Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1994-09-22
2003-09-02
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S075000, C514S179000
Reexamination Certificate
active
06613757
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a method for the prevention and treatment of atherosclerotic vascular disease (cardiovascular disease); for the prevention and treatment preeclampsia in pregnant women and for hormone replacement therapy in peri- and post-menopausal women, and for the treatment of hypertension in women and men.
Epidemiological data indicate that approximately one half of the deaths in economically developed countries are attributable to a single major cause, viz., cardiovascular disease, including coronary heart disease, stroke and other forms of vascular disease (Green, A., Bain, C., 1993). The commonest and most lethal form of cardiovascular disease is coronary heart disease. In men, there is a continuous increase in the prevalence of cardiovascular disease after the age of 30-40 years. On the other hand, the rate of cardiovascular disease, especially coronary heart disease, is relatively low among premenopausal women but rises sharply with increasing age, suggesting that sex steroids (estrogens and progesterone) have a protective effect in women. The increased risk of coronary heart disease among women with bilateral oophorectomy further supports the view that steroid hormones may play a protective role with regard to cardiovascular disease.
Cardiovascular disease can be prevented in postmenopausal women by hormone replacement therapy (HRT) with estrogens. The recently performed meta-analysis of 29 studies has demonstrated a reduced cardiovascular disease risk among estrogen users in 23 of these studies (Stampfer et al., 1991). There is also experimental evidence from studies in monkeys that the development of coronary atherosclerosis induced by oophorectomy and diet may be reversed by estrogen supplementation (Adams et al., 1992). On the other hand, there are no effective methods for the prevention of cardiovascular disease in man, since estrogen cannot be used because of side-effects.
The mechanism of the protective effect of female sex hormones is not fully understood. An impact on the lipid profile may be possible. Among postmenopausal women, estrogens reverse the atherogenic changes in lipid profile which is associated with early menopause such as the increase in LDL-cholesterol and serum triglyceride levels and the decrease in HDL-cholesterol. However, new data suggest that both estrogens and progesterone may have a direct effect on the blood vessels. The presence of estrogen and progesterone receptors in arterial endothelial and smooth muscle cells supports the view that sex steroids may have a direct effect on the blood vessels (Lin et al., 1986). It has also been demonstrated that estrogen treatment results in the redistribution of arterial estrogen receptors and in the increase in arterial progesterone receptors in baboons (Lin et al, 1986). Monkey studies suggest that the estrogens may prevent ovariectomy-induced atherosclerosis by inhibiting the uptake and degradation of LDL in the arterial wall (Adams et al., 1992). The effects of estrogens and/or progesterone on arterial tone may also explain some of the beneficial effects of HRT on arterial disease risk. From animal models it is known that estrogens increase uterine blood flow by regulating the vascular tone (Greiss & Anderson, 1970, Ganger et al., 1993). The effects of a sex steroid on the vascular tone suggest that sex steroids may play a role in the pathogenesis of hypertension.
The effects of steroids on the vessels can be mediated by various locally produced hormones including nitric oxide, prostacyclin and endothelin. Both nitric oxide and prostacyclin induce vascular relaxation and inhibit platelet aggregation. On the other hand, endothelin has a strong vasoconstriction effect. Nitric oxide is produced by endothelial cells and is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991). Nitric oxide, formerly known as EDRF (endothelin-derived relaxing factor) (Furchgott und Zawadzki, 1980; Moncada, Palmer and Higgs, 1991), is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of a flavin-containing enzyme, nitric oxide synthase (Moncada, Palmer and Higgs, 1991). Nitric oxide elevates levels of cGMP (1,3,5-cyclic guanosine monophosphate) within the vascular smooth muscle to produce relaxation and to reduce blood vessels tone (Moncada, Palmer and Higgs, 1991).
Prostacyclin is a potent endogenous platelet inhibitory and antithrombogenic substance acting as a local regulator of cell-vessel wall interaction (Willis and Smith 1989). The pharmacological effects of prostacyclin are similar to those of nitric oxide. It is a potent vasodilator which dose-dependently lowers peripheral arterial resistance and blood pressure. The clinical use of prostacyclin is limited due to its chemical instability. Therefore, a prostacyclin analog is preferred, i.e., a prostaglandin derivative with a structure related to prostaglandin which exhibits an effect on the cardiovascular system, e.g., inhibitions of platelet aggregation. Iloprost an cicapristost are stable analogs of prostacyclin. Iloprost was the first compound synthesized that combined the biological profile of prostacyclin with chemical stability (Skuballa et al., 1985). Cicaprost is a metabolically and chemically stable prostacyclin analog which shows high bioavailability and prolonged duration of action (Skuballa et al., 1986). It is highly specific prostacyclin mimic, exhibiting only minor if any effects on organ systems sensitive to other prostaglandins.
There is evidence that prostacyclin analogs exert protective effects on the endothelium. Beneficial effects of cicaprost and iloprost on atherosclerosis were described in animal models. Oral treatment of cholesterol-fed rabbits with cicaprost reduced aortic atheromatous plaque formation and partially prevented hypercholesterolemia-induced impairment of endothelium-dependent relaxation (Braun, M., et al., 1992). In addition, cicaprost reduced hypercholesterolemia-induced platelet and neutrophil hyperactivity in rabbits (Hohfeld et al., 1992). Platelets and leukocytes are believed to contribute to atherogenesis. Furthermore, studies in rabbits showed that oral cicaprost has a beneficial effect on the hypercholesterolemia-induced impairment of coronary vasodilatation (Woditsch I, et al., (1992). Iloprost has been found to protect microvascular arteriolar endothelium from damage by cyclosporin (Burton GA et al., 1992).
These animal studies suggest that prostacyclin analogs alone may be protective against atherosclerosis. There are no experimental or clinical studies with a combination of prostacyclin analogs with a progestin or an estrogen.
Preeclampsia is a pregnancy-specific disease classically defined as the triad of hypertension, pathologic edema and proteinuria normally associated with fetal hypotrophy. The etiology and pathogenesis of this common disease (approximately 10% of all pregnancies) is poorly understood. It is generally believed that preeclampsia is linked to prostacyclin deficiency and increased thromboxane A2 production. The current therapy is restricted to bed rest (mild form), symptomatic medication with antihypertensive drugs and early delivery with attendant risks of operative delivery and iatrogenic prematurity. In preeclampsia, there is a reduced preload, low cardiac output and an elevated after-load which is consistent with a decreased intravascular volume and an increased peripheral vascular resistance. The increased peripheral resistance has been explained by (1) the increased vascular sensitivity to pressor agents and (2) the presence of a vasoactive substance. There is considerable evidence that preeclampsia is associated with an increased sensitivity to the pressor effects of angiotensin 11 and other vasoactive agents (Abdul-Karim 1961, Gant 1973, Gant 1974), platelet activation (Bonnar 1971, Perkins 1979, Giles 1981), and endothelial cell injury (Roberts 1989, Shanklin 198
Chwalisz Kristof
Garfield Robert E.
Board of Regents , The University of Texas System
Criares Theodore J.
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