DK169017B1 - Combination preparation for concomitant use when treating thrombotic and thromboembolic clinical pictures, which preparation comprises prostacyclins, analogues thereof, or prostaglandins (PC/PCA/PG) and thromboxane receptor antagonists (TXAA), and the use of PC/PCA/PG and TXAA for producing a medicament. - Google Patents

Abstract

Combination products containing a prostaglandine (PG), a prostacycline (PC) or a prostacycline analogue (PCA) and a thromboxane receptor antagonist (TXAA), suited for joint use in the treatment of forms of thrombotic or thrombo-embolic illnesses.

Description

DK 169017 B1

The invention relates to a combination composition for common use in the treatment of thrombotic and thromboembolic disease images with states of elevated intravasal platelet activation and thus elevated platelet aggregation and platelet adhesion, prosthesis or prosthesis, as well as elevated blood clotting attachment, a prostaglandin (PC / PCA / PG) and a thromboxane receptor antagonist (ΤΧΑΆ).

The invention also relates to the use of PC / PCA / PG in combination 10 with a thromboxane receptor antagonist for the preparation of compositions for use in thrombotic and thromboembolic disease images: prophylaxis and therapy of coronary heart disease, coronary thrombosis, heart attack, peripheral artery disease, diabetic artery disease, diabetic 15 stroke, prophylaxis and therapy of central nervous system ischemic attacks, migraine, treatment of shock, inhibition of bronchoconstriction and inhibition of gastric acid secretion. Additional uses for the combination are cytoprotection of gastrointestinal mucosa, hepatic, renal and pancreatic cytoprotection, lowering of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal bleeding, use in place of heparin or as an aid in dialysis. , haemofiltration, preservation of blood plasma for storage, especially of platelet products, inhibition of birth defects, treatment of gestational toxicosis, elevation of cerebral hemorrhage, etc. In addition, the combination preparation can be used as an antiallergic and as an antiproliferative agent.

The combination can e.g. also used with calcium antagonists, thromboxane synthetase inhibitors, typical anticoagulants such as heparin, coumarin or aspirin and similar active substances, with phosphodiesterase inhibitors, with angiotensin converting enzyme (ACE) inhibitors, with vasodilating agents substances, especially with β-receptor blockers, antiphlogistics, antipyretics and antiallergics etc.

DK 169017 B1 2

It is already known that in the treatment of acute and chronic thrombotic and thromboembolic diseases, prostaglandin E1, prostacyclin and prostacyclin analogs [use information for prostavasin® from Fa. Sanol Schwarz GmbH; Mon-5 cada. S., Br. J. Pharmacol. 76/1, 3-31 (1982); Schillinger, E., T. Krais, G. Stock, New Drug Annual: Cardivascular Drugs, Raven Press, in press].

In addition to the benefits of these therapies, which include a strong inhibition of all platelet aggregation stimulators, these therapies are limited by cardiovascular side effects, particularly the lowering of the pronounced blood pressure.

Also, the combination of aggregation inhibitor, antioxidant and / or thromboxane A2 synthetasein inhibitor described in CH-A-637298 causes such a strong blood pressure lowering that it is even referred to as antihypertensive agent for the treatment of high blood pressure.

For the TXAA in the previous clinical trials, there is insufficient evidence to show the effect of this treatment principle.

20 To arrive at better anti-aggregationally effective principles via a plasma mirroring of the endogenous prostacyclin in combination with a TXAA [Chan, C-C., A. Ford-Hutchinson, Europ. J. of Pharmacol. 110, 323-328, (1985) 3 must be considered insufficient, especially since a dosability and in general a safe and reproducible elevation of the endogenous prostacyclin is not possible. In addition, with endogenous prostacyclin, it is not possible, as with the use of synthetic PC / PCA / PG, to separate the desired effects of the prostacyclin from side effects.

