[Acute glyphosate-surfactant poisoning with neurological sequels and fatal outcome]. / Akutno trovanje glifosat-surfaktantom sa neuroloskim sekvelama i letalnim ishodom.

INTRODUCTION: Clinical picture of severe glyphosate-surfactant poisoning is manifested by gastroenteritis, respiratory disturbances, altered mental status, hypotension refractory to the treatment, renal failure, shock. Single case report indicated possible neurotoxic sequels of glyphosate-surfactant exposure with white matter lesions and development of Parkinsonism. We described a patient with massive white matter damage which led to vigil coma and lethal outcome. CASE REPORT: A 56-year old woman ingested about 500 mL of herbicide containing glyphosate isopropylamine salt. The most prominent manifestation of poisoning included hypotension, coma, hyperkaliemia, respiratory and renal failure. The patient was treated in intensive care unit by symptomatic and supportive therapy including mechanical ventilation and hemodialysis. The patient survived the acute phase of poisoning, but she developed vigil coma. Nuclear magnetic imagining revealed extensive bilateral lesions of the brain stem white matter and pons. CONCLUSION: The outcome of reported poisoning may be the consequence of glyphosate-surfactant neurotoxic effect or/and ischemia, especially in the episodes of marked hypotension during hemodialysis. Considering recommendation of early hemodialysis as the treatment of choice, even before renal failure development, we point out the importance of careful planning of dialysis modality in hemodynamically instable patient and recommend continuous dialysis methods.

[Pharmacodynamic and pharmacokinetic effects of flumazenil and theophylline application in rats acutely intoxicated by diazepam].

BACKGROUND/AIM: The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively poli-synaptic routes by stimulating inhibitory action of GABA. The aim of the present study was to examine the effects of combined application of theophylline and flumazenil on sedation and impaired motor function activity in acute diazepam poisoning in rats. METHODS: Male Wistar rats were divided in four main groups and treated as follows: group I--with increasing doses of diazepam in order to produce the highest level of sedation and motor activity impairment; group II--diazepam + different doses of flumazenil; group III--diazepam + different doses of theophylline; group IV--diazepam + combined application of theophylline and flumazenil. Concentrations of diazepam and its metabolites were measured with LC-MS. The experiment was performed on a commercial apparatus for spontaneous motor-activity registration (LKB-Farad, Sweden). Assessment of diazepam-induced neurotoxic effects and effects after theophylline and flumazenil application was performed with rotarod test on a commercial apparatus (Automatic treadmill for rats, Ugo Basile, Italy). RESULTS: Diazepam in doses of 10 mg/kg and 15 mg/kg produced long-time and reproducible pharmacodynamic effects. Single application of flumazenil or theophylline antagonized effects of diazepam, but not completely. Combined application of flumazenile and theophylline resulted in best effects on diazepam-induced impairment of motoric activity and sedation. As a result of theopylline application there was better elimination of diazepam and its metabolites. CONCLUSION: Combined application of flumazenil and theophylline resulted in the best antidotal effects in the treatment of diazepam poisoned rats. These effects are a result of different mechanisms of their action, longer half-life of theophylline in relation to that of flumezenil and presumably the diuretic effect of theophylline.

A pharmacokinetic comparison of three pharmaceutical formulations of nimesulide in healthy volunteers.

BACKGROUND/AIM: Switching the patient from one pharmaceutical formulation of the same drug to another, may lead to therapeutic inadequancy in some cases. To minimize the risk, careful pharmacokinetic studies are desired in the pre-registration period and afterwards. METHODS: A randomized, crossover design with one-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 15 hours, were analyzed for nimesulide content by a high-performance liquid chromatographic method with ultraviolet (LU) detection. The pharmacokinetics and relative bioavailability of three different pharmaceutical formulations containing nimesulide, manufactured by the same pharmaceutical factory, were studied prospectively in 12 healthy subjects of both sexes. A single 100-mg oral dose of nimesulide was given to the volunteers in the form of conventional tablets, mouth dissolving tablets or as a suspension. Analysis of variance, power analysis, 90% confidence intervals, and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. RESULTS: The tolerability of all preparations was excellent. The respective confidence intervals of the ratios of geometric means of C(max) and AUC(0-infinity) of nimesulide were out of acceptable limits either for conventional tablets in comparison with suspension or for mouth dissolving tablets when compared with conventional tablets. A comparison of mouth dissolving tablets with suspension showed a statistically significant difference between C(max) values (suprabioavailability of mouth dissolving tablets), while the point estimate of the ratio of geometric means of AUC(0-infinity) was 0.945 with the corresponding 90% confidence interval of 0.902-0.991. At the 5% level of significance, there were no differences between the formulations under the study in times elapsed to peak serum concentrations, as revealed by the non-parametric Wilcoxon signed ranks test. CONCLUSION: Only a 90% confidence interval for the relative differences of log-transformed AUC(0-infinity) values of nimesulide absorbed from mouth dissolving tablets vs. suspension was included in the 80% to 125% interval proposed by the Food and Drug Administration (FDA). On that basis, mouth dissolving tablets (Nimulid-MD) were considered bioequivalent to Nimulid suspension according to the extent of drug absorption. Concerning the comparable amounts of nimesulide available in the systemic circulation after application of these formulations the one might not expect therapeutic failure after switching the patient from one to another.