IE59338B1 - Prostacyclins, their analogues or prostaglandins and thromboxane antagonists for the treatment of thrombotic and thrombo-embolic syndromes - 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

The invention relates to a combination product for combined administration in the treatment of thrombotic and thromboembolic syndromes with conditions of increased intravasal platelet activation and hence an increased tendency towards platelet aggregation and platelet adhesion and an increased tendency towards blood coagulation, containing a prostacyclin, a prostacyclin analogue or a prostaglandin (PC/PCA/PG) and a thromboxane receptor antagonist (TXAA).

The invention also relates to the use of a PC/PCA/PG in combination with a thromboxane receptor antagonist for administration for: prophylaxis and therapy of coronary heart diseases, coronary thrombosis, cardiac infarction, peripheral arterial disease, diabetic vascular changes, arteriosclerosis and thrombosis, apoplexy, prophylaxis and therapy of ischaemic attacks of the CNS system, migraine, shock therapy, inhibition of broncho-constriction, inhibition of gastric acid secretion; further possible uses of the combination are cytoprotection of the mucous membrane of the stomach and intestine, cytoprotection in the liver, kidney and pancreas, reduction in the pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use for the preparation of medicaments for use instead of heparin or for use as an adjuvant during dialysis or haemofiltration, preservation of conserved blood plasma, especially conserved blood platelets, inhibition of labour pains, treatment of pregnancy toxaemia, increasing of cerebral blood flow etc.; the combination product can additionally be used as an antiallergic and as an antiproliferative active substance.

The combination can also be administered, for example, together with calcium antagonists, thromboxane synthetase inhibitors, typical anticoagulants, such as heparin, coumarin or aspirin and corresponding active substances, with phosphodiesterase inhibitors, with angiotensin converting enzyme (ACE) inhibitors, with vasodilating active substances, especially with β-receptor blockers, anti-inflammatories, antipyretics and antiallergics, etc..

It is already known that prostaglandin Elz prostacyclin and 10 prostacyclin analogues are used for the treatment of acute and chronic thrombotic and thrombo-embolic diseases [Information on the use of Prostavasin® from Sanol Schwarz GmbH; Moncada.

S. , Br. J. Pharmacol. 7 6/1. 3-31 (1982); and Schillinger, E., T. Krais and G. Stock, New Drug Annual: Cardiovascular Drugs, 15 Raven Press, being printed]. Besides having the advantages of these treatment forms, which consist of potent inhibition of all stimulators of platelet aggregation, these therapies are limited by the cardiovascular side effects, in particular the marked reduction in blood pressure.

The combination of aggregation-inhibiting substance, antioxidant and/or thromboxane A2 synthetase inhibitor described in CH-A-637298 also causes such a pronounced reduction in blood pressure that it is even termed an antihypertensive for the treatment of high blood pressure.

For TXAA, no adequate detection of the action has been carried out for this therapy principle in the clinical investigations to date. It is to be considered as insufficient to achieve better antiaggregatory principles by means of an increase in the plasma levels of the endogenous prostacyclin in combination with a TXAA [Chan, C-C., and A. Ford-Hutchinson, Europ. J. of Pharmacol. 110. 323-328, (1985)], especially since dosing and any reliable and reproducible increase at all in the endogenous prostacyclin is impossible. Moreover, with endogenous prostacyclin, there is not che possibility of separating desirable effects from side effects of the prostacyclin, which exists when synthetic PC/PCA/PG is used.

It has now been found, surprisingly, than the side effects typical of PC/PCA/PG and the inadequate activity of TXAA can be avoided or compensated if the PC/PCA/PG and TXAA are used in combination in the treatment of the above-mentioned syndromes. Whilst the platelet-inhibiting antithrombotic and antithrombogenic action of both classes of active substance are mutually potentiated, the cardiovascular side effects of the PC/PCA/PG are reduced as a result of the reduction in the amounts of the individual active substances which is possible with the combination. The therapeutic range of the individual active substances is thereby increased.

It is possible to use amounts by weight of prostacyclin/ prostacyclin analogue/prostaglandin and of thromboxane receptor antagonist that are greatly reduced on their combined administration in comparison with the required dosages previously used for the individual active substances.

