Louis F. Fabre

The Efficacy and Safety of Nabilone (A Synthetic Cannabinoid) in the Treatment of Anxiety

Abstract: The anxiolytic properties of nabilone, a synthetic cannabinoid resembling the natural cannabinoids, were studied in 25 outpatients suffering from anxiety. The drug was compared with a placebo in a double‐blind manner over a 28‐day treatment period. Patients were seen weekly by the physician and were rated by the Hamilton Rating Scale for Anxiety and the Patients Global Evaluation as well as by patient‐rated evaluations. The results of the study showed a dramatic improvement in anxiety in the nabilone group when compared with placebo (P < 0.001). Side effects reported were dry mouth, dry eyes, and drowsiness. Patients did not report any of the subjective “altered state” experience of marihuana.

Preference studies of triazolam with standard hypnotics in out-patients with insomnia.

One hundred and four patients suffering from insomnia took part in four different two-night double-blind crossover trials of triazolam. In three separate studies, triazolam 0·5 mg was compared to placebo, flurazepam 30 mg and chloral hydrate 500 mg. Triazolam 0·5 mg was found to be preferred and to be superior to placebo, flurazepam and chloral hydrate in the treatment of insomnia. Analysis of sleep questionnaire data showed triazolam to be superior to the other treatments on the following: How much did the medication help you sleep, onset of sleep, duration of sleep and number of awakenings. Additionally, triazolam was superior to chloral hydrate on the feeling in the morning parameter. In another comparison of triazolam 0·25 mg to flurazepam 15 mg, triazolam was not significantly better than flurazepam on any of the efficacy parameters except that the patients felt more alert the morning following triazolam than following flurazepam. On all efficacy endpoints, trends for all parameters favoured triazolam 0·25 mg over flurazepam 15 mg. Untoward side-effects in these four studies were minimal.

An evaluation of the gas chromatographic analysis of plasma amino acids.

Abstract The accuracy and reproducibility of gas—liquid chromatography of plasma amino acids as their n-butyl N-trifluoroacetyl esters are statistically evaluated. Plasma is deproteinized with picric acid and amino acids are purified by microcolumn chromatography on Dowex 50 W-X12. Routine analysis requires only 0.2 ml of plasma with recoveries of 75–90% for the protein precipitation—ion exchange steps as determined by tracer methods. The ester derivatives are injected directly onto 0.7% EGA or 1.0% OV-17 columns. Variability due to the use of different GLC columns is minimized by careful calibration. Replicate analysis of the same sample indicates that the overall reproducibility is satisfactory for clinical usuage. The range of normal concentration for amino acids in our clinical population is within agreement with values obtained by other methods. A complete analysis can be accomplished within 12 h, however grouping samples allows processing of 8–10 plasma samples in one working day, greatly facilitating biochemical investigations such as metabolic disorders in retarded children.

Comparative efficacy and safety of bupropion and placebo in the treatment of depression.

This was a 4-week, three-center, double-blind, randomized, parallel, placebo-controlled evaluation of the efficacy and safety of bupropion in hospitalized depressed patients. Results from 27 placebo and 48 bupropion-treated patients were analyzed for efficacy and safety. Assessments of efficacy and safety were made at baseline and weekly during the study. Primary and secondary measures of efficacy included the Clinical Global Impressions for severity (CGI-S) and improvement (CGI-I) of illness, Hamilton Depression and Hamilton Anxiety Scales, and the Zung Self-Rating Scales for depression and anxiety. Assessments of safety included vital signs, electrocardiogram, clinical laboratory tests, and adverse experiences. Dosages of bupropion were 300–600 mg/day. Results showed that bupropion was significantly (P<0.01) more effective than placebo at termination of study on the CGI-S, CGI-I, Hamilton Depression and Hamilton Anxiety Scales. On the Zung Self-Rating Depression and Anxiety Scales, statistical trends favored bupropion at termination of study over placebo (P<0.10). Adverse events in the bupropion and placebo groups were minimal with notable absence of sedation and anticholinergic-and cardiovascular-related side effects. We conclude that bupropion was significantly more effective than placebo in treating depression and accompanying anxiety in depressed inpatients.

