SK121896A3 - 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

Area, techniques

The present invention relates to the use of nitrous oxide releasing and / or transferring compounds, endogenous nitrous oxide formation stimulators, as well as treatment and removal stimulators that are induced with it. According to the pharmaceutical guanylate cyclase for prevention, endothelial dysfunctions as well as diseases, the enothelial dysfunction or the invention simultaneously allows the preparation of preparations for? these indications.

BACKGROUND OF THE INVENTION

Organic nitric acid esters such as

80, 113, 15 <1879)) <Risemann et al-, U.S. Patent 2 370 437), IS 31 02 947 DE-OS , EP-PS 59 664. EP-PS US-PS 3,886 186. U.S. Patent

pentaerythr and tetrachloride (P PTH)

Circulation. Vol. XVII, 22 <195 isosorbide-5-mononitrate (ISMN) CDE 31 24 410, EP-PS 45 076. EP-PS 57 8 64 194. EP-PS 67 964. EP-PS 143 507,

No. 065,488, U.S. Pat. No. 4,417,065, U.S. Pat. No. 4,431,829), isosorbide dinitrate (ISDN) <L. Goldberg, Acta Physiolog. Scant. 15, 173 (1948) 5, propatyl nitrate CMedard. Mem. Poudres 35 = 113 (1953)), trolnitrate (FR-PS 984 523) or nicorandyl (US-PS 4 200 640) and similar compounds are vasodilators which have been used for decades as the most widespread drug of particular importance in the indication of angina pectoris or ischemic heart disease (IHK) <Nitrangin ^R. Pentalog ^R. Monolong ^R , Isoket ^R , Elantan ^R and others). Newer-type organic nitrates have comparable and improved pharmacological efficacy when used in the above indications.

such as SPM 3672 (N- [3-nitratopivaloyl] L-cysteine ethyl ester CUS-PS 5,284,872) as well as derivatives thereof. Likewise, the use of organic nitrites such as isoamyl nitrite as coronary dilators has long been known (Brunton, Lancet.: 97 (1867)). Other nitrous oxide-releasing compounds such as thionitrites, thionitrates, S-nitrosothiols or nitrosoproteins (Harrison et al., Circulation 87: 1461-1467 (1993)) as well as substituted furoxanes (1,2,5-oxadiazole- 2-oxides, furazan N-oxides) (Feelísch et al., Biochem. Pharmacol. 44, 1149-1157) (1992) or substituted sydnonimines, especially molsidomines (DE-A 16 95 897, DE-A 25 32 124, DD- PS 244 980) are also described as potent coronary dilators. All of these substances may be present on their own or in the form of their pharmacologically active metabolites, for example the molsidonin netabolites SIN 1 and SIN 1A (Noack, Nitroglycerin VII, Valter de Gruyter et al. Co., Berlin, 1991, 23-28) and derivatives thereof; structural analog (Noack und Feelisch, Molecular mechanism of nitrovascular bioactivation: in Endothelial Mechanisms of Vasomotor Control (Hrsgb. Drexler et al.), pp. 37-50, Steinkopff Verlag, Darmstadt, FRG (1991), to release or transmit in vivo , nitrous oxide.

The galenic processing of organic nitrates or nitrites, as well as other nitrous oxide-releasing or transferring compounds, into pharmaceutical preparations for the treatment of angina or ischemic heart disease are generally known. They are carried out according to the working procedures and rules which are generally common to the pharmaceutical practitioner, the choice of the technologies used and the galenic auxiliaries used being primarily determined by the active substance to be treated. In doing so, they have questions about their chemical-physical properties. the desired form of administration, the desired duration of action as well as avoiding drug and excipient incompatibilities. special meaning. For drugs with indication for angina or ischemic, especially oral. transdernal administration in solutions, sprays or heart disease is described parenterally, sublingually or in the form of tablets, dragees, capsules, patches (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, Japanese Application 59 (10513) 1982).

In addition to the use of nitrosating agents known for many years, their use for the treatment and prevention of diseases caused by pathologically elevated concentrations of sulfur-containing amino acids in body fluids is described. These disease states, caused by congenital or acquired defects in the metabolism of these amino acids, and which are characterized by an increased concentration of said amino acids in blood and urine, are classified as homocysteinemia (WCI 92/18002).

