GB2241890A - Preventing onset of or treating protein catabolism using an ace inhibitor - Google Patents

Abstract

A method is provided for preventing onset of or treating protein catabolism in hypertensive or normotensive patients and thereby preventing loss of muscle mass in such patients by administering an ACE inhibitor, especially one containing a mercapto moiety, such as captopril or zofenopril, as well as fosinopril.

Description

METHOD FOR PREVENTING ONSET OF OR TREATING PROTEIN CATABOL1SM The present invention relates to a method for preventing onset of or treating protein catabolism by administering an ACE inhibitor, for example an ACE inhibitor containing a mercapto moiety, such as captopril or zofenopril.

Bradykinin, a vasodilator, is known to improve carbohydrate and lipid metabolism of skeletal muscles and increases amino-acid metabolism as well as balance of oxygen.

Zusman, R.M., "Effects of Converting-Enzyme Inhibitors on the Renin-Angiotensin-Aldosterone, Bradykinin, and Arachidonic Acid-Prostaglandin Systems: Correlation of Chemical Structure and Biologic Activity," Am. J. Kid. Dis., Vol. X, No.

1 Suppl. 1 (July), 1987: pp 13-23 discloses that captopril stimulates prostaglandin production. At page 18, column 1, Zusman states that "although captopril has no significant effect on plasma bradykinin concentrations, Vinci and co-workers [Hypertension, 1:416-426, 1979] noted a significant increase in urinary kinin excretion in those patients experiencing a drop in B.P. Thus, although bradykinin concentrations were unaffected in plasma, the authors did observe an increase in bradykinin levels in tissue where kinins can potentially stimulate endogenous prostaglandin biosynthesis." Zusman found that enalapril and enalaprilic acid (which do not contain a sulfhydryl group) had no effect on prostaglandin biosynthesis.

Hartl, W.H. et al, "Effect of low-dose bradykinin on glucose metabolism and nitrogen balance in surgical patients," Lancet, Jan. 13, 1990, pp 69-71, disclose that low-dose bradykinin (30 ng/kg per minute) infusion in surgical patients caused a a significantly improved rate of nitrogen retention and significantly better nutritional indices.

Hartl et al, supra, at page 13, disclose that "the metabolic response to surgical trauma is associated with negative nitrogen balance, caused by insufficient compensation by protein synthesis for accelerated proteolysis" and cites Wolfe R.R., et al, "Protein and amino acid metabolism after injury," Diabetes Metab. Rev., 1989; 5:149-64.

Hartl et al, supra, further state that prostaglandins might have a beneficial effect on glycolysis, glucose oxidation, and protein synthesis without accelerating protein degradation...." Prostaglandin synthesis can be stimulated locally by intravenous infusion of bradykinin. The metabolic effects of bradykinin infusion can be attributed to stimulation of prostaglandin synthesis." Gunther, B., et al, "Hemmung der postoperativen Katabolie durch Bradykinin," Chirurg 50, 108110 (1979), disclose that during infusion of bradykinin (80 pg/h for 24 h), nitrogen balance was significantly improved in postoperative surgical patients.

Jauch, K. W., et al, "Bradykinin Anabolic Mediator in Total Parenteral Nutrition," Clinical Nutrition, Vol. 7 Special Supplement, Aug., 1988, disclose that bradykinin improves glucose flux and metabolism and nitrogen balance in postoperative patients.

U.S. Patent Nos. 4,046,889 and 4,105,776 to Ondetti et al disclose proline derivatives, including captopril, which are angiotensin converting enzyme (ACE) inhibitors useful for treating hypertension.

U.S. Patent No. 4,337,201 to Petrillo discloses phosphinylalkanoyl substituted prolines, including fosinopril, which are ACE inhibitors useful for treating hypertension.

U.S. Patent No. 4,374,829 discloses carboxyalkyl dipeptide derivatives, including enalapril, which are ACE inhibitors useful for treating hypertension.

U.S. Patent No. 4,452,790 to Karanewsky et al discloses phosphonate substituted amino or imino acids and salts thereof and covers (S)-1 [6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]- oxy]-l-oxohexyl]-L-proline (SQ 29,852, ceranapril).

