Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1991-12-02
2003-10-07
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S460000, C514S510000, C514S824000, C514S424000
Reexamination Certificate
active
06630502
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for preventing, stabilizing or causing regression of atherosclerosis in mammalian species by administering a combination of a cholesterol lowering drug, such as an HMG CoA reductase inhibitor, for example, pravastatin, and an ACE inhibitor, preferably an ACE inhibitor containing a mercapto moiety, such as captopril or zofenopril, and to a pharmaceutical combination for use in such method.
BACKGROUND OF THE INVENTION
The proatherosclerotic effect of elevated serum cholesterol on vascular tissue is well documented (Weinstein and Heider, “Protective action of calcium channel antagonists in atherogenesis and vascular injury,” Am. J. Hypertens. 2: 205-12,1989).
It is also well known that platelets which may participate in the atherogenic process do so via mediators released upon activation (thromboxane A
2
(TXA
2
), platelet aggregating factor (PAF), etc.,) which in turn stimulate smooth muscle cells to contract as well as to proliferate. The latter effect is an important step in atherosclerotic plaque formation (Hoak, “Platelets and atherosclerosis,” Semin. Thromb. Hemost. 14: 202-5, 1988). Many of the stimulatory effects of prostanoids on vascular smooth muscle can be reversed by endothelium derived relaxing factor (EDRF), a substance whose metabolic stability and/or efficacy appears to be enhanced by captopril (Goldschmidt and Tallarida, “Effect of captopril exposure on endothelium-dependent relaxation in rabbit aorta,” F.A.S.E.B. Journal 3: A1195, 1989).
In addition, it has recently been found that captopril significantly reduced serum cholesterol (−18%) and increased HDL (27%) in hypercholeserolemic patients (Costa et al, “Use of captopril to reduce serum lipids in hypertensive patients with hyperlipidemia,” Am. J. Hyperten. 1: 2219-2239, 1988). There is no evidence that these therapeutic effects result from inhibition of the cholesterol synthetic pathway. Thus, the therapeutic mechanism for ACE inhibitors is different from that of HMG CoA reductase inhibitors such as pravastatin and lovastatin.
Edelman, S. et al, N. Engl. J. Med. (320, No. 18, 1219-20, 1989), “Hyperkalemia During Treatment with HMG CoA Reductase Inhibitor,” discloses a case where a patient received lovastatin (1s) for hyperlipidemia and whose hypertension was initially well controlled with lisinopril. “LS treatment was started when cholestyramine and niacin treatment was not successful. The patient developed myositis and hyperkalemia and recovered after emergency treatment and withdrawal of LS. He later resumed taking LS (without consultation) and again developed severe myositis and hyperkalemia. He recovered when LS was withdrawn. Care is cautioned when LS and lisinopril are given in combination to patients atrisk of hyperkalemia.”
European Patent Application 0219782 to Scholkens (Hoechst) discloses the treatment of atherosclerosis, thrombosis and/or peripheral vascular disease in mammals using an angiotensin converting enzyme (ACE) inhibitor or its physiologically tolerable salts. It further discloses that because ACE is predominantly localized in the luminal plasma membrane of the endothelial cell, ACE inhibitors can interfere in platelet-endothelium interaction. In addition, Scholkens dislcoses that ACE inhibition potentiates the action of bradykinin (a strong stimulator of prostacyclin release from endothelial cells) by inhibiting its degradation and ACE inhibitors, consequently, have an inhibitory effect on platelet aggregation.
Zorn, J. et al, “Prevention of Arteriosclerotic Lesions with Calcium Antagonists or Captopril in Different Rat Hypertension Models,” J. Cardiovasc. Pharmacol. Vol. 12 (Suppl 6), 1988, discloses beneficial effects in mesenteric arteries atherosclerosis with captopril in spontaneous hypertensive Okamoto rats (SHRs), but not in salt-sensitive Dahl rats.