The anti-ischemic effect of organic nitrates and the other substances mentioned above is explained by a plurality of hemodynamic phenomena, in particular the heart facilitating phenomenon, which leads to a reduction in the oxygen consumption necessary for heart function, or in IHK corrects the mismatch between O2 supply and its need. This is due to an excellent expansion of the venous capacity of the vessels (venous pooling) or a reduction of the load and a direct coronary dilatation effect, especially in the area of coronary stenosis. This may have a positive effect on the directly post-stenosis-reduced perfusion (positive Steal-Effect), since organic nitrates appear to be more potent in atherosclerosis-affected areas of vessels than in healthy sections of vessels (Kojda et al., Endothelium 1 (Suppl.): Abstr. 299). p76 (1993), particularly in the area of coronary stenosis, a purely hemodynanic phenomenon mediated by the nitrous oxide radical.

- 4 Ν0 ·. which is released uniformly from all nitro-dilators despite the very different chemical structure of the compounds. The pathways of bioactivation that lead after all are made available in front of the site, and thus in the smooth muscle cell, are very

a. Feelisch, Molecular mechanism of tone that NO in the cell endothelium different CHoack

Mechanisms of 37-50, This could be nitrovascular bioactivation: in Endothelial Vasonotor Control “Hrsgb. Drexler et al.,

Steinkopff Verlag, Darmstadt, F.R.G. ¢ 1991)).

in recent years without any doubt to explain by direct measurement using various techniques (CMethode Noack et al., Meuroprotocols 1 = 133-139 ¢ 1992). The NO acts to act as a latent by activating soluble guanylate cyclase. This stimulates cGMP production from GTP. cGMP leads, on its part, to a variety of phosphorylation reactions (e.g., for protine kinases) that promote intracellular Ca 2 supply. Karczevski et al., Z. Kardiol. 79 (Suppl.1, 212-1990)). By reducing the intracellular levels of free Ca ²⁺ , relaxation occurs. Since 1937, it has been known that the endothelium-derived relaxing factor (EDRF) is identical to NO or a compound containing NO (Palmer et al. Nature, 327 = 524-526 ¢ 1987): Ignarro et al. Proc. Natl. Acad. Sci. 84-9265-9269 ¢ 1987) and is important for local blood flow.

Endothelial cells form continuous monolayers in the area of the inner wall of the vessels. This results in an adult surface having a total surface area of about 800 n ² with an own weight corresponding to 1.5 to 2 kg of the weight of the human liver. The functions performed by endothelial cells today relate to two: mechanical and functional. First, they act as a barrier to prevent the ingress of blood components. such as hunting-density lipoproteins (low-density lipoproteins (LDL)) to the inner vessel wall, near the lumen-intima (inner vessel wall layer). Second, it has an endocrine function. Various stimuli produce multiple synthesis of bioactive substances such as EDRF / NO and prostaglandin-12 (CPGI2), which affect the function of the flowing cells (Pohl et Eiusse, Eur. Heart

J_ll

suppl

B)

35-42 (Furchgott, Circ. Res. Vessel wall construction 1G7-172 ¢ 1984) total <Di ¢ 1990), precinct hemodynamics ^: 557-573 <1983) and structural

Corleto, Exp. Cell. Res. 153 = fundamentally. This also undoubtedly explains that in endothelial damage, whatever the cause (endothelial damage by hypercholesterolemia CT. J. Verbeuren et al., Ciro, Res. 58 ^: 552-564 C1986), endothelial damage in the post-infarction phase (MR) Sigreid et al., Circ. 86 (1): 21 ¢ 1992)), endothelial function is pathologically affected, which may have various consequences. This includes local vasoconstrictions (vascular constriction) or vascular spasm and remodeling, or vascular wall growth processes, which are considered to be initial processes and terogenesis.

Endothelial dysfunction is generally characterized as a limitation or loss of physiological vascular dilation that is mediated to observe a decrease or mediated by MO, and growth processes by the endothelium. At the same time, the relaxation of vessels, vessels, mediated NO protection of suppressed NO in the intimal (inner layer of the vessel) and in the medium in the middle layer of the vessel wall) may be increased. Endothelial dysfunction is further characterized by proliferative processes in the vessel wall due to increased mitogenesis, increased endothelial adhesion and migration of leukocytes and macrophages, as well as increased oxidation of lipoprotein 1 (LDL) which damage the endothelium. This is mainly observed in pathological conditions such as atherosclerosis, hypertension, hypercholesterolemia. diabetes mellitus and cardiac insufficiency (Creager et al., J. Clin.