These compounds are ACE inhibitors useful in treating hypertension.

U.S. Patent No. 4,316,906 to Ondetti et al discloses ether and thioether mercaptoacyl prolines which are ACE inhibitors useful in treating hypertension. This Ondetti et al patent covers zofenopril.

It has now been found that angiotensin converting enzyme inhibitors, especially mercapto containing ACE inhibitors such as captopril and zofenopril, a-.e capable of preventing onset of or treating protein catabolism in hypertensive patients and in normotensive patients.

In accordance with the present invention, a method is provided for preventing onset of or treating protein metabolism, in mammalian species, wherein a therapeuticallq effective amount of angiotensin converting enzyme inhibitor is administered systemically, such as orally or parenterally.

The ACE inhibitor may be administered to hypertensive patients or normotensive patients suffering from or to prevent protein catabolism, in accordance with the method of the present invention.

The method of the invention will be carried out to prevent or treat protein catabolism, for example, as brought on by postoperative protein catabolism, as well as to treat patients with postaggression syndrome (loss of muscle mass), patients with impaired glucose tolerance, obese patients as well as normotensives having postoperative or other insulin resistance, patients on protein or nutritional restricted diets such as nephrotic patients, and patients with impaired muscle metabolism and other catabolic conditions, and also to treat immobilized patients. The method of the invention will also be effective in promoting wound healing such as in burn victims, and diabetes patients and postsurgical patients, and immobilized patients, such as those suffering from bed sores or ulcers.

The term "postoperative insulin resistance" as employed herein refers to a condition wherein higher than normal insulin concentrations are required to maintain normal glucose levels, due to a disturbance in aminc-acd balance and glucose metabolism in skeletal muscle.

In preferred embodiments where the patient to be treated in accordance with the present invention is normotensive, the angiotensin converting enzyme inhibitor will preferably be administered in amounts below that required to cause hemodynamic effects, that is below that required to cause a reduction in blood pressure.

Where the patient to be treated is hypertensive, then the angiotensin converting enzyme inhibitor will be employed in amounts usually employed to treat hypertension.

The term "postoperative protein catabolism" as employed herein refers to surgical patients having a decrease in bradykinin levels and a negative nitrogen balance, caused by insufficient compensation by protein synthesis for accelerated proteolysis; the result is a loss of protein and therefore a loss of skeletal muscle mass.

The angiotensin converting enzyme inhibitor which may be employed herein will include those containing a mercapto (-S-) moiety such as substituted proline derivatives, such as any of those disclosed in U. S. Patent No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, l-[ (25)-3-mercapto-2-methylpropionylj-L-proline, being preferred, and mercaptoacyl derivatives of substituted prolines such as any of those disclosed in U. S. Patent No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may be employed herein include rentiapril (fentiapril, Santen) disclosed in Clin.

Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril, that is

and Yes980, that is

Other examples of angiotensin converting enzyme inhibitors which may be employed herein include any of those disclosed in U.S. patent No. 4,374,829 mentioned above, with N-(l ethoxycarbonyl-3-phenylpropyl ) -L-alanyl-L-proline, that is, enalapril, being preferred, any of the phosphonate substituted amino or imino acids or salts disclosed in U. S. Patent No. 4,452,790 with (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)- phosphinyl]oxy]-l-oxohexyl]-L-proline (SQ 29,852 or ceranapril) being preferred, phosphinylalkanoyl prolines disclosed in U. S.Patent No. 4,168,267 mentioned above with fosinopril being preferred, any of the phosphinylalkanoyl substituted prolines disclosed in U. S. Patent No. 4,337,201, and the phosphonamidates disclosed in U. S. Patent No.

4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein include Beecham's BRL 36,378 as disclosed in European patent Nos. 80822 and 60668; Chugai's MC-838 disclosed in CA. 102:725rut and Jap. J. Pharmacol. 40:373 (1986); Ciba-(;eigy's CGS 14824 (3-([1-ethoxycarbonyl-3-phenyl-(lS)-propyl]- amino)-2,3,4,5-tetrahydro-2-oxo-1-(35)-benzazepine-1 acetic acid HC1) disclosed in U.K. Patent No.