The PC/PCA/PG and TXAA are combined in one dose unit or used separately and simultaneously or sequentially in a weight ratio of essentially about 1:1 to 1:10,000 (for example in the same vehicle, a tablet or an oily solution, such as a benzyl benzoate/castor oil mixture).

Sequential treatment is of particular importance in as much as in those treatments in which a decrease in the PC/PCA/PG action occurs or is to be expected (Tachyphylaxie, [Sinzinger, H. and S. Reiter, Prostagl. Leukotr. and Medicine 13/3, 281288 (1984)]), such a reduction in action can be prevented by alternate gradually increasing and gradually decreasing therapy with PC/PCA/PG and TXAA.

V Suitable compounds of the prostacyclin/prostacyclin analogue/ prostaglandin series for use according to the invention are all substances that have aggregation-inhibiting properties on blood platelets and are described, for example, in: 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 in Advances in Prostaglandin, Thromboxane and Leukotriene Research Vol. 14, 1985, p. 309, 3. Radiichel and H. Vorbruggen in Advances in Prostaglandin, Thromboxane and Leukotriene Research Vol. 14, 1985, p. 263, and in European Patent Applications of Publication No. 0011591, 0055208, 0069692, 0086404, 0099538 and 0119949 and in DE-OS 34 08 699 and DE-OS 35 10 978.

Examples which may be mentioned are: prostacyclin PGI2, -cyclopentyl-vJ-pentanor-5 (E)-carbacyclin (ONO-41 483; Prost. and Med. 10, 53, (1983)), -{(E)-(lS,5S,7R)-7-hydroxy-6-[ (3S,4S ) -3-hydroxy-4-methylnona-1,6-diynyl]-bicyclof 3.3.0]octan-3-ylidene}-pentanoic acid (EP 0086404), (5E)-(16S)-13,14-didehydro-16,20-dimethyl-18,18,19,19tetradehydro-2,3,4-trinor-l,5-inter-m-phenylene-6acarbaprostaglandin I2 (DE-OS 3408699), -{ (E) -(IS, 5S, 6R,7R)-7-hydroxy-6-[ (3S,4RS)-3-hydroxy-4-methyll-octen-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene}-pentanoic acid (iloprost, EP 0011591), 7-{ (E) — (1S,5S, 6S, 7R)-7-hydroxy-6-[ (3S,4RS)-3-hydroxy-4-methylnona-1,6-diynyl]bicyclo[3.3.0]octan-3-ylidene}-5-oxaheptanoic acid (EP 0099538), (5Z,13E,9α,11α,15S)-2,3,4-trinor-inter-m-phenylene-6,9-epoxy11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor]prostadienoic acid (CG 4305, Arzn. Forsch. 1983, 1240) and the corresponding sodium salt (CG 4203, Drugs Future 9., 494, (1984)), β-thia-imino-prostacyclin (Hoe 892, Prost. and Med. .10, 231 (1983)), 9-methylcarbacyclin (J.Org. Chem. .48., 534 (1983)), -{(E)-(lS,5S,6S,7R)-7-hydroxy-6-[(3S,4S)-3-hydroxy-4-methylnona-1,6-diynyl ] -bicyclof 3.3.0]octan-3-ylidene}-3-oxapentanoic acid (EP 0119949), -{(Z)-(lS,5S,6S,7R)-7-hydroxy-6-[(3S,4S) - 3-hydroxy-4 methylnona-1,6-diynyl ]-bicyclo[ 3.3.0 ]octan-3-ylidene}-3-oxa5- fluoropentanoic acid (EP 0099538), 7-oxo-16-methyl-18,19-didehydro-PGI2 (DE-OS 3 035 454), 7-oxoPGI2 (DE-OS 3 035 454), prostaglandin E,, 6- ketoprostaglandin Elz (5Z,13E)-(9R,HR,15S)-9-chloro-15-cyclohexyl-ll,15-dihydroxy16.17.18.19.20- pentanor-5,13-prostadienoic acid (DE-OS 3 510 978), and 175.20- dimethyl-trans-2,3-didehydro-PGl! (ONO 1206, Drugs Future 7., 116 (1982)).

Instead of the prostanoic acids mentioned, it is also possible to use the physiologically acceptable salts thereof with inorganic or organic bases, such as, for example, sodium hydroxide, potassium hydroxide, tris-(hydroxymethyl)7 aminomethane, glucamine, N-methylglucamine, morpholine, lysine or arginine.

