BG105955A - Medicinal substance utilization for preventing nitrate tolerance - Google Patents

Abstract

The use of the medicinal substances avoids the nitrate and/or nitrate cross-tolerance and the pathological phenomena accompanying the latter. Antagonists of enzymes, metabolizing purine derivatives and antagonists of xanthinooxydase are administered. 8 claims

Description

Technical field

The invention relates to the use of medicaments to avoid nitrate and / or nitrate-transient tolerance, as well as pathological phenomena caused by it.

BACKGROUND OF THE INVENTION

Organic nitric acid esters, such as glyceroltrinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythritil tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958)), US- PS-2370437), Isosorbide-5-mononitrate (ISMN) (DE-OS • 2221080, DE-OS-2751934, DE-OS-3028873, DE-PS-2903927, DE-OS3102947, DE-OS-3124410, EP- A1-045076, EP-A1-057847, EP-A1059664, EP-A1-064194, EP-067964, EP-A1-143507, US-PS-3886186, US-PS-4065488, US-PS-4417065, US- PS-4431829), Isosorbidinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), Propyl nitrate (M6dard, Mem. Poudres 35: 113 (1953)), Trollitrate (FR-PS-984523) or nicorandil (US-PS-4200640) and the like are vasodilators, some of which have been the most widely used therapeutic for decades application mainly for the treatment of angina pectoris, for example. ischemic heart disease (IHK) (Nitrangin®, Pentalong®, Monolong®

01-265-02 / PB and others). The galenic processing of org < / RTI > nitrates for the preparation of pharmaceutical forms for the treatment of angina, respectively, ischemic heart disease, is well known. It is carried out according to customary methods and rules known to the person skilled in the art, whereby the choice of the technologies used and the galenical auxiliaries used is determined first and foremost by the active substance being processed. Of particular importance are the issues related to its physicochemical properties, in particular those related to *.

with the known properties of organic nitrates to explode, u

which require compliance with specific safety requirements and special processing technologies for the selected formulations, with the desired duration of action, and to avoid the incompatibility of the active substance with the excipients. For the medicinal product with angina pectoris indication, respectively, heart disease, the oral, parenteral sublingual or transdermal dosage forms in the form of tablets, dragees, capsules, solutions, spray or patches (DD-A5-293492, DE-ASf) are preferred. No. 2623800, DE-OS-3325652, DE-OS-3328094, DE-PS-4007705, DE-OS4038203, JP Application 59/10513 (1982). In addition to the known applications for many years, nitrosating agents have been prescribed for the treatment and prevention of diseases due to pathological increases in concentrations of sulfur-containing amino acids in body fluids. These disease states are caused by congenital or acquired defects in the metabolism of these amino acids and are characterized by an increased concentration of said amino acids in the blood and urine (homocystinuria), which are covered by the name homocysteineemia (WO-A1-92 / 18002/18002/18002/18002/18002/18002/18002/18002. Recently described

01-265-02 / PB the use of certain organic ester 'nitric acid as endothelial-protective agent (DE-A-4410997) as well as as a treatment for erectile dysfunction (WOA1-96 / 32118). Known organic nitrates (nitric acid esters) have a number of therapeutic disadvantages. For example, the so-called nitrate tolerance is observed, which is manifested in the lowering of the nitrate action at higher doses or with the use of nitrates with a longer duration

action. Side effects such as headache, dizziness, nausea, feeling weak, skin redness, and the risk of severe drop in blood pressure accompanied by reflex tachycardia (Mutschler, Arzneimittelwirkungen, Wissenschaftliccha VerlagsgesHellbells, 1991, Wissenschaftliccha Verlagsellsbellsellsellsblagtellsgartbellschlagtellsgartz . The metabolism of GTN and other organic nitrates has been extensively studied (Taylor et al.,

