Michael A. Hooks

Tacrolimus, a New Immunosuppressant—A Review of the Literature

OBJECTIVE: To review the clinical pharmacology, pharmacokinetics, adverse effects, therapeutic uses, and current status of tacrolimus. DATA SOURCES: Data from scientific literature were identified by a MEDLINE search. The data were extracted, evaluated, and summarized for presentation. Experiences from studies evaluating tacrolimus in the form of articles, abstracts, letters to the editor, or proceedings were considered for inclusion. STUDY SELECTION: Open and controlled clinical and animal trials were reviewed in evaluating the pharmacology, pharmacokinetics, and adverse effects of tacrolimus. DATA EXTRACTION: Data from animal and human studies published in the English literature were evaluated. DATA SYNTHESIS: Tacrolimus is an 822-kDa macrolide antibiotic that has potent immunosuppressive properties. The mechanism of action is similar to that of cyclosporine in that it ultimately blocks the production of interleukin 2, thereby inhibiting further T-lymphocyte proliferation. Tacrolimus is metabolized solely in the liver and the metabolites are primarily excreted in the bile. The elimination halflife of tacrolimus is approximately 8.5 h, and is prolonged in hepatic dysfunction. Tacrolimus has shown efficacy in the prophylaxis of allograft rejection in both animals and human clinical trials, and has been used effectively to rescue patients who have exhibited refractory rejection failing cyclosporine prophylaxis. Adverse effects requiring tacrolimus dosage adjustment include nephrotoxicity, neurotoxicity, alterations in glucose metabolism, and infection or susceptibility to malignancy. CONCLUSIONS: To date, trials comparing tacrolimus with cyclosporine are not available in the literature; however, tacrolimus appears to be useful in rescuing grafts, particularly liver grafts that fail cyclosporine-based immunosuppression. Direct comparisons with cyclosporine are needed to define the role of tacrolimus as primary transplant therapy.

Selective shunt in the management of variceal bleeding in the era of liver transplantation

This study reports the Emory experience with 147 distal splenorenal shunts (DSRS) and 110 orthotopic liver transplants (OLT) between January 1987 and December 1991. The purpose was to clarify which patients with variceal bleeding should be treated by DSRS versus OLT. Distal splenorenal shunts were selected for patients with adequate or good liver function. Orthotopic liver transplant was offered to patients with end-stage liver disease who fulfilled other selection criteria. The DSRS group comprised 71 Childs A, 70 Childs B, and 6 Childs C patients. The mean galactose elimination capacity for all DSRS patients was 330 +/- 98 mg/minute, which was significantly (p less than 0.01) above the galactose elimination capacity of 237 +/- 82 mg/minute in the OLT group. Survival analysis for the DSRS group showed 91% 1-year and 77% 3-year survival, which was better than the 74% 1-year and 60% 3-year survivals in the OLT group. Variceal bleeding as a major component of end-stage disease leading to OLT had significantly (p less than 0.05) poorer survival (50%) at 1 year compared with patients without variceal bleeding (80%). Hepatic function was maintained after DSRS, as measured by serum albumin and prothrombin time, but galactose elimination capacity decreased significantly (p less than 0.05) to 298 +/- 97 mg/minute. Quality of life, measured by a self-assessment questionnaire, was not significantly different in the DSRS and OLT groups. Hospital charges were significantly higher for OLT (median,

Change in hepatic function, hemodynamics, and morphology after liver transplant. Physiological effect of therapy.

113,733) compared with DSRS (

Prevalence of Invasive Cytomegalovirus Disease with Administration of Muromonab Cd-3 in Patients Undergoing Orthotopic Liver Transplantation

32,674). These data support a role for selective shunt in the management of patients with variceal bleeding who require surgery and have good hepatic function. Transplantation should be reserved for patients with end-stage liver disease. A thorough evaluation, including tests of liver function, help in selection of the most appropriate therapeutic approach.