Possible thromboxane receptor antagonists are all compounds that have a sufficient affinity for the thromboxane receptor and have no thromboxane-agonistic activity or a thromboxaneagonistic activity that is only insignificant in the dose range used, such as are described, for example, in: J5 5017315; US 4472-586-A; US 4263-207; US 4394-515-A; US 4282365; BE-883-713; J5 7093-962; J6 0004-154-A; EP—43-292; EP—82-646-A; DE-3346-047-A; WO 8400-754-A; US 4474-804-A; DE 340-1986-A; DE 3127-343; BE-897-763-A; EP—74-861; AU 8425-607-A; EP—78-668; DE 3339-019-A; EP-137-426-A and in N.H. Wilson and R.L. Jones in: Advances in Prostaglandin, Thromboxane and Leukotriene Research 24., 420-423 (1985), and by K. Stegmeier et al. in: Thrombosis Research 35., 379-395 (1984).

Examples which may be mentioned are: 4-[2-(benzenesulphonamido)ethylJphenoxyacetic acid (BM 13 177) [K. Stegmeier et al. in Thrombosis Research 35, 379-395, 1984], [1α(Z) , 2β,5α]-(±)-7-[5-[(1,1-biphenyl)-4-yl]methoxy]-2-(4morpholinyl)-3-oxocyclopentyl]-4-heptanoic acid (AH 23848) (Brit. J. Pharmac. (1985), 25./ 259), [1β,2α(5Ζ),3α,4β]-7-[[2-[(phenylamino) carbonyl]hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 29.548) (Prostaglandins 29, 785 (1985)), 4-(4-chlorobenzenesulphonylamino)-ethyl-benzene-acetic acid (BM 13 505) (Intern. Conf. Leukotrienes and Prostanoids in Health and Disease, Tel-Aviv, Oct. 1985, p. 10), — [3 — [[[ (phenylamino) carbonylJhydrozono]methyl]bicyclo[ 2.2.1]hept-2-yl]-, [Ια, 2β, (Z), 3a, 4a] (EP 405) and 7{( IS,2S, 3S , 4R)-3-[1-(3-phenylthioureidoimino)ethyl]bicyclo[2.1.1]heptan-2-yl}-5-heptenoic acid (EP 092) [both substances R.A. Armstrong et al. in Br. J. Pharmacol. 84 , 595607, 1985], dibenzo[b,f]thiepine-3-methanol 5,5-dioxide (L 640035) [C-C Chan in: Europ. J. Pharmacol. 110 (3), 323-328, 1985], 2,7(IH)-isoquinoline disulphonamide, N7-(3-chlorophenyl)-N2[[7-[[(3-chlorophenyl) amino]sulphonyl]-3,4-dihydro-2(IH) isoquinolinyl]sulphonyl]-3,4-dihydro (SKF 88046) [B.M. Weichmann et al. in: Prostaglandins Leukotrienes and Medicine 15, 167-175, 1984], The PC/PCA/PG are employed in amounts that are clearly below the amounts otherwise used for inhibition of intravasal platelet aggregation. When iloprost is used as the PCA, as a rule 10 - 1,000 ug, preferably 50 - 250 ug, per day will be sufficient according to the present invention. Administration can be effected, for example, enterally or parenterally, by inhalation or also transdermally or locally.

In the case of intravenous infusion of iloprost, for example, amounts of about 50 - 150 ug per day are required. In the case of oral administration, about 125 - 250 ug per day are employed.

One dose unit of iloprost contains about 100 ug/ml as a stock solution for dilution in customary infusion excipient solutions for intravenous administration.

For oral administration, one dose unit contains 25 - 50 ug, and in sustained release formulations 25 - 250 ug, as a tablet, drag6e, capsule, pill, suspension or solution, which can be prepared in the usual manner with the additives and excipients customary in galenical pharmacy. Systems such as skin plasters or suppositories, for example, are possible for local, topical or transdermal administration.

According to the invention, biologically equivalent amounts of other prostacyclin analogues or prostaglandins can also be employed.

