Gerhard Zbinden

Pharmacology of Benzodiazepines: Laboratory and Clinical Correlations

Publisher Summary In this chapter, an attempt is made to describe the principal pharmacologic and therapeutic effects of the benzodiazepines and to correlate the experimental findings in animals with clinical observations in normal human subjects and patients with a variety of psychoneurotic, mental, and neurological disorders. Based on experience with chlordiazepoxide and diazepam, the first benzodiazepines introduced in clinical practice and the still limited observations with a number of newer analogs, it is shown that therapeutic efficacy and side effect liability can, in part, be directly related to the pharmacologic effects in normal animals or especially prepared animal models. For other clinical observations, however, the pharmacologic basis remains speculative. The comparison with other psychotropic agents provides further data that may shed some light on the significance of animal testing for the predication of the therapeutic value of psychotropic drugs. The chapter represents an attempt to correlate on a broad basis the knowledge obtained in animal experiments with the clinical experience in human. It is clear that in the atmosphere of exploration and discovery that is always created by a new class of drugs, clinicians, and basic scientists usually tend to pursue their respective research goals without too much concern about the results of other disciplines. Drug effects on conditioned animal behavior, for example, are one of the areas where basic scientists have gained an enormous amount of data, but have not been able to correlate many of these results with clinically observed drug actions in human. The new and interesting findings on the maintenance of muscle tone through the interplay of the alpha and gamma motor neurons have greatly advanced the knowledge of motor reflexes and experimental induction of the spasticity of isolated muscles in cats.

Experimental and Clinical Aspects of Drug Toxicity

Publisher Summary This chapter discusses the experimental and clinical aspects of drug toxicity. With the development of an increasing number of new and often very potent medicaments the problem of drug-induced toxicity has become a matter of major concern. The history of every new substance is almost invariably marked by an early and enthusiastic acclaim for its novel therapeutic potential which is often followed by a condemnation due to the occurrence of the seemingly inevitable side actions. This phase is usually followed by a more realistic appraisal of the new compound and recognition of its range of usefulness, contraindications, and dangers. Since there is probably no biologically active substance which does not exhibit some undesirable effects, drug-induced toxicity will always accompany the progress made in drug therapy. It would be very desirable if the harmful effects of newly developed compounds could be recognized in animals before any damage is done to human subjects. For that reason it has become a standard practice to subject every drug to extensive trials in laboratory animals prior to their release for human use.

Experimental and clinical toxicology of chlordiazepoxide (Librium

Abstract The effects of excessive doses of chlordiazepoxide in animals and in 22 patients who had attempted suicide are described. In most subjects, single doses up to 2250 mg caused sedation, often ataxia and dysarthria, and in rare instances sleep and coma. No organs or blood changes were noted, and recovery was uneventful in all cases. In animals, similar symptoms were observed with doses of 20–40 mg/kg and higher. The depressant effects in animals could be counteracted by analeptics and intensified by high doses of sedatives and hypnotics. Only slight changes of blood pressure and respiration occurred when large doses were given. Prolonged administration of chlordiazepoxide to animals in amounts severalfold higher than the clinical dosage schedule over a period of many months failed to produce toxic alterations of blood cells and tissues. An experiment is described in which a human volunteer took a total of 9700 mg of chlordiazepoxide over a period of 12 days; the only symptoms detected were irritability, ataxia, and dysarthria, and these were completely reversible.

Inhibition of experimental myocardial necrosis by the monoamine oxidase inhibitor isocarboxazid (Marplan)

Abstract Pretreatment with the monoamine oxidase inhibitor isocarboxazid partly inhibits cardiac necroses induced in rats by subcutaneous injections of isoproterenol.

Alimentäre Beeinflussung der enterochromaffinen Zellen und des 5-Hydroxytryptamin-Gehaltes von Gehirn und Darm

SummaryThe 5-HT content of brain and intestine is markedly reduced in rabbits, guinea-pigs, rats and mice fed a tryptophan-deficient diet. In severe deficiencies also histochemical reactions of the enterochromaffin cells are diminished. In contrast to the reduction of 5-HT by reserpine, the decrease of the 5-HT content in tryptophan-deficient animals develops much more slowly; no regional differences in the gastro-intestinal tract and no histochemically detectable influence on the catecholamine content of the medulla of adrenal gland can be observed.