It has now surprisingly been found that the typical side effects for PC / PCA / PG and the insufficient effect of TXAA are avoided or offset when using PC / PCA / PG and TXAA together in the treatment of the above-mentioned disease images. While DK 169017 B1 3 mutually reinforces the platelet-inhibiting antithrombotic and antithrombogenetic effect of both classes of active substance, the cardiovascular side effects of PC / PCA / PG decrease due to the 5 possible reduction in the amount of the individual active substances. Thereby, the therapeutic width of the individual active substances is increased.

Weight amounts of prostacyclin / prostacyclin analogue / prostaglandin and of thromboxane receptor antagonist can be used, which by 10 common use is greatly reduced relative to the required dosages of the individual active substances used so far.

PC / PCA / PG and ΤΧΑΆ are used in combination in a dosage unit or separately and simultaneously or sequentially in a weight ratio of substantially approx. 1: 1 to 1: 10,000 (for example, in the same carrier, in a tablet or also in an oily solution such as a benzyl benzoate / castor mixture).

The sequential treatment must be given special importance, as in such treatments where there is or may be expected a decrease of the PC / PCA / PG effect (Tachyphylaxia, [Sinzinger, H., S. Reiter, Prostagl. Leukotr. And Medicine 13/3, 281-288 (1984)]), alternating step-up and down-step treatment with PC / PCA / PG and TXAA may prevent such a reduction in efficacy.

As compounds of the prostacyclin / prostacyclin analogue / prostaglandin series suitable for use in the combination composition of the invention, all of the substances are present which possess, inter alia, antagonist antagonist properties and e.g. are described in: 30 R.C. Nickolson, M.H. Town and H. Vorbruggen, Med. Res. Rev. 5 (1985), B.I.R. Whittle and S. Moncada, Progress in Medicinal Chemistry 21, 236 (1984), P.A. Aristoff, Advances in Prosta- glandin, Thromboxane and Leukotriene Research Vol. 14, 1985, page 309, B. Radiichel and H. Vorbruggen, Advances in Prostaglandin, Thromboxane and Leukotriene Research Vol. 14, 1985, pages 263, 5 of the European patent applications with publication numbers 0011591, 0055208, 0069692, 0086404, 0099538, 0119949 as well as in DE publication 34 08 699 and DE publication 35 10 978.

Eg. Mention should be made of: Prostacyclin PGI2 / 15-cyclopentyl- (j-pentanor-5 (E) -carbacylin (NO0-41483; Prost. and Med. 10, 53 (1983), 5- {(E) - (IS, 5S, 7R) -7-hydroxy-6- [(3S, 4S) -3-hydroxy-4-methyl-no-na-1,6-diinyl] -bicyclo [3.3.0] -octan-3-ylidene} -pentanoic acid (EP 15 No. 0086404), (5E) - (16S) -13,14-didehydro-16,20-dimethyl-18,18,19,19-tetrade-hydro-2,3,4-trinoric acid 1,5-inter-m-phenylene-6a-carba-prostaglandin I2 (DE Publication No. 3408699), 57 - {(E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - [(3S) (4RS) -3-hydroxy-4-methyl-1-octen-6-inyl] -bicyclo [3.3.0] -octan-3-ylidene} -pentanoic acid (Iloprost, EP No. 0011591), 7- {(E) - (IS, 5S, 6S, 7R) -7-hydroxy-6- [(3S, 4S) -3-hydroxy-4-methyl-nona-1,6-diinyl] bicyclo [3.3.0] -octan-3-ylidene} -5-oxa-heptanoic acid (EP No. 0099538), (5Z, 13E, 9a, 11a, 15S) -2,3,4-trinor-inter-m-phenylene-6 9-Epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prostamic acid (CG 4305, Arzn. Forsch. 1983, 1240) as well as the corresponding sodium salt (CG 4203, Drugs Future 9, 494, (1984)), 30β-thia-imino-prostacyclin (Hoe 892, Prost. and Med. 10, 231 (1983)), I ----------- - -. _____ DK 169017 B1 5 9-Methyl-carbacycline (J. Org. Chem. 48, 534 (1983)), 5- {(E) - (IS, 5S, 6S, 7R) -7-hydroxy-6 - [( 3S, 4S) -3-hydroxy-4-methyl-nona-1,6-diinyl] -bicyclo [3.3.0] -octan-3-ylidene} -3-oxa-pentanoic acid (EP No. 0119949), 5 - {(Z) - (1S, 5S, 6S, 7R) -7-hydroxy-6 - ((3S, 4S) -3-hydroxy-4-methyl-nona-1,6-diinyl] -bicyclo [ 3.3.0] -octan-3-ylidene} -3-oxa-5-fluoro-pentanoic acid (EP No. 0099538), 7-oxo-16-methyl-18,19-didehydro-PGl2 (DE Publication No. 3 035 454), 7 7-oxo-PGI 2 (DE Publication No. 3 035 454), Prostaglandin E-, 6- keto-prostaglandin E], (5Z, 13E) - (9R, HR, 15S) -9- chloro-15-cyclohexyl-11, 15-dihydroxy-16.17.18.19.20-pentanor-5,13-prostadic acid (DE Publication No. 3,510,978), 175,20-dimethyl-trans-2,3-didehydroxy PGE1 (NO 1206, Drugs Future 7, 116 (1982)).

