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Although humans hold great advantages over other species as subjects for biomedical research, they also bring major disadvantages. One is that among the many rhythmic physiological signals that can be recorded, there is no sure way to know which individual change precedes another, or which change represents cause and which represents effect. In an attempt to deal with the inherent complexity of research conducted in intact human subjects, we developed and used a structural equation model to analyse responses of healthy young men to pharmacological changes of arterial pressure and graded inspiratory resistance, before and after vagomimetic atropine. Our model yielded a good fit of the experimental data, with a system weighted R2 of 0.77, and suggested that our treatments exerted both direct and indirect influences on the variables we measured. Thus, infusions of nitroprusside and phenylephrine exerted all of their direct effects by lowering and raising arterial pressure; the changes of R-R intervals, respiratory sinus arrhythmia and arterial pressure fluctuations that these drugs provoked, were indirect consequences of arterial pressure changes. The only direct effect of increased inspiratory resistance was augmentation of arterial pressure fluctuations. These results may provide a new way to disentangle and understand responses of intact human subjects to experimental forcings. The principal new insight we derived from our modelling is that respiratory gating of vagal-cardiac motor neurone firing is nearly maximal at usual levels of arterial pressure and inspiratory motor neurone activity.

A high-performance liquid chromatography (HPLC) procedure has been developed for the determination of azapropazone and its 6-hydroxy metabolite in plasma and urine. The procedure is simple and rapid since extraction of the drug and its metabolite is not required. Plasma proteins are precipitated with methanol, and the supernate is injected onto a reverse-phase HPLC column. With photometric detection at 254 nm, the procedure can determine as little as 0.4 micrograms/ml azapropazone in plasma or urine and 1.5-3 micrograms/ml of the metabolite in urine, depending upon the level of interference. The procedure has been used successfully in single-dose pharmacokinetic and bioavailability studies of azapropazone dosage forms.

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.