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Body and mind

Creatine shows promise for the treatment of neurodegenerative and neuromuscular disorders

SupermanFor many years, the media has paid significant attention to the use of creatine supplementation by body builders and athletes as a legal strategy widely used to enhance performance. However, it is also becoming apparent that creatine may have therapeutic utility in the treatment of neurological disorders such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Creatine, or methylguanidine-acetic acid, is a naturally occurring compound that may be obtained from dietary sources such as meat or fish, or it may be synthesised internally by the liver and pancreas from the amino acids, arginine, glycine and methionine.

Approximately two grams of creatine, or about half a kilogram of fresh, uncooked steak is required daily from either internal or external sources to replace natural depletion. A 70 kilogram human male has a total creatine pool of approximately 120 grams, 95 per cent of which is found in the skeletal muscle. About 60 per cent of the total pool is present in the form of phosphorylated creatine, also called phosphocreatine. Phosphorylation of creatine is a rapid and reversible process, allowing donation of a phosphate group to adenosine diphosphate (ADP) to form adenosine triphosphate (ATP), a high-energy phosphate required for performing high-intensity, short-duration physical activity. As the combined supply of ATP and phosphocreatine is only able to sustain very high-intensity exercise for approximately 10 seconds, creatine supplementation provides athletes with a means to boost natural stores. Creatine supplementation is thought to facilitate the generation of intramuscular phosphocreatine and subsequent ATP formation to prolong the duration of high-intensity exercise in activities such as sprint running, swimming, cycling and weight lifting.

Despite the ability of creatine to improve exercise performance, its use is allowed by the International Olympic Committee (IOC). This is somewhat paradoxical given the provision in IOC anti-doping legislation that consuming a substance in abnormal quantities with the intent of artificially and unfairly enhancing sports performance may be construed as doping. However, as creatine is a natural dietary constituent, detection would be problematic with current testing procedures, even if its use was prohibited. While creatine is also officially classified as a dietary supplement by legislation in the US, the Federal Drug Administration (FDA) does not regulate the variety of creatine products available from supermarkets, nutrition stores or via the internet. While the lack of regulation may seem alarming, the availability of creatine for over half a century has generated a great deal of information in support of a therapeutic utility for creatine.

GENERIC NAME

TRADE NAME (COMPANY)

INDICATION

COUNTRY

Granisetron transdermal Sancuso (ProStrakan) Chemotherapy-induced nausea and vomiting USA
Calcipotriol/betamethasone Xamiol (LEO Pharma) Psoriasis Europe
Insulin oral Oral-lyn (Generex Biotechnology) Type-1 and Type-2 diabetes mellitus India
Tetrabenazine Xenazine (OVATION Pharmaceuticals) Huntington's disease USA


Avicena Group currently markets a medical grade, ultra-pure formulation of creatine monohydrate over-the-counter as Neotine. The product is sold in single-serve sachets produced under good manufacturing practice (GMP) to ensure creatine purity levels of at least 99.9 per cent. According to Avicena, Neotine is the only creatine product that has been clinically shown to increase levels of creatine in the brain. In collaboration with a number of research institutions, Avicena has also shown that by enhancing the production and delivery of optimal levels of energy to the brain and body, creatine may promote healthy neuronal function, support muscle control and motor function, and generally improve quality of life among patients with neurodegenerative and neuromuscular disorders. As such, the company is pursuing development of pure creatine products for pharmaceutical as well as nutraceutical purposes.

Avicena is evaluating three creatine drug candidates for the lead indication of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ALS is a progressive neurodegenerative disease of the brain and spinal cord that inhibits voluntary muscle control, eventually leading to paralysis and death. Avicena's lead development candidate for ALS, called ALS 02, has received orphan drug designation from the FDA and recently completed an initial phase III trial. Combined results from this trial and another study previously conducted by the North East ALS Consortium (NEALS) demonstrated a positive trend towards decreased mortality in patients receiving creatine. The company has also initiated phase II development with one of the other creatine candidates, ALS 08, in combination with the non-steroidal anti-inflammatory drug (NSAID), celecoxib. Presently the only drug available for the treatment of ALS symptoms – Rilutek – is able to increase life expectancy by only a few months.

Due to its role in energy production, creatine has also been investigated in diseases involving an element of mitochondrial dysfunction, such as Huntington's disease and Parkinson's disease. Avicena is exploring this avenue of research and has been granted orphan drug status from the FDA for a creatine product under evaluation for Huntington's disease. A completed phase I/II trial for Huntington's disease at Massachusetts General Hospital showed that the agent produced an increase in serum and brain creatine levels, while decreasing the levels of an oxidative marker. Similarly, a lead creatine candidate for Parkinson's disease was shown to be safe and tolerable in phase II efficacy trials at the University of Rochester. The study also demonstrated that the rate of disease progression in patients on creatine was lower than the threshold for futility, as measured by the Unified Parkinson's Rating Scale (UPDRS).

Avicena has also conducted phase I trials of purified creatine products for the treatment of Duchenne Muscular Dystrophy (DMD) and Charcot-Marie-Tooth (CMT) syndrome. Both DMD and CMT are genetic, neurodegenerative disorders resulting in progressive loss of muscle function. Since 95 per cent of creatine in the body is found in skeletal muscle, it is expected that external treatment may be useful in patients with atrophy or muscle fatigue secondary to impaired energy production. Preclinical studies by Avicena are also evaluating the utility of creatine therapies for the treatment of creatine transporter defect (CTD). Identified in 2001, CTD is an inherited error of metabolism that inhibits the ability of the human body to supply sufficient levels of creatine to the brain via the creatine transporter.

While creatine supplementation presents a legal and scientifically supported means of improving performance during high-intensity exercise, its therapeutic application is yet to be definitively demonstrated. Avicena intends to discuss its findings to date with the FDA in order to determine the appropriate development steps required to gain regulatory approval for creatine as a pharmaceutical agent.

The Author
Pipeline was written by Lauren Donley of R&D Insight, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733.
To comment on this article, email pm@pmlive.com

18th March 2009

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