Instead of the stated prostanoic acids, their physiologically compatible salts may be with inorganic or organic bases, such as e.g. sodium hydroxide, potassium hydroxide, tris- (hydroxymethyl) -aminomethane, glucamine, N-methylglucamine, morpholine, lysine, arginine, are also used.

As thromboxane receptor antagonists, all compounds having a sufficient affinity for the thromboxane receptor are present and no or in the dose range used is insignificant thromboxane agonist activity such as those e.g. are described in: JP 5017-315; US 4472-586-A; US 4263-207; US 4394-515-A; DK 169017 B1 US 4282-365; BE 883-713; JP 7093-962; JP 0004-154-A; EP 43-292; EP - A-82-646; DE 3346-047-A; WO 8400-754-A; US 4474-804-A; DE 3401-986-A; DE 3127-343: BE-897-763-A; EP - from 74 to 861; AU 8425607-A; EP - from 78 to 668; DE 3339-019-A; EP-137-426-A and by N.H.

Wilson and R.L. Jones in Advances in Prostaglandin, Thromboxane and Leukotriene Research 14, 420-423 (1985) as well as by K. Stegmeier et al. in: Thrombosis Research 35, 379-395 (1984).

Eg. mention should be made of: 4- [2- (benzenesulfonamido) ethyl] phenoxyacetic acid (BM 13 177) 10 [K. Stegmeier et al. in: Thrombosis Research 35, 379-395, 1984].

[Α (Z), 2 / 3,5a] - (±) -7- [5- [[(1,1-biphenyl) -4-yl] methoxy] -2- (4-morpholinyl) -3-oxocyclopentyl ] -4-hepatonic acid (AH 23848) (Br.

J. Pharmac. (1985), 86, 259) [1 / 3,2α (5Z), 3a, 4/3] -7- [[2- [(phenylamino) carbonyl] hydrazino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-heptenoic acid (SQ 29548) (Prostaglandins 29, 785 (1985)) 4- (4-Chlorobenzenesulfonylamino) -ethylbenzene acetic acid (BM 13 505) (Intern. Conf. Leukotrienes and Prostanoids in Health and Disease, Tel Aviv, Oct. 1985, page 10) 7- [3 - [[[(phenylamino) carbonyl] hydrazonol] methyl] bicyclo [2.2.1] hept-2-yl] -, [1a, 2/3, (Z), 3a, 4a] (EP 045) and 7- {(IS, 2S, 3S, -4R,) -3- [1- (3-phenylthioureidoimino) ethyl] bicyclo [ 2.2.1] hep-tan-2-yl} -5-heptenoic acid (EP 092) [both substances described by 25 RA Armstrong et al. in BR. J. Pharmacol. 84, 595-607, 1985].

Dibenzo [b, f] thiepin-3-methanol, 5,5-dioxide (L 640035) [C-C.

Chan in: Europ. J. Pharmacol. 110 (3), 323-328, 1985].

