WO1992006713A1

WO1992006713A1 - Pharmaceutical composition containing an ace inhibitor and an inhibitor of thromboxane a2 activity for treating nephropathies

Info

Publication number: WO1992006713A1
Application number: PCT/EP1991/001972
Authority: WO
Inventors: Patricia Salvati; Teresa Micheletti; Paolo Cozzi
Original assignee: Farmitalia Carlo Erba Srl
Priority date: 1990-10-16
Filing date: 1991-10-16
Publication date: 1992-04-30
Also published as: ZA918038B; JPH06501943A; IL99667A0; IT9021757A1; IE913585A1; AU8725191A; EP0556204A1; IT9021757A0; PT99238A

Abstract

A pharmaceutical composition containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A2 activity, or a pharmaceutically acceptable salt thereof, is useful in the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome.

Description

Pharmaceutical composition containing an ACE inhibitor and an inhibitor of thromboxane A2 activity for treating nephropathies.

The present invention relates to a product containing an angiotensin converting enzyme inhibitor (ACEI) and an inhibitor of thromboxane activity, useful in the treatment of nephropathies.

The use of inhibitors of the enzyme converting angiotensin I into angiotensin II (ACEI) in the treatment of hypertension is well consolidated. Of recent, these drugs have also been found to be useful in decreasing proteinuria of the various forms of renal desease both in animals and in man [Nutritional and Pharmacological Strategies in Chronic Renal Failure. Contrib. Nephrol. Basel. Karger, 1990, vol 81, pp. 240-247; Kidney International, Vol. 31 (1987), pp 752-759].

However, it has been observed that prolonged administration of these inhibitors in the treatment of nephropathies at therapeutically effective doses is deleterious, especially in patients with vascular hypertension caused by stenosis of one or both of the renal arteries. In fact, prolonged inhibition of the formation of angiotensin II can lead to significant deterioration of renal function. [Ferguson R. K., Vlasses P. H., eds. Angiotensin-converting enzyme inhibitors. Mount Kisco, NY: Futura Publishing, 1987:65-67; Am. J. Med. 1984; 77:43-51].

For these reasons it would be useful to reduce the dosage of ACE inhibitors during long-term treatment of nephropathies.

It has now been found that nephropathies in mammals, including man, can be treated by the combined use of an agent capable of inhibiting thromboxane A₂ activity and an ACEI, at lower doses of ACEI, otherwise not therapeutically effective. It has also been found that with the combined use of an agent capable of inhibiting thromboxane activity and an ACEI, it is possible to obtain a therapeutic effect greater than that otherwise obtainable with the single agents when administered alone.

A first object of the present invention is therefore a pharmaceutical composition containing an ACEI and an inhibitor of thromboxane A₂ activity, and a pharmaceutically acceptable carrier and /or diluent, useful in the treatment of nephropathies. An object of the instant invention is also the use of an ACEI and of an inhibitor of thromboxane A₂ activity in the preparation of a pharmaceutical composition useful in the treatment of nephropathies .

A further object of the present invention is a product containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A₂ activity as a combined preparation for simultaneous , separate or sequential use in the treatment of nephropathies .

Object of the present invention is also a combined method of treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome in mammals , including humans , in need of such treatment, said method comprising administering

1) an angiotensin converting enzyme inhibitor (or a pharmaceutical composition containing it) and

2) an inhibitor of thomboxane A„ activity (or a pharmaceutical composition containing it) , in amounts and close enough together in time sufficient to effect a useful therapeutical interaction .

The term "combined" method of treatment is meant to include both separate and substantially simultaneous administration of an ACEI or a pharmaceutical composition containing it and an inhibitor of thomboxane activity or a pharmaceutical composition containing it.

Examples of nephropathies that can be treated according to the present invention are diabetic nephropathy, nephropathy secondary to lupus erithematosus , gloraerulosclerosis, Cyclosporin-A induced nephrosis, renal damages secondary to CHF (congestive heart failure) and the several forms of glomerular and tubular damages associated with proteinuria. Moreover, the products, according to the present invention, can be useful in the treatment of hyperlipidaemia secondary to nephrotic syndrome.

The term "inhibitor of thromboxane A₂ activity" is meant to comprise both thromboxane synthase inhibitors, thromboxane receptor antagonists and compounds endowed with both said mechanisms of action.

