LT4310B - Pharmaceutical preparations and medicaments for the prevention and treatment of endothelial dysfunction - Google Patents

Abstract

The present invention describes the use of compounds which release or transfer nitrogen monoxide, of endogenous nitrogen monoxide formation stimulators, and of guanylate cyclase stimulators for preventing, treating and eliminating endothelial dysfunctions and diseases associated with or caused by said dysfunctions. The invention further describes the use of said compounds for preparing pharmaceutical products for said areas of application.

Description

Scope of the Invention

The present invention relates to the use of nitric oxide releasing and / or transporting compounds, endogenous nitric oxide synthesis stimulators and guanylate cyclase stimuli for the treatment and amelioration of endothelial dysfunction and disorders caused by or associated with endothelial dysfunction. The present invention also provides the ability to produce pharmaceutical preparations for the above indications.

Known state of the art

Organic nitric acid esters such as glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythrityltetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), US-PS) 2,370,437), Isosorbide-5-mononitrate (ISMN) (DE-OS 22 21 080, SE-OS 27 51 934, DE-OSD 30 28 873, DE-PS 29 03 927, DE-OS 31 02 947, DE) -OS 31 24 410, EP-PS 45 076, EP-PS 57 847, EP-PS 59 664, EP-PS 64 194, EP-PS 67 964, EP-PS 143 507, US-PS 3 886 186, US -PS 4 065 488, USPS 4 417 065, US-PS 4 431 829), isosorbide dinitrate (ISDN) (L. Goldberg, Acta Physiolog.Scand. 15, 173 (1948)), propyl nitrate (Medard, Mem. Poudres 35: 113 (1953)), trolnitrate (FR-PS 984 523) or nicorandil (U.S. Pat. No. 4,200,640)) and the like are vasodilators that have been used extensively for decades, particularly in the treatment of indications such as angina or ischemic attack. heart disease (CHD) (Nitrangin®, Pentalong®, Monolong®, Isoket®, Elantan®, etc.). Similarly or better pharmacologically, using the above-mentioned indications, newer types of organic nitrates, such as SPM 3672 (N- [3-nitratopivaloyl] -L-cysteine-ethyl ester (US-PS 5 284 872) and their derivatives. The use of organic nitrites such as isoamyl nitrite as a coronary dilator has also been known for some time (Brunton, Lancet: 97 (1867)) Other compounds that release or transport nitric oxide, such as thionitrite, thionitrate, S-nitrosothiol or nitrosoprotein (Harrison et al., Circulation 87: 1461-1467 (1993)) and substituted furoxanes (1,2,5-oxadiazole-2-oxides, furazan-N-oxides) (Feelisch et al., Biochem. Pharmacol. 44 : 1149-1157 (1992)) or substituted sidnonimines, in particular molsidomine (DE-AS 16 95 897, DE-AS 25 32 124, DD-PS 244 980), are also described as active coronary dilators. pharmacologically active metabolites such as molsidomine metabolites SIN 1 and SIN-1A (Noack, Nitroglycerin VII, Walter de Gruyter & Co., Berlin 1991, 23-28) and their derivatives and structural analogues (Noack and Feelisch, Molecular Mechanism of Nitrovascular Bioactivation; Endothelial Mechanisms of Vasomotor Control (published by Drexler et al.), P. 37-50, Steinkopf Verlag, Darmstadt, F.R.G (1991)), may release or transport nitric oxide in vivo.

The production of galenical pharmaceuticals from organic nitrates or nitrites and other nitric oxide releasing or transporting compounds for the treatment of angina or ischemic heart disease is well known. They are prepared in the usual manner and according to generally accepted rules for pharmaceutical practitioners, choosing the technology and the excipients used, in particular the active ingredient to be recycled. Of particular importance are issues such as its chemical and physical properties, the form of administration chosen, the desired duration of action and the avoidance of incompatibility between the medicinal product and the excipient. In particular, oral, parenteral, sublingual or transdermal routes of administration of drugs for the treatment of angina pectoris and ischemic heart disease in the form of tablets, dragees, capsules, solutions, aerosols or patches are described (DD-PS 293 492, DE-AS 26 23 800, DE). -OS 33 25 652, DE-OS 33 28 094, DE-PS 40 07 705, DE-OS 40 38 203, JP Application 59/10513 (1982)).

