Domingo M. Aviado

Clinical Pharmacology of Pentoxifylline With Special Reference to Its Hemorrheologic Effect for the Treatment of Intermittent Claudication

I n 1976, one of the authors (D.M.A.) proposed a classification of drugs for the treatment of intermittent claudication.’ The five categories are as follows: (1) musculotropic vasodilators to increase blood flow; (2) alpha-adrenergic blockers to improve blood flow; (3) beta-adrenergic activators to augment blood flow; (4) nonadrenergic drugs to retard blood clotting and antagonize serotonin, bradykinin, and calcium ions; and (5) drugs with multiple actions involving vascular and nonvascular areas. At that time, the drugs that were available in the United States belonging to categories 1, 2, and 3 were judged by the Food and Drug Administration (FDA) to be ineffective or possibly effective because of lack of evidence of clinical efficacy and safety.2 Drugs belonging to categories 4 and 5 were already available in Europe and were undergoing clinical investigation in the United States for review by the FDA. Presently, the situation in the United States is essentially unchanged in that no vasodilator,

Toxicity of aerosol propellants on the respiratory and circulatory systems: I. Cardiac arrhythmia in the mouse☆

Abstract The propellants used in aerosols were investigated in anesthetized mice. The 15 propellants studies can be placed into the following three groups: 6 propellants that induce arrhythmia and sensitize the heart to epinephrine; 6 propellants that sensitize the heart to epinephrine-induced arrhythmia; and 3 propellants that neither induce arrhythmia nor sensitize the heart. The most toxic with respect to the induction of cardiac arrhythmia is trichlorofluoromethane (FC 11) which is, coincidentally, the most widely used low pressure propellant in aerosols.

Toxicity of aerosol propellants in the respiratory and circulatory systems IV. Cardiotoxicity in the monkey

Abstract The 15 fluorocarbons which can be used to propel aerosols have been grouped into 4 classes, depending on their potential to elicit cardiac arrhythmia and depression of myocardial contractility. The most toxic propellant, trichlorofluoromethane (FC 11) produces both forms of cardiotoxicity when inhaled in concentrations of 2.5–5%. The minimal proarrhythmic concentration in the monkey is reduced by i.v. infusion of epinephrine or by production of myocardial ischemia. The combination of the two effects reduced the minimal proarrhythmic concentration to 0.5%. This phenomenon suggests that the hazard of exposure to aerosol propellants is increased in persons with heart disease.

Toxicity of aerosol propellants on the respiratory and circulatory systems: II. Respiratory and bronchopulmonary effects in the rat

Abstract The seven propellants tested in the anesthetized rat have the following patterns of action: FC21 and FC12 do not increase pulmonary resistance; FC11, FC C-318 and isobutane decrease pulmonary compliance and tidal volume; FC114 and FC115 increase respiratory rate. FC11 is the most toxic substance with a lethal inhaled concentration of 19% and FC C-318 the least toxic with a lethal concentration of 48%.

Responses of the Bronchial Veins in a Heart-Lung-Bronchial Preparation

Blood collected from the bronchial veins of a heart-lung-bronchial preparation consists of two components: (a) fraction from the bronchial arteries, and (b) pulmonary to bronchial shunt It is estimated that the latter is more than half of total bronchial venous flow. The pulmonary to bronchial shunt is reduced by procedures which increase pulmonary arterial pressure. An intrinsic nervous reflex mechanism is suggested to explain such a response, particularly because the bronchial veins are more sensitive than the bronchial arteries to the vasoconstrictor action of epinephrine and norepinephirine, and to the vasodilator action of isoproterenol. acetylchohine, histamine, and DMPP. Alterations in bronchial venous flow induced by such chemical agents are independent of bronchoconstriction or bronchodilatation.

Cardiopulmonary toxicity of propellants for aerosols.