Examples of inhibitors of thromboxane synthetase in accordance with the present invention, are for instance the imidazole derivatives described in the English patent GB-B-2122997 , International patent application WO 90 0 3970 and English patent application GB 9004347.2. Accordingly, preferred compounds among those described in CB-B-2122997 and WO 9003970 are those of following formula (I)

wherein n is 0 or 1; R is COR₁, in which R₁ is OH, NH₂ or OR₂ wherein R₂ is C₁-C₄ alkyl;

A is a group C wherein R₂ is hydrogen or C₁-C₄ alkyl, or a

group and the pharmaceutically acceptable salts thereof.

Specific examples of compounds of formula (I) are:

5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid (FCE 22178); ethyl 5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylate;

7,8-dihydro-6-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid;

5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxamide;

5,6-dihydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphtalenecarboxylic acid;

5,6-dihydro-8-ethyl-7-(1H-imidazol-1-yl)-2-naphtalenecarboxylic acid;

5,6-dihydro-7-(1H-imidazol-1-ylmethyl)-8-methyl-2-naphthalenecarboxylic acid; 5,6,7,8-tetrahydro-7-(1H-imidazol-1-ylmethyl)-8-methyl-2-naphthalene- carboxylic acid;

ethyl 5,6-dihydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphthalene- carboxylate;

5,6-dihydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxamide; ethyl 5,6-dihydro-7-(1H-imidazol-1-ylmethyI)-8-methyl-2-naphthalene- carboxylate;

5,6-dihydro-8-ethyl-7-(1H-imidazol-1-ylmethyl)-2-naphthalenecarboxylic acid; and

7,8-dihydro-6-(1H-imidazol-1-ylmethyl)-5-methyl-2-naphthalenecarboxylic acid; and the pharmaceutically acceptable salts thereof.

Preferred compounds among those described in the English patent application N_o 9004347.2, are those of formula (II)

(II)

wherein Z is -CH₂-,-CH(CH₃)-, -CH₂-CH₂- or -CH(CH₂Ph)- in which

Ph means phenyl optionally substituted by a halogen atom;

R₃ is C₃-C₇ alkyl; a phenyl, pyridyl or thienyl ring unsubstituted or substituted by halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy or trifluoromethyl; or a cyclohexyl or cycloheptyl ring;

T is a C₂-C₄ alkylene or phenylene group

x is a bond or a -O-CH₂ group;

R₄ is hydrogen or C₁-C₄ alkyl and the pharmaceutically salts thereof.

Specific examples of compounds of formula (II) are: 5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid; ethyl 5-[1-(3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene] aminoxypentanoate;

5-[1-(3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene]

aminoxypentanoic acid;

5-[1-(3-bromophenyl)-2(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

3-oxa-5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

3-oxa-5-[1-(3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene] aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yl)ethyIidene]aminoxypentanoic acid;

5-[1-phenyl-2-(imidazol-1-yl)-2-methylethylidene]aminoxypentanoic acid;

5-[1-(n-hexyI)-2-(imidazol-1-yI)ethyIidene]aminoxypentanoic acid;

3-oxa-5-[1-cyclohexyl-2-(imidazol-1-yI)ethyIidene]aminoxypentanoic acid;

5-[1-n-heptyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

5-[1-phenyI-2-(imidazol-1-yI)-2-benzylethyIidene]aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yl)-2-benzylethylidene]aminoxypentanoic acid; ethyl 5-[1-phenyl-2-imidazol-1-yI)-2-benzylethylidene]aminoxypentanoate; ethyl 5-[1-cyclohexyl-2-(imidazol-1-yI)-2-benzylethylidene]aminoxypentanoate; 5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)-2-(4-fluorobenzyl)ethylidene] aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yl)-2-(4-fluorobenzyl)ethylidene]

aminoxypentanoic acid; and

3-oxa-5-[1-phenyl-2-(imidazol-1-yl)-2-benzylethylidene]aminoxypentanoic acid; and pharmaceutically acceptable salts thereof.

Further examples of inhibitors of thromboxane synthetase, in accordance with the present invention, are imidazo [1,5-a] pyridine-5-hexanoic acid [Ku et al. Biophys. Res. Comm. 112 (3)-889, 1983], RS-5186 (Thrombosis research, 51, 507, 1988): DP-1904 (J. Med. Chem. 32, 1326, 1989): and (E)-3,4-(1-imidazolylmethyl)phenyl-2-propenoic acid and their pharmaceutically acceptable salts.

Examples of antagonists of thromboxane receptors, in accordance with the present invention are:

EP045 and EP092 (Armstrong et al., Br. J. Pharmacol. 84,595, 1985), 4-[2-(4-chloro-benzensulfonamido)-ethyl] phenylacetic acid (U. S.