In addition to the long-known use of nitrating agents, their use in the treatment and prophylaxis of diseases caused by pathologically elevated concentrations of amino acids containing sulfur in body fluids is described. Such pathological conditions resulting from congenital or acquired defects in the metabolism of these amino acids and resulting in elevated levels of said amino acids in the blood and urine (homocystinuria) are referred to as the generic term for homocysteinemia (WO 92/18002).

The anti-ischemic action of the organic nitrates and other classes of substances mentioned above is explained by the hemodynamic effects, in particular the cardiac unloading effect, which leads to a more conservative oxygen uptake in the heart or corrects the imbalance between O2 content and need. The cause is low-pressure vein dilation (venous pooling) or reduction of returning blood volume and direct dilated coronary function, especially in coronary stenosis. In this way, it is likely that the post-stenotic diminished perfusion (positive Steal effect) is particularly beneficial, since organic nitrates show significantly more potency in atherosclerotic vascular sites than in healthy vascular sections (Kodja et al., Endothelium 1 (Suppl.): Abstr. 299, p.76). 1993)), especially in the field of coronary stenosis. This purely hemodynamic effect is caused by the radical nitric oxide NO released from all nitrovasodilators, despite the very different chemical composition of the compounds. However, the pathways of bioactivation that ultimately lead to NO delivery at the site, i.e., vascular endothelial cell and smooth muscle cell, are very diverse (Noack and Feelisch, Molecular Mechanism of Nitrovascular Bioactivation; Endothelial Mechanisms of Vasomotor Control, Drexler et al., P. 37). -50, Steinkopf Verlag, Darmstadt, FRG (1991)). This has been unequivocally clarified in recent years by direct measurement of NO by various techniques (Methode Noack et al., Neuroprotocols 1: 133139 (1992)). NO acts vasodilatory by activating soluble guanylate cyclase. This stimulates cGMP synthesis from GTP. cGMP, in turn, leads to various phosphorylation (e.g., protein kinase) reactions that promote intracellular Ca accumulation (Karczewski et al., Z. Cardiol. 79 (Suppl. 1): 212 (1990)). As the intracellular level of free Ca ²⁺ decreases, relaxation is obtained. Since 1987, endothelial-derived release factor (EDRF) has been known to be identical to NO or NO-containing material (Palmer et al., Nature, 327: 524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sci. 84: 9265-9269 (1987)) and have important implications for local blood flow.

Endothelial cells in the area of the inner wall of blood vessels form a single, monolayer culture. So does an adult get around 800m? a common surface with a specific weight of 1.5 to 2 kg and corresponding to a specific weight of the human liver. At present, endothelial cells have a dual function: mechanical and functional. First, they act as a barrier to prevent the penetration of blood components such as Low-Density Lipoprotein (LDL) into the inner blood vessel wall (intima). Second, they have endocrine function. Exposure to a variety of stimuli enhances the synthesis of bioactive substances such as EDRF / NO and prostaglandin I2 (PGI2), which play a fundamental role in blood cell function (Pohl and Busse, Eur. Heart J.: 11 (Suppl.B) 35-42 (1990) )), regional hemodynamics (Furchgott, Circ. Res. 53: 557-573 (1983)) and structural vascular wall structure (Di Corleto, Exp. Cell Res. 153: 167-172 (1984)). As such, it turns out that, regardless of the cause, endothelial damage (endothelial damage due to hypercholesterolemia (TJ Verbeuren et al., Circ. Res. 58: 552-564 (1986)), endothelial damage in the postinfarction phase (MR Sigreid et al., Circ. 86 (Suppl.l): 21 (1992)), have a pathological effect on endothelial function, which may have a variety of consequences, including regional vasoconstriction or vasospasm and remodeling or growth processes in the vascular wall, considered as the initial processes of atherogenesis.

