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J Milei

Publications and source records attributed to J Milei.

At least 91 records · Page 5Linked to original sources
PubMed1982

An overall review on prenylamine mechanisms of action in experimental models of myocardial damage.

In this review we present the effects of a well-known antianginal drug, prenylamine (PNL), in experimental models of acute myocardial damage induced by a beta-agonistic drug, isoproterenol (ISP), in several trials conducted in our laboratory in both rats (n = 204) and monkeys (n = 26). PNL significantly inhibited ISP-induced lesions, protecting the majority of animals studied. Studies dealing with the site of action of the drug, such as 45Ca, 3H-PNL and 3H-ISP trials, showed a clear membrane effect slowing down Ca transport. Correlation between ECG (inhibition of ST depression after ISP) and pathological findings in monkeys was also obtained in one of our experiments. These series of assays were useful in obtaining a more complete idea of activity and site of action of the drug. It seems that, in acute models, PNL acts as a calcium antagonistic drug rather than an adrenergic moderator.

Angina Pectoris↗
PubMed1982

Normal and pathological electrocardiographic patterns in the Cebus monkey.

The normal electrocardiographic (ECG) pattern was determined for Cebus monkeys and compared with those obtained in animals subjected to experimental heart damage. ECG patterns were related to the anatomopathological findings in both normal and treated animals. The anatomic study revealed a vertical heart in which both ventricles constituted the frontal aspect. The experimental heart injury either through the inoculation of Trypanosoma cruzi or after the treatment with isoproterenol induced ECG changes which were correlated with specific anatomopathological lesions.

Animals↗
PubMed1980

Double-blind controlled trial of molsidomine in hypertension.

Molsidomine (M), a new long-lasting antianginal compound, was studied in 38 hypertensive patients to assess its antihypertensive properties. Six patients were selected for an acute, single dose comparative trial with placebo over 8 h after treatment. The remaining 32 patients were used in a 1 month trial to study the effect on BP of more prolonged treatment. Systolic, diastolic and mean BP were significantly reduced after a single dose of M 4 mg, and the effect lasted for about 8 h. M also inhibited the hypertensive response to isometric exercise in handgrip tests performed 1 and 8 h after M ingestion. A dose-related decrease in systolic and diastolic BP in the one month trial was also observed. In addition to its antianginal properties, M appears to possess an interesting effect on BP in mildly to moderately hypertensive patients. A fall in BP is also a valuable effect in coronary patients with augmented metabolic demands of the heart.

Antihypertensive Agents↗
PubMed1979

Prenylamine. Autoradiographic and neuropathological studies on myocardial mechanisms of action.

Myocardial localization of prenylamine (PNL), a well known antianginal drug, was studied by means of an autoradiographic technique to detect microscopical distribution of tritiated PNL (3H-PLN). Forty Wistar rats received 35 muCi/kg b. w. 3H-PNL i. p., the animals being killed 30 min after injection. Heart slices, 1 mm thick, were processed for both autoradiographic and conventional histological techniques. 3H-PNL was observed, mainly, as striae along sarcolemma; sarcolemmal/intramyocardial 3H-PNL distribution ratio was 6 : 1. Preferential membrane deposition of 3H-PNL is probably related to the calcium transport inhibiting action of the drug, previously described.

Animals↗
PubMed1979

Isoproterenol-induced 45ca uptake into myocardium of rats.

Myocardial lesions induced by isoproterenol (ISP) are similar to those of human "coagulative mycocytolysis" or "myofibrillar degeneration". The localization of tritiated ISP in the damaged myocardium of rats has been recently described. Since H3-ISP was noted in "grooves" along the sarcolemma of ischemic and necrotic fibers, an action on the membrane with exaggerated calcium inflow was suggested. For this reason, the quantity of 45Ca in rats treated with ISP was studied. Thirty rats were given 5 mu Ci of 45Ca. Twenty (Group B) of them were also given ISP 10 mg/kg. Animals were killed at 1 h after the injections. The hearts were sectioned transversally and autoradiography was performed. Serial sections were examined to localize the 45Ca, and its topographic distribution. In Group A (injected only with 45Ca) the myocardium showed + of 45Ca (600 dots in a field x 400) inside the fibers. In Group B (injected also with ISP) 45Ca was deposited +++ (more than 1,200 dots) and related to extensive myocytolysis. These findings confirm that the crucial point in the ISP-induced lesions is the increase of calcium inflow, and if the pathogenesis of human myocytolysis is related to catecholamine effects pharmacological measures may be adopted to prevent these myocardial lesions.

