Organ transplantation and broader chronotherapy with lmplantable pump and computer programs for marker rhythm assessment

The effects of timing cyclosporine (Cs) administration were tested on nephrectomized dogs bearing an allografted kidney. 1.5 mg/kg of cyclosporine per day were given via an externally programmable implanted Medtronic pump at a continuous injection rate or with one of 6 changing rates, each involving 8 different doses, increasing and then decreasing sinusoidally every day, with the total dose per day equal to that in dogs infused at a constant rate. With both the constant and the sinusoidal rate, Cs prolonged graft function with statistical significance. Moreover, some sinusoidal infusion schedules were better than others. The assumption that the differences among dogs treated with different sinusoidal schedules varied randomly was rejected by the fit of a 24-hour cosine function. This approach demonstrated a statistically significant circadian rhythm in response to sinusoidal Cs treatment. The timing of the best schedule during the dark span is surprising in view of a similar timing found for the optimal Cs effect in nocturnal rats bearing heart or pancreas allografts. Further research will have to examine whether this similarity of timing is reproducible, as seems to be the case for melatonin in blood or urine of human beings and noctural rodents. The experimental design including the use of a programmable implantable pump and the procedures for cosinor analysis, in conjunction with diagnostic regression tests, represents an approach to chronotherapy that is more generally applicable. Although chronopharmacokinetic changes have also been explored here and their rhythmicity documented, this contribution is not likely to account fully for the results here obtained.