WO2000061154A1

WO2000061154A1 - Composition, containing sublimed sulphur, for altering plasma homodyst(e) levels in humans

Info

Publication number: WO2000061154A1
Application number: PCT/CA1999/000892
Authority: WO
Inventors: Airudin S. Khan
Original assignee: Khan Airudin S
Priority date: 1999-04-08
Filing date: 1999-09-27
Publication date: 2000-10-19
Also published as: AU5844799A

Abstract

Plasma homocysteine values > 10.2νmol per litre are associated with an increased risk of atherothrombosis, but normal values are considered to be 4 to 15 νmol per litre. An initial test subject with Hyper-homocystinemia and lactose intolerance was treated with Sublimed Sulfur 300 mg orally twice daily for 45 days. An additional 46 randomly selected subjects were treated with Sublimed Sulfur 200 mg orally daily for 30 days. Basal control plasma homocysteine, erythrocyte folic acid and serum vitamin B12 and lipids were compared with follow-up results obtained 24 hours and 30 days after discontinuation of Sublimed Sulfur. In the initial test subject, basal plasma homocysteine of 77 νmol per litre decreased by 95.7 percent. In the 46 patients, the effect of Sublimed Sulfur varied according to the initial basal plasma homocysteine concentration; basal levels of 2.3 to 7 νmol per litre increased by 58.5 percent (p < 0.001) 24 hours after discontinuation of treatment, and by 85.4 percent 30 days later; basal levels of 7.1 to 9.9 νmol per litre showed no consistent changes, and basal levels of 9.9 to 22.1 νmol per litre decreased to 63.9 percent (p < 0.005) of basal levels 24 hours after discontinuation of Sublimed Sulfur, and to 70.7 percent of basal levels 30 days later. Sublimed Sulfur therapy eliminated the initial plasma homocysteine differences between low, intermediate and high basal levels. Sublimed Sulfur therapy normalized plasma homocysteine by causing a regression towards the mean of basal plasma homocysteine levels.

Description

COMPOSITION_, CONTAINING SUBLIMED SULPHUR, FOR ALTERING PLASMA HOMODYST(E) LEVELS IN HUMANS

DESCRIPTION

Background Hyper-homocysteinemia is a risk factor for venous thrombosis

and atherothrombosis of the coronary, carotid, cerebral, central and peripheral arteries ^1"13 Elevated plasma homocysteine concentrations have been reported in chronic renal failure,^14"15 hypothyroidism, pernicious anemia,¹⁶ advancing age and several types of carcinoma, including breast, ovarian and pancreatic,¹⁷ and in deficiencies of vitamin B12, folic acid,^18"19 vitamin B6,²⁰ methionine synthase

and cystathionine-Beta-synthase ²¹ The complications due to atherothrombosis are reported to be associated with plasma homocysteine concentrations > 10.2

μmol per litre²² but the normal laboratory values are considered to be 4 to 15

μmol per litre.²³ The apparent contradiction between plasma homocysteine

concentrations reported to be normal and the values associated with an increased risk of atherothrombosis suggested that one or more additional factors

may be necessary for alteration of plasma homocysteine concentrations

Elemental sulfur, an integral component of the sulfur-containing essential ammo acids and sulfur-containing enzymes, was considered to be a possible

necessary factor, and a clinical study was undertaken to determine the effect of

orally administered elemental Sulfur on the Sulfur -containing essential ammo

acid, homocysteine Orally administered Sublimed Sulfur USP, and also precipitated sulfur, has been mixed with molasses and used as a laxative ^24'26 Methods An initial test subject with hyper-homocysteinemia of 77 μmol per

litre was treated with Sublimed Sulfur. An additional 46 subjects, 31 men and 15 women were randomly selected. The subjects had single or multiple diagnoses of generalized atherosclerosis, hypertension, myocardial infarction, angina

pecto s, peripheral vascular disease, coronary angioplasty, diabetes mellitus, hyperlipidemia, hypothyroidism, past history of carcinoma, hiatus hernia, osteoarthritis and osteoporosis, depression, obstructive airways disease, bronchial asthma, essential tremour, hiatus hernia and the postmenopausal

state. A 30 day course of Sublimed Sulfur 200 mg, 1 capsule orally pc breakfast daily, was added to existing medical therapy which was continued unchanged for

the duration of the study. Each subject's basal plasma homocysteine was compared with results obtained 24 hours and 30 days after discontinuation of Sublimed Sulfur. Basal and follow-up comparisons were also made for

erythrocyte folic acid and serum levels of vitamin B12 and lipids. The subjects did not receive betaine, vitamin B12, folic acid and vitamin B6 during the course of the study.

The Wilcoxon T test was used to evaluate the quantitative data. Numerical

values indicate the mean and standard error of the mean.

Results The initial test subject's basal plasma homocysteine of 77 μmol per litre

decreased by 95.7 percent. In the 46 additional subjects, the effect of the

Sublimed Sulfur varied according to the initial basal plasma homocysteine concentration; low basal plasma homocysteine levels generally increased and high basal plasma homocysteine levels usually decreased after completion of

the 30 day course of Sublimed Sulfur; basal levels of 2.3 to 7 μmol per litre

(N=15) increased by 58.5 percent (P<0.001 ) 24 hours after discontinuation of

treatment, and by 85.4 percent 30 days later; basal levels of 7.1 to 9.9 μmol per

litre (N=15) showed no consistent changes, and the basal levels of 9.9 to 22J

μmol per litre (N= 16) decreased to 63.9 percent (P <0.005) 24 hours after

discontinuation of Sublimed Sulfur, and to 70.7 percent of basal levels 30 days later.

