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ATP Executive Summary

By Eliezer Rapaport, Ph.D.

ATP in Physiology and Medicine

ATP, short for adenosine 5'-triphosphate, is a major human metabolite that powers all human activity. It exists both inside and outside virtually every cell of the body. How much ATP you have inside your cells determines how well they function and survive. It has been well established that intracellular ATP—the ATP within cells—is:

the major cellular energy source
a phosphate and adenylyl groups donor
an intermediate in numerous cellular biosynthetic reactions
a regulator of a variety of cellular proteins

Yet only in the past fifteen years has research revealed that extracellular ATP—the ATP outside cells—is important too. In fact, extracellular ATP plays a key role in supporting the health of the blood vessels, heart and muscles. These roles are attracting significant attention within the field of drug development.

Our bodies naturally manufacture ATP all the time, but there are certain factors—such as age, exercise and other stressors—that can deplete its levels. The seminal studies of Dr. Eliezer Rapaport, along with corroborating studies performed by other research groups, have shown that intravenous administration of ATP immediately increases levels of liver, red blood cell and extracellular ATP. Here's how: once it enters the body, the ATP is broken down into two other compounds: adenosine and inorganic phosphate. These compounds are incorporated into and expand the body's liver ATP pools. The liver ATP pools supply adenosine to the red blood cells, which use it as a building block to manufacture ATP. Then, the expanded red blood cell ATP pools are slowly released into the blood plasma.

Recently, it was convincingly demonstrated in animals and humans that orally administered ATP can also elevate ATP levels in the liver, red blood cells and extracellular blood plasma. In other words, you don't have to get an injection of ATP to increase your internal supplies— it's as convenient as taking a dietary supplement. Based out of Missoula Montana, TSI, Inc. has developed an ATP powder that can be formulated into a variety of dietary supplement products: powders, tablets and capsules. This represents a major advance in the ability to use exogenous ATP to benefit a variety of physiological functions in humans. It is especially important considering that articles in highly regarded scientific journals indicate that significant purine (adenosine and ATP) losses are associated with age, with impaired organ and muscle function, and are reported in a variety of harmful physiological conditions and diseases in experimental animals and in humans.

Development of ATP as a Dietary Supplement

Decades of exhaustive research by Dr. Rapaport have resulted in a unique portfolio of ATP patents. Under an agreement with Dr. Rapaport, TSI acquired exclusive license to seven issued patents and three pending patent applications. From his landmark research and expertise, TSI was able to introduce the first legitimate entry of ATP into the supplement marketplace. TSI's PEAK ATP® is the only product of its kind that is clinically tested to elevate internal levels of ATP, and the only ATP backed by Dr. Rapaport's research and patents.

A variety of published pre-clinical and human clinical trials have found that extracellular ATP and its major degradation product, adenosine, activate specific ATP and adenosine receptors on the cells that line the blood vessel walls, improving:

blood vessel tone and increasing vasodilation
the flow of blood to the heart, brain and peripheral areas, especially to skeletal muscles
the delivery of glucose, nutrients and oxygen to working and recovering muscles
the removal of catabolic waste products

The end result of these actions is that PEAK ATP increases energy and vitality as well as improves athletic performance and recovery.

The two overwhelming reasons for the past lack of development of ATP as an approved drug or a dietary supplement were the lack of adequate patent protection, as well as lack of an effective oral delivery form, of ATP. Both issues have been resolved by TSI's unique PEAK ATP ingredient.

Scientifically Documented Benefits of ATP Administration

Elevated ATP Levels

A large volume of scientific, pre-clinical and human clinical data indicating the benefits of ATP administration for a variety of human indications has recently been reviewed.^1,2 Dr. Rapaport was the first to demonstrate that administration of ATP in experimental animals elevated liver, red blood cell and extracellular pools of ATP.³ Subsequent human clinical trials have shown that ATP administered to humans readily expands intracellular ATP pools.^4,5 In other words, administering ATP increases the body's levels of ATP both inside and outside the cells.

