William G. Clark

A rotating diffusion chamber for C14O2 determination as applied to inhibitor studies on mouse mast cell tumor histidine decarboxylase

Abstract A convenient, reliable, and efficient method for the estimation of histidine decarboxylase was developed. This method, which employs CO 2 formation, was compared with methods utilizing histamine formation. The difficulties of measuring histidine decarboxylase by estimating the histamine formed are discussed. By measuring the radioactive CO 2 , liberated by enzymic decarboxylation of histidine-1-C 14 , various compounds were studied for their inhibitor action.

Teaching Medical Interviewing: The Lipkin Model

This chapter describes the evolution of a unique faculty development course and innovative educational model designed by Mack Lipkin, Jr. for teachers of medical interviewing. His approach integrates principles of learner-centered (or self-directed) learning with core human values, such as unconditional positive regard for others and attention to affect. We first describe some experiences that led Lipkin to the development of the course model. We then discuss the educational context and principles of the course and detail its structure, process, and problems. We end with some short examples of other applications of this approach in medical education.

Comparison of the dopaminergic effects of apomorphine and (-)-N-n-propylnorapomorphine.

(-)-N-n-propylnorapomorphine (NPA) was found to be 2.3 times more active than apomorphine in producing stereotypy in novice mice. This potency ratio was not changed by reserpine pretreatment (4 h prior). However, when mice pretreated with reserpine 24 h earlier were used, NPA was found to be 6.5 times more active in producing locomotor stimulation and 8.7 times more active in producing stereotypy than apomorphine. In these mice, a second dose of reserpine or alpha-methyl-p-tyrosine (alphaMT) given 4 h prior to NPA administration considerably reduced the locomotor effects of NPA. Such treatments did not modify the effects of apomorphine. Phenoxybenzamine failed to alter the responses of both these drugs. It was concluded that, while apomorphine possesses direct dopamine (DA) receptor stimulant effect, that of NPA is partly direct and partly indirect in nature. In novice mice, NPA was 91 times more active than apomorphine in inhibiting the alphaMT-induced depletion of brain DA. The question is raised why the powerful DA receptor agonistic effect of NPA did not produce equivalent behavioral responses in mice. The likely explanation would be that, in addition to its effect on the striatonigral DA system from which the stereotypic response originates, NPA also exerts a predominant effect on the mesolimbic areas. The combined effect of NPA on these two components of the DA system is reflected in the biochemical results. The overall dopaminergic effect of NPA is several times greater than that of apomorphine.

Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (-) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or gamma-acetylenic GABA caused a dose-dependent inhibition of thelocomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (-) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for gamma-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (-) baclofen may prove to be useful in the management of PCP intoxication. Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (-) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (-) baclofen and PCP. The possible use of (-) baclofen as an adjuvant to general anesthetic is discussed.

Histidine decarboxylase activity of basophils from chronic myelogenous leukemic patients. Origin of blood histamine.

It is well established that relatively large amounts of histamine are present in tissue mast cells (1–3), and leukocytes (4–6), especially the granulocytes and probably largely the basophils (4,7).† Eosinophils have also been claimed to contain histamine (7). A polemic has existed since the first report of Code in 1936 (4) regarding the origin of histamine in the body. Some argued that it originated solely from ingestion with food and from decarboxylation of histidine by intestinal flora, and others asserted that it also originated by the action of a tissue decarboxylase. The bulk of evidence supports the concept that tissue mast cells of mammalian organisms decarboxylate histidine to histamine (1–3,11) although some workers have denied this (8). Only a few investigators have ruled out bacterial decarboxylation in their in vitro studies. These are Werle, et al. (12) who used sterile precautions and tested for contamination after incubation; Gustafsson, Kahlson and Rosengren who worked with germ-free rats (9); and Schindler, Day and Fisber who worked with sterile tissue cultures of malignant murine mast cells (11).

Effect of some benzylhydrazines and benzyloxyamines on dopa and 5-hydroxy-tryptophan decarboxylasein vivo

Abstract A number of benzylhydrazines and benzyloxyamines have been compared for their ability to inhibit the decarboxylation of 5-hydroxytryptophan (5HTP) and 3,4-dihydroxy-phenylalanine (dopa) in mice. Three different methods have been employed: 1. Inhibition of the decarboxylation of injected C 14 -carboxyl-labeled dopa and 5HTP as measured by respiratory C 14 O 2 . 2. Inhibition of 5HTP-induced tremors. 3. Inhibition of formation of 5-hydroxytryptamine in the brain after injection of 5HTP in mice pretreated with a monoamine oxidase inhibitor. The most active hydrazines were dl -α-hydrazino-α-methyl-3,4-dihydroxyphenylpropionic acid, N′-(3-hydroxybenzyl)-N′-methylhydrazine; N′-(4-bromo-3-hydroxybenzyl)-N′-methylhydrazine and N-( dl -seryl)-N′-(2, 3, 4-trihydroxybenzyl)hydrazine. Of the oxyamines, the 3, 4-dihydroxybenzyloxyamine and 3-hydroxybenzyloxyamine were the most potent.

