Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-07
2000-09-26
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514415, 514423, 514460, 514547, 514601, 514602, 514603, 514604, 514625, 514824, A61K 3118, A61K 3116, A61K 31435, A61K 31405, A61K 3140, A61K 3135, A61K 31225
Patent
active
061243094
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The treatment of patients with or at risk of developing ischemic syndromes with doses of an HMG-COA reductase inhibitor to lower total and LDL cholesterol is known. This is done in order to restore endogenous vascular endothelium-dependent activities including, but not limited to vasodilatory responses modulating vascular tone and blood flow, antiadherent properties of the blood vessel wall, and anticoagulation of platelets (International Publication Number WO 95/13063).
There is evidence from animal models that compounds which inhibit the enzyme, acyl-coenzyme A:cholesterol acyltransferase (ACAT) will be effective anti-atherosclerotic agents,(Curr. Med. Chem., 1994;1:204-225). It is well-established that when the majority of cholesterol in plasma is carried on apolipoprotein B-containing lipoproteins, such as low-density lipoproteins (LDL-C) and very-low-density lipoproteins (VLDL-C), the risk of coronary artery disease in man is increased (Circulation, 1990;81:1721-1733). Conversely, high levels of cholesterol carried in high-density lipoproteins (HDL-C) is protective against coronary artery disease (Am. J. Med., 1977;62:707-714). Thus, a drug which reduces the levels of atherogenic LDL-C and VLDL-C and elevates levels of protective HDL-C will produce a less atherogenic lipoprotein profile and thus a beneficial effect on atherosclerotic disease and its complications. This beneficial effect was demonstrated in man in the Helsinki Heart Study with the lipid regulator gemfibrozil which decreased LDL-C, increased HDL-C, and reduced the incidence of coronary artery disease (N. Engl. J. Med., 1987;317:1237-1245).
SUMMARY OF THE INVENTION
We have now shown that a combination of ACAT inhibitor and HMG-COA reductase inhibitor when administered in a chow/fat diet results in a greater reduction in apo B-containing liproprotein than either alone and that a normalization of the plasma lipoprotein profile can be achieved. This means the combination treatment results in plasma lipoprotein profile associated with a decreased risk of coronary artery disease.
We have also shown that a combination of ACAT inhibitors and HMG-COA reductase inhibitors reduces the cholesteryl esters (CE) enrichment of pre-existing atherosclerotic lesions to the same extent as the HMG-COA reductase inhibitor alone but that the histologic character of the atherosclerotic lesions is less complicated. This means that the lesions are less prone to induce myocardial infarction.
DETAILED DESCRIPTION OF THE INVENTION
The novel method of treatment of this invention and the novel pharmaceutical compositions comprise the administration to a patient at risk of developing atherosclerosis or a patient in whom the disease has been diagnosed with an ACAT inhibitor and HMG-COA reductase inhibitor which will restore endogenous vascular endothelium-dependent activities including improving the normal dilation capacity of the endothelium. This method may be used to induce vasodilation to modulate vascular tone and blood flow. Other improvements in vascular endothelium-dependent activities include decreasing the adherent properties of the blood vessel walls and decreasing the coagulation of platelets. Suitable subjects for the method of the present invention include those individuals who currently exhibit symptoms of atherosclerosis and those who are at risk of developing various acute ischemic syndromes including individuals with high blood pressure, diabetes, or hyperlipidemia, and individuals who smoke.
The various acute ischemic syndromes that may be treated by the method of the present invention include: angina pectoris, coronary artery disease (CAD), hypertension, cerebrovascular accidents, transient ischemic attacks, chronic obstructive pulmonary disease, chronic hypoxic lung disease, pulmonary hypertension, renal hypertension, chronic renal disease, microvascular complications of diabetes, and vaso-occlusive complications of sickle cell anemia.
An HMG-COA reductase inhibitor for use in the novel method may be selected from
REFERENCES:
patent: 4739073 (1988-04-01), Kathawala
patent: 5273995 (1993-12-01), Roth
patent: 5491172 (1996-02-01), Lee et al.
CA 116:15643, Bocan et al., 1991.
Anderson Elizabeth M.
Jordan Kimberly
Warner-Lambert & Company
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