2103614 and CGS 16,617 (3(S)-[[(1S)-5-amino- 1-carboxypentyl]amino]-2,3,4,5-tetrahyc;ro-2-oXo- lH-l-benzazepine-l-ethanoic acid) disclosed in U. S. Patent No. 4,473,575; cetapril (alacepril, Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986); ramipril (Hoechst) disclosed in Eur. Patent No. 79-022 and Curr.

Ther. Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung 35:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc. Pharmacol. 9:39 (1987); Ro 31-2201 (Hoffman-LaRoche) disclosed in FEBS Lett. 165:201 (1984); lisinopril (Merck) disclosed in Curr.

Therap. Res. 37:342 (1985) and Eur. patent appl.

No. 12-401, indalapril (delapril) disclosed in U. S. Patent No. 4,385,051; indolapril (Schering) disclosed in J. Cardiovasc. Pharmacol. 5:643, 655 (1983); spirapril (Schering) disclosed in Acta.

Pharmacol. Toxicol. 59 (Supp. 5):173 (1986); perindopril (Servier) disclosed in Eur. J. Clin.

Pharmacol. 31:519 (1987); quinapril (Warner-Lambert) disclosed in U. S. Patent No. 4,344,949 and CI 925 (Warner-Lambert) ([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1- (ethOxycarbonyl)-3-phenylpropyl]amino[-1-oxopropyl]- 1,2,3, 4-tetrahydro-6, 7-dimethoxy-3-isoquinoline- carboxylic acid HC1) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221 (Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred are those ACE inhibitors which are proline or substituted proline derivatives and most preferred are such ACE inhibitors which include a mercapto group, such as captopril and zofenopril as well as phosphorus containing ACE inhibitors such as fosinopril and ceranapril.

The above-mentioned U.S. patents are incorporated herein by reference.

In carrying out the method of the present invention, the angiotensin converting enzyme inhibitor may be administered to mammalian species, such as horses, cattle, dogs, cats, and humans, and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable, as well as suppository dosage forms that release ACE inhibitor in the bloodstream.

The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, bulking agent (such as mannitol), antioxidants (ascorbic acid of sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms such as intramuscular, intraperitoneal, or intravenous enema and suppository forms are quite satisfactory as well.

The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

Thus, for oral administration, a satisfactory result may be obtained employing the ACE inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 25 mg/kg.

A preferred oral dosage form , such as tablets or capsules, will contain the ACE inhibitor in an amount of from about 0.1 to about 500 mg, preferably from about 2 to about 200 mg, and more preferably from about 3 to about 150 mg.

For parenteral administration, the ACE inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.01 mg/kg to about 1 mg/kg.

The composition described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose and work up gradually to a high dose.

Tablets of various sizes can be prepared, e.g., of about 5 to 700 mg in total weight, containing the active substance in the range described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses.

Gelatin capsules can be similarly formulated.

Liquid formulations can also be prepared by dissolving or suspending the active substance in a conventional liquid vehicle acceptable for pharma ceutical administration so as to provide the desired dosage in one to four teaspoonfuls.

Such dosage forms can be administered to the patient on a regimen of one to four doses per day.

Suppository formulations containing from about 5 to about 250 mg ACE inhibitor may be prepared as well using a conventional suppository base (such as disclosed in U.S. Patent Nos.

4,344,968, 4,265,875, and 4,542,020) so as provide the desired dosage in one to four suppositories per day.

As indicated, where the patient to be treated is normotensive, then smaller amount of angiotensin converting enzyme inhibitor preferably will be employed, that is below that required to reduce blood pressure. For example, for oral dosage forms, normotensives may be treated with from about 0.01 mg/kg to about 1 mg/kg or from about 1 mg to about 6 mg, one to four times daily.

IS formulating the compositions, the active substances, in the amounts described above, are compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form.

Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as orange, peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both.A syrup of elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.

The formulations as described above will be administered for a prolonged period, that is, for as long as it is necessary to prevent onset of or to treat protein catabolism. Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. A dosing period of at least one to two weeks are required to achieve minimal benefit.

The following Examples represent preferred embodiments of the present invention.

Example 1 A captopril formulation suitable for oral administration in preventing onset of or treating protein catabolism in hypertensive or normotensive patients is set out below.

1000 tablets each containing 100 mg of 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline were produced from the following ingredients.

1-[(2S)-3-Mercapto-2-methylpropionyl]- L-proline (captopril) 100 g Corn starch 50 g Gelatin 7.5 g Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g The captopril and corn starch are admixed with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 100 mg of active ingredient which is used for preventing onset of or treating protein catabolism and preventing loss of muscle mass as described above, and promoting wound healing.

Example 2 1000 tablets each containing 200 mg of captopril are produced from the following ingredients: Captopril 200 g Lactose 100 g Avicel 150 g Corn starch 50 g Magnesium stearate 5g The captopril, lactose and Avicel are admixed, then blended with the corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg tablets each containing 200 mg of active ingredient. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6. The resulting tablets are useful in preventing onset of Type II diabetes in hypertensive or normotensive patients and preventing or treating protein catabolism and preventing loss of muscle mass in such patients, and promoting wound healing.

Example 3 Two piece #1 gelatin capsules each containing 5 mg of fosinopril are filled with a mixture of the following ingredients: Fosinopril 5 mg Magnesium stearate 7 mg USP lactose 193 mg.

The resulting capsules are useful in preventing onset of or treating protein catabolism in normotensive patients and preventing loss of muscle mass in such patients, and promoting wound healing.

Example 4 An injectable solution for use in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass in such patients.

Captopril 500 mg Methyl paraben 5 mg Propyl paraben 1 mg Sodium chloride 25 g Water for injection qs. 5 1.

The captopril, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into presterilized vials which are then closed with presterilized rubber closures. Each vial contains 5 ml of solution in a concentration of 100 mg of active ingredient per ml of solution for injection.

Example 5 to 8 Dosage forms for use in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass in such patients and promoting wound healing are prepared as described in Examples 1 to 4 except that N- (l-ethoxycarbonyl-3-phenylpropyl )-L-alanyl-L- proline (enalapril) is used in place of captopril.

Example 9 and 10 A suppository formulation containing conventional suppository base such as any of those disclosed in U.S. Patent Nos. 4,344,968, 4,265,875 or 4,542,020, and N-(l-ethoxy-carbonyl-3-phenylpropyl)-L-alanyl-L-proline (40 mg), (enalapril) or captopril (25 mg), is prepared and is used to prevent onset of or treat protein catabolism in hypertensive or normotensive patients and prevent loss of muscle mass in such patients and promoting wound healing.

Example 11 A zofenopril formulation suitable for oral administration in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass in such pat:.ents and promoting would healing is set out below.

1000 tablets each containing 100 mg of zofencI)ril are produced from the following ingreC1:ents.

[1( > ;,4(S)]-1-[3-(benzoylthio)-2- methyl-l-oxopropyl-4- (phenylthio )- L-proline (zofenopril) 100 g Corn starch 50 g Gelatin 7.5 g Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g The zofenopril and corn starch are admixed with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 100 mg of active ingredient which is used for treating or preventing onset of protein catabolism in hypertensive or normotensive patients and thereby prevent ing loss of muscle mass and promoting wound healing in such patients as described above.

Example 12 A modified release beadlet formulation capable of slowly releasing the angiotensin converting enzyme inhibitor captopril over a period of up to 6 hours and having the following composition was prepared as described below.

Amount in Ingredient Parts by Weight Captopril 27 Citric aicd 30 Microcrystalline cellulose* 43 *amount may =r-,ry to reflect chemical purity of captopril The above ingredients were mixed and kneaded using water in a planetary mixer to form a wet mass. The wet mass was passed through a Nica E140 extruder to form an extrudate (al mm diameter).

