Congestive heart failure derivatives

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

Carbenoxolone (B) is a derivative of glycyrrhetinic acid, which occurs in the sap of licorice root (succus Uquiri-tiae). Carbenoxolone stimulates mucus production. At the same time, it has a mineralocorticoid-like action (due to inhibition of 11-p-hydroxysteroid dehydrogenase) that promotes renal reabsorption of NaCl and water. It may, therefore, exacerbate hypertensioa congestive heart failure, or edemas. It is obsolete. 

Parke-Davis workers have performed SAR studies on endothelin receptor antagonists derived from a dimethoxy-substituted oxicam in the search of treatments for hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia, and cerebral vasospasm <1998BMC1447>. Compound 295 displayed a 40-fold selectivity for endothelin receptor antagonist A (ETa) over endothelin receptor antagonist B (ETb) (Figure 26). 

Historically, plant-based natural products have been a source of useful drugs. The analgesic opiates come from the poppy plant. Digitalis for congestive heart failure was first isolated from the foxglove plant. Various antibiotics (penicillin) and anticancer agents (taxol) are derived from natural product sources. There are numerous other examples. 

Digitoxin and its derivatives bind to the sodium-potassium pump and prevent it from exchanging sodium and potassium ions. When given in small quantities the result, especially in cardiac tissue, is that calcium ion content will be upset and calcium will be liberated from its stores. The newly available calcium can then interact with cardiac muscle protein to cause contraction. This is a therapeutic effect for those suffering from insufficient heart-pumping action (congestive heart failure or dropsy). The heart is made to contract efficiently and forcefully (inotropic effect). However, you can see that there may be a fine line between a necessary contraction and one which... 

Glycosides of the gitoxigenin series are less active than the corresponding members of the digitoxigenin-derived series. Digitoxin is the only compound routinely used as a drug, and it is employed in congestive heart failure and treatment of cardiac arrhythmias, particularly atrial fibrillation. 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

For the appropriate development of covariate distribution models, the pharmaceutical industry has huge amount of data in their clinical databases. In addition, there are also public databases available which can be used, like the Congestive Heart Failure Database (http //www.physionet.org/) derived from patients undergoing cardiac catheterization at Duke Medical Centre during 1990-1996 (about 4000 patients, data on demographics, risk factors histories, cardiac catheterization, EKG, cardiac scores, follow-up data). 

Herbs have been used as medical treatments since the beginning of civilization and some herbal derivatives (e.g., aspirin, reserpine, and digitalis) have become a mainstay of human pharmacotherapy. For cardiovascular diseases, herbal treatments have been used in patients with congestive heart failure, systolic hypertension, angina pectoris, atherosclerosis, cerebral insufficiency, venous insufficiency, and arrhythmia. Scientific validation of several plant species has proved the efficacy of the botanicals in reducing the... 

Chlorothiazide [klor oh THYE a zide], the prototype thiazide diuretic, was the first modern diuretic that was active orally and was capable of affecting the severe edema of cirrhosis and congestive heart failure with a minimum of side effects. Its properties are representative of the thiazide group, although newer derivatives such as hydrochlorothiazide or chlorthalidone are now used more commonly. 

Acylated pyridoxal derivatives, (IV), prepared by Haque (6) were effective in the treatment of cardiovascular hypertrophy, hypertension, and congestive heart failure. 

Diuretics are highly efficient drugs for the treatment of edema associated with congestive heart failure. They are also used to increase the volume of urine excreted by the kidneys [9]. For example, duranide, 81, a dichlorinated benzene disulfonamide, is an oral carbonic anhydrase inhibitor. Duranide reduces intraocular pressure by partially suppressing the secretion of aqueous humor [11]. Diuril, 82, has an antihypertensive activity and is issued to control blood pressure [9]. Edecrin, 83, is an unsaturated ketone derivative of an aryloxyacetic acid. Edecrin is used in the treatment of the edema associated with congestive heart failure, renal disease, and cirrhosis of the liver [11]. Amiloride, 84, is also used as an adjunctive treatment with thiazide diuretics in congestive heart failure hypertension. 

Safety data derived from the controlled trials submitted in the benazepril New Drug Application for hypertension have been reviewed (1). In more than 100 trials involving 6000 patients with hypertension or congestive heart failure, the types and incidences of adverse effects were comparable with those of other ACE inhibitors. 

Feldman AM, Baughman KL, Lee WK, Gottlieb SH, Weiss JL, Becker LC, Strobeck JE. Usefulness of OPC-8212, a quinoUnone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1991 68(11) 1203-10. 

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