Prog. Drug Metab., 10 (1987), 207). In addition, organic nitrates have been found to have an extremely oxidizing effect on compounds having thiol groups (Boschan et al., Chem. Rev. 55, 485 (1955); Taylor et al., Progress in Drug Metabolism, Vol. 10, 207 (1987); Feelisch et al., Methods in Nitric Oxide Research, John Wiley & Sons, Chichester, (1996)). In addition, it is widely accepted and widely scientifically confirmed that organic nitrates through the NO mechanism inevitably resolve anti-regulatory processes, e.g. induce the formation of angiotensin II in the vascular wall, which, by activating the endothelial enzyme NADH synthase, results in the formation of large amounts of peroxide radicals, which themselves are highly oxidizing and immediately react with NO-released organic nitrates. According to present views, the state of nitrate tolerance is determined by mass

01-265-02 / PB

preparation of peroxide radicals, leading to the formation of peroxynitrite by the reaction scheme ON * + 'Og'- »ONOO, and thus to inactivation of NO. This view is reinforced by the fact that nitrate tolerance can be limited to a limited extent by administering antioxidants, such as ascorbic acid (vitamin C) or vitamin E (Miinzel et al., The physiology and pathophysiology of nitric oxide / superoxide system, Vascular Endothelium (GVR Born, CJ Schwartz e'dt., Pp. 205-220, Schattauer Verlag, New York (1997); Harrison, J. Clin. Invest. 100 (9) (1997), 2153; Miyamoto et al. , Proc Soc Soc Exp Biol Med 211 © .....

(1996), 366). Despite this knowledge, a successful combination of a therapeutic organic nitrate supplement with an antioxidant has not yet been achieved, although their action relates to bodily and, accordingly, pharmacologically available NO. Munzel et al., (J. Clin. Invest. 98 (1996), 1465) inhibit GTN-induced nitrate tolerance by using hydrazine, which is an inhibitor of membrane-bound NADH oxidase. The true mechanism underlying nitrate tolerance has not yet been elucidated (Nitroglycerin VIII, Mehmel (Hrsg.), © Verlag W. de Gruyter (1996)). Miyamoto et al., (Proc. Soc. Exp. Biol. Med. 211 (1996), 366) found that xanthine oxidase inhibitors of APPP, allopurinol and alloxanthin resulted in normal reactivity of the vessels to NO, depending on the types of minimal enhancement ( ANPP) or almost no enhancement (allopurinol) of NO-induced vasorelaxation, with allopurinol even leading to increased peroxide radical formation. In line with the present views, they conclude that xanthine oxidase promotes the formation of peroxide and the associated NO expenditure of the regulatory protein for NO action. In terms of stoichiometry

01-265-02 / PB

(over-suggestion of NO in the application of WhitrayT IR state of nitrate tolerance) this explanation is not plausible, since complete inactivation of NO by the xanthine oxidase peroxide formed cannot be accomplished, as is assumed in the clarification of nitrate Ellis tolerance et al., Europ J. Pharmacol 356 (1998), 41). In addition, peroxynitrite decomposes itself again to peroxide and NO radicals and thus acts autonomously as a source of NO (Moro et al., Proc. Nhtl. Acad. Sci. 91 (1994), 6702; Moro et al., Br J. Pharmacol. 116 (1995), 1999). Furthermore

V.

xanthine oxidase, in turn, manages to release NO from organic nitrates under hypoxide conditions (Millar et al., FEBS Lett. 427 (2) (1998), 225; Millar et al., Biochem. Biophys. Res. Commun. 249 (1998) , 767). In addition, NO itself inhibits xanthine oxidase (Fukahori et al., Free Rad. Res. 21 (4) (1994), 203; Cote et al., Am. J. Physiol. 271 (1996), L869).

The xanthine oxidase system, called the latest xanthine oxidoreductase literature, has been extensively studied (Fridovich, J. Biol. Chem. 245 (1970), 4053; Battelli et al., FEBS Lett. 113 (1980), 47; Parks et al., Acta Physiol Scand Suppl 1986;

♦ 548: 87-99; Parks et al., Am. J. Physiol. 254 (Gastrointes. Liver

Physiol. 17) (1988), G768; Kooij, Histochem. J. 26 (1994), 889; Hille, Chem. Rev. (1996), 2757) and various enzyme inhibitors have been described (Kooij, Histochem. J. 26 (1994), 889). Galenic processing of xanthine oxidase inhibitors such as allopurinol and oxypurinol (DE-A1-3839826) is also described.

