Sorell L. Schwartz

An evaluation of the nephrotoxicity of ethylenediaminetetraacetate and diethylenetriaminepentaacetate in the rat

Clinical reports and certain experimental studies have indicated that ethylenediaminetetraacetate and diethylenetriaminepentaacetate are nephrotoxic. Since these compounds have a very high order of physiologic and biochemical specificity, studies were performed in the expectation that insights of a mechanistic nature might be obtained. It was found that the tubular vacuolization produced in the rat by intraperitoneal injection of the chelates daily for 10 days was not accompanied by significant elevation of serum creatinine or urea nitrogen. In addition, there was no impairment in renal excretion of the 14C-labeled chelates or in the ability of slices of the renal cortex to accumulate p-aminohippurate. The results with labeled compounds indicated that the vacuoles were not simple repositories of accumulated chelate, and metal analyses of the kidney indicated that vacuolization could occur independent of changes in the metal spectrum. Kidneys with preexisting or evolving damage due to vitamin D2 or lead intoxication did not appear to be more vulnerable to the action of the chelates. Advice to the effect that renal function should be followed in patients receiving these chelates is consistent with good medical practice, but the label “nephrotoxin” is unjustified. There are similarities between the vacuoles produced by these chelates and those observed with sucrose and mannitol. The driving forces in these morphologic events appear to center on the moiety of these materials that gain entrance to the cell rather than on the number of osmotically active particles in the filtrate or urine volume. Observations and thoughts concerning the origin and fate of the vacuoles are discussed.

A physiologically based pharmacokinetic model for nicotine and cotinine in man

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided;chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotines physiological effects is discussed.

CMATRIX: software for physiologically based pharmacokinetic modeling using a symbolic matrix representation system.

Physiologically based pharmacokinetic (PBPK) modeling is based on an understanding of the physical and biological factors governing drug distribution. It is a procedure requiring composition of differential equations describing the distribution of drugs among physiologically defined compartments. CMATRIX is a program that facilitates development of PBPK models. In CMATRIX, the model is represented as a matrix of transfer parameters; the program generates a corresponding system of differential equations, and solves them numerically. This system dramatically improves the ease with which PBPK models can be developed, allowing the freedom to construct subcompartments down to the receptor level.

Clinical pharmacokinetics of moricizine

Moricizine is well absorbed after oral administration and undergoes extensive first-pass metabolism. The drug has a large apparent volume of distribution (approximately 4 liters/kg), exhibits extensive plasma protein binding (approximately 95%) and produces at least 30 metabolites. Indirect evidence indicates that some of those metabolites may be pharmacologically active. The elimination half-life of moricizine is 2 to 6 hours, but its duration of antiarrhythmic action is much longer suggesting active metabolites. Moricizine induces its own metabolism with no change in pharmacologic effect. It also induces the metabolism of theophylline and specific pathways of antipyrine. Cimetidine reduces metabolism of moricizine but does not alter its pharmacologic effects. This observation provides further support for the hypothesis that the metabolites of moricizine contribute to the pharmacologic actions during therapy and indicate that plasma level monitoring is not likely to be of value. There are no known clinically significant pharmacokinetic interactions between moricizine and digoxin, warfarin or propranolol. Excessive prolongation of the PR interval has been seen in some patients receiving both digoxin and moricizine, probably due to additive electrophysiologic effects of the 2 drugs.

Deaths from acute exposure to trichloroethylene.

Trichloroethylene (TCE) is a commonly used halogenated hydrocarbon in industry. We report on deaths attributed to TCE exposure that occurred between 1975 and 1992. In addition, we present a case report pom the most recent death, including tissue concentration modeling. The deaths shared a number of features. All occurred in young men who were usually working in confined spaces without adequate ventilation. These preventable deaths suggest that safety precautions are not being observed by workers and employers. Employers should ensure that their employees are adequately trained in the dangers of working with TCE, that adequate ventilation of the working environment is provided, that the proper personal protective equipment (PPE) is available to their workers, and that workers should not work alone or unobserved when using TCE in confined spaces.

Mathematical modelling of nicotine and cotinine as biological markers of environmental tobacco smoke exposure

Computer software developed in our laboratory (CMATRIX) was used to design a physiological pharmacokinetic model of nicotine absorption, distribution, metabolism and excretion in man. The model accommodates inhalation of nicotine from various environmental settings and physiological conditions in man. It was also used to predict pharmacokinetic behavior of cotinine arising from nicotine metabolism. Model-predicted variations in body-fluid nicotine levels confirm that nicotine is not an acceptable quantitative marker of environmental tobacco smoke (ETS) exposure. Though cotinine provides a more stable pattern, predicted interindividual variation suggests the need for specific strict sampling and monitoring guidelines for cotinine to be a reliable quantitative marker.

Subcellular localization of ethylenediaminetetraacetate in the proximal tubular cell of the rat kidney

Abstract Ca-EDTA- 14 C was administered to rats at three different dose levels, only one of which was capable of inducing vacuolization in proximal convoluted tubular cells within 24 hr. Differential centrifugation indicated that the percentage uptake with all three doses was similar over a period of 30 min to 24 hr. The behaviour of the particles relative to time as well as on sucrose water density gradients suggested that the EDTA- 14 C eventually shares particle space with lysosomal enzymes.

Cognitive dysfunction in a patient with long-term occupational exposure to ethylene oxide : role of ethylene oxide as a causal factor

This case illustrates a comprehensive approach to assessing causality in a woman with apparent cognitive dysfunction, as measured by neuropsychological testing, and a 10-year history of occupational exposure to ethylene oxide. The analysis included a multidisciplinary examination of the patient, which took place several years after the termination of her exposure. In addition, all of the patients prior medical and psychiatric records were reviewed, as were the records of her employer to ascertain her exposure history. Our evaluation revealed a pattern of neuropsychological findings not consistent with nervous system damage secondary to an organic effect of ethylene oxide. A more likely causal hypothesis is adopted: the patients apparent cognitive dysfunction had a psychiatric etiology. This case also illustrates the potential impact of a patients involvement in legal proceedings related to claims of neurocognitive dysfunction.

ETS‐lung cancer epidemiology: Supportability of misclassification and risk assumptions

Abstract The NAS Committee on Passive Smoking used epidemiologic data to estimate the risk of lung cancer associated with ETS exposure. Mathematical models were used to assess the influence of smoking‐ and exposure‐status misclassification. These models and the database for their application are thoroughly examined. For smoking status misclassification, the model is technically sound; for exposure misclassification, the model is empirically logical, but mathematically can require very precise data. Further effort is necessary to compensate for the paucity of data to which the models can be applied.

Procaine amide-induced vacuolation in macrophages and effects on endocytic activity.

Abstract Procaine amide (3.68 m m ) induced a readily reversible vacuolation in mouse peritoneal macrophages. This vacuologenic activity was associated with an inhibition of endocytic activity of the cells. Inhibition of pinocytosis was detected by a reduction of uptake of yeast invertase by sucrose-laden macrophages. Inhibition of phagocytosis was detected by a reduction of the incorporation of sheep red blood cells by the macrophages.