The extrudate was then passed through a Nica spheronizer to form beadlets. The beadlets were then dried at 400C for 12-18 hours in a tray drying oven or for 2-4 hours in a fluid bed dryer. A fraction of the so-formed beadlets were filled into hard shell pharmaceutical capsules for use in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Example 13 A modified release coated-beadlet formulation having the following composition was prepared as follows.

(i) Core mg/dose Captopril 5 mg Microcrystalline cellulose 159.1 mg Citric acid 37. mg Lactose 74.1 mg (ii) Sealcoat Hydroxypropyl methyl ca. 8.3 mg cellulose Polyethylene glycol ca. 2.8 mg (iii) Barriercoat Cellulose acetate ca. 4.2 mg phthalate Acetylated monogly- ca. 1.3 mg cerides (Myvacet@9-40) The beadlet cores were prepared as described in Example 12. After the dried beadlets were formed, they were coated via a two step process as follows. An aqueous solution of hydroxypropyl methyl cellulose (7.5% by weight) and polyethylene glycol (2.5% by weight) was prepared and sprayed on to the beadlets to form a sealcoat. The beadlets were then coated with a barriercoat using an aqueous dispersion of cellulose acetate phthalate (30% by weight) mixed with acetylated monoglycerides (9.5% by weight).The beadlets were then filled into hard shell pharmaceutical capsules which are useful in preventing onset of or treating protein catabolism in normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Example 14 A modified release coated-beadlet formulation having the following composition was prepared as follows.

% by Weight Ingredient of Coated Beadlet Core Captopril 26.2 Citric acid 29.1 Microcrystalline cellulose 41.8 Film coating Hydroxypropylmethyl cellulose ca. 2.6 phthalate triethyl citrate ca. 0.3 The beadlet cores were prepared as described in Example 12.

Hydroxypropylmethyl cellulose phthalate (9 parts) and triethylcitrate (1 part) were dissolved in ethyl alcohol (90 parts) and then sprayed on to the beadlets to form coated product. The so-formed beadlets were then filled into hard shell pharmaceutical capsules which are useful in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Examples 15 to 19 Following the procedure of Examples 13 to 15 except substituting the following ACE inhibitor, organic acid and binder-excipients, the following beadlet compositions may be prepared which are useful in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Ex.

No. ACE Inhibitor Organic acid Binder 15. N-(l-ethoxycar- Citric acid wicrocrys- bonyl-3-phenyl- talline propyl )-L-proline cellulose 16. (S)-l-[6-Amino-2- Malic acid Microcrys [[hydroxy(4-phenyl- talline butyl)phosphinyl]- cellulose oxyj-l-oxohexyl]-L- and hydroxy proline (ceranapril) propyl methyl cellulose 17. Lisinopril Tartaric acid Na carboxy methyl cellulose 18. Zofenopril Succinic acid Gelatin, pectin and Na carboxy methyl cellulose 19.Fosinopril Maleic acid Microcrys talline cellulose Example 20 By substituting 5 g of pivopril for the zofenopril in Example 11, 1000 tablets each containing 5 mg of the pivopril are produced which is useful in preventing onset of or treating protein catabolism in normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Example 21 1000 tablets each containing 200 mg of YS890 are produced from the following ingredients: YS890 200 g Lactose 100 g Avicel 150 g Corn starch 50 g Magnesium stearate 5 g The YS890, lactose and Avicel are admixed, then blended with the corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg tablets each containing 200 mg of active ingredient. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6. The resulting tablets are useful in preventing onset of or treating protein catabolism in hypertensive or normotensive patients and preventing loss of muscle mass and promoting wound healing in such patients.

Claims (27)

1. Use of an angiotensin converting enzyme inhibitor for the manufacture of a medicament for preventing onset of or treating protein catabolism in a mammalian specie.

2. Use of an angiotensin converting enzyme inhibitor for the manufacture of a medicament for preventing, or treating patients having, postoperative protein catabolism, postaggression syndrome, impaired glucose tolerance, postoperative or other insulin resistance or impaired muscle metabolism or for treating patients on protein or nutritional restricted diets.