Invest. 86 · 228-234 (1990). Linder et al., Circulatlon 81 =

1762-1769 (1990), Zeiher et al., Circulation 83 = 391-401 (1991)). Likewise, hypoxia and small shear forces stimulate endothelial dysfunction. This leads, inter alia, to vasoconstrictors, such as acetylcholine or serotonin, which induce normal vascular depletion, due to their direct vasoconstrictive effects on vascular smooth muscle, to induce vasoconstriction, and to affect the negative picture of the disease ¢ 601 ino et al., H. Engl. J. Med. 324 = 641-648 ¢ 19.91)). Thus, physiological vasomotor regulation is not only disturbing in endothelial dysfunction, but quite the opposite. Even more pronounced are these changes in atherosclerotic remodeling of the inner vessel wall. Ludmer et al., H. Engl. J. Med. 315 = 1046-1051 (1986)).

By its autocrine and paracrine activity, endothelium not only contributes to maintaining the health of the vessel wall, but does it influence? also the effect of exogenous M0-1 iberators such as

PETN or GTN by itself forming EDRF / NO. For example, if the endothelium is mechanically removed from the vessel wall ¢ by invasive diagnosis by catheter or extracorporeally on isolated portions of the vessel) or the endothelial NO formation is suppressed by specific inhibitors, the vasodilatory effect of nitrovazodilators such as GTN or PETN al 811336 is enhanced. Cardiovasc. Pharmacol-14 (Suppl. 11) S81-S85 (1985): Kojda et al., J. Vasc. Res. 29: 151 (1992)).

Pharmacological inhibition by endothelial NO synthesis leads to the same effect on coronary vessels Cojoj et al.,

Naunyn-Schmiedeberg Arch. Pharmacol 346 ^: R 35-19928)). It is known that the effect of calcium antagonists, especially those derived from the 1,4-dihydropyridine type (0118 s), is attenuated upon endothelial removal by Cojda et al., Bas. Res. Cardiol. 86

254-256 (1991)). Further experiments showed. they are believed to stimulate endothelial NO formation and NO release (Gunther et al., Basic Res. Cardiol. 87: 452-460 (1992)). Likewise, kinins and bradykinin develop their biological activity through increased endothelial formation and release of EDRF / NO (VA Eriner et al. - Am. J. F'hysiol. 264 = F322-F327 (1993): Kelm et al. Biochem. Biophys (Res. Conmun. 154: 236-244 (1988))

Endothelial dysfunctions are now considered to be the initiators of frequent and pathologically significant cardiac and circulatory diseases such as atherosclerosis, preventing, treating and eliminating these dysfunctions and associated or induced diseases are therefore important therapeutic necessities.

It has now been found that the use of nitrous oxide releasing and / or transferring compounds, such as endogenous nitrous oxide formation stimulators as well as guanylate cyclase stimulators. in particular, soluble guanylate cyclase stimulators, are useful for the prevention, treatment and elimination of endothelial dysfunctions. as well as progressive and / or disease-induced diseases. These endothelial dysfunctions and diseases are primarily endothelial damage by hypercholesterolemia, endothelial damage by hypoxia. endothelial damage by mechanical and chemical disorders, particularly during and after medical and mechanical recanalization of stenotic vessels, for example after percutaneous transluminal angiography (F’TA) and percutaneous transluminal vascular angiography (PTCA). endothelial damage in post-phase infarction (endothelial dysfunction in reperfusion). endothelial mediated reocclusion and bypass surgery, peripheral vascular disorders as well as cardiac and circulatory disorders such as atherosclerosis, hypertension, inclusive pulmonary and portal hypertension, hypertensive heart disease, coronary heart disease, diabetic microangiopathy, diabetic microangiopathy or other diseases caused by endothelial dysfunction.

