Enteral diet and method for providing nutrition to a diabetic

Abstract

A composition and method for providing nutrition, or a nutritional supplement, to a diabetic patient. Pursuant to the present invention, a low carbohydrate, high fat enteral formulation is provided. The fat comprises, in part, medium chain triglycerides (MCTs). Preferably, the composition includes a high percent of mono-unsaturated fats, high amylose starch, and soluble dietary fiber.

Patent number: 5470839
Filing date: Jul 6, 1994
Issue date: Nov 28, 1995
Inventors: Philip Laughlin, John Alexander, A. Reza Kamarei, Robert P. Dobbie, Paul Lin, Shen-Youn Chang, Sekhar Reddy, Etienne Grasset, Christian Melin
Assignee: Clintec Nutrition Company

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What is claimed is:

1. A method for providing nutrition to a diabetic patient without substantially increasing blood glucose levels comprising the steps of enterally administering to the diabetic patient a low carbohydrate, high fat enteral composition comprising:

a protein source;

a carbohydrate source including a slowly digested high amylose starch component; and

a fat source that includes medium chain triglycerides and has an n-6:n-3 ratio of not more than 10.

2. The method of claim 1 wherein approximately 8 to about 25% of the calories of the composition are provided as the protein source.

3. The method of claim 1 wherein less than 50% of the calories of the composition are provided as the carbohydrate source.

4. The method of claim 1 wherein approximately 30 to about 44% of the calories of the composition are provided as the fat source.

5. The method of claim 1 wherein the composition includes from about 1% to about 5% of high amylose starch based on the overall composition.

6. The method of claim 5 wherein the high amylose starch includes approximately 25 to about 75% amylose and approximately 25% to about 75% amylopectin.

7. The method of claim 1 wherein the fat source comprises approximately 40 to 70% mono-unsaturated fats.

8. The method of claim 1 wherein the composition further comprising dietary fiber.

9. The method of claim 8 wherein the dietary fiber includes both soluble and insoluble dietary fiber.

10. A method for providing nutrition to a diabetic patient comprising the steps of enterally administering to the diabetic patient a composition that comprises:

a protein source that provides at least about 8% of the total calories of the composition;

a carbohydrate source that provides less than about 50% of the total calories of the composition, the carbohydrate source including a slowly digested high amylose starch; and

a fat source that provides at least 30% of the total calories of the composition, including medium chain triglycerides (MCTs) and having an n-6:n-3 ratio of 10 or less.

11. The method of claim 10 wherein the fat source includes at least one oil selected from the group consisting of olive oil, canola oil, hi-oleic safflower oil, and hi-oleic sunflower oil.

12. The method of claim 10 wherein the composition is administered to the diabetic patient through a nasogastric tube.

13. The method of claim 10 wherein the composition is administered as a supplementation to the diabetic patient.

14. The method of claim 10 wherein the diabetic patient is non-insulin dependent.

15. The method of claim 10 wherein the fat source includes long chain triglycerides (LCTs) and the ratio of MCTs to LCTs being approximately 1:4.

16. The method of claim 10 wherein the fat source comprises approximately 30% to 70%, by calories, mono-unsaturated fatty acids.

17. The method of claim 10 wherein the high amylose starch comprises from about 1% to about 5% of the overall composition.

18. The method of claim 10 wherein the composition provides dietary fiber.

19. The method of claim 18 wherein the dietary fiber includes both soluble and insoluble dietary fiber.

20. A method for providing nutrition to a patient with diabetes without increasing blood glucose levels comprising:

enterally administering to the patient with diabetes an effective amount of a composition comprising a protein source, a carbohydrate source that includes high amylose starch, a fat source including a mixture of medium and long chain triglycerides wherein the fat source comprises approximately 30% to 70%, by calories, mono-unsaturated fatty acids, and dietary fiber.

Method for treating diabetes using DHEA compounds

Abstract

Diabetes is treated by orally administering a dehydroepiandrosterone (DHEA) compound selected from the group consisting of DHEA, DHEA sulfate and soluble DHEA compounds. The DHEA compound is preferably administered in finely dispersed form, powdered or solution, mixed with the food diet of the diabetic in a dosage range of up to 0.4% by weight of the food diet. The pharmacological activity and utility of DHEA as a potent anti-diabetic agent and anti-hyperglycemic agent over a variable range of genetic background is documented.