Animals↗
PubMed1978

Pathogenesis of isoproterenol-induced myocardial lesions: its reation to human 'coagulative myocytolysis'.

Animals develop 'infarct-like' lesions when injected with isoproterenol (ISP), a potent synthetic catecholamine. These lesions are morphologically similar to those of 'coagulative myocytolysis' (COAM) or myofibrillar degeneration, one of the findings described in acute myocardial infarction and sudden death in man. Wistar rats were divided into 8 groups: some were injected with 10 mg/kg ISP i.p. plus 5 muCi of tritiated ISP, while others served as control. Animals were sacrified at 5 and 30 min and 24 and 72 h. The ISP-induced lesions were studied by means of light microscopy, histochemistry, autoradiography and electron microscopy. Myofibrillar degeneration, positive tests for ischemia, increase of succinic dehydrogenase enzymes, hypercontraction and widening of Z bands of sarcomers were correlated with the rapid distribution of ISP. These lesions were minimized by prenylamine, a drug which inhibits catecholamine effects by slowing down Ca transport. It is concluded that myocardial necrosis induced by ISP is probably due to a primary act on the sarcolemmal membrane, followed by stimulation of adenylate cyclase, activation of Ca and Na channels, exaggreated Ca inflow, excess of excitation-contraction coupling mechanism, energy consumption and cellular death. The close resemblance of human COAM to ISP-induced lesions suggests that similar mechanisms may be involved.

Animals↗
PubMed1977

Autonomic neuropathy and painless myocardial infarction in diabetic patients. Histologic evidence of their relationship.

Myocardial infarction is considered the prime cause of death among adult diabetic patients. In a great number of cases, during myocardial infarction the patients don't feel pain or it is atypical. Diagnosis can be neglected, and mortality increases. In search of an explanation for the absence of pain in these patients, the authors studied the autonomic nerve fibers of the heart muscle with argentic and combined techniques, looking for lesions in the sympathetic or parasympathetic nerve fibers that conduct pain. In the five cases of painless myocardial infarction studied, the nerve fibers showed typical lesions of diabetic neuropathy: beaded thickenings, spindle-shaped thickenings, fragmentation of fibers, and diminution of the number of fibers in the nerves. The patients in the control group (five diabetics with painful infarction, five diabetics with infarction, five nondiabetics with painful infarction, and five nondiabetics without infarction) had no lesions. These facts led us to assume that the absence of pain in diabetics with myocardial infarction could be due to a lesion of the afferent nerves that conduct pain.

Adult↗
PubMed1976

Localization by autoradiography of tritiated isoproterenol in "infarct-like" lesions of rat myocardium.