There were no adverse effects on the pulse rate and rhythm, blood pressure and electrocardiograms. There were no significant changes of the complete blood count, urinalysis, erythrocyte folic acid and serum levels of vitamin B12, creatinine, electrolytes, uric acid, glucose, aspartate transaminase, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and calculated levels of low-density lipoprotein cholesterol and total cholesterol/high-density

lipoprotein cholesterol ratio. There were no reports of adverse effects by the subjects.

Conclusions Sublimed Sulfur therapy caused a regression towards the mean of basal plasma homocysteine levels and normalized plasma homocysteine to

between 7.5 and 8.5 μmol per litre in subjects with normal levels of erythrocyte

folic acid and serum vitamin B12. Sublimed Sulfur is an effective treatment for the alteration of plasma homocysteine in medical conditions associated with abnormal plasma homocysteine levels. References

1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J. Pathol 1969;56:111-28.

2. McCully KS. Homocysteine and vascular disease. Nat Med 1996;2:386-9.

3. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. In: Francis RB Jr, ed. Atherosclerotic cardiovascular disease, hemostasis, and endothelial function. New York: Marcel Dekker, 1992:183-236.

4. Stampfer MJ, Malinow MR. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med 1995; 332:328-9.

5. Boers GHJ, Smals AGH, Trijbels FJM, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709-15.

6. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991 ;324:1149-55.

7. Malinow MR. Hyperhomocyst(e)inemia: a common and easily reversible risk factor of occlusive atherosclerosis. Circulation 1990;81:2004-6.

8. Kang SS, Wong PWK, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992;12:279-98.

9. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.

10. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27.

11. Duell PB, Malinow MR. Plasma homocyst(e)ine: an important risk factor for atherosclerosis vascular disease. Curr Opin Lipidol 1997;8:28-34.

12. Malinow MR, Kang SS, Taylor LM, et al. Prevalence of hyperhomocyt(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989;79:1180-8.

13. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B. Homocyst(e)inemia in daily practice: levels in coronary heart disease. Coronary Artery Dis 1990;1 :215-20.

14. Wilcken DE, Gupta VJ. Sulphur containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide. Eur J Clin Invest 1979;9:301-7. References

15. Chauveau P, Chadefaux B, Coύde M, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 1993;41 :S72-S77.

16. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinants for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239-46.

17. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27.

18. Brattstrom LE, Israelsson B, Jeppsson JO, Hultberg BL. Folic acid an innocuous means to reduce plasma homocysteine. Scand J Clin Laboratory Invest 1988;48:215- 21.

19. Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocyt(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009-15.

20. Saltzman E, Mason JB, Jacques PF, et al. B vitamin supplementation lowers homocysteine levels in heart disease. Clin Res 1994;42:172A. Abstract.

21. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 1. New York: McGraw-Hill, 1995; 1279-327.

22. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993;39:1764-79.

23. Jacobsen DW, Gatautis VJ, Green R, et al. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994;40:873- 81.

24. Cushny AR, Grollman A, Slaughter D. Pharmacology and Therapeutics. Thirteenth Edition. 1947;245.

25. Goodman L, Gilman A. The Pharmacological Basis of Therapeutics. Fifteenth Printing April 1947. 1941 ;870-71.

26. Gaddum JH, Parmacology. Fifth Edition, Oxford University Press. 1959;274.

Claims

1. A regimen of treatment with Sublimed Sulfur alters plasma homocysteine levels.

2. Treatment with Sublimed Sulfur as defined in claim 1 increases low levels of plasma homocysteine and decreases high levels of plasma homocysteine.

3. Treatment with Sublimed Sulfur as defined in claim 1 and claim 2 causes plasma homocysteine levels to be maintained within the normal range.

4. Sublimed Sulfur alters plasma homocysteine levels as defined in Claim 1 , Claim 2 and Claim 3 when administered together with: folic acid, folic acid and vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin) and vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin) and folic acid, vitamin B12 (cyanocobalamin), folic acid and vitamin B6 (pyridoxine), multi-vitamins, and foods.

5. Treatment with Sublimed Sulfur as defined in claim 1 , claim 2, claim 3 and claim 4 normalizes plasma homocysteine concentrations in generalized atherosclerosis, accelerated atherosclerosis, atherothrombosis, coronary atherosclerosis, ischemic heart disease, angina pectoris, coronary thrombosis, myocardial infarction, atrial arrhythmias, ventricular arrhythmias, cardiac nerve degeneration due to atherosclerosis, carotid atherosclerosis, recurrent cerebral embolisation, cerebral atherosclerosis, transient ischemic attacks, stroke, atherosclerotic cerebral degeneration, peripheral atherosclerosis, peripheral ischemia, nerve degeneration due to atherosclerosis in peripheral ischemic neuropathy, hypertension secondary to generalized atherosclerosis, atherosclerotic complications of diabetes mellitus, nerve degeneration due to atherosclerosis in diabetic neuropathy, recurrent thromboembolism, deep vein thrombosis and pulmonary embolism, recurrent pulmonary embolism, venous thrombosis in cancer, gout,

Alzheimer's disease, nephrosclerosis, chronic renal failure, menopause, hypothyroidism, pernicious anemia, psoriasis, leukemias, cancer, breast cancer, ovarian cancer, pancreatic cancer, osteoporosis due to atherosclerosis, and the aging process due to atherosclerosis.