Patent number: 4518595
Filing date: Jul 19, 1983
Issue date: May 21, 1985
Inventors: Douglas L. Coleman, Norman Applezweig, Edward H. Leiter
Assignee: The Jackson Laboratory

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What is claimed is:

1. A method for treating diabetes and enhancing the pancreatic beta cell function of diabetics comprising administering a DHEA compound selected from the group consisting of dehydroepiandrosterone (DHEA), DHEA sulfate, and soluble compounds of DHEA.

2. The method of claim 1 comprising orally administering said DHEA compound in finely dispersed form.

3. The method of claim 2 further comprising the step of preparing said DHEA compound by dissolving the DHEA compound in a DHEA compound solvent thereby forming a DHEA compound solution.

4. The method of claim 3 further comprising the step of mixing the DHEA compound solution with the food diet of the diabetic.

5. The method of claim 4 further comprising the step of evaporating the DHEA compound solvent from the food diet prior to ingestion by the diabetic.

6. The method of claim 5 further comprising the step of orally administering the DHEA compound at a dosage in the range of up to 0.4% by weight of the food diet of the diabetic.

7. The method of claim 6 further comprising adjusting the dosage of the DHEA compound for administering the DHEA compound at a rate in the range of 120 mg to 480 mg per day per kg body weight of the diabetic.

8. The method of claim 1 wherein said soluble DHEA compounds comprise DHEA glucuronide.

9. The method of claim 2 wherein the DHEA compound comprises DHEA sulfate administered by mixing the DHEA sulfate in the drinking water of the diabetic.

10. A method for treating diabetes and for enhancing the pancreatic beta cell function of a diabetic comprising orally administering dehydroepiandrosterone (DHEA) to the diabetic.

11. The method of claim 10 comprising orally administering DHEA in a finely dispersed powdered form.

12. The method of claim 11 comprising orally administering DHEA in a finely dispersed powdered form mixed with the diet of the diabetic.

13. The method claim 12 further comprising the step of preparing the DHEA in finely dispersed powdered form by dissolving the DHEA in a DHEA solvent to form a DHEA solution, mixing the solution with the food diet of the diabetic, and substantially completely evaporating the solvent from the food diet of the diabetic before ingestion of the mixture of finely dispersed powdered DHEA and food diet.

14. The method of claim 13 comprising orally administering DHEA in dosages in a range of up to 0.4% by weight of the food diet of the diabetic.

15. The method of claim 12 comprising orally administering DHEA in the dosage range of 0.1% to 0.4% by weight of the food diet of the diabetic.

16. The method of claim 13 comprising dissolving the DHEA in acetone.

17. The method of claim 10 comprising orally administering DHEA in dosages in the range of 120 mg to 480 mg per kg of body weight of the diabetic per day.

18. A method for treating diabetes and for enhancing the pancreatic beta cell function of diabetics comprising:

preparing a soluble dehydroepiandrosterone (DHEA) compound in finely dispersed form by dissolving the DHEA compound in a DHEA compound solvent to provide a DHEA compound solution:

mixing the DHEA compound solution in the food diet of the diabetic in an amount in the dosage range of up to 0.4% by weight of the food diet of the diabetic:

substantially completely evaporating the DHEA compound solvent from the food diet after mixing and before ingestion of the food diet by the diabetic:

and adjusting the dosage in the food diet of the diabetic for administering DHEA compound in the range of 120 mg to 480 mg per day per kg body weight of the diabetic.

19. The method of claim 18 comprising continuing said treatment indefinitely.

20. The method of claim 18 comprising commencing said treatment before the blood sugar level of the diabetic exceeds a concentration of 350 mg/dl.

Method of treating diabetes and related disease states

Abstract

The instant invention is concerned with acetylphenols which are useful as antiobesity and antidiabetic compounds. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering or modulating triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility or for treating atherosclerosis are also disclosed.

Patent number: 5847008
Filing date: Jan 31, 1997
Issue date: Dec 8, 1998
Inventors: Thomas W. Doebber, Joel P. Berger, Gregory D. Berger, Mark D. Leibowitz, David E. Moller, John T. Olson, Arthur A. Patchett, Richard B. Toupence
Assignee: Merck & Co., Inc.

