John C. Krantz

The biotransformation of nitroglycerin.

Abstract The transformation of nitroglycerin (NG) was accomplished by the formation of 1,2- and 1,3-dinitroglycerin. The dinitrates were resistant to further degradation and appeared as the urinary metabolites after the administration of NG. The dinitroglycerins were less active coronary vasodilators and blood pressure depressants than NG. A heat-stable inhibitor of the spontaneous reaction between NG and glutathione (GSH) was removed by dialysis. The enzyme that catalyzes the NG-GSH reaction was not found in heart but was localized in rat liver soluble fraction and was enhanced by phenobarbital pretreatment.

Metabolism of the sugar alcohols and their derivatives.

Publisher Summary This chapter reviews the metabolism of the sugar alcohols that emphasis mainly on the isomeric hexitols. Substances such as methyl alcohol and ethylene glycol are studied under categories other than the sugar alcohols. The sugar alcohol refers to the hexahydric alcohols and their availability as food in the human diet warrants special study of their metabolic patterns. Biological metabolic processes attack most of the sugar alcohols. Glycerol, sorbitol, and mannitol are nontoxic precursors of glycogen and hence are metabolizable in the animal body. The respective anhydrides of the sugar alcohols studied in the chapter are not metabolized in the animal body.

Anesthesia. LXXIV. Biotransformation of fluroxene. I. Metabolism in mice and dogs in vivo.

Abstract Fluroxene has been found to undergo biotransformation in the mouse and dog after i.p. administration of subanesthetic doses. Trifluoroethanol glucuronide, trifluoroacetic acid, and 14CO2 (from vinyl carbons only) have been identified as metabolites. The extent of metabolism was increased in mice by pretreatment with phenobarbital sodium, 3-methylcholanthrene, and 3,4-benzpyrene, and these effects could be blocked by preadministration of actinomycin D. Phenobarbital pretreatment also enhanced the metabolism of fluroxene in the dog. Carbon tetrachloride-induced hepatotoxicity greatly reduced the metabolism of fluroxene in the mouse. SKF 525-A and Lilly 18947 had no inhibitory effect in mice but rather caused a slight enhancement of the metabolic activity. Repeated pretreatments with ethyl ether and nitrous oxide had a slight stimulatory action on the biotransformation of fluroxene in mice, whereas fluroxene and methoxyflurane pretreatments had no significant effect.

Nitrites XIX. studies of the mechanism of action of glyceryl trinitrate

Abstract Further evidence has been presented to indicate that the dilation of the coronary arteries evoked by glyceryl trinitrate is due to the intact molecule. 1-Chloro-2,3-propanediol dinitrate (CPD) containing only two nitrate groups, equipotent to glyceryl trinitrate in dilating the perfused coronary vessels of the rabbit, is more refractory to nitrite formation by the vascular bed. The coronary vessels and the vascular bed of the ear have been shown to reduce a fraction of glyceryl trinitrate perfused through them to nitrite. Isosorbide dinitrate evokes increased coronary flow in the rabbits heart and does not undergo hydrolysis and reduction. The resistance to alkaline hydrolysis has been studied with regard to glyceryl trinitrate and isosorbide and isomannide dinitrates. The latter two dinitrate esters are more resistant to alteration than is glyceryl trinitrate.

Studies on a new coronary vasodilator, 1-chloro-2, 3-propanediol dinitrate.

