Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-01-03
2001-01-30
Ceperley, Mary E. (Department: 1641)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388100, C530S388200, C530S388240, C530S388900, C530S389200, C530S389800
Reexamination Certificate
active
06180762
ABSTRACT:
BACKGROUND
Glycyrrhetinic Acid (GA), the active principal in liquorice root, has been shown to markedly inhibit 11&bgr;-hydroxysteroid dehydrogenase (11&bgr;-OHSD) and steroid 5&bgr;-reductase when incubated with these enzymes (Stewart, P. M. et al. (1987)
Lancet
2:821-823; Monder, C. et al. (1989)
Endocrinology
125:1046-1053; Latif, S. A. et al. (1990)
Steroids
55:52-58). The importance of both these enzymes has become apparent following the experiments of Ulick, New, Monder and co-workers (Ulick, S. et al. (1979)
J. Clin. Endocrin. Metab.
49:747-764; New, M. I. et al. (1982)
Endocrinology of Hypertension, Serono Symposium,
vol. 50, pp 85-101; Monder, C. et al. (1986)
J. Clin. Endocrin. Metab.
63:550-557) who demonstrated that hypertensive children with the syndrome of apparent mineralocorti-coid excess (AME) lack both 11&bgr;-OHSD and 5&bgr;-reductase activity. Alteration in these enzymatic pathways of steroid inactivation was shown to result in changes in the peripheral metabolism of cortisol. It has been postulated that higher peripheral and intrarenal concentrations of cortisol may then interact with mineralocorticoid receptors and promote sodium reabsorption (Edwards, C. R. W. et al. (1988)
Lancet
2:986-989; Funder, J. W. et al. (1988)
Science
242:583-585).
AME patients exhibit sodium retention, potassium wasting, and increased blood pressure without measurably increased circulating aldosterone. A pharmacological equivalent of this congenital condition results from the ingestion of liquorice which contains glycoside derivatives of GA (Stewart, P. M. et al. (1987)
Lancet
2:821-823; Edwards, C. R. W. et al. (1988)
Lancet
2:986-989). Because of the importance of these enzymes, it is possible that other categories of hypertension may also result from less extreme alterations of their activities.
SUMMARY OF THE INVENTION
This invention pertains to an endogenous human glycyrrhetinic-acid-like factor(s) or GALF(s) which inhibits hepatic and renal 11&bgr;-hydroxysteroid dehydrogenase (11&bgr;-OHSD) and hepatic 5&bgr;-steroid reductase (5&bgr;-SR). The factor(s) is isolatable from urine, is water soluble, is not extractable from aqueous solution into ethyl acetate and is resistant to heat and to trypsin treatment. Measurement of this factor will be useful for identification of individuals, particularly those with hypertension, who have altered enzymatic pathways for the inactivation of steroid hormones, such as cortisol and aldosterone, and may have a steroid component to, and which may be responsible for, their hypertension.
REFERENCES:
patent: 3070623 (1962-12-01), Gottfried et al.
E. Sevier et al. Clin. Chem., vol. 27, No. 11, 1797-1806 (1981).
Kanaoka et al., Chem. Pharm. Bull., 29(6), 1533-1538 (1981).
M. Kanaoka et al., Chem. Pharm. Bull 36(9), 3264-3270 (1988).
Davis and Morris, “Medicinal uses of licorice through the millennia:the good plenty of it”,Molecular and Cellular Endocrinology78 pp. 1-6 (1991).
Morris et al., “Detection of Glycyrrhetinic Acid-Like Factors (GALFs) in Huma Urine”,Hypertension20(3) pp. 1-5 (1992).
Harlow and Lane, “Monoclonal Antibodies”,Antibodies A Laboratory Manual, Chapter 6 p. 141 (Cold Spring Harbor Laboratory, New York) (1988).
Latif Syed Abdul
Morris David J.
Ceperley Mary E.
Lahive & Cockfield LLP
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