Pilot Open-Label Study of Alprazolam (U-31,889) in Anxious Alcoholic Out-Patients

Twenty out-patients suffering from anxiety and tension after withdrawal from alcohol were treated for 28 days with alprazolam. Three patients dropped out for intercurrent events, and 2 dropped out for recurrent drinking. Of the 15 patients completing the study, analysis of variance showed significant improvement in all Physicians Ratings as well as all patient self-ratings. At the 28th day, 93% of the patients rated moderate to marked improvement on the Physicians Global Impression and Therapeutic Effect, and 93% self rated at least a little better. Side-effects were generally mild and inconsequential. No adverse effects attributable to alprazolam were noted on laboratory evaluations, EKGs, or ophthalmologic examinations.

Comparison of the Therapeutic Effect, Tolerance and Safety of Ketazolam and Diazepam Administered for Six Months to Out-Patients with Chronic Anxiety Neurosis

Recently, it has been argued that benzodiazepines may not be safe or efficacious beyond 3 months continuous dosage. This study was designed to provide data regarding efficacy, safety, possible tolerance development, and possible withdrawal effects of administering ketazolam and diazepam for a 6-month period. Chronic anxiety patients were screened for participation according to specific inclusion and exclusion criteria. Of 139 patients, forty-four terminated prematurely for non-drug related reasons and are not included in the analysis. Of the ninety-five patients remaining, sixty-three were on ketazolam, and thirty-two on diazepam. Efficacy parameters included the Hamilton Anxiety Rating Scale, Physicians Global Impressions, Target Symptoms, Self-Rating Symptom Scale, and Patients Global Impressions. Patients were evaluated weekly for the first month except for Week 3, and then seen bi-weekly and rated monthly. The results of the study showed that ketazolam was as efficacious as diazepam in treating anxiety and resulted in fewer side-effects. No adverse effects were noted in either group. Both benzodiazepines were safe and well-tolerated. No tolerance or withdrawal effects were noted. The average doses were ketazolam Week 4 (50.0 mg), Week 24 (66.14 mg) and diazepam Week 4 (26.33 mg) and Week 24 (33.0 mg). An increase in anxiety occurred in a significant number of patients after termination of either drug. By 2 weeks after the last dose many patients were free of anxiety and did not require further treatment. These results demonstrate that benzodiazepines are safe and efficacious for at least 6 months of continuous dosage.

BIOCHEMICAL AND METABOLIC ASPECTS OF ALCOHOLISM

Dr. Roach and her associates have studied the effect of ethanol on glucose and amino acid metabolism in brain.2 Male hamsters were injected intraperitoneally with ethanol followed immediately by 5 pC of uniformly labeled 14Cglucose. The animals were killed by immersion in liquid nitrogen and the brains analyzed. Ethanol-treated animals showed a dose-sensitive decrease in glucose metabolism in the brain ( T A B L E 1 ). Specifically, glucose content increased over twofold with increasing ethanol dose while, as TABLE 2 shows, there was decreased incorporation of the label from W-glucose into the amino acids derived via the tricarboxylic acid cycle. Glutamine was the amino acid most affected by ethanol, with the incorporation of the label decreasing significantly even at the lowest dose. From this result and the concept of the compartmentation of brain amino acid metabolism, it was concluded that in ethanol-treated animals the radioactivity of the glutamine pool was being diluted by glutamine from unlabeled precursors. Acetate, formed from hepatic ethanol oxidation, was a possible source of this unlabeled carbon. To examine the importance of ethanol-derived acetate as a precursor for brain amino acid metabolism, Dr. Roach and coworkers3 measured the rate of incorporation and the distribution of 14C from [2-14C]ethanol into the free amino acids of hamster brain. The rate of acetate incorporation is compared with the calculated rate of glucose carbon incorporation in TABLE 3. Incorporation of acetate into glutamate, aspartate, and gamma aminobutyric acid was only about 5 % of normal glucose utilization, while incorporation into glutamine was 20% as great. This result supports the conclusion that ethanol effect o n the labeling of glutamine from 14C-glucose was due to the concomitant metabolism of ethanol-derived acetate. I t is interesting to speculate whether in chronic alcoholism an adaptive increase in acetate incorporation into the other amino acids occurs as well. Such an adaptation in the metabolism of these functionally significant amino acids might have significance in the development of alcohol tolerance and physical dependence.

