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Three Generations of Bile Acid Sequestrants

Published online by Cambridge University Press:  15 February 2011

W. Harry Mandeville ,
William Braunlin ,
Pradeep Dhal ,
Amy Guo ,
Chad Huval ,
Karen Miller ,
John Petersen ,
Steven Polomoscanik ,
David Rosenbaum  and
Robert Sacchiero
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W. Harry Mandeville
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
William Braunlin
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Pradeep Dhal
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Amy Guo
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Chad Huval
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Karen Miller
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
John Petersen
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Steven Polomoscanik
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
David Rosenbaum
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
Robert Sacchiero
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
James Ward
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
S. Randall Holmes-Farley
Affiliation:
GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02451
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Abstract

Cholestyramine, the first bile acid sequestrant to be marketed, has been in use for over 20 years. Despite its low potency, requiring 16-24 g of polymer to achieve 20% LDL cholesterol reduction in hypercholesterolemic individuals, only one other sequestrant, colestipol, has come to market in the ensuing period. GelTex Pharmaceuticals has been involved for over six years in the discovery and development of new, more potent polymeric sequestrants. Two binding mechanisms are presented — one that operates via an aggregate binding structure and one that is effective via a defined site binding structure. These two binding mechanisms are compared and contrasted through bile acid binding isotherms. The best of these new sequestrants bind bile acids through a combination of hydrophobicity and ion exchange. Optimization and balancing of each of these interactions led us to more potent materials. The first of these, colesevelam hydrochloride is expected to be three to four times more potent than cholestyramine. A third generation product is still in research at GelTex. With another twofold increase in potency possible, single tablet therapy may become a reality.

Type
Research Article
Information
MRS Online Proceedings Library (OPL) , Volume 550: Symposium GG/HH/II – Biomedical Materials-Drug Delivery, Implants and Tissue Engr , 1998 , 3
Copyright
Copyright © Materials Research Society 1999

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