Biochemical and Pharmacologic Inequivalence of Low Molecular Weight Heparins

Abstract

LMW heparin fractions obtained from various sources must not be considered as bioequivalent in both the in vitro and in vivo responses. Because of compositional variations, these agents exhibit individual behavior and should be considered as distinct drugs whose safety and efficacy profile must be determined separately. Currently, there is no valid LMW heparin standard available, however, different LMW heparins can be profiled in identical test systems. It is erroneous to assume that most LMW heparins will behave in a similar fashion in terms of safety and efficacy. The need for defined tests to characterized these agents is evident and efforts to profile their actions should be made at both the basic and applied levels. Needless to say, the true efficacy of LMW heparins can only be validated in well-designed randomized clinical trials. Optimization of LMW heparins in preclinical pharmacologic studies, as reported here, is a crucial factor in the development of these agents. The superior clinical efficacy/safety performance of some of the LMW heparins in contrast to other LMW heparins is a result of extensive preclinical pharmacologic investigations undertaken to optimize the therapeutic index of these agents. Such optimization studies have not been conducted during the development of many LMW heparins, resulting in decreased efficacy and undue complications.

Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

“…In addition, doses used for systemic anticoagulant (AC) heparinization are accompanied by the potential for hemorrhage, electrolyte shifts, and thrombocytopenia in the acute setting and osteoporosis and alopecia over longer periods of time (5). Chemically modified heparin compounds have reduced AC properties but bleeding still remains a problem in some cases (6). Alternative therapies or routes of heparin administration have been sought and, though some have succeeded in prolonging the dosing interval, none has removed the need for and risks of systemic therapy.…”

Low Molecular Weight Heparins: Differences and Similarities in Approved Preparations in the United States

“…Thu s. besides the antithrombin (AT) III affinity components responsible for the ant i-Xu activity, other factors may be relevant. Figure 5 illustrates the antithrombotic activity measured in an animal model at equivalent anti-Xa dosages in the intravenous studies (rabbit stasis model) (1)(2)(3)(4). It is noted that the lowest intravenous antithrombotic acti vity in this model is seen with ardeparin, the highest is noted with dalteparin, and intermediate antithrombotic activity…”

“…Figure 2 illustrates that percentage of each preparation that is above the low molecular weight range (i.e., >7,500 d). It is noted that approximately 37% of enoxaparin, 25% of dalteparin, and 35% of ardeparin contain moieties of molecular weight >7,500 d (i.e., heparin moieties in the un fractionated heparin range) (1)(2)(3)(4). This molecular weight range includes chain lengths containing >20 hexose units.…”

“…Figure I compares the three available FDA approved LMWHs with respect to molecular weights <2.500 d, the range where relatively lillie anti-Xa or anti-I1a activity is detected. It is noted that approximately 15% of enoxaparin, 4% of dalteparin, and 6% of ardeparin is in this range (1)(2)(3)(4) …”

Determination of the Molecular Mass of New l-Fucose-Containing Glycosaminoglycan and Its Distribution by High-Performance Gel-Permeation Chromatography with Laser Light-Scattering Detection

“…4,5 Thus, it is important to clarify the molecular masses of DHG and FGAG and their distributions. The method so far employed for determining the molecular mass of a biopolymer and its distribution includes a physicochemical technique, 6,7 high-performance gel permeation chromatography (HPGPC) [8][9][10][11][12][13] and gel electrophoresis. [14][15][16][17] Among those, HPGPC combined with low-angle laser light-scattering (LALLS) detection was a convenient and reliable technique for determining the molecular mass of a biopolymer and its distribution.…”