Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving transferase
Reexamination Certificate
2000-01-28
2003-05-20
Riley, Jezia (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving transferase
C514S001000, C514S014800, C546S026000, C546S027000, C546S063000, C546S073000, C546S233000
Reexamination Certificate
active
06566086
ABSTRACT:
BACKGROUND OF THE INVENTION
Creatine is a naturally occurring compound. Both creatine and its phosphorylated form, creatine phosphate, are found in mammalian brains, skeletal muscles, retinas, hearts, and other excitable tissues. Creatine, creatine phosphate and the enzymes that utilize them as substrates, i.e., the creatine kinases, represent an efficient system for the rapid regeneration of energy. Creatine phosphate is the product of the creatine kinase reaction which uses creatine as a substrate. Creatine and creatine phosphate can be chemically synthesized relatively easily and are believed to be non-toxic to mammals.
The creatine kinase/creatine phosphate energy system is one component of an elaborate energy-generating system found in body tissues such as nervous tissues and muscle cells (see, for example, Wallimann,
Biochem J.
(1992) 281:21-40). The components of the creatine energy system include the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the creatine transporter. Functions associated with this pathway include regeneration of energy in cells with fluctuating and high energy demands, energy transport to different parts of the cell, phosphoryl transfer activity, ion transport regulation, and signal transduction pathways involvement.
It is believed that creatine phosphate initially buffers ATP hydrolysis by regenerating ATP during high-intensity exercise. When present, creatine phosphate is thought to delay both the induction of glycolysis and the stimulation of mitochondrial oxidative phosphorylation. Unfortunately, creatine phosphate is typically depleted within ten seconds because of limited stores in muscle. Therefore, it is hypothesized that muscle performance may be favorably affected by increasing the muscle stores of creatine and creatine phosphate and, thus, delaying the depletion of creatine phosphate.
Within the last several years, creatine supplementation as an ergogenic aid has increased (for reviews, see Balsom et al.,
Sports Med.
(1994) 18(4):268-80; Greenhaff, et al. Int.
J. Sport Nutr.
(1995) Suppl:S100-110; Maughan, et al.
Int. J. Sport Nutr.
(1995) 5(2):94-101). Currently, there is widespread enthusiasm by many top athletes about the performance-boosting effects of creatine. Creatine supplementation is popular in many explosive sports such as bodybuilding, tennis, cycling, mountain biking, rowing, ski-jumping, fencing, cross-country skiing, down-hill skiing, rugby, handball, basketball, football and hockey.
Creatine oral supplementation has been shown to result in improved cell energy profiles. Improved energy profiles protect the function of cells (e.g., neural or muscle cells) by preventing oxidative damage, aberrant cell metabolism, and cell death. The improved energy profiles may be beneficial for treatment of aging by minimizing cell damage and death. Creatine and creatine compounds also may be able to be effective in other diseases which involve defective metabolic pathways, such as diabetes, obesity, and bone density related disorders.
Therapeutic uses of creatine and related compounds include the use of creatine compounds to treat neurodegenerative diseases such as Huntington's, Parkinson's, and ALS (WO 96/14063). In animal models of Huntington's disease, oral supplementation of either creatine or cyclocreatine was shown to protect the animals from malonate lesions(Matthews et al.,
J Neurosci.
(1998) 18(1):156-63).
Creatine supplementation has also been found to be useful for protecting against 3-NP neurotoxicity. Creatine has been shown to protect against MPTP-induced loss of neurons in the substantia nigra and prevented loss of dopamine and its derivatives in animal models of Parkinson's disease (Matthews et. al.,
Exp. Neurol.
(1999) 157(1):142-149). Furthermore, it was found that creatine both protects animal models from oxidative stress and improves their energy profiles. In an animal model of amyotrophic lateral sclerosis (ALS), creatine supplementation was shown to extend survival of subjects, improve their motor performance, and protect them against loss of motor neurons (Kliveny et.al,
Nat Med.
(1999) 5(3):347-50).
Creatine and creatine compounds have also been used in other therapeutic methods. For example, cyclocreatine has been found to restore functionality in muscle tissue (U.S. Pat. No. 5,091,404). Creatine and creatine compounds have been shown to inhibit cancers and the growth of certain tumors (WO94/16687; U.S. Pat. Nos. 5,324,731; 5,676,978); treat weight and energy related disorders, such as obesity; treat glucose related disorders, such as diabetes (WO 97/13507); and treat viral infections (U.S. Pat. No. 5,321,030). Creatine compounds have also been shown to increase bone density.
SUMMARY OF THE INVENTION
In one embodiment, the invention pertains to a method for determining creatine compound levels in a body sample of a subject. The method includes contacting a body sample with a creatine sensing substance, and analyzing the resulting mixture. Examples of preferred body samples include, for example, body fluids such as blood, saliva, sweat and urine. In an advantageous embodiment, the body sample is obtained non-invasively. In a particularly preferred embodiment, the creatine compound level is analyzed through a color change, e.g., a change in optical characteristics or fluorescence, of the creatine sensing substance and body fluid mixture. In a further embodiment, the method includes the step of administering a creatine compound to a subject. The subject may have, for example, sub-optimum creatine levels through out his entire body; sub-optimum levels in certain organs or areas (e.g., muscles or brain); or normal or above average creatine levels.
The invention also pertains to a kit suitable for determining creatine compound levels in a subject. Preferably, the kit includes directions for use. In one embodiment of the kit, the creatine sensing substance is embedded in a solid, permeable substrate. In another embodiment the kit includes a vial for mixing a creatine sensing substance with a body sample.
The invention further pertains to methods for comparing creatine levels to creatinine levels. The method includes contacting a body fluid of the subject with a creatine sensing compound and a creatinine sensing compound, and analyzing the resulting mixture. In one embodiment, the subject is suffering from kidney dysfunction. In another embodiment, the subject had previously been administered a creatine compound.
DETAILED DESCRIPTION OF THE INVENTION
The invention pertains, at least in part, to methods and kits for determining levels of creatine compounds in a body sample. In one embodiment, the invention pertains to a diagnostic kit that can detect levels of creatine compounds in body sample. The invention includes methods for determining the appropriate levels of a creatine compound, to administer to a subject who may be suffering from aberrant creatine compound levels due to disease or the aging process, or to a subject, for example, who may wish to optimize his creatine compound levels for its beneficial effects.
Creatine (also known as N-(aminoiminomethyl)-N-methylglycine; methylglycosamine or N-methyl-guanido acetic acid) is a well-known substance. (See, The Merck Index, Eleventh Edition, No. 2570 (1989)). Creatine can be phosphorylated chemically or enzymatically by creatine kinase to generate creatine phosphate (see, The Merck Index, No. 7315). Both creatine and creatine phosphate (phosphocreatine) can be extracted from animal tissue or synthesized chemically. Both are commercially available. Cyclocreatine is an essentially planar cyclic analog of creatine, which can be phosphorylated efficiently by creatine kinase both in vitro and in vivo. Although cyclocreatine is structurally similar to creatine, the two compounds are distinguishable both kinetically and thermodynamically (Rowley, G. L.,
J. Am. Chem. Soc.
(1971) 93:5542-5551; McLaughlin, A. C. et. al.,
J. Biol. Chem.
(1972) 247:4382-4388).
The term “creatine compounds” includes creatine, crea
Al Athel Fahad Mohammed Saleh
Bell Thomas W.
Kaddurah-Daouk Rima
Khasanov Alisher B.
FAL Diagnostics
Hanley, Esq. Elizabeth A.
Lahive & Cockfield LLP
Riley Jezia
Soroos Cynthia M.
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