According to the present invention, the thromboxane receptor antagonists are employed in amounts that are as a rule below the amounts hitherto used in human studies [Riess, Η., E. Hiller, B. Reinhardt, C. Brauning in: Thrombosis Research 35, 371-378, 1984]. In general, 100 - 2,000 mg/day, preferably 200 - 800 mg/day, of BM 13 177 or 1 - 100 mg/day, preferably 2-50 mg/day, of AH23848 or SQ 29548, or a biologically equivalent amount of another thromboxane receptor antagonist are sufficient.

The TXAA can be administered, for example, enterally or parenterally, by inhalation and also transdermally or locally.

Tablets, dragees, capsules, pills, suspensions or solutions, in particular, are possible for the preferred oral administration, and these can be prepared in the usual manner with the additives and excipients customary in galenical pharmacy.

Transdermal systems, such as skin plasters can be used, for example, for local administration.

One dose unit for oral or parenteral administration contains about 50 - 300 mg, or as a sustained release formulation 100 1,000 mg, of BM 13 177/day or a biologically equivalent amount of another thromboxane receptor antagonist.

Combined treatment with PCA and TXAA is carried out, depending on whether the pathological process is acute, subacute or chronic, for a few days up to weeks or months, the PCA and TXAA being administered in one dose unit or separately and simultaneously or sequentially.

The following Examples are intended to illustrate the galenical formulation: Example 1 Composition of a combination tablet % amount/tablet [mg] 1. iloprost 0.01 0.05 (as a 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 5. polyvinylpyrrolidone 2500 3.0 15.0 6. stearic acid 2.0 10.0 100 % 500.00 mg Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the mass is compressed to circular tablets with a diameter of 11 mm.

Example 2 Composition of a combination tablet % amount/tablet [mg] 1. iloprost 0.02 0.05 (as a solution in ethanol 50%) 2. SQ 29 458 4.0 10.0 3. lactose 65.98 164.95 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 Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the mass is compressed to circular tablets with a diameter of 11 mm.

Example 3 Composition of a combination tablet % amount/tablet [mg] I. iloprost 0.02 0.05 2. (as a solution in ethanol 50%) AH 23 848 1.0 2.5 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 Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the mass is compressed to circular tablets with a diameter of 11 mm.

Example 4 Composition of a combination tablet % amount/tablet [mg] 1 iloprost Na salt 0.0104 0.052 (dissolved in distilled water) (= 0.05 mg of iloprost) 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 A 0 . stearic acid 2.0 10.0 100 % 500.00 mg Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the mass is compressed to circular tablets with a diameter of 11 mm.

Example 5 Composition of a combination tablet % amount/tablet [mg] 1. iloprost as an inclusion compound with α, β or V-cyclodextrin, 3 % (g/g) 0.033 1.66 (= 0.05 mg of of iloprost) 2. BM 13 177 50.0 250.0 3. microcrystalline cellulose 35.67 178.34 4. corn starch 10.0 60.0 5. stearic acid 2.0 10.0 100 % 500.00 mg The constituents of the recipe, with the exception of the stearic acid, are sieved and mixed for 15 minutes. Stearic acid (sieved) is added and mixed with the other constituents of the recipe for a further 3 minutes. The mass is compressed to circular tablets with a diameter of 11 mm.

PHARMACOLOGICAL FINDINGS 1. Thrombocyte function in vitro (human PRP) BM 13 177 (BM in the text) and iloprost are tested against the stimulators U 46 619 (9,ll-dideoxy-9a,11amethanoepoxy-PGF2a, stable TXA2 agonist) and determined. Thereafter, the action of a combination of the two substances on aggregation (U 46 619 and ADP) is tested in various concentrations in several independent experiments; in particular, the combination of low dosages and dosages of the two substances in the region of the IC50 values is tested.

Method Platelet aggregation and shape change are measured as photooptical phenomena in stimulated PRP samples (platelet rich plasma). The shape change is recorded here as an increase in the density of the sample by transition from the discoid dormant shape of the platelet into a spherocytic shape with the formation of pseudopodium-like membrane developments and is shown on a recorder. The aggregation is recorded photometrically as the decrease in density due to clumping and precipitation of platelet aggregates and is shown on a recorder.

Results Iloprost inhibits, as a function of the concentration, the platelet aggregation induced by U 49 619 and the shape change. The IC50 for the inhibition of aggregation is 1.3 - 2.6 nM, and for the inhibition of shape change the IC50 is 0.52 - 1.3 nM.