4,443,477), 4-[2-(phenylsulphonylamino-ethyl] phenoxyacetic acid (U. S. 4,258,058); 5029548 (Ogletree et al., J. Pharmacol. Exp. Ther. 234, 435, 1985); ONO 3708 (Kutsura et al., Adv. pros. Thromb. LK. res. 11, 351, 1983); Bayu-3405 ( Arzneimittel Forshung 39 (II) (12), 1525, 1989); GR-32191 (Circulation 80 (11), PO 197, 1989); S-145 (Thrombosis Research 50,365, 1988); and L-655240 (Eur. J. Pharmacol. 135, 193, 1987), and their pharmaceutically acceptable salts.

Examples of ACEI, in accordance with the present invention are those described in EP-A-161801 and in EP-A-240366; in particular (+)-[(2S,6R)-6[(S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2-(2- thienyl) perhydro-1-thiazepin-4-yl] acetic acid (CS-622) and their pharmaceutically acceptable salts. Other examples of ACEI are the following: captopril ( Ondetti et al. , Science, 196 , 441 , 1977) , benazepril ( Schaller et al. , Eur. J . Clin . Pharra. 28 , 267 , 1985) , enalapril (Patchett et al. , Nature , 288 , 280 , 1980) , indolapril (Ryan et al. , J . Pharmac. Exp . Ther. 288 , 312 , 1983) , lisinopril (Haeq et al. , Kidney Int. , Vol. 36 , 272 , 1987) , delapril, alacepril, cilazapril, spirapril and their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the inhibitors of thromboxane activity and of ACEI, in accordance with the present invention, are the salts with physiologically acceptable bases and /or acids as well known to experts in the art of pharmaceutical technique.

The usefulness of the combined use of an agent capable of inhibiting thromboxane A2 activity with an ACEI in nephropathic treatment , in accordance with the present invention, has been tested for example by the following experimental data which illustrate but in no way intend limiting the scope of the present invention .

In order to test the afore-mentioned working hypothesis we developed an experimental model of nephropathy (MNS rats) which leads to spontaneous glomerulosclerosis , whose severity is related to age. In this model histologic damage is accompanied by severe proteinuria and deterioration of renal fuction.

We also demonstrated that an excessive intrarenal production of thromboxane plays a pivotal role in the development of renal pathology in MNS rats .

10-month-old MNS rats (at this age renal damage and proteinuria are already present) were treated as follows:

Group 1 : with the inhibitor of thromboxane synthase FCE 22178 (300 mg/kg p.o. , n=10) .

Group 2 : with a low dose of ACEI CS-622 not capable of lowering systemic arterial pressure in the normotensive animals (3 mg/kg p.o., n = 10).

Group 3: with a combination of the two compounds (FCE 22178, 300

mg/kg p.o. + CS-622 3 mg/kg p.o., n=9).

Croup 4: control animals received only the vehicle, i.e. water, n=13).

The results obtained show that both FCE 22178 and CS-622 lower proteinuria observed in controls (470 + 35 mg/day, mean + SEM) when administered separately:

CS-622 = 17 ± 6%

FCE 22178 = 28 ± 5% but the two products administered in combination produce a greater reduction:

CS-622 + FCE 22178 = 49 ± 7%.

This effect occurs without modification of the hemodynamic parameters, i.e. systemic arterial pressure, total renal flow and glomerular filtration rate.

The control animals also showed hyperlidemia with high cholesterol (264 ± 11 mg/dl) and triglyceride (285 ± 36 mg/dl) values.

These values were reduced in the group that had received PCE 22178 alone (19.4% and 51.2% respectively) and in the group that received the combination (27.1% and 56% respectively). No effect was observed in the group given the ACEI, CS-622 alone.

These results show that it is possible to significantly reduce (49%) proteinuria combining a low dose of ACEI and an inhibitor of thromboxane synthase given at a dosage that inhibits the thromboxane- synthetase enzyme completely for 24 hours.

In addition, the combination has a beneficial effect on secondary hyperlipidemia which is not achieved with an ACEI alone.

The doses of ACEI and inhibitor of the thromboxane activity which can be administered in accordance with the present invention obviously depends on several factors, e.g. the administration route and the disease to be treated. In particular the exact dosage must be chosen on the basis of specific conditions of the patient under treatment in order to ensure the most suitable blood levels.

