WO2002060387A2

WO2002060387A2 - Use of prostaglandin analogs for treatment of cardiac conditions

Info

Publication number: WO2002060387A2
Application number: PCT/US2002/003103
Authority: WO
Inventors: William C. Stewart
Original assignee: Pharmaceutical Research Corporation
Priority date: 2001-01-30
Filing date: 2002-01-30
Publication date: 2002-08-08
Also published as: AU2002243795A1; WO2002060387A3

Abstract

Methods to ameliorate cardiac conditions using PGF analogs which lack affinity for prostaglandin receptors is disclosed. Systemic administration of at least one PGF analog, preferably unoprostone isopropyl ester provides both therapeutic and prophylactic treatment for such conditions as congestive heart failure.

Description

USE OF PROSTAGLANDIN ANALOGS FOR TREATMENT OF CARDIAC CONDITIONS

Technical Field

The invention is in the field of treatment for cardiac associated conditions such as chronic heart failure and cardiac hypertrophy. In particular, it concerns the use of prostaglandin analogs to ameliorate such conditions.

Background Art

The utility of a group of prostaglandin F analogs, typified by unoprostone isopropyl, in the treatment of glaucoma or ocular hypertension is well established. These compounds have been shown, in particular, to have a vasorelaxant effect on preconstricted pig retinal arterioles in an in vitro model. The arterioles were preconstricted with endothelin (ET-1). In addition, during systemic infusion of ET-1 in monkeys, unoprostone isopropyl was able to inhibit vaso constriction in the choroidal vessels. See, for example, Paterson, C.A., Am. Acad. Ophthalmol, Symposium Abstracts pp. 11-12.

ET-1 and its associated receptors have been implicated in vascular conditions other than those occurring in the eye. For example, Love, M.P., et al, Clin. Sci. (Colch) (2000) 98:65-70 showed that administration of ET-1 or sarafotoxin S6C (a selective ETB receptor agonist) resulted in constriction of the dorsal hand vein, both in patients with chronic heart failure and in healthy subjects, although response to

ET-1 was blunted in heart failure patients as compared to normals. Further, Wolf, S.C., et al, Nephrol Dial. Transplant (1999) 14 Suppl. 4:29-30 showed that ET-1 was involved in the patho genesis of uraemic cardiac hypertrophy and renal failure in rats. In this study, the authors suggest that ET receptor antagonists may provide a therapeutic group for cardiac hypertrophy and renal protein excretion.

In another study, Wada, A., et al, Circulation (1999) 99:570-577 acknowledge that plasma big ET-1 and ET-1 levels are related to survival in patients with congestive heart failure (CHF) and found that in dogs where CHF was induced by rapid right- ventricular pacing, the administration of an ETA receptor antagonist and an inhibitor of endothelin converting enzyme both decreased mean arterial pressure and pulmonary capillary wedge pressure. Further, Porter, K.E., et al, J. Vase. Surg. (1998) 28:695-701 describe results of an organ culture of the human saphenous vein which appear to indicate that ETB receptors mediate intimal hyperplasia. Di Pasquale, P., et al, G. Ital Cardiol. (1996) 26:673-680 report results in

45 patients with suspected anterior myocardial infarction from studies which suggest that captopril affects plasma ET levels in acute and sub-acute phases of this condition, where it had been previously shown that ET-1 was increased.

Barton, M., Curr. Hypertens. Rep. (2000) 2:84-91 reviews the experimental and clinical evidence for involvement of ET-1 in atherogenesis.

Finally, Duchman, S.M., et al, Curr. Opin. Cardiol (2000) 15:136-140 acknowledged that ET-1 has been recognized as a target for inhibition in patients with acutely decompensated congestive heart failure and that nonselective ET-1 inhibitors have shown improvements in cardiac function. Thus, these and other papers demonstrate that ET-1 levels are important in mediating conditions of the cardiovascular system and speculate that inhibitors of ET-1 would be useful in treating cardiac diseases.

Disclosure of the Invention

It has now been found that prostaglandin F analogs, such as those described in U.S. patent 5,221 ,763 and illustrated by unoprostone isopropyl ester, which is marketed under the name Rescula for the treatment of glaucoma, are also useful in ameliorating conditions associated with cardiac problems, including atherosclerosis, myocardial infarction, chronic heart failure and the like. These analogs do not have binding affinity to prostaglandin receptors, but are similar in structure to PGF_2α. Accordingly, the invention is directed to methods to treat conditions of the cardiovascular system, especially those associated with vaso constriction, which method comprises administering to a subject in need of such treatment an effective amount of a PGF₂α analog which fails to bind substantially to prostaglandin receptors. Systemic administration of the PGF_2α analogs is greatly preferred and thus, formulations suitable for systemic administration constitute an additional aspect of the invention. Modes of Carrying Out the Invention

The invention is directed to treating conditions of the cardiovascular system in humans and other animals by administering PGF₂α analogs which do not bind prostaglandin receptors in a substantial degree. As defined herein, "PGF analogs" is specifically defined to include only those docosanoid structures analogous to PGF that have no substantial affinity for prostaglandin receptors or FP receptors or other receptors associated with glaucoma. These compounds, however, are able to prevent and reverse ET-1 induced vasoconstriction.

