Neurotoxicology has always been eclectic in its search for techniques for use in the detection of toxic changes in the nervous system. The newer electrophysiological techniques as discussed here, should be seen in the sense of new in application or a novel approach using techniques which are probably already established in neurophysiology. Neurophysiology has been the main source of ideas for the development of toxicological studies based upon the central and peripheral nervous systems.

In quail liver microsomes the metabolism of histamine is prevalently sustained by diaminoxidase (DAO). Treatment with phenobarbital (PB) and clofibrate (CF) does not modify DAO activity, while that with Aroclor 1254 (PCB) and β-naphtoflavone (BNF) significantly decreases it. The decrease of DAO activity produced by these substances is not dependent on their direct inhibition of the enzyme. DAO decrease might represent a further possibility to discriminate among different inducers; moreover, it implies that histamine metabolism might be decreased, in quail liver, by some classes of inducers.

The first attempt at developing a mathematical model to describe and predict drug distribution and elimination processes dates back only 50 years. Teorell (1937a,b) advanced a simplified scheme of the body by grouping tissues into five compartments (connected through the circulatory system). This pioneering work has served as the forerunner from which all pharmacokinetic models, physiological and compartmental, have been developed.

Purposeless chewing in rats was induced by the acute administration of the cholinergic agonist pilocarpine or by physostigmine. Pilocarpine-induced chewing was antagonised by the centrally acting anticholinergic drugs scopolamine, benzhexol and secoverine, but not by the peripherally acting anticholinergic drug methylscopolamine. Both benzhexol and secoverine caused dose-dependent inhibition of pilocarpine-induced chewing. The D-2 antagonist sulpiride and the D-1 antagonist SCH 23390 did not inhibit pilocarpine-induced chewing. The non-selective neuroleptics pimozide, trifluoperazine and thioridazine also were inactive. In contrast, clozapine caused a dose-related inhibition of pilocarpine-induced chewing. The α-1 antagonist prazosin, the α-2 antagonist idazoxan, the β-antagonists propranolol and metoprolol and the H-1 antagonist mepyramine did not reduce pilocarpine-induced chewing. Purposeless chewing behaviour induced by pilocarpine was reduced in a dose-related manner by the administration of the 5-HT antagonists methiothepin and mianserin, but not by spiperone or ketanserin. These data confirm that pilocar-pine-induced chewing behaviour in the rat is a model of central cholinergic activity, but suggest that a serotonergic component may be involved in the mediation of this behaviour.

Summary

A simple sensitive method of high specificity and selectivity for quantitative determination of the non-steroidal anti-inflammatory drug naproxen and its main metabolite, 6-demethylated derivative, in biological specimens is described. Like naproxen, its metabolite absorbs maximally at 232 om; this makes their simultaneous quantification, via direct UV-measurements at λ_max, in biological fluids quite impossible. Simple TLC-separation on silica gel F₂₅₄ using chloroform + methanol (85:15, v/v) achieved the best fractionation of the unchanged drug and its metabolite from the matrix-contents of urine. UV-quantification of fractionated components could reach concentration levels of 0.2–3.0μg ml⁻¹ (ppm) in worked up urine samples. Varying levels of unchanged antiinflammatory drug and the phenolic metabolite could be accurately traced in urine samples following a 2.9 mglk.g oral dose after different time-intervals. Synthetic preparation of the metabolite by demethylation of naproxen is briefly mentioned.

Summary

The single and multiple i.v. dose pharmacokinetics of ceftazidime were investigated in 37 acutely ill patients with normal age-related glomerular function.

Distribution was rapid with similar t_1/2a at all ages. Compared to the younger patients, elderly subjects had lower total and renal clearances and reduced urinary recovery. Ceftazidime clearance was closely correlated with glomerular function. The t_1/2β was approximately 2 h in young and middle-aged patients, 2.73 h in patients aged 60–79 years, and 3.54 h in those above 80 years. The AUC was more than doubled in the oldest patients compared to individuals younger than 40 years. V_ss did not change with advancing age, but was larger than previously reported in healthy volunteers. Elimination variables were not altered during multiple dosing, but a small but significant increase in AUC was detected in the elderly. Dose reduction by 50% in patients more than 70 years old is suggested.

Escherichia coli is the most common cause of urinary tract infections (UTI). Depending on the virulence of the organism and the efficiency of the host defense system, these UTI appear either as asymptomatic bacteriuria, acute cystitis or acute pyelonephritis. A number of putative virulence properties have been recognized in E. coli isolates associated with acute pyelonephritis in otherwise uncompromised children. One such property is the ability to express mannose-resistant (MR) hemagglutinins. Most E. coli are capable of forming type 1 pili that carry a mannosespecific adhesin. Pyelonephritogenic E. coli additionally carry one or more chromosomal gene clusters that encode pili associated with MR hemagglutination. Of the several MR hemagglutinins that are known today, the best characterized is the Galα(1–4)Gal-specific adhesin associated with P-pili. The name P-pili refers to the observation that this adhesin acts as a hemagglutinin for erythrocytes which express any of the P blood group antigens.

The starting point for my overview of some of the changes that have occurred in post-marketing surveillance at the Food and Drug Administration (FDA) during the past 3 years, is the recognition that industry, the medical community and regulators share the responsibility for ensuring that drugs are used in safe and appropriate ways. The jobs of the regulator and the drug developer are not completed when a drug is approved. We must monitor real-world drug use, through post-marketing surveillance, to gain new safety information not available when a drug is first marketed. The FDA’s activities in post-marketing surveillance can be divided into two segments: monitoring adverse drug reaction (ADR) reports and the conduct of pharmacoepidemiology.