Pharmacokinetics of cyclosporine and nephrotoxicity in orthotopic liver transplant patients rescued with FK 506.
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Biomedical subjects
Publications and source records attributed to J Fung.
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Patient and primary graft survival for 2,090 patients who received primary liver transplants at the University of Pittsburgh from 1984 through 1990 are presented. Observed (actual) 3- and 12-month patient and primary graft survival rates were compared for 3 periods: 1) January 1984 to September 1987 (cyclosporine, OKT3, and Euro-Collins preservation period); 2) October 1987 to December 1988 (University of Wisconsin solution preservation period); and 3) January 1989 to December 1990 (FK506 period). Data for results according to age group, medical urgency, and primary diagnosis are provided. In addition, estimated survivor and cumulative hazard functions (life-table method) for patient and primary graft survival out to 60 months after transplantation are presented. Overall results have improved significantly in recent experience. Most notable are the improved results seen in liver transplantation for patients with biliary atresia (especially in infants), primary sclerosing cholangitis, fulminant hepatic failure, and chronic active hepatitis B. For all but a few conditions, most of the mortality after liver transplantation occurred in the first 3 months after surgery. Less than 2% of patients were lost in each 6-month interval beyond the first 6 months after transplantation. Outcome was related to patient condition at the time of surgery. Observed survival rates at 3 and 12 months for patients called in the hospital to receive a transplant were 88.6% and 86.5%, respectively, compared with 81.9% and 73.7% for patients in critical condition. The continuing shortage of organs for transplantation, which often forces patients to wait longer for an organ than they can afford to, continues to impose a significant penalty.
The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81%) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation.
The combined effects of a noradrenergic agonist, clonidine, and a serotonergic antagonist, cyproheptadine, together with an interactive locomotor training program incorporating progressive body weight support and treadmill walking exercise, were investigated in two chronic spinal cord injured subjects. Both subjects had no independent locomotor ability due to severe spasticity. Kinematic, temporal distance and electromyographic (EMG) data were collected during treadmill walking. The EMG activity of the lower limb muscles, initially characterized by tonic discharge and abnormal timing, became more phasic with less clonus following medication, which was related to a change in the kinematic pattern. Further kinematic and functional improvement were gained by training. Previously wheelchair-bound, both patients became functionally ambulatory overground with the aid of Canadian crutches. Thus, a potentially effective strategy for facilitating the expression of the locomotor pattern following spinal cord injury is proposed. This preliminary study showed that such a treatment strategy could possibly lead to a recovery of locomotor function in some chronic, wheelchair-bound spinal cord injured patients who had previously been stabilized on conventional therapies.
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Lewis recipients of orthotopic ACI livers had permanent graft acceptance induced with 3 doses of i.m. FK506 in the early postoperative period. They were studied 100 and 300 days posttransplantation. The recipients rejected ACI as well as Brown Norway (BN) (third-party) skin grafts, and had lymphocytes with substantial reactivity by mixed lymphocyte culture testing against ACI and third-party (BN) alloantigens. Lymphocyte subset redistribution had not occurred in the peripheral blood or spleens of these animals, and there was no evidence of suppressor cell activation by in vitro and in vivo tests. Graft-versus-host reactivity in splenic lymphoid tissues of these recipients was demonstrated with the popliteal lymph node assay. Attempts at adaptive transfer with recipient lymphocytes were unsuccessful. Heart graft acceptance was far more difficult to accomplish than liver graft acceptance, and probably was never permanent. ACI heart graft prolongation in LEW recipients after a brief induction with FK506 lasted for no more than 3 months in most animals. The temporary heart graft acceptance was specific for hearts of the original ACI donor strain but not for ACI skin. Results of studies of lymphocyte subsets and suppressor cell activity were similar to those in the liver recipients. These studies illustrate how poorly graft acceptance is understood and how badly further work is needed to clarify its mechanism.
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