For those that are interested in some tnagible data, here you go.
Current Patents on GPA itself…Without using Creatine
R. P. Shields, C. K. Whitehair, R. E. Carrow, W. W. Heusner, and W. D. Van Huss: Skeletal muscle function and structure after depletion of creatine. Lab. Invest. 33: 151-158, 1975, indicates that 3-guanidinopropionic acid results in decreased exercise tolerance in rats. In T. S. Moerland, N. G. Wolf, and M. J. Kushmerick, Administration of a creatine analogue induces isomyosin transitions in muscle. Am. J. Physiol. 257:C810-C816, 1989, 3-guanidinopropionic acid was observed to have no effect on spontaneous running activity in mice.
U.S. patent application, Ser. No. 07/486,615, filed 28 Feb. 1990, discloses a method of using 3-guanidinopropionic acid to treat or prevent excess adiposity. U.S. Patent application, Ser. No. 07/712,862, filed 10 Jun. 1991, discloses a method of using 3-guanidinopropionic acid to treat non-insulin dependent diabetes mellitus (NIDDM). The following international patent applications correspond to the above U.S. patent applications: PCT/US 91/00334, filed 22 Jan. 1991, and PCT/US 91/01109, filed 27 Feb. 1991. U.S. Pat. No. 3,843,798 discloses a method for using 3-guanidinopropionic acid to treat bacterial infections and pharmaceutical compositions useful therefor.
British patents 1,195,199and 1,195,200 and 1,552,179 refer to pharmaceutical compositions of guanidinoalkanoic acids, their esters and amides, in combination with insulin or inhibitors of hepatic gluconeogensis.
Moreland, Am. J. Physiol. 257 (Cell Physiol 26): C810-816, 1989) discloses 3-GPA as ineffective on blood glucose when administered in food to rats in high concentrations.
SUMMARY OF THE INVENTION
The present invention particularly provides:
A method of increasing endurance, stamina or exercise capacity in a mammal which comprises:
the administration to the mammal of an amount of 3-guanidinopropionic acid or a pharmaceutically acceptable salt thereof effective to increase the endurance, stamina or exercise capacity of the mammal.
The present invention also provides a food product which comprises:
a) a food; and
b) 3-guanidinopropionic acid or a pharmaceutically acceptable salt thereof in an amount effective to:
1) increase the endurance, stamina or exercise capacity of a mammal in need thereof;
2) treat excess adiposity in a mammal in need thereof; or
3) treat non-insulin dependent diabetes mellitus (NIDDM) in a mammal in need thereof.
By "3-GPA" is meant 3-guanidinopropionic acid. Pharmaceutically acceptable salts of 3-guanidinopropionic acid are described in the references cited above and are well known to one of ordinary skill in the art.
By "increasing endurance, stamina or exercise capacity" is meant as increase in the ability to participate in or maintain participation in physical activity, such as exercise.
By "mammal" is meant any of a class (Mammalia) of higher vertebrates comprising man and all other animals that nourish their young with milk secreted by mammary glands and have the skin usually more or less covered with hair. Especially included in this definition are human beings, whose endurance, stamina or exercise capacity is less than optimal. Such human and non-human animals are readily diagnosed by a physician or veterinarian of ordinary skill.
By "food" or "food product" is meant a material used in the body of a mammal to sustain growth, repair, and vital processes and to furnish energy. Both solid and liquid food products are included.
By "food additive" is meant a substance that is added to a food or food product.
By "nutritional supplement" is meant a substance that supplements a mammal's nutrition, such as vitamins.
The dosage regimen for 3-guanidinopropionic acid in accord with this invention will depend on the body weight of the patient. Typically, the dose of 3-guanidinopropionic acid to be used is between 10 and 4000 mg/kg body weight daily. The preferred dose is 10-400 mg/kg/day.
3-Guanidinopropionic acid may be administered by any convenient route of administration, e.g., orally, parenterally, intranasally, intranasally, intrarectally, or topically. The oral route is preferred.
The above compositions may be administered in a sustained release formulation. By sustained release is meant a formulation in which the drug becomes biologically available to the patient at a measured rate over a prolonged period. Such compositions are well-known in the art.