The dosage of the ACEI is suitably in the range from about 0.1 mg to about 300 mg p.o. per day, for example from about 0.5 mg to about 200 mg p.o. per day. The dosage of the thromboxane A₂ inhibitor is suitably in the range from about 10 mg to about 3000 mg p.o. per day, for example from about 50 mg to about 2000 mg p.o. per day. For example, in the case of the ACEI captopril, the drug can be administered to an adult at doses ranging between about 20 and about 100 mg p.o. per day. In the case of enalapril between about 2.5 and about 20 mg p.o., 1 to 3 tiroes per day. In the case of CS-622 at doses ranging between about 0.5 to about 8 mg p.o. 1 or 2 times per day. In the case of the inhibitor of thromboxane activity FCE 22178, the oral dose in an adult can vary from about 100 mg to about 800 mg per dose 1 to 3 times per day.

The pharmaceutical formulations of the present invention suitable for the oral administration can be prepared in the form of capsules, sugar- coated tablets, each containing a preestablished amount of active principle; or in the form of powder or granulates; or as solutions or suspensions in an aqueous or non aqueous liquid; or in the form of oil- in-water or water-in-oil emulsions.

The solutions or suspensions for subcutaneous administration can contain along with the active principle a pharmaceutically acceptable excipient and/or vehicle e.g. sterile water, olive oil, ethyl oleate, glycols, such as propylenic glycol.

The suppositories can contain along with the active principle a pharmaceutically acceptable vehicle such as cocoa butter, polyethylenic glycol or lecithin. The following examples illustrate but do not intend limiting the present invention.

Example 1, capsules (100 mg)

5 ,6-dihydro-7-(1H-imidazolyl)-2-naphthalenecarboxylic acid 100 mg lactose 248 mg corn starch 50 mg magnesium stearate 2 mg

_______

Total 400 mg

Incapsulated in hard head-body gelatin capsules .

Example 2 , film-coated tablets (2 mg)

According to the usual pharmaceutical technique the follwing pharmaceutical preparation can be obtained

(+)-{(2S , 6R)-6[ (S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2-( 2- thienyl) perhydro-1-thiazepin-4-yl} acetic acid 2.0 mg low substituted hydroxypropylcellulose 12.0 mg hydroxypropylcellulose 4.5 mg lactose 100.3 mg magnesium stearate 1 .2 mg titanium oxide 0.7 mg talc 0.7 mg hydroxypropylmethylcellulose 3.6 mg

------------ total 125.0 mg

Claims

1) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as active agents, an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A₂

activity.

2) A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is a compound of formula (I)

wherein n is 0 or 1;

R is COR₁, in which R₁ is OH NH₂ or OR₂ wherein R₂ is C₁-C₄ alkyl;

A is a group wherein R₂ is hydrogen or C₁-C₄ alkyl, or

a group , or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is a compound of formula (II)

(II)

wherein Z is -CH₂-, -CH(CH₃)-, -CH₂-CH₂- or -CH₂(CH₂ Ph)- in which Ph means phenyl optionally substituted by a halogen atom; R₃ is C₅-C₇ alkyl; a phenyl, pyridyl or thienyl ring unsubstituted or substituted by halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy or trifluoromethyl; or a cyclohexyl or cycloheptyl ring;

T is a C₂-C₄ alkylene or phenylene group;

X is a bond or a -O-CH₂ group;

R₄ is hydrogen or C₁-C₄ alkyl or a pharmaceutically salt thereof.

4. A pharmaceutical composition according to claim 1, wherein the inhibitor of thromboxane activity is selected from imidazo [1,5-a] pyridine-5-hexanoic acid, RS5186, DP1904 and (E)-3,4-(1-imidazolyl- methyl)phenyl-2-propenoic acid or a pharmaceutically acceptable salt thereof.

5. A pharmaceutically composition, according to claim 1, wherein the inhibitor of thromboxane activity is selected from EP045, EP092 4-[2-(4-chloro-benzensulfonamido)-ethyl] phenylacetic acid, 4-[2- -(phenylsulphonylamino-ethyl] phenoxyacetic acid, 5029-548, ONO 3708, Bayu-3405, GR-32191, L-655240 and S-145 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, according to claim 1, wherein the agiotensin converting enzyme inhibitor is selected from (+)-{(2S, 6R)-6[(S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2-(2- thienyl) perhydro-1-thiazepin-4-yl} acetic acid (CS-622), captopril, elanapril, indolapril, lisinopril, spiraprilat, spirapril, delapril, alacepril and cilazapril or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is selected from:

5,6-dihydro-7-(1H-imidazol-yl)-2-naphthalenecarboxylic acid (FCE 22128; ethyl 5,5-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylate;