3. The use as defined in claim 1 or 2 wherein the patient to be treated is immobilized.

4. The use as defined in claim 1, 2 or 3 wherein the angiotensin converting enzyme inhibitor is a mercapto containing ACE inhibitor.

5. The use as defined in any preceding claim wherein the angiotensin converting enzyme inhibitor is to be administered to a hypertensive patient.

6. The use as defined in any one of claims 1-4 wherein the angiotensin converting enzyme inhibitor is to be administered to a normotensive patient.

7. The use as defined in claim 6 wherein the angiotensin converting enzyme inhibitor is to be administered below that amount required to effect a reduction in blood pressure.

8. The use as defined in any preceding claim wherein said angiotensin converting enzyme inhibitor is to be administered orally or parenterally.

9. The use as defined in any preceding claim wherein the angiotensin converting enzyme inhibitor is a substituted proline derivative.

10. The use as defined in claim 9 wherein said angiotensin converting enzyme inhibitor includes a mercapto moiety and is a substituted proline derivative.

11. The use as defined in any one of claims 1-8 wherein said angiotensin converting enzyme inhibitor is captopril or zofenopril.

12. The use as defined in any one of claims 1-8 wherein said angiotensin converting enzyme inhibitor is fosinopril or ceranapril.

13. The use as defined in any one of claims 1-8 wherein said angiotensin converting enzyme inhibitor is fentiapril.

14. The use as defined in any one of claims 1-8 wherein the angiotensin converting enzyme inhibitor is a phosphonate substituted amino or imino acid or salt thereof, a proline derivative, a substituted proline derivative, a mercaptoacyl derivative of a substituted proline, a carboxyalkyl dipeptide derivative, a phosphinylalkanoyl proline derivative or a phosphonamidate derivative.

15. The use as defined in claim 14 wherein said angiotensin converting enzyme inhibitor is a carboxyalkyl dipeptide derivative.

16. The use as defined in any one of claims 1-8 wherein said angiotensin converting enzyme inhibitor is a phosphinylalkanoyl proline derivative, a phosphoramidate derivative, or a phosphonate substituted amino or imino acid or salt thereof.

17. The use as defined in claim 16 wherein said angiotensin converting enzyme inhibitor is captopril or zofenopril.

18. The use as defined in any one of claims 1-8 wherein said angiotensin converting enzyme inhibitor is enalapril or lisinopril.

19. The use as defined in any one of claims 1-8 wherein said angiotensin converting Inhibitor is fosinopril or (S)-1- 6-amino-2- [rhydroxy(4-phenylbutyl)phosphinyl] oxy-1-oxohexyl2-L-proline (ceranapril) or fosinopril.

20. The use as defined in any preceding claim wherein said angiotensin converting enzyme inhibitor is to be administered in single or divided doses of from about 0.1 to about 55 mg/one to four times daily.

21. The use as defined in any preceding claim wherein said angiotensin converting enzyme inhibitor is to be administered in the form of tablets, capsules or by injection.

22. The use as defined in claim 20 wherein said angiotensin converting enzyme inhibitor is captopril or zofenopril and is to be administered systemically.

23. The use as defined in any preceding claim wherein said angiotensin converting enzyme inhibitor is to be administered over a prolonged period of treatment.

24. Use of an angiotensin converting enzyme inhibitor for the manufacture of a medicament for preventing loss of muscle mass in a postoperative, immobilized or catabolic patient, or a patient on protein or nutritional restricted diets.

25. Use of an angiotensin converting enzyme inhibitor for the manufacture of a medicament for preventing, or treating patients having, postoperative protein catabolism, postaggression syndrome, Impaired glucose tolerance, postoperative or other insulin resistance, impaired muscle metabolism, or for treating patients on protein or nutritional restricted diets.

26. The use as defined in claim 24 wherein the patient to be treated is immobilized.

27. Use of an angiotensin converting enzyme inhibitor for the manufacture of a medicament for promoting wound healing in a postoperative, immobilized or otherwise catabolic patient.