Date of Award

2017

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmacology and Experimental Therapeutics

Abstract

Heparin, a highly sulfated glycosaminoglycan (GAG), is used extensively as an anticoagulant. It consists of repeating disaccharide units, containing iduronic acid (or glucuronic acid) and glucosamine, exhibiting variable degrees of sulfation. Heparin, and its analogues, are used during surgery and dialysis, and are often used to coat indwelling catheters and other devices where the vascular system is exposed. Administered parenterally, often continuously due to its short half-life, over 0.5 billion doses are required per year. Heparin is currently obtained from mucosal tissue of meat animals, mainly porcine intestine, and to a lesser extent bovine and ovine sources. The early stages of production are poorly controlled, due to the source of the material. This problem came into sharp focus in 2008 when the presence of contaminating over-sulfated chondroitin sulfate in heparin sourced from China resulted in almost 100 deaths in the USA. Coupled with the fact that only a few doses are obtained from each animal and due to cultural and religious reasons in some countries, alternative and well controlled sources of heparins are needed. The FDA and other regulatory agencies are currently considering the introduction of bovine and ovine unfractionated heparins. Worldwide, there are 1.4 billion cattle, 1.9 billion sheep and goats and 980 million pigs. Both cow and sheep provide potential alternate sources of porcine heparin. Nowadays, with the advances in technology and manufacturing processes, higher quality bovine and ovine heparins are now available in various part of the world and have been shown to exhibit similar biologic and clinical profiles compared to porcine one.

In this dissertation, we focused on determining the extent of biosimilarity between bovine, ovine, and porcine heparins and how differences in molecular weight and strcturual composition may affect the pharmacological activity of these agents. Ten batches of each heparin were used throughout this project. These studies have shown that bovine, ovine and porcine heparins exhibit comparable molecular profiles. However bovine heparins showed weaker anticoagulant and antiprotease activities compared to ovine and porcine ones. The neutralization profiles of all heparins were comparable at the same concentrations. Studies in platelet based systems showed that the HIT antibody interactions among heparins from different species were comparable. In Vivo studies in animal model showed that, the anti-Xa and anti-IIa effects of ovine and porcine heparins were significantly stronger compared to bovine heparins after IV administration. However, bovine heparins showed significantly longer half -life (T1/2) compared to porcine and ovine heparins with no major variations in AUC, Vd and CL parameters between each agent.

In conclusion, these studies show that ovine and porcine heparins are biosimilar and can be developed as such for clinical purposes. The bovine derived heparins exhibit slightly weaker potencies in functional assays despite comparable molecular profile. Potency adjustment for in vivo usage may be required to obtain comparable anticoagulant responses for the bovine heparin. Soon, bovine and ovine heparins may fill an unmet need not only for the Muslim world but also for Western countries as a potential alternate source of heparin.

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