Preferred forms of these analogs are set forth in U.S. patent 5,221,763, the contents of which are incorporated herein by reference. The most preferred form of such PGF analogs is the compound 13,14-dihydro-15-keto-20-ethyl PGF₂α. Particularly preferred is the isopropyl ester, although additional esters such as the ethyl, n-propyl, and hexyl esters are included within the scope of the invention. The PGF analogs of the invention are useful in the treatment of cardiac conditions as further described below. By "treat" or "treatment" is meant both prevention and therapeutic administration of the compounds in question. By "prevention" or "prevent" is meant that the treatment is administered prophylactically and ameliorates any subsequent development of the undesired condition. It specifically does not necessarily mean that the condition is completely precluded or not subsequently detected. The word "prevention" has the more conventional meaning that the severity of the condition is ameliorated as compared to its intensity absent the treatment designed to "prevent" it. The PGF analogs of the invention may be used to treat cardiac conditions alone, or in combination with additional therapeutic compounds. Two or more PGF analogs may be used in a protocol for treatment. If a single PGF analog is used in combination with an additional PGF analog and/or in combination with an additional pharmaceutical, the administration may be simultaneous or sequential in any order. The design of practical protocols for administration of the PGF analogs useful in the invention is a matter of routine optimization readily conducted by the practitioner. The PGF analogs may be used to treat cardiac conditions in human subjects as well as in veterinary subjects and in laboratory contexts. The dosage suitable for administration is dependent on the nature of the subject, the route of administration, and the severity of the condition, as well as the judgment of the practitioner. Typical dosage amounts are in the range of 0.01-50 mg/kg, preferably 0.1-10 mg/kg. However, the dosage range may vary widely and include dosages outside the specified range, again, depending on the specific conditions encountered.

Suitable conditions susceptible to treatment using the PGF analogs of the invention include uraemic cardiac hypertrophy, chronic heart failure, intimal hyperplasia, pulmonary hypertension, myocardial infarctions, including acute and sub-acute forms, atherosclerosis, congestive heart failure, and hypertension in general.

For treatment of these conditions, systemic administration is preferred. Such administration may be by injection, including, without limitation, intravenous, intramuscular, intraperitoneal and subcutaneous injection; it may be by means of a transdermal patch or lotion; it may be by transmucosal delivery, such as an intranasal spray or suppository. Administration may also be through an oral route or the PGF analogs may be delivered by a sustained release formulation or osmotic pump. Any mode of administration which is effective to provide the active ingredient systemically is suitable and many such means are known in the art.

The PGF analogs of the invention will be formulated according to the mode of administration. Such formulations are well known in the art and can be found, for example, in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA, incorporated herein by reference. Thus, the preferred oral route of administration can be by, for example, tablets, capsules, powders, syrups, and the like. Formulations for transdermal or transmucosal administration require penetrants such as are known in the art. Methods of formulation amenable to these routes of administration are well within ordinary skill. The formulations will contain the active ingredient(s) in varying percentages depending on the nature of the formulation, typically between 0.5 and 95% of the composition, more commonly on the order of 20-50% of the composition wt/wt. Suitable excipients include those conventional in the art such as buffers, fillers, antioxidants, and other preservatives. Thus, cardiac conditions are readily susceptible to amelioration by or prevention by the method of the invention which comprises administering at least one PGF analog to a subject in need of such treatment.

Claims

1. A method to treat undesired cardiac conditions in a subject which method comprises administering to a subject in need of such treatment an effective amount of at least one PGF analog or a pharmaceutical composition thereof.

2. The method of claim 1 wherein the PGF analog is an ester of unoprostone.

3. The method of claim 1 wherein such administering is by a systemic route.

4. The method of claim 1 wherein the cardiac condition to be treated is atherosclerosis, chronic heart failure, cardiac hypertrophy, uraemic cardiac hypertrophy, intimal hyperplasia, pulmonary hypertension, myocardial infarctions, including acute and sub-acute forms, congestive heart failure, or hypertension.

5. The method of claim 1 which comprises administering at least two PGF analogs.

6. The method of claim 1 wherein said administering further includes administering an additional therapeutic compound.

7. A pharmaceutical composition designed for systemic administration which composition comprises an effective amount of a PGF analog along with at least one pharmaceutically acceptable excipient.

8. The composition of claim 7 which is designed for oral administration.

9. The composition of claim 7 wherein the PGF analog is an ester of unoprostone.

10. The composition of claim 9 wherein the ester of unoprostone is the isopropyl ester.