat basis the 12-month recurrence rates in the 2 groups were similar, 27% vs 20%. The latter is well below figures for untreated controls from Denmark (32%), suggesting that intermittent valproic acid at times of fever may be effective, but further studies are needed. The number of complex recurrences, however, were significantly higher in the valproic acid group than in the diazepam group. Parental non-compliance was a major problem, and in the 2 study groups only 5 and 12 children, respectively, with recurrences were treated adequately. Sixty-nine children receiving diazepam had side-effects vs 37 receiving valproic acid. None were serious.