Endothelial dysfunction is commonly manifested as a limitation or disappearance of endothelial-induced physiological vasodilation. At the same time, NO-induced vascular relaxation, NO-induced vascular protection, and NO-inhibited growth processes in the intimate and media have been observed to be enhanced or weakened. In addition, endothelial dysfunction is characterized by proliferative processes in the vascular wall due to increased mitogenesis, increased endothelial leukocyte and macrophage migration and adhesion, and increased oxidation of low density lipoprotein (LDL) that damages endothelium. It is continuously monitored for pathological conditions in atherosclerosis, hypertension, hypercholesterolemia, diabetes mellitus and heart failure (Creager et al., J. Clin. Invest. 86: 228-234 (1990); Linder et al., Circulation 81: 17625

1769 (1990); Zeiher et al., Circulation 83: 391-401 (1991)). Also, hypoxia and mild traction are moments that cause endothelial dysfunction. Among other things, it leads to the fact that vasoactive substances such as acetylcholine and serotonin, which normally cause vasorelaxation, cause vasoconstriction in vascular smooth muscle, which adversely affects the appearance of the disease (Golino et al., N. Engi. J. Med. 324: 641-648 (1991)). Thus, physiological vasomotor regulation in endothelial dysfunction is not only impaired but also reversed. Even more pronounced, these lesions are expressed in the presence of atherosclerotic lesions of the inner vascular wall (Ludmer et al., N. Eng. J. Med. 315: 1046-1051 (1986)).

Not only does endothelium, with its autocrine and paracrine activities, help maintain a healthy vascular wall, it also influences the effects of exogenous NO releasers, such as PETN or GTN, by itself synthesizing EDRF / NO. Removal of the endothelium from the vascular wall, for example mechanically (during invasive catheter diagnosis or off-body isolation of vascular segments), or by inhibiting endothelial NO production by specific inhibitors, enhances the vasodilatory activity of nitrovasodilators such as GTN or PETN (Busse et al., Cardiovasc Pharmacol 14 (Suppl 11): S81-S85 (1989); Kodja et al., J. Vasc. Res. 29: 151 (1992A)). Pharmacological inhibition of endothelial NO synthesis leads to the same effect in coronary nerves (Kodja et al., Naunyn-Schmiedeberg, Arch. Pharmacol. 346: R35 (1992B)). The activity of calcium antagonists, especially 1,4-dihydropyridine type (DHP's), is known to diminish endothelial elimination (Kodja et al., Bas. Res. Cardiol. 86: 254-256 (1991)). Further studies have shown that these substances are probably stimulants of endothelial NO synthesis and release (Gunther et al., Basic Res. Cardiol. 87: 452-460 (1992)). Likewise, the biological activity of quinines, such as bradykinin, occurs through enhanced endothelial EDRF / NO synthesis and release (VA Briner et al., Am. J. Physiol. 264: F322-F327 (1993); Kelm et al., Biochem. Biophys Res Commun 154: 236-244 (1988)).

Arrangement of the Invention

Endothelial dysfunctions are today considered to be the cause of common and pathophysiologically relevant cardiovascular disorders such as atherosclerosis. Therefore, the prevention, treatment and resolution of these dysfunctions and the conditions that accompany or cause them are an important therapeutic necessity.

The use of nitric oxide releasing and / or transporting compounds, endogenous nitric oxide synthesis stimulators and guanylate cyclase stimulators, in particular soluble guanylate cyclase stimulators, has been found to be useful in the treatment, prophylaxis and treatment of endothelial dysfunctions and disorders associated with and / or caused by these dysfunctions. These endothelial dysfunctions and diseases are primarily endothelial lesions, hypercholesterolemia, hypoxia-induced endothelial lesions, endothelial lesions, caused by harmful mechanical and chemical agents, in particular medically or mechanically reopened stenotic blood vessels, such as post-percutaneous PTS and percutaneous transluminal coronary angiography (PTC A), endothelial lesions in post-arctic phase (endothelial dysfunction in reperfusion), endothelial re-occlusion after bypass grafting, peripheral arterial blood flow disorders, and cardiovascular disorders such as atherosclerosis, atherosclerosis, , hypertonic heart disease, diabetic microangiopathy and macroangiopathy, coronary heart disease, heart failure, and other conditions caused by endothelial dysfunction.

The nitric oxide releasing and / or transporting compounds, the endogenous nitric oxide synthesis stimulators, and the guanylate cyclase stimulators of the present invention are, inter alia, compounds that act directly on indirectly acting guanylate cyclase, indirectly acting as guanylate cyclase stimulating agents or increasing the release of and / or antagonistically acting inhibitors of guanylate cyclase or otherwise decreasing its enzymatically active concentration.

