tacrolimus and Hyperparathyroidism

Tacrolimus (FK 506) was introduced into organ transplantation as a powerful immunosuppressive but with several adverse effects. In fact, an appropriate protocol for using this agent has not yet been established. On the basis of pharmacokinetic studies and the reports of its administration as a continuous intravenous infusion, we designed the regimen of every eight hours in order to reduce the daily dosage.. Tacrolimus was given to nine patients in the Japanese FK506 study. Although it was discontinued in two patients within two months because of adverse effects and acute rejection, seven other patients tolerated the agent for a long period and received the drug three times a day. Concomitant prednisolone was gradually tapered and finally withdrawn in these patients.. The smaller dosage of tacrolimus led to a higher trough concentration of 14.1 +/- 1.6 ng/mL in the three-times-a-day regimen compared with 12.7 +/- 1.9 ng/ml in twice-a-day therapy (P < 0.01). The daily dosage of tacrolimus proved to be reducible even further. Our target trough concentration was decreased finally to < 5 ng/mL. Concomitant prednisolone was withdrawn in all of the seven patients. The course of these patients has been uneventful for a year after withdrawal of prednisolone.. Our regimen of three-times-a-day oral administration of tacrolimus is a likely protocol for reduction of its daily dosage, which lowers its adverse effects while maintaining its immunosuppressive action at a lower trough concentration without concomitant prednisolone.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Hyperparathyroidism; Immunosuppressive Agents; Injections, Intravenous; Kidney Diseases; Kidney Transplantation; Male; Prednisolone; Tacrolimus; Tissue Donors

Our previous work revealed that the recipients with the highest pre-existing numbers of CD8(+) effector T cells (TE ) [hyperparathyroidism (HPT)E recipients] occupied approximately 30% of adult transplant recipients performed in our hospital. HPTE recipients demonstrated very poor clinical outcome compared with the remaining 70% of recipients with the lowest pre-existing TE (LPTE recipient). This study aimed to clarify the best combined immunosuppressive regimen related to function of cytotoxic T lymphocytes (CTLs) for HPTE recipients. Eighty-one HPTE recipients were classified into three types, according to the immunosuppressive regimens: type 1, tacrolimus (Tac)/glucocorticoid (GC); type 2, Tac/mycophenolate mofetil (MMF)/GC; and type 3, Tac/MMF. Frequencies of severe infection, rejection and hospital death were the highest in types 1 and 2, whereas the lowest occurred in type 3. The survival rate in type 3 was the highest (100%) during follow-up until post-operative day 2000. Regarding the immunological mechanism, in type 1 TE perforin and interferon (IFN)-γ were generated through the self-renewal of CD8(+) central memory T cells (TCM ), but decreased in the early post-transplant period due to marked down-regulation of interleukin (IL)-12 receptor beta-1 of TCM. In type 2, the self-renewal TCM did not develop, and the effector function could not be increased. In type 3, in contrast, the effectors and cytotoxicity were correlated inversely with IL-12Rβ1(+) TCM levels, and increased at the highest level around the pre-transplant levels of IL-12Rβ1(+) TCM . However, the immunological advantage of Tac/MMF therapy was inhibited strongly by additive steroid administration.

Topics: Aged; Female; Gene Expression; Graft Rejection; Graft Survival; Humans; Hyperparathyroidism; Immunologic Memory; Immunosuppressive Agents; Interferon-gamma; Liver Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Perforin; Receptors, Interleukin-12; Retrospective Studies; Survival Analysis; T-Lymphocytes, Cytotoxic; Tacrolimus; Unrelated Donors