Benzodiazepine-induced persisting amnestic disorder: are older adults at risk?

Currently there are approximately 31.5 million Americans 65 years and older. This number is expected to reach 39.3 million by 2010. This group represents 12% of the population, however, they use 25% to 40% of the prescription medications, averaging 4.5 medications daily; 75% of them use over-the-counter medications as well. This population has also experienced an increase in the prescription of central nervous system (CNS) medications. Benzodiazepines are the most widely prescribed class of CNS antianxiety/sedative medication. This article examines the use of benzodiazepines in relation to physiological, pharmacokintic, and pharmacodynamic changes of the older adult. The amnestic properties of these drugs in relation to the already decreasing cognitive function of the older adult are explored in relationship to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for substance-induced persisting amnestic disorder.

Pharmacokinetic factors influencing risk assessment: saturation of biochemical processes and cofactor depletion.

Models generally consider risk to be a function of the hazard (toxicity) and exposure (dose). That function is best described by the dose response of the toxic effect. For any risk assessment system to be effective, it should consider that dose-response relationship. Saturation phenomena often produce nonlinear dose curves, and any risk assessment system should be able to address such effects. Physiologically based pharmacokinetics offer an approach to deal with these nonlinear responses. Some historic risk models and common saturable processes are discussed. The impact of maximum tolerated dose (MTD) on risk evaluation and the kinetics of some saturable processes are considered. Specific examples have been selected to demonstrate the importance of saturation of processes in assessing the hazard of chemicals.

Protective effect of activated charcoal in cattle poisoned with atrazine.

Six heifers were poisoned with a lethal dose of atrazine. Three animals were treated daily for 4 days with activated charcoal. The untreated animals died within 3 days, whereas the treated animals survived the 14-day observation period. Hematology, blood chemistry and pathology findings are reported.

Evaluation of the mutagenic potential of corn (Zea mays L.) grown in untreated and atrazine (AAtrex) treated soil in the field.

Bacterial assays using extracts from field corn plants (harvested at one month, silage and mature stages) do not indicate that soil treatment with atrazine, at its maximum use rate, alters the endogenous mutagens present in these extracts, nor that atrazine itself is degraded to mutagenic products. Extracts of corn grown in soil treated with AAtrex were equally mutagenic with those of corn grown in untreated soil when tested in Salmonella typhimurium TA-100 by a reversion assay or in Salmonella typhimurium TM-677 in a forward mutation assay. Higher concentrations of histidine in corn grown in AAtrex treated soil may interfere with the reversion assay, but do not affect the forward mutation assay. The nature of the agent(s) responsible for the positive response was not determined. The mutagenicity may be due to natural plant constituents, an artifact of the sample preparation, or mycotoxins from some unrecognized plant infection. The experimental results in these field studies do not show that atrazine is degraded or metabolized by corn plants to mutagens in this sensitive bacterial assay.

The importance of metabolite identification in quantitative risk estimation.

In the search to define the mechanisms by which xenobiotics produce their toxic effects in biological systems, the importance of metabolism data is clear. Although the detection of electrophilic metabolites and reactive intermediates may challenge our analytical technology, the toxic responses manifested by these agents are often obvious. The identification of toxicologically significant minor metabolites may exceed the state of the art in analytical methodology. New advances in technology may provide the needed answers. As we begin to face the significance of activation reactions, particularly in the area of carcinogenesis, it becomes apparent that metabolism to electrophiles that react covalently with DNA, is not the only mechanism by which the tumorigenic response is produced. The production of tumors by nongenotoxic (epigenetic) means is also important. Exposure to high and sustained levels of exposure to a xenobiotic that leads to a perturbation in metabolic, endocrine or physiologic pathways or tissue injury may also produce tumors. Only through investigations which include definitive metabolite identification and quantitation can the mechanism by which these agents exert their toxicity be identified. The ramification of dose response relationships for genotoxic and nongenotoxic carcinogens will be presented to demonstrate the impact of metabolite identification in quantitative risk estimation.

Incorporation of foreign compound metabolites into plant and soil constituents.

Recent developments in the technology of removal and characterization of bound residues of two herbicides, nitrofen and profluralin, from plants and soil will be reviewed. 14C-Nitrofen was found to be metabolized into starch in wheat grain as well as bound into the lignin fraction of wheat straw. Profluralin and its metabolites were found to be bound to field aged soil in several ways probably including hydrogen bonding and covalent bonding. The bound metabolites of profluralin in soil could be categorized according to the type of bonding occurring as well as to the physicochemical characteristics of the bound pesticide. By assessing the type of bonding involved between pesticide and plants or soil, some assessment of the bioavailability of these bound residues to the environment can be made. When applied to tissues of food producing animals, these techniques would help release bound drug residues and provide technology for characterization of the released material.

Metabolism of tolmetin in rat, monkey, and man.

5-p-Carboxybenzoyl-1-methylpyrrole-2-acetic acid has been identified in the rat, monkey, and man as the major urinary metabolite of tolmetin, a new nonsteroidal anti-inflammatory agent. Conjugation of tolmetin, a major mode of disposition in man and monkey, was not observed in the rat.