Ί

Compounds suitable for increasing endogenous NO synthesis or release, such as calcium antagonists, especially 1,4-dihydropyridine type such as nifedipine, felodipine, nimodipine, amlodipine and others, are also used as indirect guanylate cyclase stimuli. It is also suitable for use with compounds which may increase the level of quinines in the endothelium. These include, in particular, quinine receptor stimulants such as quinines or analogs, endothelial kinin synthesis inhibitors and quinine degradation inhibitors, in particular angiotensin converting enzyme blockers (ACE-blockers) such as captopril, enalapril, moexipril, ramipril and related active substances. materials. The most preferred embodiment of the present invention are compounds that co-operate in the release and / or transport of endogenous and exogenous nitric oxide. Particularly suitable classes of substances and compounds herein are organic nitrates, in particular glycerol trinitrate, pentaeritrile tetranitrate, isosorbide-5-mononitrate, isosorbide dinitrate, mannitol hexanitrate, inositol hexane nitrate, propylnitrate, trolnitrate, nicorandil, newer nitrates, such as such as isoamyl nitrite, thionitrites, thionitrates, S-nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine, nitrosoproteins, nitric oxide-releasing furoxane derivatives, nitric oxide-releasing sidnonimine derivatives, in particular molside , complex nitrosyl compounds, especially iron-nitrosyl compounds such as sodium nitroprusside and nitric oxide itself. Since the release and / or transport of nitric oxide in vivo is often via pharmacologically active metabolites, the latter are in principle also suitable for use in the present invention. Pharmacologically compatible derivatives of all of the above compounds may be used simultaneously. Possible variants include, in particular, compound compounds, salts or compounds which are degraded by enzymes or by hydrolysis, such as esters, amides and the like.

Each active ingredient is selected in accordance with the general principles of pharmacology and therapeutic necessity known to those skilled in the art. In addition to the desired pharmacological effect, account should be taken of medical conditions, stage of disease, physical condition, known activity and side effects, contraindications, frequency of treatment, duration of drug interactions and concurrent drug use. Therapeutic doses are administered based on those in which the active substances are used in the indications already known. The daily dose may be up to 500 mg depending on the active substance. Usually a sufficient daily dose is 350 mg. Dose and intervals should be adjusted to achieve a steady-state therapeutic plasma concentration. The compounds used in the present invention may be administered alone or as part of a galenical preparation, as a single active ingredient or in combination with other active substances or known cardiovascular drugs such as ACE blockers, antiaterosclerotics, antihypertensive agents, β-blockers, cholesterol lowering agents, diuretics. such as calcium antagonists, coronary dilators, lipid lowering agents, peripheral vasodilators, platelet aggregation blockers, or other substances used as cardiovascular agents.

Galenic formulations are prepared according to common methodologies and rules known to the pharmaceutical artisan, selecting the technologies and galenic excipients to be used, in particular the active ingredient. Of particular importance here are issues such as its chemical and physical properties, the form of application chosen, the desired duration of action, the site of action and the avoidance of incompatibility between the pharmacy and the excipients. Therefore, it is within the skill of the artisan to select the pharmaceutical form, excipients and manufacturing technology in accordance with known materials and manufacturing process parameters. This dosage form should be such that, in order to maintain a steady state plasma concentration, the amount of active substance in the formulation will permit daily dose distribution in 1-2 single-dose controlled release systems and up to 10 single doses in other dosage forms. Continuous application by prolonged infusions is also suitable.

The compounds of the present invention may be administered orally, intravenously, parenterally, sublingually or transdermally. All medicines should preferably be presented in liquid or solid form. Suitable solutions include, in particular, drops, injections or aerosols, as well as suspensions, emulsions, syrups, tablets, coated tablets, dragees, capsules, peas, powders, lozenges, implants, suppositories, creams, gels, ointments, patches or other transdermal systems. .