2,7 (1H) -isoquinoline disulphonamide, N7- (3-chlorophenyl) -N2 - [[7- I * -----DK 169017 B1 7 [[(3-chlorophenyl) amino] sulfonyl] -3,4- dihydro-2 (1H) -isoquinanol] sulfonyl] -3,4-dihydro (SKF 88046) [BM Weichman et al. in: Leukotrienes and Medicine Prostaglandins 15, 167-175, 1984].

PC / PCA / PG is used in amounts significantly below the levels otherwise used to inhibit intravasal platelet aggregation.

When using Iloprost as PCA, according to the present invention, one can usually cope with 10 to 1000 µg, preferably 50 to 250 µg per day.

The application can e.g. occur enterally or parenterally inhalatively or also transdermally or locally.

In the intravenous infusion of Iloprost, e.g. quantities from approx. 50 to approx. 150 µg per day.

For the oral application, approx. from 125 to approx. 250 µg 15 per day.

One dose unit of Iloprost contains approx. 100 μg per ml as stock solution for dilution in usual infusion carrier solutions for intravenous use.

For oral use, a dosage unit of 25 to 50 contains 20 µg, for needle formulations or retard formulations 25 to 250 µg, as a tablet, dragee, capsule, pill, suspension or solution which may be prepared in the usual manner with those of the Galician Pharmacy. additives and carriers. For local, topical or transdermal use, e.g.

25 systems such as skin patches or suppositories on speech.

Biologically equivalent amounts of other prostacyclin analogs or prostaglandins may also be used in the combination compositions of the invention.

DK 169017 B1 8

The thromboxane receptor antagonists are used in the combination compositions of the present invention in amounts which are generally below the amounts used heretofore in human studies [Riess,,., E. Hiller, B. Reinhardt, C. Brown, i; Thrombosis Research 35, 371-378, 1984]. Usually 100 - 2000 mg / day, preferably 200 - 800 mg / day, BM 13177, or 1 - 100 mg / day, preferably 2-50 mg / day, AH23848 or SQ 29548 or a biologically equivalent amount of another thromboxane receptor antagonist sufficient.

TXAA can e.g. is administered enterally or parenterally, inhalatively, but also transdermally or locally.

Especially for the preferred oral application are tablets, dragees, capsules, pills, suspensions or solutions which can be prepared in the usual manner with the usual additives and carriers in the Galician Pharmacy.

For local use, e.g. Transdermal systems such as skin patches are used.

A dosage unit for oral or parenteral use contains approx. 50 - 300 mg, as the key formulation 100 - 1000 mg BM 20 13 177 / day or a biologically equivalent amount of another thromboxane receptor antagonist.

The joint treatment with PCA and TXAA, depending on whether it is an acute, subacute or chronic disease event, takes place over a few days to weeks and months when PCA and TXAA are administered in a unit of dose or separately and sequentially or sequentially. .

The following examples illustrate the Galenic formulation: m i - DK 169017 Bl 9 EXAMPLE 1

Composition of a combination tablet.

% Amount / tablet _M_ 5 1. Iloprost 0.01 0.05 (as solution in ethanol 50%) 2. BM 13 177 50.0 250.0 3. Lactose 34.99 174.95 4. Corn starch 10.0 50 , 0 10 5. Polyvinylpyrrolidone 2500 3.0 15.0 6. Stearic acid_2.0_10.0_ 100% 500.00 mg

The ingredients 3, 4 and 5 are sieved, mixed and granulated together with the solution of 1. After drying, mix 2 and 6 after the other, and the pressing mass is pressed into round tablets of 11 mm diameter.

EXAMPLE 2

Composition of a combination tablet.

% Amount / tablet 20 _ [mg] _ 1. Iloprost 0.02 0.05 (as solution in ethanol 50%) 2. SQ 29 458 4.0 10.0 3. Lactose 65.98 164.95 25 4. Corn starch 20.0 50.0 5. Polyvinylpyrrolidone 2500 6.0 15.0 6. Stearic acid_4.0_10.0_100% 250.00 mg

The ingredients 3, 4 and 5 are sieved, mixed and granulated together with the solution of 1. After drying, mix 2 and 6 after each other and the pulp is squeezed into round tablets with a diameter of 11 mm.

