Prospective study of FK506 side effects: Anxiety or akathisia?

Transplantation proceedings, 1991

FK 506 is used increasingly to prevent rejection in organ transplantation. Both experimental1 -3 and clinical4 ,5 studies suggest that FK 506 is a more potent immunosuppressive agent than cyclosporine (CyA), and there are indications that FK 506 may also be less toxic. The advent of any new agent such as FK 506 promises more effective immunosuppression, but also gives rise to the need for further study of potential toxic side effects. Indeed, a report by Reyes et al7 of two patients who developed speech dysfunction while on FK 506 suggests that this agent may under certain circumstances produce adverse effects on the nervous system. Thus, more information is needed about potential nervous system disturbances that may occur in association with the clinical use of FK 506 in transplant patients. We carried out this study to identify the spectrum and frequency of neurologic disturbances that may occur in transplant patients receiving FK 506.

Transplantation proceedings, 1991

FK 506 has established itself as a promising immunosuppressive drug in organ transplantation and in the treatment of autoimmune disease. Therapeutic monitoring of plasma concentrations of FK 506 is essential to ensure appropriate dosage for adequate immunosuppression and to minimize potential side effects. Routine monitoring of FK 506 plasma concentration is performed with an enzyme-linked immunoassay (ELISA) previously developed by Tamura et al 1 and modified by Cadoff et al.2 Plasma FK 506 levels also have been measured with an in vitro bioassay.3 This assay is based on the inhibition of the alloantigen driven proliferation of cloned alloreactive T cells. These activated lymphocytes show a narrow sensitivity range to FK 506 and the IC50 is 0.07 to 0.12 nmol/L. In liver allograft recipients. the FK 506 levels as determined by bioassay are consistently lower than those measured by ELISA (Fig 1). These results suggest that the plasma may contain biologically less active FK 506 metabolites, which can be detected by ELISA.

Transplantation, 1990

The principal side effects of the new immunosuppressive drug FK506 have been low-grade nephrotoxicity, a mild diabetogenic effect, and annoying but relatively minor manifestations of neurotoxicity (1). The neurotoxic symptoms have included tremors, paresthesias, insomnia, headaches, increased visual sensitivity to light, nightmares, a sense of racing, and mood changes. Such complaints, which are similar to those caused by cyclosporine, have provided a much-needed means of dose adjustment (1). However, we report here 2 examples of reversible expressive dysphasia that may have been caused by FK506 since it was reversed by dose reduction.

Transplantation Proceedings

We recently reported our initial experience with FK 506 in 36 patients undergoing renal transplantation. 1 This series was characterized by a high average complexity, and included 10 patients who also were liver recipients either concomitantly or at an earlier time. Additionally, 2 of the 10 also were given a heart or pancreas.

Journal of Gastroenterology and Hepatology, 1992

Immunosuppressive regimens are usually required for patients receiving organ transplants. The development of a post-transplant lymphoproliferative disorder is an infrequent complication of such therapy. FK 506 is a new immunosuppressant agent that has recently been used in patients receiving organ transplantation. This report describes a 20 month old Saudi child who developed post-transplant lymphoproliferative disorder while receiving FK 506 following liver transplantation. Such a complication has been recognized with cyclosporine but has not been well addressed as yet with FK 506. The child also developed progressive renal complications. There was also a difficulty in interpreting the results for IgM antibodies to different viruses. The overall features of progressive renal toxicity and those of lymphadenopathy, hepatosplenomegaly, fever, neutropenia and thrombocytopenia reversed following discontinuation of FK 506 therapy. It is concluded that all the above complications, though reversible, may well be linked to the new immunosuppressant agent FK 506.

PubMed, 1990

Therapeutic Drug Monitoring, 1995

is a new immunosuppressive agent. recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection. even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection. 75% of patients were still alive at 3 years following FK506 conversion. and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials. freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due. in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression. FK506 was shown to be effective. as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation. as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results . of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects. many of which are similar. and some of which are peculiar to a given organ transplant.

Clinical …, 1993

Transplantation, 1995

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/ prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8 ± 13.7 years (range 17.6-78). The mean donor age was 34.0 ± 20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 ± 8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22 ± 4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P = ns compared with double therapy), and a one-year actual graft survival of 82% (P < 0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P < . 07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8 ± 0.8 mg/dl. The mean BUN was 33 ± 21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192 ± 49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus-14%; new-onset diabetes-16% (half of which was reversible); and posttransplant lymphoproliferative disorder-1%. There was a high incidence of crossover between the two groups, 27% of the patients in the double therapy group requiring the addition of azathioprine, and 45% of the patients in the triple therapy group requiring its discontinuation (usually temporary). These results show that FK506 is an excellent immunosuppressive agent after renal transplantation and that azathioprine is not routinely effective 1

Transplantation, 1990