Erythropoietin (EPO) appears to be assuming larger and more important role in medicine, and in sports doping. EPO, a natural hormone produced in the kidney stimulates (regulates) the production of red blood cells (RBCs). RBC, by utilizing hemoglobin, carry oxygen loaded in the lungs to all the 'peripheral tissues' like heart, brain, muscles, gonads, etc.. Hemoglobin then captures CO2 -- a waste product from cellular metabolism -- to be carried back to the lungs where the waste C02 is exchanged for oxygen.
EPO can be abused by cyclists, and track athletes, based on the improvement of oxygen delivery to the muscles, and even the CNS. However the use of EPO is dangerous, causing blood clots in critical vessels (like heart).
EPO became useful for the treatment of kidney failure. Kidney failure can be caused by many diseases: hypertension, diabetes, genetic metabolic conditions etc. Those patients suffered from anemia, treated with EPO. From Medscape:
The use of erythropoietin (Epo) in treating anemia of chronic kidney disease (CKD) has transformed the lives of millions of individuals.[1] In the pre-epoetin era, patients had to live with the symptoms of severe anemia, multiple transfusions, and frequent hospitalization. Recombinant erythropoietin (rhEpo) was approved in 1989 for the treatment of CKD anemia. Widespread use of Epo in the management of CKD anemia ensued. Over the past 2 decades, the market for Epo has dramatically increased. It is now estimated that $22 billion worth of Epo has been sold.[2] This vast market opportunity has not gone without notice in the pharmaceutical industry, and many Epo analogues and derivatives have entered the marketplace. These newer Epos are now grouped under the term erythropoietin-stimulating agents or ESAs. In addition, follow-on epoetins (FOEs), similar to the innovator epoetin, are now commonplace, particularly in emerging countries.
Here is a review of EPO's structure:
Epo is an acidic glycoprotein with a molecular weight of 30.4 kDa (Table ).[3,4]
The carbohydrate part of the molecule (approximately 40%) is composed of 3 N-linked and 1 O-linked glycan moieties. N-glycans are key to the biological activity of Epo; the addition of N-glycans into rhEpo increases the carbohydrate content and results in prolonged survival of the molecule. From a structural perspective, Epo has a basic structure like other cytokines (eg, the interleukins). It is composed of 4 amphipathic {alpha}-helical bundles. There are 2 domains located on Helix C and Helix D that are necessary for binding to the Epo receptor (EpoR). Following binding to the EpoR, a JAK2-mediated signal transduction cascade ensues (Figure 1). Epo's binding affinity is also critical to its action. Epoetin-alfa has a high binding affinity, whereas newer derivatives such as continuous erythropoietin receptor activator (CERA) have much lower affinities that are thought to contribute to the longer
half-life of these molecules...
In the years following the launch of rhEpo, it became apparent that N-linked glycosylation increased the half-life of the Epo molecule. In 2001, darbepoetin, a longer-acting derivative of epoetin-alfa, was approved. In 2007, CERA, a derivative of epoetin-beta, received regulatory approval. Both darbepoetin-alfa and CERA have a prolonged half life compared with epoetin-alfa or epoetin-beta (Figure 2); these agents have been extensively tested in phase 2 and 3 programs and allow less frequent dosing of Epo in the management of CKD anemia...
If it means something to you, CERA is pegylated EPO:
CERA is a pegylated form of epoetin-beta. CERA is a 60-kDa molecule, approximately twice the molecular weight of epoetin-alfa.[12,13] A large methoxy-polyethylene glycol polymer is incorporated into the epoetin molecule, essentially doubling its molecular weight compared with epoetin. This modification markedly prolongs CERA's half-life in humans to about 135 hours. In addition, CERA binds to EpoR more slowly than Epo. These 2 attributes result in CERA triggering the JAK2 Epo signal transduction cascade without being internalized. Consequently, CERA has more sustained biologic activity. CERA has been tested extensively and can be used less frequently than epoetin-alfa or darbepoetin-alfa -- it can be administered either once every other week or once monthly.[14-16]
If you are a anti-doping agency you will not be happy to read that different ways to stimulate EPO are on the way.
Small-molecule Epo mimetic peptides (EMPs) provide a novel paradigm to stimulate Epo. EMPs are peptide sequences that bind and activate EpoR. For example, Wrighton and colleagues[25,26] have identified a 20-amino-acid peptide (GGTYSCHFGPLTWVCKPQGG) that binds EpoR and has both in vivo and in vitro biologic activity. An example of an EMP that has entered clinical trials with much promise is Hematide (Affymax Inc., Palo Alto, California).[27] This is a pegylated dimeric EMP that has no sequence homology to Epo but binds and activates EpoR. PEGylation enhances the stability and prolongs the half-life of the molecule (t1/2 of up to 60 hours). Hematide is now being evaluated in phase 2 studies both in renal patients and in patients with cancer.[28,29] Other EMPs are also in the pipeline.
EPO can be a very effective performance enhancing agent. Given the advances in the molecular pharmacology of EPO, it will be a formidable task to prevent EPO abuse in sport.
The medical world will take its benefit from it, i consider it a good discovery though.
Posted by: golf clubs | 01/31/2011 at 04:25