Compounds releasing and / or transferring nitrous oxide, endogenous nitrous oxide stimulators as well as guanylate cyclase stimulants are, inter alia, directly or indirectly guanylate cyclase-acting compounds within the meaning of the invention, wherein guanylate cyclase stimulants are used as indirect guanylate cyclase stimulants. or otherwise increase their enzymatically acting concentration and / or act as antagonists to the guanylate cyclase inhibitor or otherwise reduce their enzymatically acting concentration. Indirect guanylate cyclase stinulators have been used, inter alia, for compounds which are suitable to enhance the formation or release of NCI, especially those of the 1,4-dihydropyridine type, as calcium antagonists. for example, nifedipine, felodipine, nimodipine, amlodipine, and others. Compounds which are capable of increasing the endothelial kinin content are also suitable for use. In particular, they are kinin receptor stimulators, such as kinins or analogous agents, endothelial kinin production stimulators, as well as kinin degradation inhibitors, in particular angiotensin-converting enzyme inhibitors (CEE inhibitors) such as capopropril, enalapril. moexipril, ramipril and related active substances. The use of compounds which exert their action in general by the release and / or transfer of endogenous or exogenous nitrous oxides belongs to a particularly suitable embodiment of the present invention. Classes of substances

- g, Ί · .ΙΛΛ.

and the compounds which are particularly suitable are organic nitrates. in particular glycerol nitrate, pentaerythritol tetranate, isosorbide-5-mononium, isosorbide dinitrate, mannitol hexanitrate, inositol hexane, propatyl nitrate, trolnitate, nicorandil, newer nitrates such as SF'M 3672, as well as their pharmacologically zincites , thionitrates,

S-nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine, nitrosoproteins, nitrous oxide-releasing furoxane derivatives, nitrous oxide-releasing sydnonimine derivatives, especially molsidomine, mesocarb as well as analogues thereof, nitrosyl complex compounds, especially nitrosyl compounds with nitrosyl compounds iron such as sodium nitroprusside as well as nitrous oxide. Since the release and / or transfer of nitrous oxide often takes place in vivo via pharmacologically active metabolites, these are in principle also suitable for use in the context of the invention. At the same time, pharmacologically tolerable derivatives of all the above compounds can be used. In particular, conventional addition compounds, salts or enzymatically or hydrolytically cleavable compounds such as esters, amides and the like are possible variants.

The choice of active ingredients is governed by the general pharmacological principles and therapeutic requirements that are common to the skilled person. In addition to the desired pharmacological effect, the patient's health, disease state, physical condition, known effects and side effects, contraindications, number, treatments, duration of use, drug interactions, as well as parallel drug use are also taken into account.

The dosages are carried out in therapeutic doses which are oriented according to the doses used for existing indications already known. The total daily dose may be up to 500 mg depending on the active ingredient. In general, daily doses of up to 350 ng are sufficient. Dosage and interval between doses should be selected. so. to create the most constant therapeutic plasma level. The compounds used according to the invention can be used alone or as part of a galenical preparation, as a single active ingredient or in combination with known therapeutics for the treatment of heart and circulatory diseases, for example with ÄC.EE inhibitors, antiatherosclerotics. anti-hypertensive drugs, beta-blockers. cholesterol lowering drugs, diuretics, calcium antagonists, coronary dilators, lipid lowering drugs, peripheral vasodilators, platelet aggregation inhibitors or others, as well as therapeutics for cardiac and circulatory diseases used in combination.

The preparation of the galenical preparations is carried out according to the procedures and rules known to the person skilled in the pharmaceutical art, the choice of the technologies used and the galenic auxiliaries to be used depends primarily on the active substance to be treated. In this connection, questions of its chemical-physical properties, the selected dosage form, the desired duration of action, the site of action as well as the prevention of drug and excipient incompatibilities are of particular importance! It is therefore the responsibility of the skilled person to select the form of the drug, the excipients and the drug production technology in a trivial manner using the parameters of the known substances and the method. In order to achieve a constant therapeutic plasma level, the drug form in question should contain the active ingredient in an amount which makes it possible to divide the daily dose into 1 to 2 for controlled release systems and up to 10 individual doses for other drugs. Long-term administration by long-term infusion is also suitable.