Biphasic Stimulation of Aldosterone Secretion during Hemorrhage in Dogs

The increase of aldosterone secretion in response to hemorrhage has been reevaluated with the aid of a newly developed micromethod using gas-liquid chromatography. Pentobarbital-anesthetized large male dogs were slowly exsanguinated through the lumboadrenal vein while sequential 15-minute samples of adrenal venous effluent were collected. Mean arterial blood pressure and blood loss were monitored. The response to hemorrhage was found to be biphasic; a significant increase in aldosterone secretion occurred before blood pressure changed significantly, the secretory rates then fell toward control, and rose again as the blood pressure fell to shock levels. Statistical evaluation of the data confirmed the quartic nature of the response and indicated a best-fit equation of y = 169.14x − 800.22x2 + 1258.46x3 − 619.24x4. These results demonstrate that control of aldosterone secretion is dependent on complex functions of blood volume and blood pressure. Volume receptor mechanisms as well as pressure receptor mechanisms would seem to be involved. Any investigation of the aldosterone response to hemorrhage, to be valid, must take these complex relationships into consideration.

A Double-Blind Comparison of Prazepam with Diazepam, Chlorazepate Dipotassium and Placebo in Anxious Out-Patients

This study compared prazepam with diazepam, chlorazepate dipotassium, and placebo in the treatment of anxious out-patients. Patients were screened for participation in the study to be sure they met the criteria for inclusion. Patients were excluded if they had complicating physical or mental problems. All patients signed an informed consent. Seventy-three patients entered the study, thirteen did not complete at least two weeks of treatment and were not used in the data analysis. Of these thirteen, ten did not return and were lost to follow-up, two entered the hospital for reasons unrelated to the drug study, and one patient on diazepam was terminated because of increased anxiety. Sixty patients were used in the data analysis, thirty-six males and twenty-four females with an age range of 21–61 years. Side-effects were minimal. Drowsiness was reported by two people in the placebo group, one taking chlorazepate dipotassium, three on prazepam and one on diazepam. One diazepam patient reported nausea and vomiting. Scores on the Zung Self-Rating Scale for Anxiety showed all three drug groups to be superior to placebo. The Hopkins Symptom Check-list found prazepam and diazepam to be superior to placebo and chlorazepate. No differences among the groups were found in the Hamilton Anxiety Scale. Prazepam may offer advantages over the other available benzodiazepines since it may be more readily absorbed than chlorazepate and has less side-effects than diazepam.

Research training in alcoholism.

The research and training programs of the Texas Research Institute have attempted, over the past several years, to coordinate multidisciplinary studies related to the physiopathology of alcohol dependence. Four basic research divisions of the Institute have investigated the neurochemical, biochemical, neuroendocrinological, and behavioral pharmacological concomitants of the addictive processes. In discussing some of the projects that have emanated from our program, we hope to be able to relate our research experience to the issue of medicalstudent education-with the precaution that, in our limited experience, we do not feel encouraged about the future of research training in the standard medical school curriculum in general, and, in alcoholism, the problem appears particularly difficult. The term “alcohol dependence“ is used here in recognition of the fact that, although regarded sociologically and administratively as a separate entity, alcoholism is classified by the World Health Organization (WHO) Expert Committee on Addiction-Producing Drugs (1952) as reported by Eddy and colleagues ( 1966) along with other drugs of abuse. In the natural history of the development of alcoholism as a clinically recognizable syndrome, the individual, as a rule, enjoys a period of social drinking of variable length, but frequently of many years’ duration. During this time, with the exception of occasional “sprees” with the accompanying hangovers and embarrassment, often taken in good humor, little obvious damage is done to the physical health or social relations of the person. This period might be referred to as a stage of elective drinking. The onset of alcohol dependence as a definable condition is insidious and may cover a considerable span of time (a stage of transition) with markedly varied individual manifestations; the establishment of the stage of compulsive drinking may occur without a sharp break in continuity. Once well under way, however, the compulsive drinking leads the subject into the behavior patterns all too familiar to the family, physician, employer, and social worker who must deal with the individual. For all practical purposes, the stage of compulsive drinking may presently be considered irreversible, with the exception of the small percentage of persons who find recovery in Alcoholics Anonymous or under intensive psychiatric care. In our thinking, then, an extremely important goal of our research is to develop means for the detection of the potential alcoholic during the stage of transition, when a permanent cure may be effected. This, of course, may be difficult indeed. Of every hundred persons in the stage of elective drinking, more than 90 will continue indefinitely-with no apparent degeneration into true alcohol dependence. Further, of the 10% (more or less) who will contribute to the final group of hard-core compulsive drinkers, only a few may come to be recognized as such by the physician before the development of the full-blown disease, for many reasons: the protection of the family, reluctance or inability of the individual to recognize what is happening, unwillingness to communicate the problem to the doctor, and the like. It would seem that the heart of the matter is the nature of the alcohol de-