SUMMARY OF THE INVENTION

It is an object of the invention to counteract nitrate and / or nitrate transient tolerance and pathological phenomena caused by the use of suitable medicaments.

01-265-02 / PB • · · · · ····

It is an object of the invention to solve antagonists of enzymes metabolizing purine derivatives for the prevention or reduction of nitrate and / or nitrate transient tolerance and pathological phenomena caused by it. As antagonists within the meaning of the present invention are meant substances competing with purine derivatives or enzyme inhibitors. The terms competing or non-competing inhibitor are also suitable for explaining the term antagonist. A particularly preferred embodiment of the invention is the use of xanthine oxidase antagonists for the prevention or reduction of nitrate and nitrate transient tolerance and pathological phenomena thereof, wherein the antagonist may have the above meaning. Allopurinol or oxypurinol are e.g. two typical already therapeutically applied xanthine oxidase inhibitors. Other suitable compounds are particularly those described by Janero et al. (Life Sci. 44 (1989), 1579) and Kooij (Histochem. J. 26 (1994), 889), which publications are contemplated in this connection.

In a surprising way, it has now been found that by the approach according to the invention, e.g. By inhibiting xanthine oxidase with allopurinol or with its active metabolite, oxypurinol (alloxanthin) counteracts nitrate tolerance and reactivates the observed vessels, which, in a state of nitrate tolerance, do not respond adequately to the available NO. It is surprising to the person skilled in the art that the state of extinguished (non-manifesting) action of NO is eliminated and the action of exogenously introduced NO is restored with the constant supply of nitrate. For the first time, it is now apparent from the use of the invention that no

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The construction of peroxide radicals is an etiological cause of the nitrate tolerance condition, and probably the increased purine catabolism caused by the activation of xanthine oxidase. The resulting lack of adenosine triphosphate (ATP) and guanosine triphosphate (GTF) hinders the unfolding of the physiological action of NO inside the cells: both guanilate cyclase and Ca-ATPase lack direct action of the substance leading to the readiness of the second cyclic guanisine triphosphate * (cGMP) carrier, as well as the reduced transfer of cytosolic calcium to the cellular organelle depots. Another unexpected finding is that in a state of nitrate tolerance, xanthine oxidase is activated. The results of the disclosures according to the invention are that it is the pharmacological inhibition of xanthine oxidase with allopurinol and its derivatives that leads to an improvement in the action of nitrates, which is contrary to previous views. It is now the first time to resolve the problem of using organic nitrates from the therapeutic use of organic nitrates for hundreds of years, thereby opening up new perspectives on compounds of this class, as they are now very versatile and widely applicable, especially with regard to dosage, frequency of applicability, side and combination action and associated enhanced activity. For example,

they can now also be given at normal or elevated doses for the long-term treatment of hypertension. All cases of administration according to the invention have the advantage that there will be no need to use, over a wide range of expensive and more side-effects, concomitant or self-medication drugs, such as sydonimine derivatives, calcium antagonists, ACE inhibitors or the like.

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The following examples are intended, in particular, to clarify the invention with respect to its nature and use cases, without limiting its scope.

Examples of carrying out the invention

Example 1

2083 g of 8% glyceroltrinitratatadorbate polyvinyl alcohol (PVA) (12% vinyl acetate content) 'is heated for 30 minutes at 60 ° C and then mixed with 1583 g PVA (12% vinyl acetate content) , 1250 g of allopurinol and 84 g of magnesium stearate and the mixture was compressed into tablets with a mean mass of 400 mg.

Example 2

Tablets containing 20 mg, 40 mg or delayed-release tablets containing 40 mg or 60 mg isosorbid mononitrate, and at the same time 100 mg allopurinol are packaged in blisters and supplied with a data sheet for use. .

Example 3

Delayed-release tablets containing 20 mg, 40 mg, 60 mg, 80 mg or 120 mg of isosorbide dinitrate, together with 100 mg of allopurinol, are supplied in blisters and in packs provided with a of use.

Example 4

Tablets containing 20 mg of pentaerythritol tetranitrate as well as 100 mg of allopurinol are packaged in blisters and packaged in a package leaflet for use.