The known compounds according to the invention can in particular be administered orally, intravenously, parenterally, sublingually or transdermally. The drug formulation in question is preferably formulated in liquid solutions, in particular for aerosol sprays.

or in solid form. They are suitable for the preparation of drops, injections or further suspensions, emulsions, syrups, tablets, film-coated tablets, dragees, capsules, pellets, powders, lozenges, implants, suppositories, creams, jellies, ointments, patches or other transdermal systems.

The pharmaceutical preparations contain conventional, galenically usable organic carriers and excipients which are chemically indifferent to the existing active substance. Suitable for this purpose are water, polyethylene glycol solutions, without limitation, salts, alcohols, vegetable oils , gelatin. lactose. amylose, magnesium stearate. talk. highly disperse silica, paraffin, higher carboxylic acid monoglycerides and diglycerides, cellulose derivatives, polyvinylpyrrolidone and the like. The formulation may be sterilized and, if necessary, supplemented with adjuvants such as fillers, binders, mold release agents, lubricants, disintegrants, adsorbents or disintegrants, preservatives, stabilizers , emulsifiers, solubilizers, saline for affecting the osmotic pressure, buffer solutions, dyes, fragrances, flavorings or sweeteners. A person skilled in the pharmaceutical art will make a suitable choice using known substance parameters to avoid incompatibilities of drugs and excipients.

With the present invention, a new therapeutic option is available to combat pathological situations such as hypoxia. high serum cholesterol, elevated blood pressure, diabetes, promoting post-stenotic reperfusion, for example in myocardial infarction and mechanical and chemical damage, and. i. promote endothelial dysfunction or prevent endothelial dysfunction altogether. The therapeutic use of suitable compounds, irrespective of the galenical preparation, therefore makes it possible, for the first time, to prevent and up-to-date therapy of diseases of the heart and blood vessels of this etiology (teaching of the causes of the disease), such as atherosclerosis. Tone includes coronary heart disease (coronary artery disease), arterial narrowing and peripheral arterial blood flow disorders, microangiopathy, macroangiopathy within diabetes nellitus, etc. Surprisingly, the compounds described above exhibit a separate endothelial effect which is independent of the hitherto known, at least purely hemodynanic and antiischenic properties, for example organic nitrates or their efficacy in honocysteinenia. Their use is therefore able to stop or reverse their pathological events. as long as they are still reversible. They are therefore unexpected, new components of action which have not yet been described and could not be expected in this form.

- 13

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate the invention in more detail as to its nature and embodiment without. that the invention would be limited to them.

Example 1

Attempts at pharmacacoogical model and in vivo (to New Zealand rabbits) • Feed with cholesterol is suitable at try with

animals to ton. to create endothelial dysfunction in weeks to months. which makes it possible to test and quantify the effects of drugs (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 rabbits were fed standard or feed (40g / kg / day) cholesterol-enriched (0.75%) feed for 15 weeks. Feed with cholesterol led to an increase in its plasma levels from

69.8 ± 10.4 to 907.1 ± 85.5 ng / dl and induced atherosclerotic lesions in the aorta region, which were quantified after Sudan IV staining using a Laser-Scanning computer technique. The aortic changes on the aortic arches were 73.3 ±

1.9 thoracic (thoracic) aorta area of 46.3 ± 2.5% and in the abdoninal (abdominal) aorta area 49.6 ± 3.5% (Fig. 2 control).

Example 2

Atherosclerotic vessels showed unchanged contractility after phenylephrine, endothelium-mediated vasorelaxation was 1 µΜ acetylcholine compared to controls (standard diet), but their function may be best described as endothelial dysfunction. The thoracic aorta segments of cholesterol-fed animals (+) showed significantly less sensitivity to acetylcholine than the aorta segments of control animals (Fig. 1). The degree of endothelial dysfunction measured correlated directly with increasing severity of atherosclerotic lesions (r = 0.67, p <0.0001) (Fig. 3). These data demonstrate that endothelial dysfunction developed after cholesterol fed.

Example 3

Two additional groups of nine white New Zealand rabbits were additionally given pentaerythrityltetranitrate (PETN) (6 mg / kg / day), which was incorporated into the compressed feed. Animals treated concomitantly with PETN significantly reduced atherosclerotic lesions. The lesion size was determined analogously to Example 1. A significantly reduced proportion of atherosclerotic lesions was found in all parts of the aorta (aortic arch · - 58.6 ± 2.1%, thoracic aorta =

34.7 ± 2.0% and abdominal aorta 39.3 ± 3.1% (Fig. 2).

