To assess the separate contributions of the sleep and circadian systems to changes in cardiac autonomic nervous system (ANS) activity, 12 supine subjects participated in two 26-h constant routines, which were counterbalanced and separated by 1 wk. One routine did not permit sleep, whereas the second allowed the subjects to sleep during their normal sleep phase. Parasympathetic nervous system activity was assessed with respiratory sinus arrhythmia as measured from the spectral analysis of cardiac beat-to-beat intervals. Sympathetic nervous system activity was primarily assessed with the preejection period as estimated from impedance cardiography, although the 0.1-Hz peak from the spectral analysis of cardiac beat-to-beat intervals, the amplitude of the T wave in the electrocardiogram, and heart rate were also measured. Respiratory sinus arrhythymia showed a 24-h rhythm independent of sleep, whereas preejection period only showed a 24-h rhythm if sleep occurred. Thus the findings indicate that parasympathetic nervous system activity is mostly influenced by the circadian system, whereas sympathetic nervous system activity is mostly influenced by the sleep system.

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We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

The pharmacokinetics, tissue distribution, and toxicity of free amphotericin B (free AmB) or amphotericin B encapsulated in liposomes (L-AmB) were characterized in experimental diabetic rats and compared with data obtained from nondiabetic rats. After 7 days of insulin-controlled diabetes or saline, each rat was administered a single intravenous bolus dose of free AmB or L-AmB (0.8 mg/kg body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, nephrotoxicity, and biochemical parameters. Before drug treatment, diabetic rats demonstrated marked increases in serum cholesterol and triglyceride levels compared with levels in nondiabetic rats. A significant increase in serum creatinine levels was observed in nondiabetic rats given free AmB but not in other groups. Whereas AmB pharmacokinetics were significantly altered in diabetic rats administered free AmB, no kinetic differences were found between groups given L-AmB. Renal AmB levels were markedly increased in nondiabetic rats given free AmB compared with those in all other groups. Furthermore, significantly greater concentrations of free AmB were found in lung tissue of rats administered L-AmB independent of disease state. Hepatic levels of AmB were reduced in diabetic rats administered free AmB. The disposition and nephrotoxicity of L-AmB were independent of vascular lipid composition.