Incidence of adverse reactions to cyclosporine after liver transplantation is predicted by the first blood level.

Despite the availability of whole-blood cyclosporine assays, the different responses of individual patients to its administration after transplantation continue to pose clinical problems, particularly with respect to toxicity. Fifty-seven recipients of first orthotopic liver transplants were studied between January 1992 and July 1992. Initial immunosuppression was carried out with azathioprine, methylprednisolone and cyclosporine, at a dose of 1 mg/kg/day adjusted to achieve blood levels between 400 and 600 ng/ml. Cyclosporine levels were measured 12 hr after the start of intravenous administration and correlated with the occurrence of toxic complications. Twelve patients experienced toxic complications in the first 7 days after orthotopic liver transplantation. These were neurological in six patients (of whom four also had kidney failure) and renal complications in the other six patients. All complications were reversed by reducing or stopping administration of cyclosporine. We noted excellent correlation between the occurrence of complications and cyclosporine whole-blood levels (p < 0.0001) despite the fact that levels did not exceed the therapeutic range. However, no correlation was observed between toxicity and cumulative dosage. In this study we were able to demonstrate that a standardized dose of cyclosporine does not prevent the occurrence of toxic side effects even when cyclosporine whole-blood levels are subsequently maintained in the therapeutic range. This highlights the importance of the first dose of cyclosporine and consequent early postoperative blood levels and indicates that these problems are unlikely to be overcome until a method of predicting individual requirements can be established in clinical practice.

Can cellular transplantation improve function in doxorubicin-induced heart failure?

BACKGROUND: Transplantation of fetal cardiomyocytes has been shown to improve function of regionally infarcted myocardium, but its effects on global heart failure are still unknown. METHODS AND RESULTS: Heart failure was induced in female mice by intraperitoneal injection of doxorubicin (2 mg/kg twice per week over 2 cycles of 2 weeks separated by a 2-week drug-free period). One week after the end of treatment, left ventricular function was assessed by transthoracic echocardiography (baseline). Animals were then randomized into 3 groups: The treated group (n = 12) received an intramyocardial injection of fetal cardiomyocytes (1 x 10(6) in 10 microL) harvested from transgenic mice expressing the gene of beta-galactosidase, the control group (n = 15) received an equivalent volume of culture medium alone, and 10 sham mice had no surgery. Two weeks and 1 month after transplantation, function was again assessed echocardiographically. At baseline, fractional shortening was not significantly different between the 3 groups. It then significantly increased in cell-treated mice at 2 weeks and 1 month after transplantation (P < 0.002 and P < 0.03 versus baseline, respectively), whereas it did not change in untreated animals. Transplanted cells could not be identified by beta-galactosidase activity or presence of Y chromosome (with 1 exception). CONCLUSIONS: Cellular transplantation can improve function of globally failing hearts by a mechanism that might not necessarily involve the sustained presence of transplanted cells but rather the effects of cardioprotective factors released by them.