Example 4

At the same time, there was no significant difference in endothelium-mediated maximal (1 μΜ acetylcholine) relaxation compared to non-cholesterol-fed animals (endothelial dysfunction) after feeding with PETN, so these results show a clear protective effect of PETN. . since this prevented endothelial dysfunction within the meaning of the present invention, (Figs. 3 and 4, Table 1)

FIG. 3 with FIG. 4 shows the dimension of atherosclerotic lesions and can endothelium. A worse correlation coefficient u points to this. that PETN leads to dissociation of the close relationship between atherosclerotic lesions and endothelial function.

that PETN diminishes to improve the function of the PETN group

Table 1 shows the effect of PETN (6 mg / kg / day) on the development of endothelial dysfunction in the thoracic aorta of white New Zealand rabbits. that was induced by dieting. containing cholesterol (0.75%; 15 weeks). The magnitude of the effect of the acetylcholine vasodilator. endothelium dependent. is expressed as the concentration (in logM: pDa value) that, at a cumulative dose, exerts half the opposite effect of the vasoconstrictor of phenylephrine (the higher this value, the stronger the effect of acetylcholine). The maximal dilatation effect is expressed as a percentage of the effect of vasoconstrictor phenylephrine, which had the opposite effect at the maximum effective concentration of acetylcholine (1 μΜ). Endothelial dysfunction induced by cholesterol diet alone (control) is detectable by significantly reduced potency and maximal effect of acetylcholine (**. P <0.05). There is no longer any difference in PETN feeding. In addition, PETN significantly improves (* .p < 0.05) the potency of acetylcholine action and hence endothelial function after cholesterol feeding. whereas after standard feed, there is a significant deterioration in endothelial function. Overall, it appears that there is a protective effect of PETN on endothelial function in experimentally induced atherosclerosis. P'Resorption and accumulation of PETM in plasma can also be demonstrated 24 hours after the last animal feeding by measuring the concentration of pentaeryth.hri lnononitrate (PEMN) metabolites in plasma (Fig. 5).

Table 1 -

inspection PETM standard cholesterol standard cholesterol Cardinality, effect of acetylcholine (pl values) 2) 6.91 ± 0.02 6.12 ± 0.05 * ^< 6.62 ± 0.06 * 6:47 ± 0.13 ** Max. dilatation effect of acetylcholine (in%) 84.8 + 1.2 60.7 ± 8.5 ^xt 74.7 ± 4.9 ~ 65.0 ± 4.7

Example 5

A typical tablet has the following composition:

pen taerytr i tyltetran i trát ISIS PHAKMA 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 Silicon dioxide (high DAB 10 6 mg

dispersion)

273 mg

Example 6

A tablet containing 20 mg pentaerythrityl trinitrate (CPETriM) has the following composition ¹

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 Cvysoko DAB 10 G mg

dispersion)

273 mg

Example 7

A tablet containing 20 mg pentaerythrityldinitrate (CPEDN) has the following composition:

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 Cvysoko DAB 10 G mg

dispersion)

273 mg, Example 8

A tablet containing 20 ng CETN erythrit1) has the composition

EDN 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 Cvysoko DAB 10 6 mg

dispersion) "

273 mg

Example 9

The 20 mg isosorbide mononitrate (ISMN) tablet has the following composition:

ISMN 20 mg 1aktóza 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 Silicon dioxide (high DAB 10 6 mg

dispersion)

273 mg

Example 10

20 ng isosorbide dinitrate (ISDN) tablet -

ISDN 20 ng 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 Silicon dioxide (high DAB 10 6 mg

dispersion)

273 mg

Example 11

A tablet containing 40 mg of pentaerythryl tyltetranltrate (PETN) and 40 mg of propranolol hydrochloride has the following composition:

PETN 40 mg propranol hydrochloride i d 40 mg lactose 224 ng Potato starch 80 mg gelatin 3 mg talk 22 mg magnesium stearate 5 mg Silica (highly dispersed) 6 mg

420 mg

Figure 1

Development of endothelial dysfunction after feeding white New Zealand rabbits with a cholesterol diet (0.75 15 weeks). An endothelium-dependent vasoreilator of acetyicholine vasodilator, and thus endothelial functional ability, expressed as a percentage of the anticontraction remaining at each contraction induced by the vasoconstrictor phenylephrine, is shown.

