Graham Chen

A Facilitation Action of Reserpine on the Central Nervous System

Summary 1. Data are presented to show a facilitation action of reserpine on the central nervous system. The drug hastens the onset of maximal tonic extensor seizures in mice receiving intravenous Metrazol or caffeine (but not strychnine). It lowers the convulsive seizure threshold of mice to electrical stimuli and antagonizes the anticonvulsant action of Dilantin. 2. Some possible mechanisms of action and certain clinical implications of this property of reserpine are suggested.

Evaluation of five methods for testing anticonvulsant activities.

Summary 1. Anticonvulsant activities of 10 CNS depressants were determined by the following 5 procedures: (a) Supramaximal electroshock; (b) supramaximal chemoshock (Metrazol); (c) “psychomotor” seizure; (d) subcutaneous Metrazol; and (e) intravenous Metrazol (a minimal convulsive dose). 2. Results indicate that intensity of convulsive stimuli, electrical or Metrazol, is the important factor in determining anticonvulsant property of a compound. The order of anticonvulsant activities of these compounds is the same whether determined according to the first two methods by the abolition of hind leg extensor seizure, or according to the latter three methods by the inhibition of a minimal clonic seizure response. 3. Reasons are given for our preference of the supramaximal electroshock and the subcutaneous Metrazol method for screening for potential antiepileptic compounds.

Drug effects on the disposition of active biogenic amines in the CNS

Abstract Imipramine, desipramine, amitriptyline, desoxyephedrine, cocaine and phencyclidine were shown to prevent the depressant and the ExST lowering effect of tetrabenazine to produce with tetrabenazine a greater elevation of ExST in mice to electroshock. These drugs appeared to impede the elimination of the active biogenic amines released by tetrabenazine, thus giving rise with the amines and additive effect on ExST. The excitatory activity of the “accumulated” biogenic amines might account also for the absence of depression by tetrabenazine.

Pyrazapon (CI-683): A new antianxiety agent

Pyrazapon, a pyrazolodiazepinone, exerts strong disinhibitory effects on behavior in a variety of animal tests (ingestion of a novel food substance, conditioned conflict, hypothalamic self-stimulation). In tests for sedation, motor depression, and ataxia, weak effects were seen relative to chlordiazepoxide and diazepam. Pyrazapon also shows considerable ability to protect against pentylenetetrazol-induced convulsions in acute tests. However, much tolerance develops to this effect in the course of daily treatments. Tolerance does not develop, on the other hand, to the behavioral disinhibitory effect. No untoward pharmacodynamic effects were observed at doses several fold greater than those producing the principle pharmacologic effects. Pyrazapon may well be an effective antianxiety drug with very weak sedative side effects.

Antagonism Studies on Reserpine and Certain GNS Depressants

Summary 1. Quantitative studies with electrically induced convulsions have been carried out in mice on antagonism between reserpine and the following CNS depressants-Dilantin, N-methyl-α-methyl-α-phenylsuccinimide (PM 396), phenobarbital, Milontin, phenacemide, carbromal, barbital, pentobarbital, and mephenesin. 2. Antagonism between reserpine and Dilantin appears to be competitive in nature, a facilitatory and an inhibitory effect respectively, acting on the spread of seizure discharge. 3. Antagonism data for reserpine and phenobarbital as well as those for reserpine and PM 396 were found to bear a relationship similar to that between reserpine and a combination of Dilantin and barbital, indicating a dual mechanism in their anticonvulsant effect, inhibition of seizure spread and elevation of the threshold for seizure discharge. 4. Quantitative differences in antagonism between reserpine and the various CNS depressants are apparently due to differences in the extent to which the two mechanisms are involved in their anticonvulsant effects.

Anticonvulsant Properties of 1-(1-phenylcyclohexyl) piperidine · HCl and Certain Other Drugs

Summary 1-(1-phenylcyclohexyl) piperidine · HC1 was found to be a very effective agent in suppression of audiogenic seizures in mice. It was approximately 7 times more potent than Dilantin and phenobarbital and 25 times more potent than barbital. PCP was likewise the most active anticonvulsant in electrically induced tonic extensor seizures. Like Dilantin, on the other hand, PCP was devoid of any anti-clonic seizure activity in pentylenetetrazol-induced convulsions. A comparison was also made of the anticonvulsant effects of Dilantin, phenobarbital and barbital in audiogenic, pentylenetetrazol and electrically induced convulsions.

Effect of 1,1-dimethyl-4-phenylpiperazinium iodide on peristaltic reflexes of isolated guinea pig ileum.

Summary DMPP has been shown, like nicotine, to augment the peristaltic reflex of an isolated ileum to increasing pressure at low concentrations but inhibits it at high concentrations. This is apparently due to its stimulating and paralyzing action on the parasympathetic ganglion at low and high concentrations, respectively. The fact that the paralyzing effect of DMPP on the ganglia was not evident on repeated administrations in animals of submaximal doses may be explained by the rapid elimination of it from the site of action. Whereas physostigmine antagonized the blocking effect of d-tubocurarine, it does not influence that of DMPP on peristaltic reflexes of the ileum.

Pharmacology of Para-substituted Derivatives of Diphenhydramine

Summary The antihistaminic, anticholinergic and musculotropic spasmolytic properties of the para-halogen, para-methoxy and some para-alkyl derivatives of 2-benzhydryloxy-dimethylethyl amine have been investigated. Para-substitution with methyl, ethyl and halogen atom results in an enhancement of antihistaminic activity, a decrease in acute toxicity, or both. It lowers the atropine-like action but does not produce a significant change in musculotropic spasmolytic activity.

Influence of Diphenhydramine on Blood Pressure Response to Epinephrine in the Dog under Adrenergic Blockade

Conclusion Diphenhydramine was found to convert the vasodepressor effect of epinephrine and arterenol in the dog under adrenergic blockade with SY-28 to a vasopressor effect. The para-methyl substituted derivative of diphenhydramine as well as cocaine, tripelennamine, pyranisamine maleate, dtubocurarine, dibutoline and ergotamine can produce the same effect. Atropine (anticholinergic), papaverine (antispasmodic) and 2-N-propoxy-4, 6-diamino-s-triazine (antihistaminic) are ineffective. An inhibition of the vasodepressor mechanism is suggested as a possible made of action of these compounds on the reversal of the vasodepressor response and the potentiation of the vasopressor response to epinephrine and arterenol.

A Study of Convulsants Under the Influence of Reserpine and α-Benzoylamino-β-(3Pyridyl) Acrylic Acid Piperidide

Summary The influence of reserpine and α-benzoylamino-β-(3 pyridyl) acrylic acid piperidide (BA3P) upon the response of mice to the convulsive action of 19 drugs has been investigated. Reserpine was found to facilitate tonic extensor seizures induced by COP, BA4P, caffeine, bulbocapnine, THBA, beme-gride, PM-1090, camphorimide, TMTH, nikethamide, Metrazol, IDCI, DMAA and IPBI. It did not affect the tonic extensor seizures induced by strychnine, 1757I.S., picrotoxin, DAPA, and hydralazine. BA3P produced (a) potentiation, (b) suppression, or (c) no affect toward convulsions induced respectively by (a) strychnine, 1757I.S., COP, BA4P, and picrotoxin; (b) hydralazine, PM-1090, camphorimide, TMTH, nikethamide, Metrazol, IDCI, and DMAA; and (c) DAPA, caffeine, bulbocapnine, THBA, bemegride and IPBI.