EXAMPLE 3

Composition of a combination tablet.

5% Amount / tablet _fmcrl 1. Iloprost 0.02 0.05 (as solution in ethanol 50%) 2. AH 23 848 1.0 2.5 10 3. Lactose 68.98 172.45 4. Corn starch 20.0 50.0 5. Polyvinylpyrrolidone 2500 6.0 15.0 6. Stearic acid_4.0_10.0_ 100% 250.00 mg 15 The ingredients 3, 4 and 5 are sieved, mixed and granulated together with the solution of 1. After drying, mix 2 and 6 one after the other, and the pressing mass is squeezed into round tablets with a diameter of 11 mm.

EXAMPLE 4 Composition of a combination tablet.

% Amount / tablet _Cxncrl 1. Iloprost-Na salt 0.0104 0.052 (dissolved in distilled water) (s 0.05 mg Iloprost) 25 2. BM 13 177 50.0 250.0 3. Lactose 34.99 174, 95 4. Corn starch 10.0 50.0 5. Polyvinylpyrrolidone 2500 3.0 15.0 6. Stearic acid_2.0_10.0_ 100% 500.00 mg DK 169017 B1 11

The ingredients 3, 4 and 5 are sieved, mixed and granulated together with the solution of 1. After drying, mix 2 and 6 in succession, and squeeze the pulp into round tablets of 11 mm diameter.

EXAMPLE 5

Composition of a combination tablet.

% Amount / tablet _ [mql 1. Iloprost 0.33 1.66 10 as inclusion compound (== 0.05 mg Iloprost) with ex-, β- or γ-cyclodextrin 3% (g / g) 2. BM 13 177 50.0 250.0 3. Microcrystalline cellulose 35.67 178.34 4. Corn starch 12.0 60.0 5. Stearic acid_2.0_10.0_ 100% 500.00 mg

The recipe ingredients except the stearic acid are sieved and mixed for 15 minutes. Stearic acid (sieved) is added and blended for an additional 3 minutes with the other recipe ingredients. The pulp is squeezed into round tablets with a diameter of 11 mm.

PHARMACOLOGICAL STUDIES

1. In vitro platelet function (Human-PRP).

25 ---------------------------------------- BM 13 177 (in the text BM) and Iloprost is tested for their effect on thrombocyte aggregate ion and thrombocyte shape change against stimulators U 46 619 (9,11-dideoxy, 9a-11Q-methanoepoxy - PGF2Q, stable TXA2-30 agonist) and ADP and the IC IC values are determined. Then, in several independent experiments, the effect of a combination of both substances on the aggregation (U 46 619 and ADP) at different concentrations is tested; in particular, the combination of low doses and doses around the IC50 values of the two substances is tested.

5 Methodology

Platelet aggregation and deformity are measured as light-optic phenomena in stimulated PRP (platelet-rich plasma) samples. Thus, the shape change is recorded as the sample density increase upon platelet conversion from the discoid resting form to a spherocyte shape with the development of pseudopoietic membrane formation and displayed on a printer. The aggregation is photometrically recorded as density decrease by clumping and "precipitation" of platelet aggregates and displayed on a printer.

results

Iloprost inhibits concentration-dependent platelet aggregation induced by U 46 619 and the shape change. The IC 50 for the aggregate inhibition is 1.3 - 2.6 nM and for the inhibition inhibition, the IC 1 Q is 0.52 - 1.3 nM.

The second wave of the aggregation induced by ADP is inhibited concentration-dependent with an IC 50 of 0.26 - 0.65 nM.

BM 13 177, depending on concentration, inhibits platelet aggregation induced by U 46 619 25 and the shape change. The IC50 for the aggregate ion is 1.65 - 6.6 μΜ and for the shape change 1.65 - 3.3 μΜ.

The second wave of ADP-induced aggregation is inhibited by concentration, with an IC50 of 0.33 to 0.66 μΜ.