Experimenteller Beitrag zur Frage von Nierenschäden bei Abusus von phenazetinhaltigen Schmerzmitteln

In view of the chronic interstitial nephritis observed in man after years of abuse of phenacetin-containing analgesics, rats were subjected to oral loading-tests with Saridon and its active components. It was not possible, however, to induce interstitial nephritis experimentally. Trials with Saridon will be continued on rats having undergone additional renal loading-tests and in which renal damage has been previously induced.In view of the chronic interstitial nephritis observed in man after years of abuse of phenacetin-containing analgesics, rats were subjected to oral loading-tests with Saridon and its active components. It was not possible, however, to induce interstitial nephritis experimentally. Trials with Saridon will be continued on rats having undergone additional renal loading-tests and in which renal damage has been previously induced.

EXPERIMENTAL PATHOLOGY OF IPRONIAZID AND RELATED COMPOUNDS

Many hydrazine derivatives have monoamine oxidase (MAO) inhibiting activity in vivo that is often as strong as or even markedly stronger than that exerted by iproniazid (Mardid*). Other compounds of the same chemical type exhibit only a weak MA0 inhibition or none. These observations suggest that there are differences in absorption, breakdown, organ distribution, or detoxification of these drugs that may contribute to the variation in their biochemical properties. In the first part of this paper it will be shown that hydrazides and hydrazines of a similar type, all of which inhibit MA0 very strongly, may lead to different organ changes when given in relatively high doses. This study was initiated in order to select new MA0 inhibitors with fewer side effects for clinical use.

Histochemische Untersuchungen über den Einfluss von Iproniazid (Marsilid) auf die durch Reserpin erzeugte Freisetzung von Adrenalin und Noradrenalin aus dem Nebennierenmark

A single injection of 10 mg/kg reserpine causes marked decrease of catecholamine in the medulla of the adrenal gland of rats. Histochemically, this can be shown by the disappearance of chromaffinity and of the potassium iodate reaction. After pretreatment with 100 mg/kg of iproniazid, reserpine injection induces little or no decrease in the histochemical reactions of adrenalin and noradrenalin. In animals pretreated with equimolar doses of isoniazid, however, histochemical catecholamine reactions are well preserved in all cells of the adrenal medulla. These results suggest that monoamine oxidase plays a part in the reserpine-induced release of catecholamine.

Theoretic background of therapy with monoamine oxidase inhibitors in cardiology

Abstract In human subjects the main cardiovascular effects of the MAO inhibitors of the hydrazine type are orthostatic hypotension and decrease or abolishment of chest pain in angina pectoris. Site and mechanism of action are not yet known but various theories based on clinical and pharmacologic observations have been discussed. The hypotensive effect could be due to a slowly developing ganglionic or postganglionic blockade or be related to adrenolytic properties of the drugs. The therapeutic action in angina pectoris may be a consequence of central stimulation or blockade of pain transmission, but the possibility of an improvement of the myocardial metabolism, either by coronary dilatation or an influence on oxygen requirement of the heart muscle, has also been proposed.

THERAPEUTIC USE OF VITAMIN B1 IN DISEASES OTHER THAN BERIBERI

It must have been a fascinating experience for physicians in 1936 and the following years to observe the therapeutic action of vitamin B1 in severe beriberi. The incapacitating signs of polyneuritis and the life-threatening cardiovascular decompensation disappeared in a few days after the first thiamine injection. Grossly enlarged hearts regained normal size, massive edemas were eliminated, and intractable pains vanished. It must have been equally fascinating for the biochemists who subsequently discovered a large number of biochemical reactions in the intermediary carbohydrate metabolism for which thiamine was an essential part of the catalyzing enzymes, The enthusiasm of the vitamin pioneers in underdeveloped countries and the biochemists at home was not without influence on us physicians who are privileged to practice in well-nourished countries where a true case of beriberi would be a sensational rarity. It is thus understandable that we were and still are giving this vitamin to patients whose symptomatology is similar to beriberi, whose dietary history is suggestive of a certain degree of vitamin B deficiency or who have disturbances of the carbohydrate metabolism.