The 2nd wave of aggregation induced by ADP is inhibited, as a function of the concentration, with an IC50 of 0.26 0.65 nM.

BM 13 177 inhibits, as a function of the concentration, the platelet aggregation induced by U 46 619 and the shape change. The IC50 for the aggregation is 1.65 - 6.6 μΜ, and that for shape change is 1.65 - 3.3 μΜ.

The 2nd wave of aggregation induced by ADP is inhibited, as a function of the concentration, with an IC50 of 0.33 0.66 μΜ.

Combination of thromboxane receptor antagonist and iloprost The platelet aggregation induced by U 46 619 and the platelet shape change, and the 2nd wave of aggregation induced by ADP are greatly inhibited by the combination of BM 13 177 with iloprost at concentrations of the two active substances that are in the threshold or subthreshold range. The inhibiting effects of the two active substances potentiate each other here (see Table).

Tables Example 1: Aggregation by 100 ng/ml U 46 619 active substance concentration % inhibition 1 BM 13 177 0.66 μΜ 16 % 2 iloprost 0.1 ng/ml 2 % 1 + 2 65 % Example 2: Shape change by 50 ng/ml U 46 619 active substance concentration % inhibition 1 BM 13 177 0.66 μΜ 28 % 2 iloprost 0.1 ng/ml no inhibition 1 + 2 61% Example 3: 2nd wave of aggregation by 0.5 x 10'6M ADP active substance concentration % inhibition 1 BM 13 177 0.165 μΜ no inhibition 2 iloprost 0.1 ng/ml no inhibition 1 + 2 60% 2. Intravasal thrombocyte aggregation in anaesthetised rats Method The influence on intravasal thrombocyte aggregation is investigated on urethane-anaesthetised rats.

Collagen (100 ug/kg i.v. bolus) produces transitory thrombocytopenia (a temporary decrease in blood platelet concentration), measured by continuous withdrawal of blood from the a. carotis (50 μΐ/min) and counting the thrombocytes in a Technicon-Autocounter. The change in collagen-induced thrombocytopenia (% decrease) in comparison with the starting value (= 2nd collagen injection) serves as a measure of the inhibition of intravasal platelet aggregation.

Results Iloprost (0.1 - 0.33 - 1.0 ug/kg/min) inhibits collageninduced thrombocytopenia as a function of the dose. BM 13 177 inhibits thrombocytopenia in the lowest dosage (0.5 mg/kg/min) by 27 ± 6% (MV + SE), an effect which cannot be increased by increasing the dose (1.0 - 2.0 mg/kg/min). The combination of a threshold dose of iloprost (0.1 ug/kg/min) with the lowest dose of BM 13 177 tested (0.5 mg/kg/min) produces a significantly t°< = 0.05; Lord test) more powerful inhibition of 45 ± 2% in respect of the individual doses. 3. Mesenteric arteriole thrombosis on anaesthetised guinea pigs Method A mesenteric loop is prepared for vital microscopy on anaesthetised guinea pigs. After electrical lesion of an arteriole, ADP is applied topically, under control conditions and after administration of the substance, until a thrombogenic dose is discovered (occlusion by platelet thrombus).

Parameters: Increase in the thrombogenic ADP concentration against the initial value; i.v. infusion of iloprost, i.v. injection of BM 13 177.

Results On the electrically predamaged mesenteric arterioles of anaesthetised guinea pigs, BM 13 177 (25 mg/kg i.v.) significantly increases, by about a factor of 4, the ADP concentration required to trigger occluding platelet thrombi. Iloprost increases the thrombogenic ADP concentration by a factor of 2.8 in the threshold dose 0.1 μg/kg/min i.v. A combination of BM 13 177 (25 mg/kg i.v.) followed by an i.v. infusion of iloprost (0.1 μg/kg/min) increases the thrombogenic ADP concentration by a factor of 12.

On an experimental model for arterial platelet-induced thrombosis, a combination of the TXA2 antagonist BM 13 177 and the prostacyclin analogue iloprost leads to a potentiated antithrombogenetic action.

Jugular vein thrombosis in anaesthetised rats Method The vessels are predamaged by loading the jugular vein of urethane-anaesthetised rats with a metal stamp cooled to -15°C (200 g, 2 min). The thrombus which grows at this point within 3 hours is quantified by determinations of its Hb content (difference between the damaged and undamaged vascular segment) (Hb content, moist weight).

