Benzodiazepines: half-life and daytime sleepiness.
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Biomedical subjects
Publications and source records attributed to R Fontaine.
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In this double-blind, placebo-controlled study of 4 weeks of benzodiazepine treatment followed by 3 weeks of abrupt or gradual drug withdrawal, 16 patients whose benzodiazepine was withdrawn abruptly were worse (p less than .05) than 13 who had received placebo in terms of change in mean anxiety scores from the pretreatment level. The scores of seven patients (44%) whose benzodiazepine was withdrawn abruptly increased 10% or more on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale. There were no cases of rebound anxiety in 14 patients whose benzodiazepine was withdrawn gradually; fewer cases of rebound anxiety were seen with a benzodiazepine that had a long half-life.
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Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious. Clonazepam, an anticonvulsant which increases 5HT synthesis, was more efficacious than lithium in reducing manic symptoms. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.
In a double-blind, placebo-controlled study, 48 anxious outpatients with a primary diagnosis of generalized anxiety disorder were randomly assigned to 4 weeks of treatment with bromazepam (18 mg/day), diazepam (15 mg/day), or placebo, after a 1-week washout period. From week 1 onward both active drugs were superior to placebo in relieving anxiety symptoms. Bromazepam was found to be significantly more effective than diazepam with respect to the somatic anxiety factor and the total score for the Hamilton Anxiety Rating Scale and the fear/anxiety factor of the Patient's Self-Rating Symptom Scale. Plasma concentrations of diazepam plus active metabolites were correlated significantly (r = 0.60, p less than 0.05) with the percentage reduction in self-rating anxiety scores. Bromazepam plasma concentration measurements showed greater variability than those of diazepam and were not found to be correlated significantly with clinical response. It is suggested that the use of strict diagnostic criteria (1978 draft of the third edition of Diagnostic and Statistical Manual of Mental Disorders), adequate sample sizes, and a 4-week study period gave increased sensitivity for the detection of significant differences between the two benzodiazepines.
In a double-blind controlled study lasting 8 weeks, 50 anxious psychoneurotic outpatients with a primary diagnosis of generalized anxiety or panic disorder were randomly assigned to alprazolam (n=30), a new benzodiazepine, or placebo (n=20), after a washout period of 1 week. Alprazolam at dosages between 0.25 and 3 mg/day was found to be significantly better than placebo in the treatment of either disorder. The finding that alprazolam was effective in the treatment of panic disorder is of interest as this diagnostic category is usually treated with tricyclic antidepressants or MAO inhibitors.
Anxious patients have a higher incidence than the general population for cardiovascular disorders and sudden death. Several studies have emphasized abnormal pulse rate, abnormal heart response conditioning, high incidence of arrhythmia, and abnormal blood pressure. Essential hypertension has been studied in relation to stress, and chronic hypotension ('low blood pressure syndrome') has been clinically recognized for decades, but rarely systematically studied. We investigated these abnormal blood pressures in anxious patients, during controlled trials with 80 patients having generalized anxiety disorder as defined in DSM III, for at least 6 months duration, and of moderate to severe intensity. They were randomly assigned to placebo, or bromazepam, 18 mg/day. Blood pressure, pulse, and several other measurements were taken on a weekly basis for 2 months (washout phase--1 week, treatment phase--4 weeks, and withdrawal phase--3 weeks). One third of these patients had an abnormal blood pressure (hypertension or hypotension) while untreated, and this is statistically significant when compared to a matched control group of nonanxious patients. Bromazepam improved several patients having either hypertension or chronic hypotension. These findings are relevant for long-term treatment of anxious patients, since cardiovascular psychosomatic complications are a major health problem.
Two surveillance systems were initiated in Texas in 1980 to detect cases of dengue fever. Physicians throughout the state were requested to report cases of dengue (passive surveillance), and 27 out-patient facilities serving geographically and ethnically high risk populations were asked to report cases of dengue-like illness weekly (active surveillance). Additionally, two clinics participating in active surveillance submitted acute-phase blood specimens weekly for dengue virus isolation. Sixty-three cases of illness due to dengue type 1 infection (dates of onset 2 August-10 November) were documented by virus isolation or serologic testing; 52 of them (83%) occurred n countries adjacent to the Texas-Mexico border. Fifty-six patients (89%) were Hispanic; 46 (73%) were females. Twenty-seven patients (43%) had not traveled outside the U.S. before becoming ill. Since no clinically apparent outbreak of dengue was ever recognized by public health officials in Texas in 1980, the active surveillance system in other Gulf Coast states should be considered when the risk of introduction of dengue is considered high.
Acute, subacute and chronic toxicity-carcinogenicity studies of 2-[1-(2,6-dichlorphenoxy)-ethyl]-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor) were conducted in rats, dogs, and/or mice. The oral LD50 values for these species were similar. Lofexidine given orally to rats and dogs for up to 12 months produced no significant adverse effects at doses up to 1 mg/kg and only marginal effects at 3 mg/kg; moderate to severe effects were noted at doses of 5-25 mg/kg. When given orally to rats for 24 months at doses of 0.1-1.0 mg/kg, lofexidine failed to elicit any evidence of carcinogenicity. Phentolamine and tolazoline may be useful as antidotes in cases of overdosage.
The toxicity and side-effects of the antihypertensive and diuretic combination 2-[1-(2,6-dichlorphenoxy)-ethyl-2-imidazoline-hydrochloride (lofexidine, Lofetensin and Loxacor) hydrochlorothiazide were studied in toxicity and teratogenicity tests and the possibility of interactions was investigated. In terms of lofexidine, there was no evidence of any adverse interactions with hydrochlorothiazide either following a single, oral administration to rats and mice or following short-term and long-term repeated oral dosing of rats and dogs. In the subchronic and chronic toxicity studies it was actually found that the familiar, unwanted sedative effect of lofexidine failed to occur when the combined preparation was given. With repeated oral administration to rats and dogs definite drug-related toxic findings, such as a reduction in serum potassium, mineralization of a few organs and crystal formation in the urine, only occurred at dose levels far above the therapeutic dose. The results of these studies along with historical data on the individual components would suggest a lack of carcinogenic potential for this combination. No teratogenic or embryotoxic effects were noted in rats or rabbits.
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