Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study.

The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P-glycoprotein (P-gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1-2 weeks at 28-32 weeks gestation, and the same order was repeated at 6-10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography-mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/F(unbound) (593 +/- 237 l/min vs. 345 +/- 103 l/min; P = 0.007), digoxin CL(Renal, unbound) (272 +/- 45 ml/min vs. 183 +/- 37 ml/min; P < 0.002) and digoxin CL(secretion,) (unbound) (109 +/- 34 ml/min vs. 58 +/- 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P-gp activities during pregnancy.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

Who gets a heart? Rationing and rationalizing in heart transplantation.

National policy on organ transplantation is made by the United Network for Organ Sharing (UNOS), a representative body composed of health care professionals and patients. Standardized criteria for determining when a patient should be placed on the waiting list for heart transplantation are now in effect nationwide. Current and future directions to maximize the utilization of available donated organs are explored.

Treatment of hyperlipidemia after heart transplantation and rationale for the Heart Transplant Lipid Registry.

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.

E-selectin expression in human cardiac grafts with cellular rejection.

BACKGROUND: E-selectin expression has recently been documented to occur with lymphocytic infiltration in the skin and synovium. The question of whether E-selectin is expressed in the context of cardiac graft rejection was addressed in this study. METHODS AND RESULTS: One hundred ninety-five human posttransplant cardiac biopsy specimens were immunoreacted with antibodies to E-selectin and VCAM-1, and endothelial expression of both adhesion molecules was recorded as present or absent. Cardiac graft rejection was graded in blinded fashion. The frequency of E-selectin expression was 11% in biopsies without rejection, 36% in mild rejection, and 58% in moderate rejection, a significant correlation (P < .001). VCAM-1 expression was present in 11% of biopsies with no rejection, 37% with mild rejection, and 85% with moderate rejection, corroborating the previously reported strong correlation between VCAM-1 expression and graft rejection (P < .0001). In 71% of specimens, E-selectin expression coincided with VCAM-1 expression. In the remaining 29% of specimens in which E-selectin and VCAM-1 expression were not both present, isolated E-selectin expression was found more frequently in biopsies with early, increasing rejection, whereas isolated VCAM-1 expression was found more frequently in specimens with established moderate rejection and later, resolving rejection. CONCLUSIONS: E-selectin is expressed in cardiac allograft rejection and may play a role in recruitment of lymphocytes into the graft. Rejection trend analysis suggests that E-selectin expression may be prominent early in the course of rejection.

Limited cytomegalovirus-specific immunoglobulin M and immunoglobulin G profiles in heart transplant recipients.

Twenty heart transplant recipients were assayed serially with cytomegalovirus cultures and with Western blot techniques for development of anticytomegalovirus immunoglobulin M (IgM) and immunoglobulin G (IgG). Patients were followed up 3 to 29 months (mean, 15 months) after transplantation. All but three patients received a 5-week perioperative course of passive immunization with immune globulin. Of nine seronegative patients with seropositive grafts, positive cytomegalovirous cultures developed in all, secondary organ involvement (gastrointestinal or pneumonia) developed in four of nine. Four of nine patients produced limited IgM profiles, consisting of only one to three bands; six of the nine patients had atypical, restricted IgG profiles. Three of four patients in whom secondary organ invasion developed had limited IgM profiles, and all four had atypical IgG profiles. Four of five patients with primary infection without symptoms produced full IgM profiles. Delay of IgM production until a time coincident with or after evidence of viral shedding was documented in all patients with primary infection and secondary organ involvement. Among 11 seropositive patients, five received seropositive grafts and six seronegative grafts. Of the five patients with seropositive grafts, positive cultures (reinfection) developed in three; all three responded with full IgM profiles. However, secondary organ involvement developed in two of these three in spite of full IgM profiles. Symptomatic illness did not develop in any patient with a seronegative donor, even in the presence of positive cultures (reactivation). Persistence of IgM for up to 26 months was found in all patients with primary infection or reinfection. In heart transplant recipients, limited IgM and IgG profiles in primary infection may confer increased risk of secondary organ invasion whereas the early development of full IgM profiles may correlate with disease without symptoms. In seropositive patients, production of full IgM profiles may not protect from reinfection with secondary organ involvement if the organ donor is seropositive, a potential source of a new viral strain.