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What is claimed is:

1. A method for the treatment or prevention of diabetes which comprises administering to a diabetic patient a pharmaceutically effective amount of a compound of formula XI or XII: ##STR15## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR16## Y' is sulfur, sulfoxide,sulfone; ##STR17## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR18## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR19## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR20## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR21## or R.sub.4 OCH.sub.2 --.

2. A method according to claim 1 wherein the compound is Y is oxygen and Y' is sulfur, sulfoxide, sulfone, amino or cyanamido.

3. A method according to claim 1 wherein each m is 1.

4. A method according to claim 1 wherein the compound is

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3 -dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneacetic acid and its methyl ester;

Sodium Salt of 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneacetic acid, monohydrate and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2-fluorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneacetic acid; and 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)- 1 -propenylsulfonyl)-2-fluorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-3-fluorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzeneacetic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio)-3 -chlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-thio)benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-propylthio)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3 -fluorobenzoic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio)-3 -fluorobenzoic acid-S-oxide, methyl ester and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-fluorobenzoic acid and its methyl ester; and

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-cyanamido)-benzeneacetic acid and its methyl ester.

5. A method for the treatment or prevention of diabetes which comprises administering to a diabetic patient an effective amount of a compound of claim 1 in combination with a sulfonylurea, fibrate, HMG-CoA reductase inhibitor, beta-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, .alpha.-glucosidase inhibitors, insulin secretogogue or insulin.

6. A method for treating obesity which comprises administering to a patient in need thereof an effective amount of a compound of formula XI or XII: ##STR22## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR23## Y' is sulfur, sulfoxide,sulfone; ##STR24## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR25## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR26## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR27## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of I to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of I to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR28## or R.sub.4 OCH.sub.2 --.

7. A method according to claim 6 in combination with a fenfluramine, dexfenfluramine, phentiramine or .delta.3 adrenergic receptor agonist.

8. A method for lowering triglyceride levels which comprises administering to a patient needing lower triglyceride an effective amount of a compound of formula XI or XII: ##STR29## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR30## Y' is sulfur, sulfoxide,sulfone; ##STR31## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR32## wherein R .sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR33## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR34## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR35## or R.sub.4 OCH.sub.2 --.

9. A method for halting, preventing or reducing the risk of developing atherosclerosis and related diseae events in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula XI or XII: ##STR36## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR37## Y' is sulfur, sulfoxide,sulfone; ##STR38## R.sub.1 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR39## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR40## each R.sub.6 is independently H or atkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR41## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR42## or R.sub.4 OCH.sub.2 --.

10. A method according to claim 9 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta.binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta.transactivation assay.

11. The method of claim 10 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

12. The method of claim 11 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

13. The method of claim 12 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

14. A method for raising high densisty lipoprotein plasma levels in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula XI or XII: ##STR43## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR44## Y' is sulfur, sulfoxide,sulfone; ##STR45## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR46## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR47## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR48## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR49## or R.sub.4 OCH.sub.2 --.

15. A method according to claim 14 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. transactivation assay.

16. The method of claim 15 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

17. The method of claim 16 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

18. The method of claim 17 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

19. A method for halting, preventing or reducing the risk of developing atherosclerosis and related disease events which comprises administering to a patient in need thereof an effective amount of a compound of claim 9 in combination with a sulfonylurea, fibrate, HMG-CoA reductase inhibitor, beta-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, .alpha.-glucosidase inhibitors, insulin secretogogue or insulin.

20. A method according to claim 19 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. transactivation assay.

21. The method of claim 20 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

22. The method of claim 21 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

23. The method of claim 22 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

System and method for continuous monitoring of diabetes-related blood

Abstract

A system and method for sensing and providing an indication of one or more diabetes-related blood constituents of a patient, the system being based upon an ECG sensor which processes patient ECG signals, either surface, or intracardiac or epicardial, for determining a measure of a blood constituent such as insulin or glucose, or both insulin and glucose. The system has processing capability for correlating selected parameters of the ECG signal with patient blood insulin or blood glucose, to provide the insulin or glucose level. Additionally, the system is provided with input capability for enabling the patient to input data such as the time of meal intake, which is representative of glucose intake, which data is incorporated in making a determination of patient insulin need. The system can be in a first external wearable embodiment, or in a second implantable embodiment which utilizes a pacing-type lead for picking up intracardiac or epicardial...