01-265-02 / PB • · t. Q * · · · · · · · · · · · · 9 · · · · · · · · · · · · · · · · 9

9 9 9 9 9 9 99

9999 99 99 99 99999

Example 5

Tablets containing 50 mg of pentaerythritil tetranitrate and 300 mg of allopurinol are packaged in blisters and packaged with a package leaflet for use.

Example 6

Tablets containing 80 mg of pentaerythritil tetranitrate and 100 mg of allopurinol are packaged in blisters and packaged with a package leaflet for use.

Example 7

and.

Tablets containing a coronary therapist and tablets containing a xanthine oxidase inhibitor are individually packed in blisters and placed in a single package, provided with a data sheet for use.

Example 8

Tablets containing 40 mg of pentaerythritol tetranitrate and 40 mg of propranolol hydrochloride are placed in blisters and packaged.

Example 9

Endothelial and pig aortic smooth muscle cell cultures were incubated natively (control) with 0.1 mM GTN or 0.1 mM GTN, as well as with 10 μΜ, 50 μΜ, 100 μΜ, respectively, 150 μΜ oxypurinol for 24 hours at 37 ° C. Subsequent stimulation with 2 μΜ nitroprusside sodium (SNP) for 3 minutes resulted in a significantly attenuating increase in intracellular cGMP concentration (48.7% ± 5.9% relative to control) only in GTN pretreated cultures, as evidenced by a specific radioimmunoassay (Biotrend, Cologne). After simultaneous incubation with 10 μΜ oxypurinol SNPstimulation leads to an increase in cGMP concentration to about 56.4% ± 7.5%, at 50 μΜ oxypurinol to about 87.6% ±

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9.3% and at 100 μΜ oxypurinol to about

93.% * ± 9.1%. In addition, the formation of reactive oxygen groups (ROS) was determined by electron spin resonance spectrometry. This is done by measuring the formation of TEMPONE-nitroxyl radicals by ΤΕΜΡΟΝΕ-Η (1-hydroxyl-2,2,6,6-tetramethyl-4-oxopiperidine hydrochloride). Contrary to the baseline of 25 nM / min / mg protein, stimulation with 0.5 mM GTN resulted in an 82.6% ± 8.3% increase in Ha'ROS formation. Pre-incubation with 10 μΜ oxypurinol for 24 hours resulted in an increase in ROS to about 75.5% ± 8.6%, with 50 μΜ oxypurinol to about 35.9% ± 5.3% and with 100 μΜ oxypurinol to about 28.7% ± 4.9%. Through these experiments, it has been shown for the first time that a decrease in intracellular cGMP concentration characteristic of nitrate tolerance is attenuated by inhibition of xanthine oxidase and this can simultaneously significantly reduce the increase of GTN-induced reactive oxygen groups via xanthine oxidase inhibitors.

Claims (8)

Use of antagonists of enzymes metabolizing purine derivatives to prevent or reduce nitrate and / or nitrate transient tolerance in a method for the therapeutic treatment of the human body. Use according to claim 1, characterized in that the antagonist is (a) a substance competing with purine derivatives; or b) an enzyme inhibitor. Use of xanthine oxidase antagonists to prevent or reduce nitrate and / or nitrate transient tolerance in a method for the therapeutic treatment of the human body. Use according to claim 3, wherein the antagonist is (a) a substance competing with purine derivatives; or b) xanthine oxidase inhibitor. Use according to claim 4, characterized in that the xanthine oxidase inhibitor is allopurinol or oxypurinol. Use of antagonists of enzymes metabolizing purine derivatives or of xanthine oxidase antagonists for the preparation of a pharmaceutical agent for preventing or reducing nitrate and / or nitrate transient tolerance in a method for the therapeutic treatment of the human body. A pharmaceutical agent for the prevention or reduction of nitrate and / or nitrate transient tolerance comprising an xanthine oxidase inhibitor for use in a method of therapeutic treatment of the human body. 01-265-02 / PB 8. A pharmaceutical agent containing a therapeutic substance for the treatment of the heart or blood vessels, in particular a coronary therapist based on organic nitrates, preferably pentaerythritol tetranitrate, pentaerythryltrinitrate, pentaerythryldithinitrate or pentaerythrylmonitonitrate, sequential use in a method of therapeutic treatment of the human body.