Some of the propellants used in aerosols have the potential to produce bronchoconstriction, reduce pulmonary compliance, depress respiratory minute volume, reduce mean blood pressure, and accelerate heart rate. The most toxic propellant is trichlorofluoromethane (FC 11), which exerts all of these undesired effects except bronchoconstriction and a reduction of pulmonary compliance. Coincidentally, FC 11 is the most widely used low-pressure propellant. The least toxic propellant is difluoroethane (FC 152a), which is rarely used in aerosols. Additional investigation is needed to determine which toxic effects are the important ones in deciding on the future use of these propellants. It will also be necessary to examine the influence of pathological lesions in the heart and lung on the sensitivity of these organs to the various aerosols. 5 references, 2 figures, 1 table.

Toxicity of aerosol propellants in the respiratory and circulatory systems VIII. Respiration and circulation in primates

The low-pressure propellants influence predominantly the circulation, whereas the high pressure propellants affect the respiration in anesthetized monkeys. There are four groups according to the level of toxicity: Class 1, low-pressure propellants of high toxicity that cause tachycardia and hypotension; Class 2, low-pressure propellants of intermediate toxicity that influence either circulation or respiration or both; Class 3, high-pressure propellants of intermediate toxicity that cause bronchoconstriction; and Class 4, high-pressure propellants of low toxicity that do not influence respiration or circulation even when inhaled at levels of up to 20 percent concentration.

Cardiac Effects of Sodium Selenite

The classical idea that selenium is toxic to the heart at levels higher than available in a balanced diet is not supported by experimental work. In mice, treatment with sodium selenite increased the LD50 of ouabain and 2,4-dinitrophenol, and increased the tolerance to nitrogen inhalation. Although sodium selenite had no effect on the dog heart with circulation intact, there was a reduction in coronary vascular resistance in the heart-lung preparation. In the isolated ventricular segment perfused with blood, the administration of sodium selenite caused a positive inotropic effect which appeared even after blockade of beta-adrenergic receptors and in segments perfused with a Krebs-bicarbonate solution that was deficient in oxygen. These results cannot be explained merely as the correction of a selenium deficiency but rather as a positive influence of sodium selenite on the heart that has been acutely stressed by oxygen lack, ouabain, or 2,4-dinitrophenol.

Pharmacological significance of biogenic amines in the lungs: noradrenaline and dopamine

1 . The noradrenaline concentration in the lung was less than 0·5 μg/g in eight animal species. 2 . In the cat, dog, rabbit and goat, tyramine produced a fall in pulmonary resistance, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline increased the content of this amine in the lung of the cat, previously depleted by reserpine, the bronchodilator property of tyramine was not restored. The infusion of isoprenaline did not restore the response to tyramine. The role of either catecholamine in mediating the bronchomotor response to tyramine could not be ascertained. 3 . The concentration of dopamine was as high as 6·4 μg/g in the goat lung and less than 0·5 μg/g in the lungs of the cat, rabbit, dog, rat, mouse, guinea‐pig and man. Dopamine, injected intravenously into the cat, dog, rabbit and goat, produced a slight rise in pulmonary resistance. This increase was blocked by tolazoline, indicating that the response was mediated by α‐adrenoceptors in the bronchial passages. No procedure has been observed to influence the dopamine content of the lung. The release of dopamine cannot, however, be excluded until the blood in the bronchial veins has been analysed.

Toxicity of aerosol propellants in the respiratory and circulatory systems

The acute inhalational toxicity of trichlorofluoromethane (FC 11) is summarized in this paper. There is a striking similarity in threshold concentrations between the mouse and the rat on one hand and the dog and the monkey on the other. The mouse and rat require lower levels of concentration, i.e. (1 to 2.5%) to influence the respiratory system but higher levels (2.5 to 5.0%) to affect the circulatory system. The respiratory systems of the monkey and the dog have about the same sensitivity as those of the other two species in that the threshold level of FC 11 is 2.5 to 5%. The circulatory systems of the monkey and the dog can be influenced by a concentration of 0.5%.