Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-18
2003-11-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C514S415000, C514S423000, C514S426000
Reexamination Certificate
active
06653336
ABSTRACT:
The present invention relates to the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo-capillary microcirculatory disorders.
It is known that the majority of degenerative vascular diseases, for example arterial hypertension (N. M. Kaplan, “
Microvascular Rarefaction”,
Clinical Hypertension, 6
th
Ed., Baltimore, Wilkinson and Wilkins, 1994, 86; A. S. Greene et al., “
Microvascular rarefaction and tissue vascular resistance in hypertension”,
Am. J. Physiol., 1989, 256 (Heart Circ. Physiol., 25), H 126-H 31; A. S. Izzard et al., “
Hypertension and the vasculature: arterioles and the myogenic response”,
J. Hypertens., 1995, 13, 1-4; A. M. Heagerty et al., “
Small artery structure in hypertension”,
Hypertension, 1993, 21, 391-7), but also vascular complications of certain metabolic diseases, for example diabetes mellitus (G. Reach et al., “
Causes et mécanismes de la microangiopathie et de la neuropathie—“L'hypothèse glucose” et ses implications
[Causes and mechanisms of microangiopathy and neuropathy—“The glucose hypothesis” and its implications]”, in: G. Tchobroutsky, G. Slama, R. Assan, P. Freychet, Paris: Pradel, 1990, 448-57), or certain dyslipidemias (J. F. Toole, “
Atherosclerosis”,
Cerebrovascular Disorders, New York, Raven Press, 1984, 199-213) are accompanied by detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation (J. C. M. L. Le Noble et al., “A functional morphometric study of the cremaster muscle microcirculation in young spontaneously hypertensive rats”, J. Hypertens., 1990, 8,741-8; I. I. H. Chen et al., “
Microvascular rarefaction in spontaneously hypertensive rat cremaster muscle”,
Am. J. Physiol., 1981, 241, H 306-10).
The detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation can take different forms, such as, for example:
an arteriolo-capillary rarefaction (P. Gasser, “
Nailfold microcirculation in normotensive and essential hypertensive subjects as assessed by video
-
microscopy”,
J. Hypertens., 1992, 1, 83-6),
a lack of arteriolo-capillary recruitment (B. W. Zweifach, “
Micropressure
-
flow relationships in a skeletal muscle of spontaneously hypertensive rats”,
Hypertension, 1981, 3, 601-14),
and, more generally, poor adjustment of the distribution of the blood in the tissues to metabolic requirements, any detrimental change capable of inducing or perpetuating a tissue hypoperfusion or an ischemia, absolute or relative (E. Vicaut, “
Hypertension and the microcirculation: a brief overview of experimental studies”,
J. Hypertens., 1992, 10, suppl. 5, S59-S68).
It is also known that the detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation described above can precede, for example, the rise in pressure values in arterial hypertension, creating for some a true vicious circle (A. J. Zweifler et al., “
Diminished finger pulse in borderline hypertension: evidence for early structural vascular abnormality”,
Am. Heart J., 1982, 104, 812-15; J. M. Sullivan et al., “
Attenuation of the microcirculation in young patients with high
-
output borderline hypertension”,
Hypertension, 1983, 5, 844-51).
Finally, it is known that a great many factors are involved simultaneously in the regulation of general hemodynamics (outputs, resistances, pressures, and the like) and in the regulation, or rather adjustment, of the distribution of blood in the tissues according to the context (hierarchization depending on the nature of the organs, and the like) and the metabolic requirements of the moment (M. J. Mulvany, “
The structure of the resistance vasculature in essential hypertension”,
J. Hypertens., 1987, 5, 129:H; H. A. J. Struijker-Boudier et al., “
The microcirculation and hypertension”,
J. Hypertens., 1992, 10 (suppl. 7), S147-S156).
A great many vasoactive substances have been identified, with very particular interest in recent years in, by way of example, substances originating from or having an effect on smooth muscle fibers and the vascular endothelium (S. Laurent et al., “
Physiopathologie et pharmacologie du remodelage artériel dans l'hypertension artérielle
[Physiopathology and pharmacology of arterial remodeling in arterial hypertension]”, the letter from the pharmacologist, 1997, 11, 146-54; Taddei et al., “
Hypertension causes prematurate [sic] aging of endothelial function in humans”, Hypertension,
1997, 29, 736-43).
The complexity of these different regulations, the number of factors involved and their interactivity, better understood today, have led us to provide the combination of several medicaments, directly or indirectly vasoactive, for both preventing and treating:
on the one hand, the clinical attack, for example arterial hypertension, when the rise in pressure values reaches, or indeed exceeds, the standards recommended by the international scientific community;
on the other hand, its repercussions on tissue perfusion in the context of macro/microcirculatory disorders which, it is known, can precede, maintain and aggravate the clinical entity described above by way of example (arterial hypertension but also, for example, vascular complications of certain metabolic diseases, and the like) (H. A. J. Struijker-Boudier et al., “
Assessment of the microcirculation in cardiovascular disease”,
Clin. Sci., 1996, 91, 131-9).
The actions of different vasoactive substances can thus usefully complement one another and provide an improved therapeutic effect in the basic treatment of degenerative vascular diseases, or indeed in the prevention of the incidents and accidents which they induce.
It is also known that some CEIs have a beneficial effect on arteriolar or coronary microcirculation but at no time has a beneficial effect on the functional unit represented by an arteriola and the adjacent capillaries been demonstrated in the literature.
It has now been shown, which is the subject of the present invention, that the combination of a CEI with a diuretic, in addition to the known properties of this combination, made it possible, surprisingly, to correct microcirculatory disorders at both the arteriolar and capillary level, whereas no property of this nature had ever been described or claimed in prior publications or patents relating to combinations, in particular of CEI and of diuretics, to CEIs or to diuretics.
The novelty of this type of combination of vasoactive agents lies in addition in the fact, in particular, that each of the constituents of the combination is generally used at low doses, generally lower than those used in each of their first indications.
The usefulness of this type of combination thus lies in the production of pharmaceutical compositions of use in the treatment of arteriolo-capillary micro-circulatory disorders. These compositions can thus be used in all pathologies where microcirculatory disorders are involved, such as, for example, degenerative vascular diseases, arterial hypertension, cardiac insufficiency, cerebral ischemia, heart attacks, arteritis of the lower limbs, the prevention and treatment of cardiovascular complications of type-II diabetes, retinopathies, nephropathies, and the like, as main or secondary treatment.
The CEIs which can be used in these compositions are, without implied limitation: Perindopril, Captopril, Enalapril, Lisinopril, Delapril, Fosinopril, Quinapril, Ramipril, Spirapril, Imidapril, Trandolapril, Benazepril, Cilazapril and Temocapril, and their addition salts with a pharmaceutically acceptable acid orbase.
The preferred CEIs are Perindopril, Captopril, Enalapril, Lisinopril, Benazapril, Quinapril and Delapril and their salts and more particularly Perindopril and its salts.
The diuretics which can be used in these compositions are, without implied limitation: Indapamide, Hydrochlorothiazide, Furosemide, Altizide, Trichlormethiazide, Triflumethazide, Bemetizide, Cyclothiazide, Methylclothiazide, Azosemide, Chlorothiazide, Bu
Guez David
Levy Bernard
Schiavi Pierre
Delacroix-Muirheid C.
Henley III Raymond
Les Laboratoires Servier
The Firm of Hueschen and Sage
LandOfFree
Combination of hypertensin converting enzyme inhibitor with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Combination of hypertensin converting enzyme inhibitor with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination of hypertensin converting enzyme inhibitor with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3120870