Pharmaceutical formulations contain conventional organic or inorganic transporting and auxiliary substances used in galenical formulations with respect to the chemically indifferent active substance itself. Suitable examples include water, saline solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, high dispersion silica, paraffin, fatty acid monoglycerides and diglycerides, cellulose derivatives and polyvinyl derivatives. The preparation may be sterilized and, if necessary, mixed with excipients such as fillers, binders, emollients, formers, oily, disintegrating, hygrostatic agents, adsorbents, preservatives, stabilizers, emulsifiers, solvents, salts for osmotic pressure, buffers, coloring, flavoring, flavoring or sweetening agents. The person skilled in the art will select according to known parameters of the substance to avoid incompatibility between the drug substance and the excipients.

The present invention opens new therapeutic possibilities for the treatment of pathological conditions that promote endothelial dysfunction such as hypoxia, high serum cholesterol, high blood pressure, diabetes, poststhetic reperfusion, such as myocardial infarction and mechanical and chemical injury, etc., or completely prevent it. pathway to the onset of endothelial dysfunction. Therefore, the therapeutic application of suitable compounds, in whatever form of galenic formulation, allows, as has been said, for the prophylaxis and topical treatment of cardiovascular diseases such as atherosclerosis and related diseases, in particular. These include coronary heart disease, vascular stenosis and peripheral arterial blood flow disorders, microangiopathies and macroangiopathies due to diabetes, and so on. The aforementioned compounds unexpectedly showed independent endothelial protective effects independent of properties known to date, in particular purely hemodynamic and anti-ischemic, such as organic nitrates, or their action in homocysteinemia. Therefore, their administration may stop these pathological processes or even reverse them, unless they are irreversible. So it's about an unexpected, new operating component that hasn't been described so far and hasn't been expected in this form.

The following examples and graphs are intended to illustrate in more detail the spirit and scope of the invention without limiting its scope.

Performance examples

An example

Experiments with an in vivo pharmacological model (New Zealand rabbit)

In animal studies, feeding them with cholesterol is an appropriate way to induce endothelial dysfunction over a period of several weeks or months, allowing the study and evaluation of drug effects (Jayakody et al., Can. J. Physiol. Pharmacol. 63: 1206-1209 (1985); Verbeuren). et al., Circ Res 58: 552-564 (1986); Freiman et al., Circ Res 58: 783-789 (1986).

Groups of 9 New Zealand female rabbits were fed standard or cholesterol-enriched (0.75%) food (40 g / kg / day) for 15 weeks. Cholesterol feeding resulted in an increase of its plasma level from 69.8 ± 10.4 to 907.1 ± 85.5 mg / dl and caused atherosclerotic lesions in the aorta, which were evaluated by CT scan using Sudan IV. Aortic lesions included 73.3 ± 1.9% in the aortic arch, 46.3 ± 2.5% in the thoracic aorta, and 49.6 ± 3.5% in the abdominal aorta (Fig. (Fig.2), control).

An example

The vascular contractility of atherosclerotic lesions after phenylephrine treatment remained unchanged, but the endothelial vasorelaxation function was altered with 1 μΜ acetylcholine compared to control animals (standard diet) in a manner that can best be described as endothelial dysfunction. In the (+) thoracic aorta segments of cholesterol-fed animals, there was a marked decrease in sensitivity to acetylcholine compared to control animals (Fig. (Fig.1). 1). There was a direct correlation (r = 0.67, p <0.0001) between the measured degree of endothelial dysfunction and the severity of atherosclerotic lesions (Fig. (Fig.3). 3). These data demonstrate that endothelial dysfunction has developed with cholesterol feeding.

An example

Two other groups received 9 pentaerythrityltetranitrate (PETN) (6 mg / kg / day) in 9 New Zealand white rabbits when added to pressed feed. Animals co-administered PETN showed significant reduction in atherosclerotic lesions. The extent of these lesions was determined as in Example 1. Significantly reduced proportion of atherosclerotic lesions were found in all parts of the aorta (aortic arch: 58.6 ± 2.1%, thoracic aorta 34.7 ± 2.0%, abdominal aorta 39.3 ± 3.1%) (Fig. 2). .

An example

Similarly, no significant difference in maximal (1 μΜ acetylcholine) endothelial relaxation was observed in PETN-fed animals compared to cholesterol-free animals (endothelial dysfunction), thus demonstrating the unequivocally positive effect of the nitrovascular diluent PETN, as this prevents endothelial dysfunction. Figures 3 and 4; Table I).

