Single-dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration

Fluphenazine decanoate is commonly used as part of maintenance treatment of schizophrenia, but its pharmacokinetics are poorly understood. We administered a single intramuscular dose of fluphenazine decanoate to nine patients and found that plasma fluphenazine level did not decline to 50% of the peak level by day 26 in any of the patients. This means that it has a long half-life measurable in months rather than weeks.     

Influences of ischemia and reperfusion on the feline small-intestinal mucosa

The alterations of several small-intestinal mucosal enzymes have been examined in cats that underwent different periods (1-4 hr) of occlusion of the superior mesenteric artery, followed by 4 hr of reperfusion. The damage progressed during ischemia and reperfusion from the villus tips to the crypts: first, there was a rapid decrease in the activity of maltase, a brush-border enzyme; a slower decline occurred in two cytoplasmic enzymes, aldolase A (with preferential location in feline villus cells) and lactate dehydrogenase (with an ubiquitous distribution); a lag preceded the decrease in aldolase B (a cytoplasmic enzyme shown to occur mainly in feline crypt cells). For all these enzymes, the initial period of reperfusion was associated with a greater decrease in enzyme activity than persisting ischemia. By determination of the unsedimentable proportion of glutamate dehydrogenase (a mitochondrial matrix enzyme) and of acid phosphatase (a lysosomal enzyme) it was demonstrated that ischemia caused important mitochondrial damage before the cells were lost, whereas no lysosomal damage was observed in any condition. These sensitive parameters of cell damage can serve as a criterion for an adequate evaluation of potential cytoprotective agents.     

Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

Propionic acidemia: report of a case that is successfully managed by peritoneal dialysis and sodium benzoate therapy

Propionic acidemia is a rare hereditary disease which is an autosomal recessive disorder. Defect of propionyl CoA carboxylase results in abnormal accumulation of propionate and its metabolites which interfere the pathway of glycine cleavage and the urea cycle. This organic acidemia is characterized by a wide spectrum of clinical and biochemical findings, including recurrent vomiting, difficult feeding, lethargy, hypotonia, metabolic ketoacidosis, hyperglycinemia and hyperammonemia during the acute episodes. We present a male newborn infant who sustained this disorder and was managed successfully with blood exchange transfusion, peritoneal dialysis, supplemented with sodium benzoate and sodium bicarbonate therapy. Urine gas chromatography disclosed significant elevation of propionate and its metabolites which subsided 2 days after peritoneal dialysis. Special designed formula was then given with restriction of protein intake and supplement with sodium benzoate and sodium carbonate. Prenatal genetic counseling is necessary in further pregnancy. Diagnosis can be obtained when propionyl CoA carboxylase activity is low in cultured amniotic fluid cells or chorion villi sample or when there is abnormally high methylcitrate level in amniotic fluid.     

Chronic ethanol ingestion enhances catabolism and muscle protease activity in acutely uremic rats

Skeletal muscle wasting in men as well as enhanced urea production in animals due to ethanol consumption has been demonstrated by numerous authors. Furthermore, the outcome of acute renal failure is closely related to the extent of catabolism. The present study was performed to investigate whether chronic ethanol exposition prior to binephrectomy (BN) may represent a predisposing factor for enhanced protein breakdown. Rats underwent BN after exposure to ethanol or isocaloric substrate for 4 weeks. Blood chemistries and muscle samples were obtained 48 h after BN. Animals fed with ethanol revealed significantly higher levels of serum urea nitrogen (SUN) and urea nitrogen appearance (UNA) in comparison to controls. Preconditioning on ethanol-derived calories induced an accelerated fractional degradation rate of myofibrillar protein as demonstrated by a significantly enhanced serum Nt-methylhistidine/creatinine ratio. The increase in serum indicators of enhanced myofibrillar breakdown correlated with the stimulated activities of alkaline myofibrillar protease and cathepsin B. Finally, serum corticosterone levels were enhanced in the experimental group in comparison to controls, indicating an ethanol-related adrenocortical stimulation to be a possible mediating factor of enhanced catabolism in ARF. Thus, chronic ethanol intake prior to the onset of ARF seems to be a risk factor for enhanced catabolism in the course of acute uremia.