Comparison of whole-blood cyclosporine levels measured by radioimmunoassay and fluorescence polarization in patients post orthotopic liver transplant

Orthotopic liver transplantation (OLT) has become standard therapy for patients with acute hepatic necrosis and end-stage liver disease. This study measured change in hepatic function (galactose elimination capacity [GEC]), liver blood flow (low dose galactose clearance: flow), hepatic volume (CT scan; volume) and morphology after OLT. The aim was to measure the physiologic response after OLT and compare this response with that after selective shunt (SS) and sclerotherapy (ES) to determine which patients should receive specific therapy. Between January 1987 and November 1988, 37 patients underwent OLT. Operative mortality was 18%, which was similar to that of SS in Childs C cirrhotics. GEC and volume were less in transplant patients than in cirrhotics treated with SS or ES. GEC, flow, and volume normalized after OLT; GEC was preserved after ES and SS, but volume decreased. Three preoperative patterns were observed that can aid in selection of OLT candidates. Patients with chronic cirrhosis (chronic active hepatitis; cryptogenic) need OLT when GEC is less than or equal to 225 mg/min and volume is less than or equal to 50% normal. Patients with Budd-Chiari Syndrome require OLT if cirrhosis has evolved. Patients with sclerosing cholangitis and primary biliary cirrhosis qualify for transplants when complications of the portal hypertensive syndrome develop. The studies can also direct therapy for ES failures. Selective shunt is indicated in those patients with stable disease whose GEC is greater than or equal to 300 mg/min and liver volume is greater than 75% normal; OLT is indicated for cirrhotics with GEC that is less than 225 mg/min and liver volume that is less than 50% predicted normal.

A hypercoagulable state follows orthotopic liver transplantation

OBJECTIVE: To assess the association of cytomegalovirus (CMV) disease with the administration of muromonab CD-3 (OKT-3) in patients undergoing liver transplant; specifically, to assess the risk of OKT-3 use as an agent for rejection prophylaxis and as an agent for therapy of rejection. DESIGN: Retrospective review of medical records. STUDY POPULATION: 83 liver transplant recipients (43 men, 40 women) with a mean age of 41.5 years (range 16–62). DATA EXTRACTION: The medical record for each liver transplant recipient was reviewed and analyzed for the following variables: (1) preoperative recipient CMV serology, (2) donor CMV serology, (3) incidence of invasive CMV disease, (4) administration of OKT-3, (5) postoperative administration time of OKT-3, and (6) the relationship between the administration of OKT-3 and the prevalence of invasive CMV disease. RESULTS: OKT-3 was administered to 34 of 83 (40.9 percent) liver recipients, 7 of whom received OKT-3 as rejection prophylaxis; the remainder received OKT-3 as rejection rescue. All patients received OKT-3 5 mg iv for 14 days. Seventeen of the 34 patients receiving OKT-3 (50 percent) developed invasive CMV disease; 58.8 percent of the patients (20/34) receiving OKT-3 were given the agent within the first 14 postoperative days. Sixteen of these 20 patients (80 percent) developed invasive CMV disease. One of 14 patients (7.1 percent) who received OKT-3 after the first 14 postoperative days developed invasive CMV disease. Of those patients 94 percent (16/17) received OKT-3 in the first 14 postoperative days. This prevalence differed significantly from those receiving OKT-3 after the 14th postoperative day and those who did not receive OKT-3 at any time during their hospital course. CONCLUSIONS: The patients who received early administration of OKT-3 in our study had a greater risk of invasive CMV disease than did those who received OKT-3 later in the hospital course.

High cardiac output of advanced liver disease persists after orthotopic liver transplantation.

Summary: This study compared the analysis of whole blood cyclosporine concentrations measured by fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA) polyclonal and monoclonal procedures. Fifteen orthotopic liver transplant patients with a mean age of 39 \pm 11.06 years were included in the study. One hundred thirteen levels were analyzed using FPIA, RIA polyclonal, and RIA monoclonal procedures. There was no difference statistically in comparing FPIA and RIA polyclonal results (p > 0.05). There was a statistical difference between FPIA and RIA monoclonal results (p = 0.0001). With use of least squares simple linear regression analysis, FPIA results showed good correlation with RIA polyclonal results (R2 = 0.87). Poor correlation was shown between FPIA and RIA monoclonal results (R2 = 0.51). In this study population, FPIA produced results 2.5% higher than the RIA polyclonal procedure.