Abstract
Purpose. The purpose of this study was to investigate the effect of experimental renal failure and hypotonic hyponatremia on the pharmacodynamics of cefazolin (CEZ)-induced seizures.
Methods. Rats received an intravenous infusion of CEZ until the onset of seizures. Renal failure was produced by bilateral ureteral ligation (UL) or uranyl nitrate (UN) injection. Hypotonic hyponatremia was produced by intravenous infusion of 5% dextrose in water or intraperitoneal infusion of distilled water after arginine vasopressin injection.
Results. The serum and brain concentrations of CEZ at the onset of seizures increased with increasing infusion rate, but the CSF concentration of CEZ at the onset of seizures was not affected by the infusion rate. The concentration of CEZ in CSF at the onset of seizures was significantly lower in UL rats than control rats, whereas there was no difference between UN rats and their controls. Serum concentrations of Na+ and serum tonicity were lower in UL rats than UN rats. Hypotonic hyponatremia had no apparent effect on the CSF concentration of CEZ. The CSF concentration of CEZ at the onset of seizures was significantly lower in UN rats with hypotonic hyponatremia than their controls.
Conclusions. Renal failure with severe hypotonic hyponatremia is associated with increased central nervous system sensitivity to CEZ-induced seizures.
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References
T. P. Bechtel, R. L. Slaughter, and T. D. Moore. Seizures associated with high cerebrospinal fluid concentrations of cefazolin. Am. J. Hosp. Pharm. 37:271–273 (1980).
R. L. Yost, J. D. Lee, and J. P. O'Leary. Convulsions associated with sodium cefazolin: a case report. Am. Surg. 43:417–420 (1977).
M. Nishida, T. Matsubara, T. Murakawa, Y. Mine, and Y. Yokota. Cefazolin, a new semisynthetic cephalosporin antibiotic. III. Absorption, excretion and tissue distribution in parenteral administration. J. Antibiotics 23:184–194 (1970).
M. Nagata and M. Yasuhara. Effect of experimental renal failure on the pharmacodynamics of cefoselis-induced seizures in rats. Biol. Pharm. Bull. 24:1049–1052 (2001).
I. M. Ramzan and G. Levy. Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats. J. Pharmacol. Exp. Ther. 240:584–588 (1987).
I. Ramzan and G. Levy. Kinetics of drug action in disease states XXXIII: Disparate effects of pentylenetetrazol in rats as a function of renal disease model and pharmacologic endpoint. J. Pharm. Sci. 78:142–145 (1989).
Y. Nakada, K. Yamamoto, J. Kawakami, Y. Sawada, and T. Iga. Effect of acute renal failure on neurotoxicity of cimetidine in rats. Pharm. Res. 12:1953–1957 (1995).
I. Ramzan. Theophylline neurotoxicity is unaffected by glycerol-induced renal failure. Pharmacol. Biochem. Behav. 37:583–585 (1990).
F. J. Gennari. Current concepts. Serum osmolality. Uses and limitations. N. Engl. J. Med. 310:102–105 (1984).
M. Danhof and G. Levy. Kinetics of drug action in disease states. I. Effect of infusion rate on phenobarbital concentrations in serum, brain and cerebrospinal fluid of normal rats at onset of loss of righting reflex. J. Pharmacol. Exp. Ther. 229:44–50 (1984).
S. Hori, S. Kurioka, and M. Matsuda, and J. Shimada. Inhibitory effect of cephalosporins on γ-aminobutyric acid receptor binding in rat synaptic membranes. Antimicrob. Agents Chemother. 27:650–651 (1985).
A. I. Arieff, F. Llach, and S. G. Massry. Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine (Baltimore) 55:121–129 (1976).
J. C. Ayus, R. K. Krothapalli, and D. L. Armstrong. Rapid correction of severe hyponatremia in the rat: histopathological changes in the brain. Am. J. Physiol. 248:F711-F719 (1985).
O. Arisaka, N. Shimura, A. Hosaka, Y. Nakayama, K. Kaneko, M. Maeda, and K. Yaubta. Water intoxication in asthma assessed by urinary arginine vasopressin. Eur. J. Pediatr. 148:167–169 (1988).
D. Milford and C. M. Taylor. Hyponatraemia and haemolytic uraemic syndrome. Lancet 25:439(1989).
V. Vanapruks and K. Prapaitrakul. Water intoxication and hyponatraemic convulsions in neonates. Arch. Dis. Child. 64:734–744 (1989).
H. J. Adrogue and N. E. Madias. Hyponatremia. N. Engl. J. Med. 342:1581–1589 (2000).
J. Zhi and G. Levy. Kinetics of drug action in disease states. XXXVII. Effects of acute fluid overload and water deprivation on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline in rats. J. Pharmacol. Exp. Ther. 251:827–832 (1989).
A. Hoffman and G. Levy. Kinetics of drug action in disease states. XXXIX. Effect of orally administered activated charcoal on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline administered intravenously to rats with renal failure. Pharm. Res. 7:242–246 (1990).
P. P. De Deyn, R. D'Hooge, P. P. Van Bogaert, and B. Marescau. Endogenous guanidino compounds as uremic neurotoxins. Kidney Int. 59:S77-S83 (2001).
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Nagata, M., Fujichika, T. & Yasuhara, M. Effect of Experimental Renal Failure and Hypotonic Hyponatremia on the Pharmacodynamics of Cefazolin-Induced Seizures in Rats. Pharm Res 20, 937–942 (2003). https://doi.org/10.1023/A:1023855723584
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DOI: https://doi.org/10.1023/A:1023855723584