Characterization of toxicity involving haemorrhage and cardiovascular failure, caused by parenteral administration of a soluble polyacrylate in the rat
✍ Scribed by R. Hicks; A. K. Satti; G. D. H. Leach; I. L. Naylor
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- English
- Weight
- 912 KB
- Volume
- 9
- Category
- Article
- ISSN
- 0260-437X
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✦ Synopsis
Adverse effects, involving a combination of hypotension and widespread haemorrhages, as well as evidence of vascullar and other tissue dissociation, associated with various systemic malfunctions (cyanosis, cardiac arrhythmias, neuromuscular disorder and death) were observed in the rat, from parenteral administration of a high-molecular-weight soluble polymer, sodium polyacrylate (EN21). Experiments to elucidate the mechanism of this effect involved comparisons with a low-molecular-weight sodium polyacrylate (EN5), either drug being given to groups of 5-8 rats, male or female, in doses of 5-100 mg/kg i.v., i.p. or s.c., or up to 1000 mg/kg p.0. Effects were observed visually up to the death of the animals, and these plus survivors killed after 10 h were prosected for macroscopic and histopathological examination of internal organs. Characteristic EN21 effects were only observed in animals treated by the i.p. and i.v. routes, death occurring in 4 1 0 h or rapidly (1 h) after i.v. dosage. No such effects were observed from EN5 by any dose or route. There were no differences between effects in male and female animals.
In rats anaesthetized with sodium pentobarbitone and cannulated for blood pressure recording (arterial and venous), no hypertensive effects were observed to explain haemorrhagic effects. Instead, i.v. and i.p. injections gave depressor effects, insidious in the latter case, with a precipitous fall only in the delayed terminal stage. Effects were accompanied by cardiac arrhythmias. Depressor effects were prevented by prior treatment of the animals with calcium chloride solution. These effects could not be evoked by EN5, nor by injection of methylcellulose solutions of equivalent high viscosity. It is suggested that, in the absence of pressor effects, haemorrhages must be explained by vascular fragility (angiostaxis), associated with disintegration of other tissues (e.g. intestinal villi). Other malfunctions, too rapid to be dependent on loss of blood, could be explained in terms of hypocalcaemia.
It is suggested that localization of this viscous, high-molecular-weight material in vascularized compartments, together with its known ability to form insoluble precipitates with calcium, leads to the operation of a calcium 'sink'. Resulting hypocalcaemia would explain neuromuscular and cardiac malfunctions, while radical loss of tissue calcium could lead to decrease in cellular adhesion. Resultant loss of tissue integrity could be consistent with observed haemorrhage and disintegrative lesions. physical properties have been shown to have only low oral t o x i ~i t y . ~, ~ However, some polyacrylamides and a uoMethvlene oxide) were shown to exert some