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Although indapamide has been used for many years as a first-line treatment of hypertension, it is onlY recently that some of its activities on the changes of the cardiovascular system, brought on by age and high Wood pressure, have been studied.. indapamide appears to reduce blood pressure by a combined diuretic and direct vascular activity reducing vascular reactivity and total peripheral resistance. In addition, h has discrete effects on a number of interrelated systems that may protect the cardiovascular system. indapamide reduces intracellular calcium levels, maintains magnesium ions, but reduces phosphate ions that may be involved in arterial rigidity. Circulating catecholamines remain unchanged but there is a reduction in normetanephrine, suggesting a reduction in sympathetic tone. It stimulates prostacylin synthesis, increases levels of circulating protacyclin, reduces platelet aggregation and stimulates the vasodilation elicited by endothelium-derived relaxing factor in the presence of bradykinin. in addition, it inhibits the formation of the vasoconstrictor prostanoid, thromboxane A[ sub.2]. The free radical scavenging activity of indapamide could also protect the vascular smooth muscle from the reperfusion injury of cerebral and myocardial ischemia. Indapamide induces a reduction in cerebral ischemia after carotid ligation. Unlike some other antihypertensives, it does not upset the high-density/low-density lipoprotein-cholesterol balance, reducing the possible risk of atherosclerosis. Moreover, the combination of binding to elastin and reduction in uptake of calcium and phosphate into the smooth muscle could be a mechanism for reducing arterial rigidity seen in the elderly and hypertensive patient. in hypertensive patients, these properties induce an improvement in arterial compliance, and in the long term a reduction in left ventricular hypertrophy. These pharmacologic and clinical results, together with a good antihypertensive efficacy and acceptability, suggest that indapamide may be a preferential agent in the long-term cardiovascular protection of the hypertensive patient. (Am J Cardiol 1990;6S:11H-27H), Although hypertension is an important risk factor in coronary artery disease, stroke, and kidney failure, the reduction of blood pressure does not affect all risks equally. In particular, although the reduction of blood pressure dramatically reduces the risk of cerebral hemorrhage and stroke, the reduction of cardiovascular disease is incomplete, and there is little or no associated reduction in the risk of myocardial infarction. Clearly, there are other factors involved besides hypertension. It may be clinically important, therefore, to choose antihypertensive medication not only for its ability to reduce blood pressure, but also to provide additional cardiovascular protection as well. Indapamide is a widely prescribed antihypertensive drug that has both diuretic and artery-relaxing effects. Some of the properties of indapamide suggest that it may provide additional protective benefits besides those achieved from the reduction in blood pressure. One important mechanism of cardiac damage is the formation of a thrombus which blocks a coronary artery, a process which may begin with the aggregation of platelets. By stimulating the production of prostacyclin, indapamide may push the balance between prostacyclin and thromboxane A2 away from the direction of platelet aggregation. There is some evidence that indapamide inhibits thromboxane A2 synthesis as well. Many antihypertensive agents reduce the ratio of high-density lipoproteins to low-density lipoproteins, which may result in an increased risk of atherosclerosis. This is not the case with indapamide, suggesting that this drug may achieve the benefits of reduction of blood pressure without a concomitant increase in another cardiovascular risk. Another feature of coronary artery disease is the gradual loss of arterial flexibility that occurs with age. Research in laboratory rats indicates that indapamide can increase the compliance of key arteries, both in normal and hypertensive animals. Kidney damage is another important consequence of hypertension, and evidence has accumulated that indapamide provides improvement in kidney function in patients with type II diabetes. Since indapamide is a widely-prescribed antihypertensive agent, the accumulation of data should permit the determination of whether the long-term use of indapamide actually results in the improvements in cardiovascular protection that might be supposed on the basis of physiological research. (Consumer Summary produced by Reliance Medical Information, Inc.)

It has been known for many years that many physiological functions are proportional to the body weight when scaled across species. Similar allometric considerations generally hold for metabolic and renal clearances of compounds, and it can be expected for a given dose that small animals will generally have lower unchanged drug levels but higher metabolite levels than man. Acceptable safety margins between animals and man previously based on mg.kg.−1dosage may, therefore, need to be revised lower when using toxicokinetic measures of exposure. In the past, however, allometric scaling to man has required at least three species, and often the prediction of human clearance from this data has proved unreliable, minimizing its practical use in drug development. This preliminary review examines data from 51 drugs using various allometric methods and shows that an acceptable predictive accuracy, within 20%, may be found using the clearance corrected for differences in maximum life span obtained from Old World Monkeys. Further information on the suitability of a particular species can also be sought from comparisons of in vitro metabolic rates and profiles, and knowledge of specific cytochrome P450isozyme metabolism.