Improved Blood Flow

Studies in humans show that as we age, or when we are afflicted with cases of advanced disease, intracellular levels of ATP drop significantly.^6,7 Similar studies in animals have shown that with age, there is a dramatic reduction in extracellular levels of ATP, which negatively affects blood pressure and the health of the blood vessels.^8,9 Administration of ATP can reverse this. Recent preclinical studies have demonstrated that oral administration of ATP in animals raises intracellular ATP pools.¹⁰ In similar doses, it also produces significant improvements in the health of the blood vessels and arterial oxygen pressure—without any adverse effects on blood pressure or heart rate.¹¹

Here's how it works: red blood cells release small amounts of ATP, which interact with ATP receptors on the layer of cells lining the blood vessels. This improves the tone of the blood vessels and relaxes the vessel walls so that more blood can get through to the heart, lungs and peripheries, especially skeletal muscles.^12,13

One of the most significant results of increased circulation is the beneficial effect on athletic performance. When ATP is infused into the leg arteries of healthy subjects, it can increase muscle blood flow as powerfully as exercise.¹⁴ Because of the increase in blood flow, more nutrients accumulate near the exercising muscle, supplementing it with the oxygen, glucose and other essential nutrients it needs to keep working. The stimulation of blood flow also enhances the removal of waste products such as lactic acid and ammonia from the muscles. This speeds recovery, which may enable athletes to train faster. ATP administration additionally increases cerebral blood flow, so it boosts mental acuity and may lessen the perception of fatigue and exercise-associated pain.¹⁵

It is now established that circulating extracellular ATP is the major regulator of local blood flow and oxygen delivery to exercising skeletal muscles in humans. Its ability to dilate blood vessels overrides the constriction of blood vessels that occurs when muscles contract.¹⁶

Increased Muscle Strength

In an editorial published in the prestigious Journal of Clinical Oncology, the authors refer to an advertisement which describes how supplemental ATP "helps athletes get bigger and stronger." Because the benefits of ATP administration are well documented, they state that "unlike so many popular claims for increasing strength and energy, this one may prove true."¹⁷

A recent unpublished study provides support for this assertion. The randomized, double-blind, placebocontrolled trial, performed at the Cooper Institute Centers for Integrated Health Research, studied the effects of PEAK ATP on 27 male bodybuilders aged 18-45. Men who took a high dose (225 mg) of the supplement daily for two weeks were able to do 18.5% more reps than before they started the treatment and total lifting volume increased by 1,552 pounds—a 28.2% gain.

Agretesch et al. provide data to suggest that ATP may actually help refractory, terminal cancer patients "get bigger and stronger." These investigators observed that ATP seems to favorably impact lung cancer patients who have failed chemo-and/or radiation therapy by allowing them to maintain body composition and to regain appetite.¹⁸ In an earlier publication from this same trial, the researchers also reported that ATP improves weight, strength, and quality of life.¹⁹ Additionally, ATP administration produced distinct benefits in muscle strength in elbow flexor and knee extensor muscle groups, as compared to patients that received only best supportive care.²⁰ As importantly, lean body mass and arm muscle area improved in the ATP-treated group as compared to the best supportive care group.²¹

1 Agretesch HJ, Dagnelie PC, van den Berg JWO, and Wilson JHP. Adenosine triphosphate, Established and potential clinical applications. Drugs 1999; 58:211-232.

2 Williams M., and Bhagwat SS. P2 Purinoceptors: a family of novel therapeutic targets. Annual Reports in Medicinal Chemistry 1996; 31:21-30

3 Rapaport E, and Fontaine J: Anticancer activities of adenine nucleotides in mice are mediated through expansion of erythrocyte ATP pools. Proc. Natl. Acad. Sci. USA 1989; 86:1662-1666

4 Haskell CM, Wong M, Williams A, and Lee LY. Phase I trial of extracellular adenosine 5′-triphosphate in patients with advanced cancer. Medicinal and Pediatric Oncology 1996; 27:165-173.