Patent number: 5741211
Filing date: Oct 26, 1995
Issue date: Apr 21, 1998
Inventors: Alexis C. M. Renirie, Richard Houben, Frank van Leeuwen
Assignee: Medtronic, Inc.
Primary Examiner: Bryan K. Yarnell

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What is claimed is:

1. System apparatus for providing an indication of at least patient blood insulin, comprising:

ECG sensor means for obtaining signals representative of the patient ECG,

signal processing means for processing said ECG signals to provide first parameter data indicative of the patient's blood insulin level, wherein the signal processing means include means for comparing the sensed ECG signals against a reference value, and

response means for providing a response as a function of said data.

2. The system apparatus as described in claim 1, wherein said response means comprises means for outputting an indication of the patient's blood insulin level.

3. The system apparatus as described in claim 1, wherein said system apparatus is implantable in said patient and said response means comprises pump means for injecting insulin into said patient as a function of said insulin data.

4. The system apparatus as described in claim 1, comprising a wearable housing for housing said apparatus and adapted to be worn by a patient, and wherein said response means comprises output means for providing an output signal receivable by said patient, said output signal being representative of the patient's insulin level.

5. The system apparatus as described in claim 1, wherein said signal processing means further comprises glucose means for processing said ECG signals and obtaining second parameter data indicative of the patient blood glucose level.

6. The system apparatus as described in claim 5, wherein said signal processing means further comprises analyzing means for analyzing said insulin and glucose data, and additional response means for providing a response as a function of said analyzed insulin and glucose data.

7. The system apparatus as described in claim 1, comprising keyboard input means for inputting data representative of patient glucose intake.

8. A system for providing an indication of blood insulin level of a patient, comprising

ECG sensor means for sensing ECG signals of said patient,

processing means for processing said ECG signals and obtaining therefrom a measure of patient blood insulin, wherein the processing means include means for comparing the sensed ECG against a reference value, and

output means responsive to said insulin measure for outputting an indication of patient insulin level.

9. The system as described in claim 8, comprising an implantable housing for housing said system within said patient.

10. The system as described in claim 8, wherein said signal processing means comprises parameter means for separating out predetermined parameters of said patient ECG which correlate to patient blood insulin level.

11. The system as described in claim 8, comprising storage means for storing patient blood insulin levels, and wherein said signal processing means further comprises extrapolation means for extrapolating anticipated time of insulin need as a function of said stored patient blood insulin levels.

12. The system as described in claim 8, further comprising second processing means for processing said ECG signals and obtaining therefrom an indication of patient blood glucose.

13. The system as described in claim 12, further comprising delivery means for delivering insulin to the patient, and control means for controlling said delivery means to provide indicated insulin in response to indicated patient insulin and glucose levels.

14. A system for determining insulin need of a diabetic patient, comprising

ECG sensing means for sensing the patient ECG and deriving therefrom an indication of patient blood insulin level,

glucose input means for inputting data indicative of patient glucose intake,

processing means for determining patient insulin need as a function of said indicated blood insulin level and said glucose intake data, wherein the processing means include means for comparing said indicated blood insulin level against a reference value, and

response means for outputting an indication of said determined patient insulin need.

15. The system as described in claim 14, wherein said ECG sensing means comprises first processing means for processing ECG signals and deriving therefrom selected parameter data.

16. The system as described in claim 15, wherein said ECG sensing means comprises second processing means for determining time variations of selected ECG parameters and for calculating anticipated insulin need as a function of said variations.

17. The system as described in claim 14, wherein said glucose input means comprises an input terminal adapted to enable said patient to enter said glucose intake data.

18. The system as described in claim 17, wherein said input means comprises time means for storing data representative of the time of patient glucose intake.

19. The system as described in claim 14, wherein said processing means comprises glucose variation means for calculating anticipated glucose variation as a function of said glucose intake data, and wherein said response means comprises comparing means for comparing anticipated glucose variation with measured patient insulin level.

20. The system as described in claim 14, comprising second processing means for processing said ECG signals to obtain a measure of patient glucose, and wherein said response means comprises dual parameter response means for responding as a function of determined insulin and glucose levels.