Figure 2

Extent of atherosclerotic lesions on the luminal area of the aorta sections after feeding with cholesterol diet (0.75%, 15 weeks) (uncontrolled) and concomitant dose of PETN (6 ng / kg / day). Atherosclerotic lesions (lesions) were stained with Sudan IV and the percentage of stained area (based on total area) was determined using a Laser-Scanning method with a computer. PETN causes a significant reduction in the formation of atherosclerotic lesions (p <0.05).

r

Figure 3

Relationship between the dimension of atherosclerotic lesions (lesions) on the luminal area of the thoracic aorta sections after feeding with a cholesterol diet (0.75%, 15 weeks) and the maximum relaxation, determined in the same section, induced by 1 μΜ acetyicholine (endothelial function). The larger the lesion area. the worse is the relaxation or endothelial function.

Figure 4

The same representation as in FIG. 3 after concomitant feeding with cholesterol and F’ETM.

Figure 5

-The pentaerythrityl mononitrate level of white New Zealand rabbits 24 hours after the last feeding before the blood collection that preceded the acute experiment. The standard feed contained pentaerythritol tetranitrate (150 mg / kg) in both cases and 0.75% cholesterol in the cholesterol group. The concentration of pentaerythrityl mononitrate was determined quantitatively after treatment of plasma samples by gas chromatography / mass spectroscopy.

Claims (2)

Use of compounds releasing and / or transmitting nitric oxide for the manufacture of pharmaceutical compositions for the prevention, treatment and elimination of endothelial dysfunctions as well as diseases continuing and / or induced by these dysfunctions selected from the group consisting of a) damage of the endothelium by hypercholesterolemia, b) endothelial damage by hypoxia, chemical mechanical (c) damage to the endothelium by mechanical and harmful agents, in particular when and after the medication and reopening of constricted blood vessels, for example after percutaneous transluminal angiography referred to as PTA and percutaneous transluminal coronary angiography referred to as PTCA; d) damage to the endothelium in the postinfarct phase, ie endothelial dysfunction in reperfusion, e) Enothothelial mediated reocclusion after bypass surgery f) peripheral arterial perfusion disorders due to atherosclerotic vascular changes as well as atherosclerosis in general; g) hypertension, including pulmonary and portal hypertension, (h) hypertonic heart disease; (i) diabetic microangiopathy and macroangiopathy; and (j) cardiac insufficiency, excluding genetically determined or acquired homocysteinemia due to an enzymatic defect, as well as diseases caused by it. Use according to claim 1, wherein the nitric oxide releasing and / or transfer compounds are selected from the group consisting of: (a) organic nitrates, in particular glycerol trinitrate, GTN; pentaerythritol tetranitrite, PETN; isosorbide-5-mononitrate, ISMN; isosorbide dinitrate, ISDN; mannitol hexanitrate, inositol hexexitrate, propatyl nitrate, trolnitrate, nicorandil or SPM 3672, and their pharmacologically tolerable derivatives, (b) organic nitrites such as isoamyl nitrite; c) thionitrites, d) thionitrates, e) nitrosothiols such as S-nitroso-N-acetyl-D, L-penicillamine, SNAP; (f) nitrosoproteins; (g) furoxane derivatives releasing nitric oxide; (h) nitric oxide-releasing sydnonimine derivatives, in particular mesocarb, molzidomine or their pharmacologically active metabolites; (i) complex nitrosyl compounds, such as nitrosyl compounds of iron, in particular sodium nitroprusside; and (j) nitric oxide itself of the formula NO. ** «* Use according to claim 1 or 2, wherein the nitric oxide releasing and / or transfer compounds are combined with other active substances used for the treatment of cardiac and circulatory diseases, in particular substances selected from the indication groups of ACE inhibitors, anti-atherosclerotics, calcium depressants, coronary lipids, peripheral vasodilators, or platelet aggregation inhibitors. antihypertensive agents, beta-blockers, cholesterol, diuretics, dilatant antagonists, lowering agents