Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-08-11
1995-10-03
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
054552575
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/00276 filed Feb. 8, 1992.
This invention relates to the use of lacidipine in the treatment or prevention of arteriosclerosis.
UK Patent Application GB 2164336A describes a novel group of 1,4-dihydropyridine derivatives which reduce intracelluar calcium in concentration by limiting transmembranal calcium in influx and thus the compounds may be useful for the treatment of cardiovascular disorders such as hypertension, anginopectories, myocardial ischaemia, congestive heart failure, cerebral vascular and peripheral disorders. A particularly preferred compound is (E)-4-[2[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]-1,4-dihydro-2,6-d imethyl-3,5-pyridinedicarboxylic acid diethyl ester, which now has the approved name lacidipine. This compound has been found to exhibit a particularly marked selectivity for inhibiting transmembrane calcium movement in vascular smooth muscle compared to activity on cardiac muscle. This vascular selectivity coupled with a particularly prolonged duration of action indicated that it should be especially useful as an antihypertensive agent and this has been confirmed by clinical studies.
We have now found that lacidipine possesses a useful anti arteriosclerotic activity in addition to the known action on vascular smooth muscle. The anti arteriosclerotic activity of lacidipine may be demonstrated in a number of standard tests. Thus for example lacidipine was found to significantly reduce cholesterol esterification in cultured mouse peritoneal macrophages. Lacidipine also significantly reduces plaque formation in a cholesterol-fed rabbit test.
The compound may therefore be useful for the treatment or prevention of atherosclerosis, hypertensive arteriosclerosis, Monckebergs arteriosclecrosis, hyperplastic arteriosclerosis and further cardiovascular disorders induced thereby or associated with arteriosclerosis such as angina pectoris, myocardial infarction hypertension, apoplexy, intermittent claudication, gangrene, arteriosclerosis of the aorta, arteriosclerotic aneurysms and arteriosclerosis of the renal arteries.
The invention therefore provides for the use of lacidipine in the treatment or prevention of arteriosclerosis in mammals. A further aspect of the invention provides for the use of lacidipine in the manufacture of a medicament for the treatment or prevention of arteriosclerosis in mammals.
In yet a further aspect of the invention there is provided a method for the treatment and or prevention of arteriosclerosis in mammals which comprises administering lacidipine to said mammal.
For the treatment and or prevention of arteriosclerosis and cardiovascular diseases induced thereby lacidipine may be formulated in a conventional manner with one or more pharmaceutical excipients and or carriers.
Thus a further aspect of the invention provides for a pharmaceutical composition for use in the prevention or treatment of arteriosclerosis which comprises lacidipine and one or more pharmaceutical excipients and or carriers formulated for oral, sublingual, transdermal parenteral or rectal administration.
For oral administration the pharmaceutical composition may take the form of for example tablets, which may be film or sugar coated, capsules, powders, granules, solutions including syrups, or suspensions prepared by conventional means with acceptable excipients. For sub lingual administration the composition may take the form of tablets or lozenges formulated in conventional manner.
For parenteral administration lacidipine may be given as a bolus injection or by continuous infusion. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such forms as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a vehicle
REFERENCES:
Triggle et al., Drug News Perspect., vol. 4, No. 10, Dec. 1991, pp. 643-646.
Bernini et al., Journal of Cardiovascular Pharmacology, vol. 18, suppl 10, 1991, pp. S42-S45.
Journal of Cardiovascular Pharmacology, vol. 17, suppl. 4, 1991, pp. S94-S99.
Mason et al., FASEB Journal, vol. 6, No. 1, Jan. 1992, p. A399, abstract No. 2301.
Keogh et al., Journal of Cardiovascular Pharmacology, vol. 16, suppl 6, 1990, pp. S28-S35.
Weinstein et al., The American Journal of Medicine, vol. 86, suppl. 4A, 1989, pp. 27-32.
Glaxo SpA
Henley III Raymond
Spivack Phyllis G.
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