21. A system for sensing one or more diabetes-related blood constituents of a patient, comprising an implantable apparatus and an external apparatus, said implantable apparatus comprising sensor means for continuously sensing ECG signals from said patient; processing means for continuously processing said ECG signals and obtaining therefrom data indicating the level of at least one selected blood constituent, wherein the processing means include means for comparing the sensed ECG signals against a reference value; and transfer means for transferring said data to said external apparatus, and

said external apparatus comprising indicator means for indicating said patient blood constituent level based upon said transferred data.

22. The system as described in claim 21, wherein said at least one selected blood constituent is blood insulin, and said data is insulin data, and said indicating means comprises display means for displaying a measure of patient blood insulin.

23. The system as described in claim 22, comprising external data transfer means for transferring data from said external apparatus to said implanted apparatus, and wherein said implanted apparatus comprises receiving means for receiving said data transferred from said external apparatus.

24. The system as described in claim 23, wherein said external transfer means comprises means for transferring data representative of patient glucose intake.

25. The system as described in claim 24, wherein said implanted apparatus comprises processing means for processing said insulin data and said glucose intake data, and response means for delivering insulin to said patient based on said insulin data and said glucose data.

26. The system as described in claim 25, wherein said response means comprises an insulin pump for injecting insulin directly into said patient's body.

27. The system as described in claim 23, wherein said external apparatus comprises input means for inputting data representative of patient glucose intake and transfer means for transferring said glucose intake data to said implantable apparatus, said implantable apparatus having receiving means for receiving said transferred glucose intake data.

28. The system as described in claim 21, wherein said blood constituent is glucose and said data is blood glucose data, and said indicating means comprises display means for displaying a measure of patient blood glucose.

29. The system as described in claims 28, comprising validity means for storing data indicative of whether said ECG signals correlate with blood glucose for said patient.

30. The system as described in claim 21, wherein said sensor means comprises means for sensing patient intracardiac signals.

31. The system as described in claim 21, wherein said sensor means comprises means for sensing patient epicardial signals.

32. The system as described in claim 21, wherein said processing means comprises VCG means for deriving the patient VCG from said ECG signals.

33. A system for continuously determining a measure of at least one diabetes-related blood constituent of a patient, said constituent selected from the group of blood insulin and blood glucose, comprising:

sense means for continuously sensing patient ECG signals, the ECG having a QRS portion and a T wave portion;

programmable means for storing data reflective of preselected ECG parameters corresponding to a selected one of said blood constituents;

first signal processing means for substantially continuously extracting from said ECG signals portions representative of said ECG parameters;

second signal processing means for processing said extracted signal portions and obtaining data therefrom which correlates with said selected constituent; and

third signal processing means for continuously determining a measure of said selected constituent as a function of said obtained data wherein said third signal processing means include means for comparing said obtained data against a reference value.

34. The system as described in claim 33, comprising a housing for containing said system whereby said system is adapted to be wearable by a patient.

35. The system as described in claim 33, comprising external means for programming said ECG parameters.

36. The system as described in claim 33, wherein said sense means comprises subcutaneous electrodes.

37. The system as described in claim 33, wherein said first signal processing means comprises averaging means for beat-to-beat averaging over a predetermined number of consecutive patient cardiac beats.

38. The system as described in claim 33, wherein said second signal processing means comprises means for determining from said extracted signals a measure of at least one of the QRS and the T wave portions of said patient ECG signals.

39. The system as described in claim 38, wherein said determining means comprises means for getting a measure of a RMS value of both said QRS and the T wave portions.

40. The system as described in claim 33, wherein said sense means has means for sensing intracardiac patient ECG signals.

41. The system as described in claim 38, further comprising means for storing basal values of preselected ECG parameters, and wherein said determining means comprises statistical means for comprising said determined parameter values with corresponding stored basal values.

42. The system as described in claim 33, wherein said at least one diabetes-related constituent is patient blood insulin, and comprising output means for providing an output representative of patient blood insulin.

43. The system as described in claim 33, wherein said at least one diabetes-related constituent is patient blood glucose, and comprising output means for providing an output representative of patient blood glucose.

44. The system as described in claim 33, wherein said at least one diabetes-related constituent is blood glucose, and further comprising validity means for enabling determination of patient blood glucose.