[A case of neutropenia and agranulocytosis induced by clozapine. The importance of a drug surveillance program for their early detection]. / Un caso de neutropenia y agranulocitosis inducidas por clozapina. Importancia de un programa de farmacovigilancia para su detección precoz.

Clozapine is an atypical antipsychotic drug with a very low incidence of extrapyramidal effects, used in the treatment of schizophrenic patients refractory or intolerant to classical neuroleptics. Its use is limited due to the potential risk of producing agranulocytosis in 1 to 2% of patients. Despite the severity of this complication, the Federal Drug Administration allowed its use as long as its prescription is associated to a drug surveillance program that controls regularly the white cell count of patients using the drug. Three hundred three patients (210 male) have been admitted to a clozapine drug surveillance program. Two patients had a transitory leukopenia with less than 2000 leukocytes/ml and less than 1000 neutrophyls/ml, that reverted after discontinuing the drug. One patient, whose case is described, had a severe agranulocytosis with less than 500 neutrophyls/ml that required hospital admission.

Neuropathological changes in the rat brain cortex in vitro: effects of kainic acid and of ion substitutions.

The ionic mechanisms that may contribute to the neurotoxicity of kainic acid, were studied in a system of rat thin neocortical slices superfused in vitro. Slices superfused for 3 h under control conditions showed an essentially normal aspect when studied by light microscopy. Presence of 30 microM kainate in the superfusion fluid induced neuronal swelling, nuclear condensation and signs of necrosis in some cells, while other neurons, especially in deeper layers, appeared dark and condensed, with microvacuolation. The neuropil presented numerous profiles of swollen dendrites. When the slices were superfused with chloride-free medium, a large number of pyknotic neurons was seen. This was further enhanced by 30 microM kainate, which produced no swelling in this medium. These effects of Cl-free medium were almost entirely prevented in Cl-free medium without calcium and with 0.1 mM of EGTA. Sodium-free medium induced a marked neuronal swelling that was not much changed by kainate. When calcium in an otherwise normal superfusion fluid was reduced to 0.1 mM, a large number of pyknotic neurons, some with incrustations, were seen. Kainate (30 microM) in this low calcium medium led to a very large swelling and destruction of neurons, and to a spongy neuropil. These effects of kainate were greatly intensified in calcium-free-EGTA (0.1 mM) medium. Ca-free-EGTA medium by itself induced considerable neuronal and neuropil swelling. It is concluded that kainate induces neuronal swelling by a sodium- and chloride-dependent mechanism, and the enhancement of swelling in low calcium is due to an increased sodium uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Kainate, N-methylaspartate and other excitatory amino acids increase calcium influx into rat brain cortex cells in vitro.

Kainate (0.62-5 mM) was found to increase the initial rate of influx of 45Ca and of 22Na into the non-inulin space of rat thin brain cortex slices incubated in vitro, and to shorten the equilibration time for both these ions. N-methyl-DL-aspartate (50-1000 microM), L-glutamate (0.62-5 mM), DL-homocysteate (0.62-2.5 mM), and ibotenate (6-170 microM) also significantly increased the influx of 45Ca into the non-inulin space of this preparation, while the non-neurotoxic acidic amino acids N-acetyl-L-aspartate, and alpha-methyl-DL-aspartate (both 1.25-5 mM), did not increase such influx. We suggest that enhanced calcium uptake may represent the basis for the neurotoxic effects of these compounds.

The effect of complete biliary obstruction on bile secretion. Studies on the mechanisms of postcholestatic choleresis in the rat.

It has been previously shown that rats subjected to obstructive cholestasis demonstrate in the postcholestatic period, after release of common duct obstruction, a marked increase in canalicular bile flow relative to bile acid excretion. To characterize this phenomenon further, we investigated whether changes in canalicular permeability and in the activity of (Na+-K+)-ATPase in isolated liver surface membranes are associated with postcholestatic choleresis. With this purpose, the clearances of 14C-erythritol and 3H-insulin were simultaneously measured in rats subjected to a 3-day obstructive cholestasis and in controls, during spontaneous choleresis as well as during the intravenous infusion of sodium taurocholate at both submaximal and saturating rates. In additional groups of bile duct-ligated rats and controls, liver surface membrane fractions were isolated, and the activity of appropriate marker enzymes and (Na+-K+)-ATPase was determined. In both groups 14C-erythritol clearance closely approximated total bile flow, suggesting that bile flow was of canalicular origin. However, cholestatic rats showed a sixfold increase in 3H-inulin clearance compared to controls. These results suggest that canalicular permeability to inulin is markedly increased in cholestatic rats. On the other hand, (Na+-K+)-ATPase activity was significantly higher in cholestatic rats than in controls in both homogenate (1.27 +/- 0.07 and 0.89 +/- 0.07 U/mg of protein, respectively, p less than 0.001) and liver surface membranes (22.6 +/- 1.2 and 17.5 +/- 1.2 U/mg of protein, respectively, p less than 0.001). Thus enhanced choleretic response to bile acids in the postcholestatic period is associated with an increased permeability of canalicular structure to inulin and with a significant increase in both homogenate and surface membrane (Na+-K+)-ATPase activity. In addition, this study points out some important differences between bile secretory function of rats subjected to obstructive cholestasis and that described in models of bile secretory failure induced by drugs or monohydroxy-bile acids.