Since the introduction of glyceryl trinitrate in the treatment of angina pectoris by Murrell in 1879, there has not been a drug to compete adequately with it in the treatment of coronary insufficiency. Previous work in this laboratory showed that the number of nitrate groups in the molecule was not a salient factor in determining vasodilating potency. Also it was demonstrated that the activity depended upon the intact molecule of the ester and was terminated by its hydrolysis. The oil/water distribution coefficient of the ester was likewise found to be a factor in

Toxicity and convulsive activity of a series of theophylline derivatives

The toxicities and convulsive activities of a series of 7-substituted, 8-hydroxybenzyl theophyllines were determined in different species by various routes of administration. The CD50s and LD50s for the five compounds under study varied from 7 to 180 mg/kg in mice after intravenous injection. The therapeutic indexes were highest for the diisopropylamino (1.5) and the diethylamino derivative BZL (1.3), and the margin of safety increased in higher species. A fourfold increase in the effective dose was found between the intravenous, intraperitoneal, and oral administration of BZL in mice. This is a larger difference than reported for other xanthine derivatives, such as aminophylline and theophylline. Subacute toxicity studies with BZL did not reveal any pathologic damage in rats and dogs, making this compound acceptable for further neuropharmacologic evaluation and its application to human therapy.

An approach to the action of the cardiac glycosides at a cellular level

T HERE are few drugs in the physician’s armamentarium that have withstood the ever-increasing keenness of nearly two centuries of the pruning knife of time. Digitalis is one of these. The voice of the astute clinician, William Withering, rings clearly through the ever-lengthening past as he asserts, “It has a power over the motion of the heart, to a degree yet unobserved by any other medicine, and that this power may be converted to salutary ends.” Withering’s original directions for the use of digitalis were exacting, and prevail today, when he declared, “Let the medicine be continued until it acts on the kidneys, the stomach, the pulse, or the bowels: let it be stopped upon the appearance of any one of these effects.” For more than a century after the work of Withering, digitalis was believed to contain diuretic and cardiac principles. The diuretic principles were presumably extracted by water, and the infusion of digitalis was used in edema other than that of cardiac origin. The tincture containing a high alcoholic menstruum was used in arrhythmias. In 1911 the distinguished English clinician, Sir James Mackenzie, and the pharmacologist, A. R. Cushny, rediscovered the action of digitalis. They attached electrodes to the beating auricles of the heart of a dog. By means of a mild tetanizing current they disturbed auricular rhythm and produced a condition comparable to the clinical picture of auricular fibrillation. This disordered auricular rhythm affected the beat of the ventricles and their beat became rapid and less effective. Digitalis was given ; the tetanizing current was continued. The auricles continued in their state of fibrillation, but the ventricles were C.C. and JOHNSON S. L. LING, PH.D.

Sustained exposure to hexafluorodiethyl ether (indoklon) in mental illness.

Abstract The sustained exposure to the vapor of Indoklon has been studied in monkeys and dogs. The repetitious tonic-clonic seizures and the comatose state do not appear to produce demonstrable damage to the nervous system, blood, or viscera. Based on this observation a preliminary study of the effect of the sustained exposure to Indoklon in man was instituted.

Myokinase Activity of Coronary Arteries

In exploring the mechanism of action of vasodilating drugs an attempt has been made to study the enzyme systems of the blood vessels. A transphosphatase of the myokinase type has been found to be present in the coronary arteries of the steer. The activity has been studied under the optimal conditions for this enzyme system. Coronary arterial tissue may be maintained at the temperature of dry ice for a number of days without significant loss of enzyme activity. This will permit an investigation of the effects of drugs upon the activity of these enzymes.

The antipyretic activity of certain fluorine-substituted benzoates

Of the fluorobenzoates studied, sodium o-fluorobenzoate and 2,4-difluorobenzoate elicit effective antipyretic action in rats. The antipyresis did not prevail in the rabbit. Sodium o-fluorobenzoate and 2,4-difluorobenzoate are less potent as antipyretics than sodium salicylate; however, they are less toxic. The LD50 in rats of sodium salicylate is 650 mg/kg. Sodium o-fluorobenzoate and sodium 2,4-difluorobenzoate did not kill at a level of 2000 and 2500 mg/kg, respectively. It is of interest that sodium o-fluorobenzoate and 2,4-difluorobenzoate also elicit analgesis action in mice as evidenced by the antiwrithing test.