Chronobiology and chronotoxicology of antibiotics and aminoglycosides.

Few investigators have examined the circadian variation in the symptom intensity of infectious diseases. Seasonal patterns in a variety of infectious are well know. Less appreciated are the circadian patterns in the symptom expression of infections. Studies indicate that fever which accompanies the common cold peaks at 4 p.m., and this is in agreement with other studies indicating that the elevation of body temperature, fever, due to bacterial infections is higher in the evening while that due to viral infections is more likely in the morning. Animal and human studies reveal also administration-time-dependent differences in the pharmacokinetics and toxicity of antimicrobial agents. This is particularly true for the aminoglycosides, as their nephrotoxicity is greatest when administered during the resting period of laboratory animals and human beings. Food intake and low urinary pH has been found to be protective of the toxicity of aminoglycosides at this time of the day. Knowledge of the administration-time-dependence of aminoglycosides and the underlying mechanisms can be used to develop once-a-day formulations that are significantly less toxic, in particular to the kidney, in patients who require around-the-clock antimicrobial therapy.

Protein-rich diet attenuates cyclosporin A-induced renal tubular damage in rats.

OBJECTIVE: The objective of the present study was to look at the effect of a protein-rich diet on cyclosporine A (CsA)-induced acute nephrotoxicity in rodents using markers of tubular damage. DESIGN: Female Sprague-Dawley rats were conditioned to either a standard or a casein-rich diet for 2 weeks. Then, they were given CsA intraperitoneally (25 mg/kg/24 h or an equivalent volume of vehicle (Cremophor EL; Sigma Chemical Co, St. Louis, MO) for 7 days at 7 AM. RESULTS: During CsA treatment, bodyweight, caloric consumption, water intake, and urine output were not significantly different in animals fed with the standard Rat Chow and those on the high-protein feeding. On days 1 and 7, the 24-hour urine excretion of N-acetyl-beta-d-glucosaminidase (NAG) and beta-galactosidase (beta-GAL) were significantly (P < .001) lower in CsA-treated rats on the high-protein diet than in those on the standard Rat Chow. After 7 days of treatment with CsA, no significant difference in the renal function level was found between rats fed with the standard or the casein-rich diet. The post-necrotic cellular regeneration in renal cortex was significantly lower (p<0.001) in CsA-treated rats on the high-protein than on the standard diet. In CsA-treated rats on the standard diet, immunogold labeling showed a massive and specific concentration of the drug into lysosomes of proximal tubular cells. Contrastingly, no gold particle was found over the lysosomes of animals given the rich-protein feeding. CONCLUSION: In our current experimental conditions, a protective effect of high-casein diet against CsA-induced proximal tubular damage was observed in Sprague-Dawley rats.

Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice.

Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.

Protective effect of fleroxacin against the nephrotoxicity of isepamicin in rats.

The protective effect of fleroxacin on isepamicin-induced nephrotoxicity was investigated. Wistar rats were administered either fleroxacin 100 mg/kg orally, isepamicin 300 mg/kg subcutaneously, or fleroxacin and isepamicin in combination for 14 d. The animals given 300 mg/kg of isepamicin showed a significant increase in urine N-acetyl-beta-D-glucosaminidase (NAG) levels as compared with the control animals which received saline (p<0.01). However, the increase in NAG level was markedly less when isepamicin was administered in combination with fleroxacin (p<0.01). Fleroxacin alone had no effect on urine NAG activity. Serum creatinine and blood urea nitrogen (BUN) levels were significantly higher in animals treated with isepamicin alone than in the control animals (p<0.01) or animals receiving the isepamicin fleroxacin combination (p<0.01). Histopathologically, fleroxacin induced very few cellular alterations, but considerably reduced the manifestation of typical signs of isepamicin nephrotoxicity. This investigation demonstrates that fleroxacin protects animals against isepamicin-induced nephrotoxicity.

Influence of a circadian-stage-dependent dosing schedule on the pharmacokinetics of isepamicin in humans.

These experiments were conducted in order to determine the influence of the time of day of drug administration on the pharmacokinetics of isepamicin. Six healthy volunteers were given 400mg isepamicin IM, on 2 separate occasions, either in the morning (8 AM) or in the evening (8 PM). Within-subject differences in the pharmacokinetic parameters between the morning and evening dosing regimens were evaluated. The plasma concentrations of isepamicin were not significantly different between the morning and evening trials, but significant time-dependent changes were found with a lower elimination rate constant and a longer elimination half-life in patients administered isepamicin at night. Our finding suggests that isepamicin may have the same clinical effects irrespective of whether dosing takes place in the morning or in the evening, but its clearance tends to be depressed when taken in the evening. Therefore, morning therapy is desirable because of possible interference from aminoglycoside toxicity.