Rhythmic pattern in pain and their chronotherapy.

Pain control is one of the most important therapeutic priorities; nonetheless, inadequate pain relief remains a significant health care issue. Thus, it is important to determine whether the analgesic effect can be improved by using the chronopharmacological approach. This paper reviews the data on the rhythmic patterns in pain level and their chronotherapy. It underlines the major issues and problems related to the development of chronotherapeutic strategies, and it examines emerging aspects of new drug-delivery systems for achieving such.

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.

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.

Comparison of hydromorphone continuous subcutaneous infusion and basal rate subcutaneous infusion plus PCA in cancer pain: a pilot study.

In this pilot randomized, double-blind, cross-over study, the effectiveness and safety of hydromorphone administration by continuous subcutaneous (s.c.) infusion (mode A) and by continuous basal rate s.c. infusion + PCA (mode B) were compared in 8 cancer patients. Patients experimented with each infusion mode during 48 h. Statistical analysis was performed on data collected in 7 patients during 36 h from 22:00 h on day 1 to 10:00 h on day 3 and from 22:00 h on day 3 to 10:00 h on day 5. Mean hydromorphone dose +/- S.D. was 56.6 +/- 30.1 and 40.4 +/- 24.5 mg/36 h for modes A and B, respectively. There was no statistically significant difference observed in mean pain intensity, but the absence of significant difference may be related to the small sample size and high individual variability. Both methods provided adequate overall pain control in most patients. However, a large interindividual variation was detected. Indeed, some patients reported in the subjective questionnaire that they felt marked discomfort during hydromorphone administration with mode B. Only 2 patients chose mode B at the end of the study, but it was interesting to note that those 2 patients were the youngest of the group. This study demonstrated the effectiveness and safety of both modes of hydromorphone administration. The data suggest that it may be possible to identify particular cancer patients which can really benefit from an association of a basal rate infusion and PCA for opiate administration.