By comparing Figs. 3 and 4 show that PETN can reduce the extent of atherosclerotic lesions and improve endothelial function. The inferior correlation coefficient in the PETN group suggests that PETN also leads to a close breakdown of the relationship between atherosclerotic lesions and endothelial function.

Table I shows the influence of PETN (6 mg / kg / day) on the development of endothelial dysfunction in the thoracic aorta of New Zealand rabbits induced by cholesterol diet (0.75%; 15 weeks). The potency of the endothelium-dependent vasodilator acetylcholine is expressed as a concentration (-logM; pD2 value) which, when administered at cumulative doses, antagonizes half the effect of the vasoconstrictor phenylephrine (the higher the size, the stronger the action of acetylcholine). The maximal dilatory effect was expressed as the percentage of the vasoconstrictor phenylephrine, which was antagonized by acetylcholine (1 μΜ) at maximum active concentration. Only cholesterol-fed (control animals) -induced endothelial dysfunction is seen in the markedly reduced potency and maximal effect of acetylcholine (*, p <0.05). At the same time, the difference is no longer detectable with PETN. Furthermore, PETN significantly (#, p <0.05) significantly improves acetylcholine potency and concomitant endothelial function after cholesterol feeding, whereas a significant reduction in endothelial function is obtained after standard feeding. Taken together, this demonstrates the positive effect of PETN on endothelial function when experimentally induced atherosclerosis. Plasma PETN resorption and proliferation can also be demonstrated 24 hours after the last animal feeding by measuring plasma concentrations of pentaerythrilmononitrate (PEMN) metabolites (Fig. (Fig.5). 5).

Table I:

Control PETN Standard Cholesterol Standard Cholesterol Acetylcholine action strength [pū2 sizes] 6.91 ± 0.02 6.12 ± 0.05 * 6.62 ± 0.06 # 6.47 ± 0.13 # Max. dilated effect of acetylcholine [%] 84.8 ± 1.2 60.7 ± 8.5 * 74.7 ± 4.9 * 65.0 ± 4.7

An example

Typical tablet composition:

Pentaerythritol tetranitrate ISIS PHARMA 20 mg Lactose DAB 10 137 mg Potato starch DAB 10 80 mg Gelatin DAB 10 3 mg Talk DAB 10 22 mg Magnesium stearate DAB 10 5 mg Silica, high dispersion DAB 10 6 mg

237 mg

An example

The composition of the tablet containing 20 mg pentaerythrityltrinitrate (PETriN):

PETriN 20 mg Lactose DAB 10 137 mg Potato starch DAB 10 80 mg Gelatin DAB 10 3 mg Talk DAB 10 22 mg Magnesium stearate DAB 10 5 mg Silica, high dispersion DAB 10 6 mg

237 mg

An example

The composition of the tablet contains 20 mg pentaerythrityl dinitrate (PEDN):

PEDN 20 mg Lactose DAB 10 137 mg Potato starch DAB 10 80 mg Gelatin DAB 10 3 mg Talk DAB 10 22 mg Magnesium stearate DAB 10 5 mg Silica, high dispersion DAB 10 6 mg

237 mg

An example

The composition of the tablet contains 20 mg of erythrityltetranitrate (ETN):

ETN 20 mg

Lactose DAB10 137 mg

Potato starch DAB 10 80 mg

Gelatin DAB 10 3 mg

Talc DAB 10 22 mg

Magnesium Stearate DAB 10 5 mg

Silica, high dispersion DAB 10 6 mg

237 mg

An example

Composition of 20 mg isosorbide mononitrate (ISMN) tablet:

ISMN 20 mg

Lactose DAB 10 137 mg

Potato starch DAB 10 80 mg

Gelatin DAB 10 3 mg

Talc DAB 10 22 mg

Magnesium Stearate DAB 10 5 mg

Silica, high dispersion DAB 10 6 mg

237 mg

An example

Composition of 20 mg isosorbide dinitrate (ISDN) tablet:

ISDN 20 mg Lactose DAB 10 137 mg Potato starch DAB 10 80 mg Gelatin DAB 10 3 mg Talk DAB 10 22 mg Magnesium stearate DAB 10 5 mg Silica, high dispersion DAB 10 6 mg

237 mg

An example

Tablets containing 40 mg pentaerythrityl tetranitrate and 40 mg propranolol hydrochloride:

PETN 20 mg

Propranolol hydrochloride 40 mg

Lactose 224 mg

Potato starch 80 mg

Gelatin 3 mg

Talc 22 mg

Magnesium Stearate 5 mg

Silica, high dispersion 6 mg

420 mg

Graphs illustrate the essence of the invention.