7,8-dihydro-6-(1H-imidazol-1-yl)-2-naphthalenecarboxyclic acid;

5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxamide;

5,6-dihydro-7(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxylic acid;

5,6-dihydro-8-ethyl-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid;

5,6-dihydro-7-(1H-imidazol-1-ylmethyl)-3-methyl-2-naphtnalene- carboxylic acid;

5,6,7,8-tetrahydro-7-(1H-imidazol-1-yI-methyl)-3-methyl-2- naphthalenecarboxylic acid; ethyl 5,6-dihydro-7-(1H-imidazol-1-yI)-3-methyl-2-naphthalene- carboxylate;

5,6-dihydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphthalene-carboxamide; ethyl 5,6-dihydro-7-(1H-imidazol-1-yl-methyl)-8-methyl-2- naphthalenecarboxylate;

5,6-dihydro-8-ethyl-7-(1H-imidazol-1-yl-methyl)-2naphthalene- carboxylic acid;

7,8-dihydro-6-(1H-imidazol-1-yl-methyl)-5-methyl-2-naphthalene- carboxylic acid;

5-[1-pheny1-2-(imidazol-1-yI)ethylidene]aminoxypentanoic acid; ethyl 5-[1-(3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene] aminoxypentanoate;

5-[1-(3-bromophenyl)-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

3-oxa-5-[1-phenyl-2-(imidazol-1-yI)ethylidene]aminoxypentanoic acid;

3-oxa-5-[1-[3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene] aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

5-[1-phenyl-2-(imidazol-1-yl)-2-methylethylidene]aminoxypentanoic acid;

5-[1-(n-hexyl)-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

3-oxa-5-[1-cyclohexyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid;

5-[1-n-heptyl-2-(imidazol-1-yI)ethylidene]aminoxypentanoic acid;

5-[1-phenyl-2-(imidazol-1-yI)-2-benzylethylidene]aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yI)-2-benzylethyIidene]aminoxypentanoic acid; ethyl 5-[1-phenyl-2-imidazol-1-yI)-2-benzylethylidene]aminoxypentanoate; ethyl 5-[1-cyclohexyI-2-(imidazol-1-yI)-2-benzylethyIidene]aminoxypentanoate; 5-[1-(4-fluorophenyl)-2-(imidasol-1-yl)-2-(4-fluorobenzyl)

ethylidene]aminoxypentanoic acid;

5-[1-cyclohexyl-2-(imidazol-1-yl)-2-(4-fluorobenzyl)ethylidene] aminoxypentanoic acid; and

3-oxa-5-[1-phenyl-2-(imidazol-1-yl)-2-benzylethylidene]aminoxy- pentanoic acid; or a pharmaceutically acceptable salt thereof.

8. The use of an ACEI and an inhibitor of thromboxane A₂ activity in the preparation of a medicament for use in the

treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome.

9. Products containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A₂ activity as a combined preparation for simultaneous, separate or sequential use in the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome.

10. Products according to claim 9, wherein the inhibitor of

thromboxane A₂ is 5,6-dihydro-7-(1H-imidazolyl)-2-naphthalenecarboxylic acid and the angiotensin converting enzyme inhibitor is (+)-{2S,6R)-5[(S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2- -(2-thienyl) perhydro-1-thiazepin-4-yl} acetic acid, or a pharmaceutically acceptable salt thereof.

11. An agent for the treatment of nephropathies and

hyperlipidaemia secondary to nephrotic syndrome

comprising a pharmaceutically acceptable carrier or diluent and, as active agents, an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A₂ activity in a quantity producing a synergistic

therapeutic effect.

12. A method of treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome, the method comprising administering to a patient in need of such treatment;

(1) an agent selected from an angiotensin converting enzyme inhibitor and a pharmaceutical composition comprising such an inhibitor, and

(2) an agent selected from an inhibitor of thromboxane A₂ activity and a pharmaceutical composition comprising such an inhibitor, the said agents being administered simultaneously or sequentially and in such amounts that a synergistic therapeutic effect is achieved.

13. A method of treatment, of nephropathies and hyperlipidaemia secondary to nephrotic syndrome, the method comprising administering to a patient in need of such treatment;

(2) an agent selected from an inhibitor of thromboxane A₂ activity and a pharmaceutical composition comprising such an inhibitor, the said agents being administered in amounts and close enough together in time to effect a useful therapeutic interaction.

14. An agent for use in treating nephropathies and hyperlipidaemia secondary to nephrotic syndrome comprising an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A₂ activity.