Someya, N. et al, “Suppressive Effect of Captopril on Platelet Aggregation in Essential Hypertension,” J. Cardiovasc. Pharmacol. 6:840-843, 1984, discloses at page 840 that “hypertension is closely related to the genesis and progress of atherosclerosis,” and that “platelet function plays an important role in atherosclerosis, with platelet dysfunction demonstrable in several vascular diseases. It has been reported that platelet aggregation is increased in hypertensives . . . ” At page 842, it is indicated that the “data demonstrated the inhibition of platelet aggregation in vivo after administration of captopril to hypertensive subjects . . . ” At page 843, it is indicated that “platelet aggregability is greater in hypertensives than in normotensives . . . platelet abnormalities may be a risk factor in atherosclerosis . . . If captopril possesses an antiplate aggregability effect in addition to its hypotensive effect, it may be very useful for the prevention of atherosclerosis and thrombotic diseases associated with hypertension.” Mizuno, K. et al “The effects of the angiotensin I-converting enzyme inhibitor, captopril, on serum lipoperoxides level and the renin-angiotensinaldosterone and kallikrein-kinin systems in hypertensive patients,” Nippon Naibunpi Gakkai Zasshi, Feb. 20, 1984, discloses that captopril is a beneficial antihypertensive agent for preventing serum lipoperoxides concentration (LPX)-induced atherosclerosis in hypertensive patients.
Mizuno, K. et al “Acute effects of captopril on serum lipid peroxides level in hypertensive patients,” Tohoku J. Exp. Med., May, 1984, 143(1) p. 127-8, suggests that inhibition of angiotensinconverting enzyme by captopril offers a possible therapeutic approach to the treatment of atherosclerosis complicated with hypertension.
The role of the renin-angiotensin system in atherosclerosis is not clear. Campbell-Boswell & Robertson, Exp. and Mol. Pathol. 35:265 (1981) reported that angiotensin II stimulated proliferation of isolated human vascular smooth muscle cells while Geisterfer et al, Circ. Res. 62: 749-756 (1988) showed no proliferation (but stimulation of growth) of isolated rat vascular smooth muscle cells.
Overturf, M. et al, Atherosclerosis, 59:383-399, 1986, discloses that studies with ACE inhibitors in cholesterol fed rabbits show no significant effects in the development of atherosclerosis.
Cecil, Textbook of Medicine, 16 Ed., pp 239 to 241, indicates at page 240 that blood pressure is an accelerator of atherosclerosis.
U.S. Pat. Nos. 4,046,889 and 4,105,776 to Ondetti et al disclose proline derivatives, including captopril, which are angiotensin converting enzyme (ACE) inhibitors useful for treating hypertension.
U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoyl substituted prolines, including fosinopril, which are ACE inhibitors useful for treating hypertension.
U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivatives, including enalapril, which are ACE inhibitors useful for treating hypertension.
U.S. Pat. No. 4,452,790 to Karanewsky et al discloses phosphonate substituted amino or imino acids and salts thereof and covers (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]-oxy]-1-oxohexyl]-L-proline (SQ 29,852, ceranapril). These compounds are ACE inhibitors useful in treating hypertension.
U.S. Pat. No. 4,316,906 to Ondetti et al discloses ether and thioether mercaptoacyl prolines which are ACE inhibitors useful in treating hypertension. This Ondetti et al patent covers zofenopril.
There are several different classes of compounds which have serum cholesterol lowering properties. Some of these compounds are inhibitors of the enzyme HMG CoA reductase which is essential in the production of cholesterol, such as mevastatin (disclosed in U.S. Pat. No. 3,983,140), lovastatin also referred to as mevinolin (disclosed in U.S. Pat. No. 4,231,938), pravastatin (disclosed in U.S. Pat. No. 4,346,227) and velostatin also referred to as synvinolin (disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171).
Other compounds which lower serum cholesterol may do so by an entirely different mechanism than the HMG CoA reductase inhibitors. For example, serum cholesterol m
Bergey James L.
Kawano James C.
Tschollar Werner
Yonce Cary S.
Criares Theodore J.
Duncan, Jr. Sammy G.
E.R. Squibb & Sons, Inc.
Kim Jennifer
Rodney Burton
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