DK 169017 B1 13

Combination of thromboxane receptor antagonist and Iloprost

By the combination of BM 13 177 with Iloprost, the platelet aggregation induced by U 46 619 and the platelet change and the second wave of the ADP-induced aggregation at concentrations of both active substances located in the threshold region or below the threshold region become strong. inhibited. The inhibitory effects of both active substances are thereby enhanced (see table).

Table 10 Example 1: Aggregation using 100 ng / ml U 46 619.

Active substance Concentration% Inhibition 1 BM 13 177 0.66 μΜ 16% 15 _ 2 Iloprost 0.1 ng / ml 2% 1 + 2 65% 20 Example 2: Change in shape by 50 ng / ml U 46 619.

Active substance Concentration% Inhibition 1 BM 13 177 0.66 μΜ 28% 25 ___ DK 169017 B1 14 2 Iloprost 0.1 ng / ml no inhibition 1 + 2 61% 5 Example 3: 2nd wave of aggregation using 0, 5 x 10-6M ADP.

Active substance Concentration% Inhibition 10 1 BM 13 177 0.165 μΜ no inhibition 2 Iloprost 0.1 ng / ml no inhibition 1 + 2 60% 15 _ 2. Intravasal platelet aggregation in anesthetized rats.

Methodology 20 -------

The influence of intravasal platelet aggregation is investigated on urethane-anesthetized rats.

Collagen (100 μg / kg i.v. bolus) produces transient thrombocytopenia (a transient decrease in platelet concentration), as measured by continuous blood test from A. ca-rotis (50 μΐ / min) and platelet count in a Technicon Autocounter. As a measure of inhibition of intravasal platelet aggregation, the change in collagen-induced thrombocytopenia (% decrease) serves in comparison with the initial value (= 2nd collagen injection).

Results 5 Iloprost (0.1 - 0.33 - 1.0 Mg / kg / min) dose-dependently inhibits the collagen-induced thrombocytopenia. BM 13 177 inhibits thrombocytopenia in the lowest dose (0.5 mg / kg / min) by 27 + 6% (mean ± standard deviation), an effect that cannot be increased by dose increase (1.0-10.0 mg / kg / min). The combination of a threshold dose of Ilo prost (0.1 Mg / kg / min) with the lowest dose studied of BM 13 177 (0.5 mg / kg / min) gives a significant (oc = 0.05) relative to the single administration. Lord-Test) stronger inhibition of 45 + 2%.

15 3. Mesenterial arteriolar thrombosis in narcotic guinea pigs.

methodology

In narcotic guinea pigs, a mesenterial tube 20 is prepared for vital microscopy. Following electrical lesion of an arteriole, topical is applied under control conditions and after drug application ADP until a thrombogenic dose (ok inclusion due to platelet thrombus) is found.

Parameter: Increase of thrombogenic ADP concentration 25 to initial value; intravenous infusion of Iloprost, intravenous injection of BM 13 177.

results

In electrically pre-damaged mesenteric arterioles in 30 anesthetized guinea pigs, BM 13 177 (25 mg / kg intravenous venous), the ADP concentration needed to trigger occluding platelet thrombus is significant by approx. the factor 4.

Iloprost elevated at the threshold dose of 0.1 µg / kg / min intravenously thrombogenic ADP concentration by the factor of 2.8.

The combination of BM 13 177 (25 mg / kg intravenously) followed by an intravenous infusion of Iloprost (0.1 rye / kg / min) elevated is the thrombogenic ADP concentration with the factor 12.

In an experimental model for the arterial platelet-induced thrombosis, the combination of the TXA2 antagonist BM 13177 and the prostacyclin analog Iloprost results in an enhanced antithrombogenetic effect.

4. Jugular vein thrombosis in anesthetized rats.

15 ----------------------------------------------

methodology

When loading the jugular vein of urethane-anesthetized rats with a metal stamp cooled to -15 ° C (200 g, 2 20 min), the vessels are damaged in advance. The thrombus that grows at this site during 3 hours is determined quantitatively (Hb content determined by moist weight) by determinations of its Hb content (difference between damaged and undamaged vessel segment).

The infusion of the test substances begins 15 minutes before injury to the vein and is continued until the end of the experiment.