Infusion of the test substances starts 15 min before the vein is damaged and is continued until the end of the experiment.

Results The infusion of iloprost in a dosage that is not significantly effective as an individual dose (30 ng/kg/min, i.v.) in combination with a dose of BM 13 177 that is also ineffective as monotherapy that has no haemodynamic or antiaggregatory action completely suppresses thrombus growth.

. Blood pressure of spontaneously hypertensive (SH) rats Method The behaviour of the blood pressure and heart rate under infusion of the test substances is observed on conscious SH rats in which a vein catheter is implanted for administration of the substance and an artery catheter is implanted for measurement of the blood pressure. Iloprost in a threshold dose of 0.3 gg/kg/min (20% reduction in the diastolic blood pressure) and a high dose of BM 13 177 of 2 mg/kg/min (see platelet inhibition in vivo. 27% inhibition at 2 mg/kg i.v. infusion) are infused together for 20 minutes (n = 6 animals).

Result The haemodynamic changes of drop in blood pressure and increase in heart rate caused by iloprost are only slightly influenced by BM 13 177.

Whilst the maximum reduction in blood pressure under iloprost is not influenced by BM 13 177, the action subsides more rapidly after the end of the infusion under the combination treatment.

An intensification in the anti-hypertensive action of iloprost by BM 13 177 must not be expected even at high dosages of BM 13 177.

Claims (14)

1. Combination product for combined administration in thrombotic and thrombo-embolic syndromes, containing prostacyclin, a prostacyclin analogue or a prostaglandin (PC/PCA/PG) and a thromboxane receptor antagonist (TXAA).

2. Product according to claim 1, characterised in that the PC/PCA/PG and TXAA are in a weight ratio of from 1:1 to 1:10,000.

3. Product according to claim 1, characterised in that the PC/PCA/PG and TXAA are present in separate dose units.

4. Product according to claim 1, characterised in that the PC/PCA/PG and TXAA are present together in one dose unit.

5. Product according to claim 1, characterised in that one PC/PCA/PG dose unit contains 25 - 250 pg of iloprost = 5( (E)- (IS,5S,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy4-methyl-l-octen-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene)pentanoic acid or a biologically equivalent amount of another PC/PCA/PG.

6. Product according to claim 1, characterised in that one TXAA dose unit contains 50 - 1000 mg of BM 13 177 = 4[2-(benzenesulphonamido)-ethyl]-phenoxyacetic acid or a biologically equivalent amount of another TXAA.

7. Use of PC/PCA/PG and TXAA for the manufacture of medicaments for simultaneous separate or time-lapsed administration for the treatment of thrombotic or thrombo-embolic syndromes.

8. Use of PC/PCA/PG and TXAA present in one dose unit for the manufacture of medicaments for administration in the treatment of thrombotic or thrombo-embolic syndromes.

9. Use of PC/PCA/PG and TXAA for the manufacture of medicaments according to claim 7 or 8, characterised in that the PC/PCA/PG and TXAA are in a weight ratio of from 1:1 to 1:10,000.

10. Use of 25 - 250 ug of iloprost = 5-{(E)-{IS,5S,6R,7R)-7hydroxy-6- [ ( E) - ( 3S, 4RS )-3-hydroxy-4-methyl-l-octen-6ynyl]-bicyclo[3.3.0]octan-3-ylidene}-pentanoic acid as the PC/PCA/PG or a biologically equivalent amount of another PC/PCA/PG for the manufacture of medicaments according to claim 7 or 8.

11. Use of 50 - 1000 mg of BM 13 177 = 4-[2-(benzenesulphonamido)-ethyl]-phenoxyacetic acid as the TXAA or a biologically equivalent amount of another TXAA for the manufacture of medicaments according to claim 7 or 8.

12. Use of PC/PCA/PG and TXAA for the manufacture of medicaments for sequential administration of avoid attentuation of the platelet aggregation inhibiting action in the treatment of thrombotic and thrombo-embolic syndromes.

13. A combination product substantially as hereinbefore described with reference to the Examples.

14. Use of PC/PCA/PG substantially as hereinbefore described with reference to the Examples.