Effect of thiazol-4-ylmethoxyamine, a new inhibitor of histamine biosynthesis on brain histamine, monoamine levels and behavior☆

Abstract FIVE histidine decarboxylase inhibitors, two of which are new, were tested for their effects on brain histamine (Hm) levels in rats. Of these, only one of the new ones, thiazol-4-ylmethoxyamine (TMA) lowered brain Hm under the experimental conditions applied. A single dose of 100 mg/kg I.P. TMA caused a gradual fall in Hm level, reaching the lowest level, 10% of control, at 72 hours. A dose of 300 mg/kg caused the maximum effect at 24 hours. With either dose, recovery occurred within 4 days. In a dose of 100 mg/kg, the only dramatic brain monoamine change observed was a 40% depletion of dopamine, seen at 72 hours. Some preliminary correlative pharmacological and behavioral effects are also reported.

Effect of Adrenalectomy upon Intestinal Absorption of Sodium Chloride

It is well established that adrenal insufficiency provokes a negative salt and water balance in most mammalian organisms which have been studied, and that this condition can be corrected for the most part by cortical hormone and/or salt therapy. Several workers have reported that this negative balance is due to a primary renal effect; some have indicated it to be due also to primary extra-renal disturbances; and still others have stated that the electrolyte disturbances are secondary to disturbances in carbohydrate metabolism. In another study 1 it was found that healthy adrenalectomized rats, maintained on Rubin-Krick salt drinking-fluid and stock diet for periods up to 2 weeks, absorbed glucose at the same rate as controls. A modified Cori technic was used, employing the intact rat. This finding confirmed Deuel, et al. 2 , who also used this technic; and failed to confirm the conclusions of Wilbrandt and Lengyel, 3 and Verzar, et al. 4 who used the isolated intestinal loops of rats, cats, and dogs. The present study indicates that healthy adrenalectomized rats absorbed NaCl more slowly than controls. The Cori technic was used in preliminary studies, and both sodium 5 , 6 and chloride 7 , 8 of the minced, leached gastrointestinal tract was determined in most cases, although this was not essential since stomach-emptying of control and adrenalectomized rats was comparable for both sodium and chloride. The stomach-emptying of the adrenalectomized rats varied far more than that of the controls, however, so that for small differences in intestinal absorption, the stomachs should be separately analyzed. The intestinal absorption rates of both Na and Cl were comparable and those of the adrenalectomized animals were considerably less than the controls, although more variable.

The effects of peripherally administered 6-hydroxydopamine on rat brain monoamine turnover.

Abstract Peripheral chemical sympathectomy by 6-hydroxydopamine in rats accelerated turnover of cerebral noradrenaline, but did not change turnover of cerebral dopamine and 5-hydroxytryptamine. This increase in noradrenaline turnover was long lasting and was observed in the first degenerative phase of the action of 6-hydroxydopamine as well as after established degeneration of the peripheral sympathetic nerves.

Blockade of the central effects of d-amphetamine sulfate by amantadine hydrochloride

Abstract Amantadine hydrochloride, unexpectedly, was found to block certain effects of d-amphetamine sulfate. In mice pretreated with amantadine, 150 mg/kg, d-amphetamine, 2 mg/kg or 5 mg/kg, failed to produce hyperactivity. This pretreatment also protected aggregated mice from the lethal effects of d-amphetamine, 30 mg/kg. Both d-amphetamine, 15 mg/kg, and chlorpromazine hydrochloride, 10 mg/kg, caused elevations in the homovanillic acid (HVA) concentrations in the caudate nucleus of mice, and amantadine pretreatment blocked this response to d-amphetamine but not that to chlorpromazine. Due to the many similarities in the pharmacological, behavioral, biochemical and clinical effects of amantadine and d-amphetamine, they may act at the same receptor and the observed antagonism may be due to a competitive blockade so that d-amphetamine fails to reach its site of action.