Results 30 The infusion of Iloprost in a single dose did not show a sufficiently effective dose (30 ng / kg / min intravenously) in combination with a monotherapy inactive dose of BM 13 177 (20 mg / min). kg intravenous bolus + 50 µg / kg / min intravenously) provides a significant reduction in the HBs content of the thrombi to values in undamaged control animals.

5 BM 13 177 as monotherapy in the jugular vein thrombosis model for rats is not antithrombotic. The combination with a hemodynamic and antiaggregatory inactive dose of Iloprost completely suppresses thrombus growth.

5. Blood pressure in spontaneously hypertonic (SH) rats.

10 --------------------------------------------

methodology

In awake SH rats that have implanted a venous catheter for drug delivery and an arterial catheter for blood pressure measurement, the behavior of blood pressure and heart rate is observed during infusion of the test substances.

Iloprost is infused at a threshold dose of 0.3 / zg / kg / min (20% decrease in diastolic blood pressure) along with a high dose of BM 13 177, 2 mg / kg / min (see blood platelet inhibition in vivo , on 27% inhibition at 2 mg / kg intravenous infusion) for 20 minutes (n = 6 animals).

results

Hemodynamic changes, blood pressure drop and increase in heart rate caused by Iloprost are only negatively affected by BM 13 177.

While the maximal blood pressure drop due to Iloprost is not affected by BM 13 177, this effect disappears more rapidly upon completion of the infusion by combination therapy.

Claims (12)

A combination composition for common use in thrombotic and thromboembolic disease images, characterized in that it contains prostacyclin, a prostacyclin analogue or a prostaglandin (PC / PCA / PG) and a thromboxane receptor antagonist (TXAA). Composition according to claim 1, characterized in that PC / PCA / PG and TXAA are in a weight ratio of 1: 1 to 1: 10,000. Composition according to claim 1, characterized in that 15 PC / PCA / PG and TXAA are available in separate dosage units. Composition according to claim 1, characterized in that PC / PCA / PG and TXAA are present together in a dosage unit. Composition according to claim 1, characterized in that a PC / PCA / PG dosage unit contains 25 - 250 µg of Iloprost = 5 - {(E) - 20 (1S, 5S, 6R, 7R) -7-hydroxy- 6 - [(E) - (3S, 4RS) -3-hydroxy-4-methyl-1-octen-6-inyl] -bicyclo [3,3,0] -octan-3-ylidene} -pentanoic acid or a biological equivalent amount of another PC / PCA / PG. Composition according to claim 1, characterized in that a TXAA dosage unit contains 50 - 1000 mg BM 13 177 = 4- [2- (benzenesulfonamido) ethyl] phenoxyacetic acid or a biologically equivalent amount of another TXAA. Use of PC / PCA / PG and TXAA for the manufacture of a medicament for simultaneous, separate or temporal use in the treatment of thrombotic and thromboembolic disease car-DK 169017 B1 conductors. Use of PC / PCA / PG and TXAA in a dosage unit for the preparation of a composition for use in the treatment of thrombotic and thromboembolic disease images. Use according to claim 7 or 8, characterized in that PC / PCA / PG and TXAA are in a weight ratio of 1: 1 to 1: 10,000. Use of 25 - 250 µg Iloprost = 5 - {(E) - (IS, 5S, 6R, 7R) - 7-hydroxy-6 - [(E) - (3S, 4RS) -3-hydroxy-4 -methyl-1-octene-6-inyl] - 10 bicyclo [3.3.0] -octan-3-ylidene} -pentanoic acid as PC / PCA / PG or a biologically equivalent amount of another PC / PCA / PG to produce compositions according to claim 1. Use of 50 - 1000 mg BM 13 177 = 4- [2-benzenesulfone-amido) -ethyl] -phenoxyacetic acid as TXAA or a biological equivalent of another TXAA for the preparation of compositions according to claim 1. Use of PC / PCA / PG and TXAA for the preparation of a drug for sequential use to avoid the platelet aggregation inhibition effect in the treatment of 20 thrombotic and thromboembolic disease images.