3-GPA may be administered orally in conventional foodstuffs. For example, 3-GPA may be dissolved in juices, such as orange juice, preferably at a concentration of 75 mg/ml and taken by mouth. 3-GPA is adaptable to making a flavored dry mix which is constituted into a flavored beverage by simply adding water. These flavored mixes typically contain a viscosity inducing agent such as a gum or low molecular weight synthetic polymer; flavoring agents such as sucrose, aspartame or sodium saccharin; colorants; wetting agents or surfactants such as dioctyl sodium sulfosuccinate or sodium lauryl sulfate; agents to provide tartness and control acidity such as citric acid, ascorbic acid, potassium citrate or sodium citrate; flavorants such as lemon or orange; and preservative such as BHA. Similarly, 3-GPA can be used as an additive to powdered food products, including pudding and pie filling mixes, gelatin, cake mixes, powdered eggs and powdered potatoes, instant breakfast drinks, gravies and sauces (e.g., Hollandaise), prepared cereal products (e.g., oatmeal, cream of wheat, hominy grits), and drink mixes (e.g., powdered fruit punches, powdered fruit drinks). Likewise, 3-GPA can be used in prepared foods themselves; for example, it can be used as an additive in cakes, pasta products, candy, cookies, confections, yogurts, including frozen yogurt products, ice cream and ice ream products and prepared meats (hamburger, sausages and the like).
The effective amount of 3-GPA is liquid food products ranges from 10 to 400 mg/ml. Preferably the amount ranges from 70 to 300 mg/ml, with 75 mg/ml being most preferred. The effective amount of 3-GPA in solid food products ranges from 1 to 500 mg/g.
In the present invention, it has been found that 3-GPA increases exercise tolerance in normal mice (FIG. 1 and Table 1). Thus the present invention may be useful in treating muscular dysfunction, such as post-poliomyelitis chronic muscle fatigue syndrome or muscular and therefore is beneficial in treating or preventing disease states involving tissue hypoxia, e.g., peripheral claudication and exercise intolerance in diabetic humans, and angina, myocardial infarction and stroke in diabetic and normal humans.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is seen more fully by the example below.
EXAMPLE 1
Effect of 3 -GPA on Exercise Performance in Normal Mice
C57BL6J mice, 105-150 days of age, were obtained from Charles River Laboratories (Portage, Mich.). Mice were individually caged and maintained at 21.+-.1.degree. C. using a 12 h light cycle. They were allowed free access to tap water and powdered Purina 5015 mouse chew containing 20 mg/g .beta.-GPA, resulting in a daily intake of 4 g/kg body weight, or unsupplemented chow.
Briefly, mice were placed on a standard rodent exercise wheel, 22 inches in circumference, in a pan with water to a depth of approximately 1/4 inch, so that it was necessary for them to run in order to remain above the water. When a mouse ceased running the wheel was tapered by the operator to stimulate further activity. The procedure was recorded on video tape to permit data analysis.
The results of this study are presented in FIG. 1 and Table 1 below. 3-Guanidinopropionic acid increased exercise performance when administered to C57BL6J mice in the diet for one month. The total distance run, the running time, and the latency to exhaustion were increased by 3-guanidinopropionic acid.
BRIEF DESCRIPTION OF THE DRAWING
FIGURE Effect of 3-GPA on exercise performance in C57BL6J mice. Data are shown as means.+-.S.E.M. for revolutions of the exercise wheel. Data for each 5 min interval are expressed as moving averages calculated from t=0. N=5 mice/group. 3-GPA refers to mice administered chow supplemented with 20 mg/g 3-guanidinopropionic acid for 32 days. ##STR1##
TABLE 1
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Effect of 3-guanidinopropionic acid on running performance in
C57BL6J mice. Compound were mixed in the chow at 20 mg/g for
one month or unsupplemented chow was provided.
3-Guanidinopropionic
P-
CONTROL acid VALUE
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Running rat
16 .+-. 1 26 .+-. 3 <0.05
(0-45 min) (ft/min)
Total distance run 719 .+-. 65 1175 .+-. 136 <0.05
(0-70 min) (ft)
Total distance run 719 .+-. 65 1839 .+-. 205 <0.05
(0-70 min) (ft)
Latency to 45 >70
exhaustion (min)
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Running performance was measured in mice on an exercise wheel, 22 inches in circumference. The procedure was recorded on video tape in order to permit data analysis. Exhaustion was indicated by an abrupt decrease in running performance. In the case of 3-GPA treated mice exhaustion did not occur and the procedure was terminated by the technician after increased endurance was clearly demonstrated.