FIG. I:

Development of endothelial dysfunction in fed New Zealand white rabbits on a cholesterol diet (0.75%; 15 weeks). The vasodilator activity of the endothelium-dependent vasodilator acetylcholine is shown, together with its endothelial functionality as a percentage of the pre-existing vasoconstrictor phenylephrine-induced contraction at the concentrations indicated.

FIG. 2:

Volume of atherosclerotic lesions on the lumenal surface of various aortic segments after feeding on cholesterol diet (0.75%; 15 weeks) (without control) with simultaneous administration of PETN (6 mg / kg / day). Atherosclerotic changes were stained with Sudan IV, and the percentage of stained surface (relative to the total surface) was determined by computer laser scanning. PETN causes a significant reduction in the occurrence of atherosclerotic lesions (p <0.05).

FIG. 3:

Ratio of volume of atherosclerotic lesions on the luminal surface of thoracic aortic segments after feeding with cholesterol diet (0.75%; 15 weeks) to the same segment previously determined with maximal relaxation induced by 1 μΜ acetylcholine (endothelial function). The larger the damaged surface, the worse the relaxation or endothelial function.

FIG. 4:

Same schedule as Fig. 3 with cholesterol and PETN fed simultaneously.

FIG. 5:

Plasma levels of pentaerythritylmononitrate in white New Zealand rabbits, 24 hours prior to withdrawal, after withdrawal of feed. The standard feed contained pentaerythrityltetranitrate (150 mg / kg) in both cases, with an additional 0.75% cholesterol in the cholesterol group. The concentration of pentaerythrityltetranitrate in plasma samples was determined by gas chromatography / mass spectroscopy.

Claims (3)

Definition of the Invention Use of nitric oxide releasing and / or transporting compounds in the manufacture of a medicament for the treatment of endothelial dysfunctions and disorders associated with and / or caused by these dysfunctions, such as (a) endothelial lesions due to cholesterolemia, (b) endothelial lesions due to hypoxia, (c) endothelial damage due to damaging mechanical and chemical agents, in particular medication and mechanical reoperation of stenotic blood vessels, such as after percutaneous transluminal angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), (d) endothelial lesions in the post-infarction phase (endothelial dysfunction during reperfusion), (e) endothelial reocclusion after bypass grafting; (f) peripheral arterial blood flow disorders due to atherosclerotic vascular wall lesions and atherosclerosis in general, (g) hypertension, including pulmonary and portal hypertension, h) hypertonic heart disease, (i) diabetic microangiopathy and macroangiopathy, (j) the prevention, treatment and treatment of heart failure, with the exception of the induction or acquisition of homocysteinemia caused by genetically modified enzyme defects. Use according to claim 1, characterized in that it utilizes nitric oxide releasing and / or transporting compounds, such as (a) organic nitrates, in particular glycerol trinitrate (GTN), pentaerythritol tetranitrate (PETN), isosorbide 5-mononitrate (ISMN), isosorbide dinitrate (ISDN), mannitol hexanitrate, isonitol hexanitrate, ditharitrat, (b) organic nitrites such as isoamyl nitrite, (c) thionitrite, (d) thionitrates, (e) nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine (SNAP), (f) nitrosoproteins, nitric oxide-releasing furoxane derivatives, (g) nitric oxide-releasing sidnonimine derivatives, in particular mesocarb, molsidomine or their pharmacologically active metabolites, (h) complex nitrosyl compounds such as iron-nitrosyl compounds, in particular sodium nitroprusside; and (i) nitric oxide (NO) itself. 3. The use according to claim 1 or 2, characterized in that for the preparation of pharmaceutical preparations, nitric oxide releasing and / or transporting compounds are combined with other active substances for the treatment of cardiovascular diseases, in particular with substances from ACE blockers, antiaterosclerotics, cholesters, betablockers. inducers, diuretics, calcium antagonists, coranary dilators, lipid lowerers, peripheral vasodilators, or platelet aggregation blockers.