5 Agretesch HJ, Dagnelie PC, Rietveld T, van den Berg JWO, Danser AHJ, and Wilson JHP. Pharmacokinetics of intravenous ATP in cancer patients. Eur. J. Clin. Pharmacol. 2000; 56:49-55.

6 Rabini RA, Petruzzi E, Stafolani R, Tesei M, Fumelli P, Pazzagli M, and Mazzanti L. Diabetes mellitus and subjects' ageing: a study on the ATP content and ATP-related enzyme activities in human erythrocytes. Eur. J. Clin. Invest. 1997; 27:327-332.

7 Leij-Halfwerk S, Agretesch HJ, Sijens PE, and Dagnelie PC. Adenosine triphosphate infusion increases liver energy status in advanced cancer patients: an in vivo 31P magnetic resonance spectroscopy study. Hepatology 2002; 35:421-424.

8 Hashimoto M, Shinozuka K, Bjur RA, Westfall DP, Hattori K, and Masumura S.. The effects of age on the release of adenine nucleosides and nucleotides from rat caudal artery. J. Physiol. 1995; 489:841-848.

9 Shinozuka K, Hashimoto M, Kwon YM, Fukuda M, Tamashiro A, Kagota S, Yamaguchi Y, Masumura S, and Kunitomo M: Possible participation of ATP in changes of blood pressure in SHR and old rats. Jpn. Heart J. 1998; 39:535-537.

10 Kichenin K, and Seman M. Chronic oral administration of ATP modulates nucleoside transport and purine metabolism in rats. J. Pharmacol. Exp. Therap. 2000; 294:126-133.

11 Kichenin K, Decollogne S, Angignard, and Seman M. J. Appl. Physiol. 2000; 88:1962-1968).

12 Sprague RS, Ellsworth ML, Stephenson AH, and Lonigro AG. ATP: the red blood cell link to NO and local control of the pulmonary circulation. Am. J. Physiol. Heart Circ. Physiol. 1996; 271:H2717-H2722.

13 Dietrich HH, Ellsworth ML, Sprague RS, and Dracy Jr. RG. Red blood cell regulation of microvascular tone through adenosine triphosphate. Am. J. Physiol. Heart Circ. Physiol. 2000; 278:H1294-H1298.

14 Gonzalez-Alonso J, Olsen DB, Saltin B. Erythrocyte and the regulation of human skeletal muscle blood flow and oxygen delivery. Circ. Res. 2002; 91:1046-1055.

15 Forrester T, Harper AM, Mackenzie ET, Thompson EM. Effect of adenosine triphosphate and some derivatives on cerebral blood flow and metabolism. J Physiol. 1979; 296:343-355.

16 Rosenmeier JB, Hansen J, Gonsalez-Alonso J. Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle. J. Physiol. 2004; 558:351-365.

17 Jatoi A, and Loprinzi CL. Adenosine triphosphate: Does it help cancer patients "get bigger and stronger"? J. Clin. Oncol. 2002; 20:362-363.

18 Agteresch HJ, Rietveld T, Kerkhofs LGM, van den Berg JWO, Wilson JHP, and Dagnelie PC. Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: A randomized clinical trial. J. Clin. Oncol. 2002; 20: 371-378.

19 Agteresch H, Dagnlie PC, van der Gaast A, and Wilson JHP: Beneficial effects of adenosine triphosphate on quality of life in patients with advanced lung cancer: a randomized clinical trial. Proc. Amer. Soc. Clin. Oncology 1999;18:A2240.

20 Agteresch HJ, Dagnalie PC, van der Gaast A, Stijnen T, and Wilson JHP. Randomized clinical trial of adenosine 5`-triphosphate in patients with advanced non-small cell lung cancer. J. Natl. Cancer Inst. 2000; 92: 321-328. Original submission 9/25/02; Edited April 13, 2005

21 Dagnelie PC and Agteresch HJ. Promising effects of adenosine triphosphate infusion on nutritional status and quality of life in advanced non-small-cell lung cancer: a randomized clinical trial. Drug Development Research 2003; 59:146-151.