Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
1998-09-30
2001-03-06
Moezie, J.D., Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C424S655000, C426S074000
Reexamination Certificate
active
06197816
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods of using the chromium(III) complex represented by the formula [Cr
3
O(O
2
CCH
2
CH
3
)
6
(H
2
O)
3
]
+
as a nutritional supplement, and for treating medical disorders associated with chromium deficiency. The invention also relates to nutritive and pharmaceutical compositions containing this chromium(III) complex.
2. Background of the Invention
The biologically-active, naturally-occurring oligopeptide low-molecular-weight chromium-binding substance (LMWCr) has been found to activate the insulin-dependent tyrosine protein kinase activity of insulin receptor (IR) approximately eightfold with a dissociation constant of circa 250 pM.
1
This activity is directly proportional to the Cr content of the oligopeptide (being maximal at four chromic ions per oligopeptide), while substitution of chromium with metal ions commonly associated with biological systems results in inactivating the oligopeptide. Similarly, LMWCr has been reported to activate a membrane-associated phosphotyrosine phosphatase; this activation also requires four chromic ions per oligopeptide to be maximal, while chromic ions could not functionally be replaced with other transition metal ions.
2
A role for LMWCr in amplification of insulin-signaling has been postulated.
1,3
Chromium is mobilized from the blood and taken up by insulin-dependent cells in response to insulin.
4
LMWCr is maintained in its apo form
5
but possesses a large chromic ion binding constants(s) as it is capable of removing chromium from Cr-transferring.
5,6
The holo LMWCr is then capable of stimulating IR kinase activity, amplifying the signal of insulin into the insulin-dependent cells. An association between chromium and insulin-dependent glucose and lipid metabolism has been reported for nearly four decades;
7
however, only recently since procedures for isolation of quantities of LMWCr suitable for kinetic and spectroscopic studies have been developed
3
has progress been made in understanding the association on a molecular level.
An association between the essential nutrient chromium and adult-onset diabetes has also been postulated.
8
Most recently Anderson and coworkers found improved glycemic control for 180 adult-onset diabetic patients following chromium supplementation,
9
while Ravina and Slezack using 138 adult-onset diabetic patients found reduced insulin requirements.
10
Unfortunately, the form of chromium used as a dietary supplement in these studies, chromium(III) picolinate, has been found to cause chromosome damage.
11
This suggests that a new form of chromium for use as a dietary supplement and as part of a potential treatment for adult-onset diabetes is required.
LMWCr would appear to be a possibility. It has a high LD
50
6
and is biologically active, opposed to chromium picolinate and glucose tolerance factor (a material isolated from acid-hydrolyzed Brewer's yeast extracts) which serve only as sources of readily absorbable chromium.
12
However, LMWCr is susceptible to hydrolysis under acidic conditions
14
and consequently could not be taken orally without degradation.
Despite the apparent significance of Cr, as much as ninety percent of the American population and half of the population of developed nations fail to intake the daily recommended safe and adequate quantities of Cr.
13
Accordingly, there remains a need for improved chromium-containing dietary supplements.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that the chromium(III) complex having the formula [Cr
3
O(O
2
CCH
2
CH
3
)
6
(H
2
O)
3
]
+
(complex (1)) activates tyrosine kinase activity, e.g., insulin receptor tyrosine kinase activity. Complex (1) catalyzes the transfer of the gamma phosphate of ATP to tyrosine residues of proteins or polypeptides. The complex can thus be used as a biomimetic, i.e., a synthetic enzyme, in applications where generation of phosphotyrosine is desired. As phosphorylation of tyrosine is an essential step in many signal transduction pathways such an artificial tyrosine protein kinase may have numerous medicinal applications. In addition, the complex is biologically active, stable under acidic conditions, and readily and inexpensively synthesized.
Complex 1 may be used a nutritive supplement for augmenting the diets of animals with chromium. The cationic complex may also be used to treat medical conditions associated with a decrease in chromium and/or responsive to enhanced bodily levels of chromium, e.g., adult-onset diabetes and other conditions associated with glucose intolerance, and cardiovascular disorders.
Complex 1 may be used alone for these purposes, or may be combined with excipients and/or other animal nutrients to provide a nutritive composition for bolstering chromium levels. The complex may also be combined with additional pharmaceutical agents.
REFERENCES:
patent: 5872102 (1999-02-01), Vincent et al.
patent: 0 037 144 A2 (1981-07-01), None
Glass et al, Nuclear magnetic resonance studies of multinuclear chromium assemblies. Polyhydron, vol. 12(2) pp. 133-140, 1993.
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Yu, “Study on the Dual Mu . . .”,Hua Hsueh Hsueh Pao. Acta Chimica Sinica, 1993, vol. 51, No. 6, pp. 579-585.
R. Weinland et al., “Über Salze Einer Grünen und Einer Violetten Propionato-Chrombase”,Zeitschrift fur Anorganische Chemie, 1911, vol. 69, pp. 158-178.
J. Vincent, “Heterotrinuclear Carboxylates of Chromuim(III) and Iron(III): Mixtures or Pure Compounds?”,Inorg. Chem., 1994, vol. 33, pp. 5604-5606.
Zelentsova et al., “Magnetism of Chromium(III) and Iron(III) . . .”, 1975, vol. 1, No. 2, pp. 194-201.
Szymanska-Buzar et al., “Mu.3-Oxotrimetalcarboxylates of 3D Elements . . .”,Koordinatsionnaia Khimiia, 1976, vol. 2, No. 9, pp. 1172-1191.
J. K. Speetjens et al., “The Nutritional Supplement Chromium(III) Tris(Picolinate) Cleaves DNA”,Chemical Research in Toxicology, Jan. 28, 1999, vol. 12, No. 6, pp. 483-487.
J. Vincent, “Mechanisms of Chromium Action: Low-Molecular-Weight Chromium-Binding Substance”,Journal of the American College of Nutrition, 1999, vol. 18, No. 1, pp. 6-12.
C. Davis et al., “Synthetic Multinuclear Chromium Assembly Activates Insulin Receptor Kinase Activity: Functional Model for Low-Molecular-Weight Chromium-Binding Substance”,Inorganic Chemistry, vol. 36, No. 23, pp. 5316-5320, Oct. 15, 1997.
R. Anderson et al., “Dietary Chromium Effects on Tissue Chromium Concentrations and Chromium Absorption in Rats”,The Journal of Trace Elements in Experimental Medicine, 1996, vol. 9, pp. 11-25.
M. Morita et al., “N2Laser-Excited Luminescence of Antiferromagne
Davis Catherine M.
Vincent John B.
Moezie, J.D. Minna
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
University of Alabama
Wang S.
LandOfFree
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