METHOD OF TREATMENT AND PREVENTION OF NITRIC OXIDE DEFICIENCY-RELATED DISORDERS WITH CITRULLINE AND CITRULLINE DERIVATIVES

• US 20010056068A1
• Filed: 03/04/1998
• Published: 12/27/2001
• Est. Priority Date: 03/04/1998
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: GARFIELD, ROBERT E., CHWALISZ, KRISTOF, SHI, SHAO-QUING
• Application Number:
  US09/034,351
• Publication Number:
  US 20010056068A1
• Time in Patent Office: Days
• US Class Current: 514/310
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61K 38/1709 from mammals

Abstract

The invention provides methods for control, management, treatment and prevention of conditions related to nitric oxide deficiency such as hypertension, cardiovascular disease, osteoporosis, diabetes mellitus, preeclampsia HELLP, syndrome and fetal growth retardation; uterine contractility disorders such as preterm labor and dysmenorrhea, cervical dystocia, infertility and early pregnancy loss; male impotence; urinary incontinence; intestinal tract disorders (e.g. altered motility and pyloric stenosis), respiratory system diseases (e.g. asthma, neonatal respiratory distress syndrome, pulmonary hypertension, and adult respiratory distress syndrome); inflammatory diseases (e.g. acute inflammation, resistance to infection, SLE-lupus, anaphylactic reaction, allograft rejection); Alzheimer'"'"'s disease, stroke, growth hormone disorders, and behavior changes; dermatological conditions such as atopic eczema, topical hair loss, and burn injury; by administering citrulline or a citrulline analogue, optionally in combination with other enhancing or modulating agents, e.g., an estrogenic, partial estrogenic, progestagenic, or androgenic agent, and pharmaceutical preparations for such uses.

Claims

1. A method of treating or preventing a nitric oxide deficiency syndrome or a disease which can be treated or prevented by increasing endogenous nitric oxide levels in a mammal, comprising

administering to the afflicted mammal an effective amount of

a first agent which enhances the level of endogenous nitric oxide in the target tissue,

optionally, in further combination with a second agent which modulates or enhances nitric oxide synthesis,

with the proviso that the agents are not a natural food source.

2. A method according to

claim 1

, wherein said agent is citrulline or a citrulline analogue.

3. The method of

claim 1

, wherein the disease is atherosclerosis, restenosis, hypertension, preeclampsia and/or intrauterine fetal growth retardation.

4. The method of

claim 1

, wherein the female mammal is a human who has exhibited or is a susceptible to develop preterm labor, early pregnancy loss, infertility or cervical dystocia.

5. The method of

claim 1

, wherein the female mammal is a human who has exhibited symptoms of climacterium or is a candidate for hormone replacement therapy.

6. The method of

claim 1

, wherein the disease is altered motility of the intestinal tract, pyloric stenosis or diabetes mellitus.

7. The method of

claim 1

, wherein the disease is asthma, neonatal respiratory distress syndrome, pulmonary hypertension or adult respiratory distress syndrome.

8. The method of

claim 1

, wherein the disease is acute inflammation, resistance to infection, SLE-lupus, anaphylactic reaction or allograft rejection.

9. The method of

claim 1

, wherein the disease is Alzheimer'"'"'s disease, stroke, growth hormone disorders or behavior changes.

10. The method of

claim 1

, wherein the modulating agent is L-arginine.

11. The method of

claim 1

, wherein the mammal is a human and a nitric oxide donor is administered.

12. The method of

claim 11

, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryltrinitrite, SIN-1, isosorbidmononitrite or isosorbiddinitrite.

13. The method of

claim 12

, wherein the nitric oxide donor is administered orally.

14. The method of

claim 1

, wherein the female mammal is a human and the nitric oxide substrate or donor is administered in combination with an estrogen.

15. The method of

claim 1

, wherein the female mammal is a human who has exhibited symptoms of or is a candidate to develop preterm labor.

16. The method of

claim 14

, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17β

-estradiol, estrone or estriol.

17. The method of

claim 1

, wherein the female mammal is a human and the nitric oxide substrate or donor is administered in combination with a progestin.

18. The method of

claim 17

, wherein the progestin is progesterone, dydrogesterone, medroxyprogesterone, norethisterone, levonorgestrel, drospirenone, or norgestrel.

19. The method of

claim 1

, wherein the female mammal is a human and the estrogen or progestin are administered continuously.

20. The method of

claim 1

wherein the female mammal is a human and estrogen and progesterone are administered sequentially.

21. A pharmaceutical composition comprising an admixture of

(a) citrulline,

(b) a nitric oxide synthesis substrate, a nitric oxide donor or both, and

optionally, one or more of (c) an estrogen and (d) a progestin, in amounts effective to ameliorate the symptoms of an optionally climacterium in a menopausal or postmenopausal female mammal when administered thereto in an amount of estrogen bioequivalent to 1-2 mg of estradiol and an amount of the progestin bioequivalent to 50-300 mg of injected progesterone and an amount of the nitric oxide synthase substrate, nitric oxide donor or both effective to raise the blood level of circulating L-arginine to at least about 10-50 nmolar above the normally 50-100 nmolar circulating levels or raise the nitric oxide donor levels to about 1-1000 nmolar, (e) a cardiovascular agent.

22. A composition of

claim 21

, wherein (b) is a nitric oxide synthesis substrate.

23. A composition of

claim 22

, wherein the nitric oxide synthesis substrate (b) is L-arginine.

24. A composition of

claim 21

, wherein (b) is a nitric oxide donor.

25. A composition of

claim 24

, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryltrinitrie, SIN-1, isosorbidmononitrite or isosorbiddinitrite.

26. A composition of

claim 21

, wherein the estrogen (c) is present and is estradiol valerate.

27. A composition of

claim 21

, wherein the progestin (d) is present and is norgestrel.

28. A composition of

claim 21

, wherein the cardiovascular agent (e) is propranolol, methyldopa, guanethidine, nifedipine or nicardipine.