A number of physiopathogenic mechanisms have been outlined to explain the "infarct-like" lesions produced by isoproterenol (ISP) in the hearts of various animals: Excess of oxygen consumption and inotropic effect, coronary vasoconstriction, deleterious action on glucose and lipid metabolism, direct cardiotoxic effect, platelet aggregation in the small cardiac vessels and formation of microclots, excessive mobilization of fatty acids, fluid and electrolytic imbalances, loss of high-energy intracellular coupling, and inadequate activation of the "calcium pump." For this reason, localization of the tritiated ISP in the normal myocardial fibers and in the induced lesions was studied. The first control group (G-1), consisted of 40 Wistar rats, weighing from 180 to 200 grams; they were injected intraperitoneally with ISP sulfate (10 mg. per kilogram) and were killed under ether anesthesia after periods of 5, 30, and 120 minutes, and 12 and 24 hours. A similar group (G-2) was injected intraperitoneally with an equal dose of ISP plus 5 muCi of tritiated ISP sulfate (3H). In this group animals were killed at the same periods as above. In rats treated with ISP-3H an abundant amount of the labeled drug was observed on the sarcolemma surface and a smaller quantity was noted inside the myocardial fibers. This observation was noted in the autoradiographs obtained 5 minutes after the injection and persisted in all subsequent observation times. In those animals which were killed 5 and 30 minutes after injection, the deposit was noted in "grooves" along the edge of the sarcolemma, strongly suggesting a primary action on the cellular membrane. These findings and the peculiar topography suggest that (1) myocardial necrosis induced by ISP is probably due to an increased activation of the "calcium pump"; the early presence of contracture bands and the positivity of the ischemia test further emphasize this statement; (2) the ISP effect is rapid; (3) the morphologic alterations are similar to those recently described as "coagulation myocytolysis" and present in human infarctions or following sudden death.

Animals↗
PubMed1976

Prenylamine inhibition of isoproterenol induced myocardial lesions. Histochemical and ultrastructural findings.

Eighty Wistar rats were divided into 4 groups. All of them received 10 mg/kg i.p. isoproterenol (ISP). The animals were sacrificed at 5 min. (groups A and B) and 24 hours (groups C and D). Groups A and C served as control of group B and D. Group B also received 9 mg/kg prenylamine (P), 30 min before ISP and group D 9 mg/kg P, 1 hour before and 1 hour after ISP. Transversal slices of each heart underwent the following procedures: hematoxilineosin, Barbeito-Lopez trichromic, "ischemia stain", acid phosphatase stain and standard electron microscopy. Group A and C showed positivity for ischemic techniques; necrotic and ischemic zones represented, in average 25.1 +/- 1.4% of the myocardial volume. Group B and D (ISP + prenylamine) showed no significant lesions. Group D (ISP + prenylamine, sacrificed at 24 hours) presented complete absence of "infarct-like" lesions in 17 out of the 20 studied animals. No evident changes in acid-phosphatase enzymes were detected. Animals treated with ISP alone presented "contraction bands" at electron microscopy as well as myofibrillar fragmentation. Those receiving also P showed only light alterations, in the electron microscopy specimens. A primary action of ISP on the calcium pump might explain the infarct-like lesions found in our study. The inhibition of these above mentioned lesions by prenylamine, a drug which acts by slowing down the ca transport, also supports this interpretation.

Animals↗
PubMedDate not supplied

The role of prenylamine in the prevention of adriamycin-induced cardiotoxicity. A review of experimental and clinical findings.

Experimental and clinical trials to determine the potential of prenylamine in the prevention of adriamycin-related cardiotoxicity are reviewed. In mice given 4 mg/kg body weight adriamycin, the incidence of myocardial damage after 19 days' treatment was lower than in those given adriamycin and placebo. Rabbits were given adriamycin (total dose 10.8 mg/kg body weight), adriamycin plus prenylamine (1.5 mg/kg body weight), and adriamycin plus vitamins A (250 IU) and E (40 mg) for 9-11 weeks. Adriamycin-induced electrocardiogram changes were observed to a lesser extent in animals also receiving prenylamine. Heart homogenates from adriamycin-treated animals showed enhanced hydroperoxide-initiated chemiluminescence which was not affected by the simultaneous administration of prenylamine. The extent of adriamycin-induced myocytolysis and the degree of alterations observed on electron microscopy were markedly reduced by prenylamine. In a double-blind clinical trial with 26 oncological patients, no cardiomyopathy, arrhythmia or adverse reactions were observed in the group given adriamycin plus prenylamine. In those given adriamycin plus placebo, two patients developed congestive cardiopathy and another showed severe supraventricular arrhythmias together with hypotension and dyspnoea. The mechanisms of adriamycin-related cardiotoxicity, the effects of prenylamine and the benefit from combined treatment are discussed.

Aged↗