Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-04-19
2003-07-01
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S255060
Reexamination Certificate
active
06586416
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the control of hypertension in patients suffering from aldosteronism and conditions wherein aldosterone may be elevated secondary to pathophysiological conditions as seen in patients with cardiac insufficiency such as in post-myocardial infarction. Simultaneous administration of an epithelial sodium channel (ENaC) blocker in combination with an agent that inhibits the mineralocorticoid receptor provides a new and effective means of treatment.
BACKGROUND ART
Aldosterone is involved in salt and water homeostasis. The main effect is thought to involve genomic mechanisms. These mechanisms are thought to be mediated by the mineralocorticoid receptor. However, the existence of plasma membrane steroid receptors has also been postulated.
The mineralocorticoid hormone aldosterone has the ability to cause an increase the reabsorption of salt and water. A part of this process appears to involve the stimulation of amiloride-sensitive sodium channels in the cortical collecting duct of the kidney. The classical mechanism of this regulation is that aldosterone activates a cytosolic mineralocorticoid receptor that, in turn, has genomic effects resulting in increased transcription of the genes that produce serum-glucocorticoid-regulated kinase SGK and Na
+
—K
+
ATPase. A compelling reason for suspecting a genomic mechanism of regulation is that in vitro effects of aldosterone are not acute, but rather take as long as four hours to develop and can be blocked by inhibitors of transcription and translation. It is important to consider that the vast majority of experiments to elucidate the mechanism of action of aldosterone have been carried out on model systems such as rat tissue and cells and A6 epithelial cells derived from
Xenopus lavis
. The mechanism of action of aldosterone in other species, including humans, is more complex than in those model systems.
A body of evidence has been accumulating that suggests that in species other than the rat, aldosterone produces acute effects at picomolar concentrations. For example, rapid aldosterone-mediated effects on cellular processes in human smooth muscle cells and human lymphocytes have been observed when the mineralocorticoid receptor has been inhibited with spironolactone. Spironolactone is converted in the body to canrenone, the active metabolite, a compound of the formula:
or to the canrenoic acid ion in the body. Canrenone, too, has been used as an aldosterone antagonist. (See U.S. Pat. No. 2,900,383, which is incorporated herein by reference in its entirety.).
Several articles compare use of spironolactone and amiloride in treatment of patients. For example, Jeunemaitre, et al. teaches use of, in the alternative, spironolactone, hydrochlorothiazide/amiloride combination or cyclothiazide/triamterene combinations in treatment of patients with elevated blood pressure. (See
American Journal of Cardiology,
62 (16), pp 1072-7 (Nov. 15, 1988.) There is no suggestion therein to use spironolactone with amiloride.
Millar, et al report a study comparing amiloride and spironolactone (
British Journal of Clinical Pharmacology,
18(3), pp. 369-75 (September, 1984)). (See, also,
Clinical Pharmacology
&
Therapeutics,
27 (4), pp 533-43 (April, 1980).).
The administration of spironolactone in accord with present dosage standards, whether used alone or using previously taught combinations, is known to cause several serious and uncomfortable side effects, including dangerous alterations in blood potassium causing hyperkalemia. Endocrine disturbances, including enlargement of breasts in males, also occur.
BRIEF SUMMARY OF THE INVENTION
Co-administration of a channel blocking epithelial sodium channel (ENaC) blocker in conjunction with a mineralocorticoid receptor inhibitor makes it possible to achieve desired lowering of blood pressure with use in the range of 20% to 75% or less of the presently used dosage of the mineralocorticoid receptor inhibitor (MRI), thus avoiding many of the deleterious side effects usually associated with administration of an MRI. Usually the dosage of MRI is about 20% to 50% of that required when administered without an ENaC blocker, though as little as 10% of the usual dosage of MRI may, in some cases, be efficacious. When used at the lower levels, it is possible to avoid or decrease the more serious and/or distressing untoward reactions to the MRI.
DESCRIPTION OF THE INVENTION
It is the purpose of this invention to provide means for treatment/control of hypertension in patients suffering from aldosteronism, including conditions wherein elevated aldosterone levels may be secondary to other pathophysiological processes such as heart failure.
The rational for inhibiting the effects of aldosterone in patients with post-myocardial heart failure is that subsequent to damage to the heart muscle, the ability of the heart to function as an efficient pump is reduced. This reduction in pumping efficiency is the source of reduced cardiac output. When the body senses a reduction in cardiac output, the renin-angiotensin-aldosterone axis is activated as a compensatory mechanism. Activation of this mechanism causes the blood vessels to constrict and the blood volume to increase by retention of salt and water. This compensatory attempt by the body to adjust for the reduced cardiac output puts more strain on the damaged heart. Ultimately, the feed-back mechanism meant to protect the organism causes the damaged heart to be damaged further. Reducing the effects of salt and water retention resulting from the increased aldosterone breaks the feed-back cycle, thereby reducing the workload for the heart and preserving cardiac function. It has now been found that simultaneous administration of an epithelial sodium channel (ENaC) blocker in combination with an agent that inhibits the mineralocorticoid receptor (an aldosterone antagonist) as disclosed herein provides a new and effective means of treatment for patients suffering from untoward effects of both primary and secondary aldosteronism.
The most commonly used ENaC blocker is amiloride. However, related compounds may be used in practice of the invention. Some pteridines have been shown to have properties similar to amiloride. The most common substituted pteridine in use is triamterene. Similarly, other mineralocorticoid receptor inhibitors such as analogues of spironolactone, including as those identified in this disclosure, may be used in practice of the invention. It is possible, when using the combination therapy, to reduce the amount of the MRI by 25% to 90%. For example, spironolactone is usually given at dosage of 25 to 100 mg. When used with a ENaC blocker such as amiloride, the dosage of as little as 5 mg. may be used. An aspect of the invention comprises compositions containing an ENaC blocker in combination with much smaller doses of an MRI than was previously delivered to have clinical significance.
Materials and Methods:
Principal Cell Preparation
Collecting ducts were manually dissected from sagittal slices obtained from 50 gram Sprague Dawley rats and 0.5 Kg New Zealand White rabbits. The dissected collecting ducts were suspended in RPMI 1640 culture medium supplemented with 1.5 mg/ml collagenase A (Boehringer Mannheim, Mannhein, Germany). The collecting ducts were enzymatically digested for 1.5 hours to isolate individual cells. The digested cells were washed in serum-free RPMI and placed in a perfusion chamber mounted on the stage of an inverted microscope. The whole-cell patch clamp configuration was established and initial current measurements were made in un-supplemented RPMI. The bath solution was changed (by perfusion of the entire bath chamber) to RPMI supplemented with aldosterone (100 nM), vasopressin (250 nM), amiloride (2 &mgr;M), spironolactone (1 &mgr;M), or various combinations of these compounds. To block the cytosolic mineralocorticoid receptor, some cells were suspended in RPMI supplemented with spironolactone for 1 hour prior to whole-cell patch clamping.
Preparation of Lymphocytes
Human and canine lympho
Criares Theodore J.
Hendricks Glenna
Hicks Lucy
Kim Jennifer
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