Mundy J

KETOCONAZOLE TO REDUCE THE NEED FOR CYCLOSPORINE AFTER CARDIAC TRANSPLANTATION

BACKGROUND Because ketoconazole can markedly reduce the need for cyclosporine and because it also has antimicrobial properties, it may offer benefits in the treatment of patients after cardiac transplantation. METHODS We randomly assigned 43 patients at the time of cardiac transplantation to receive ketoconazole (200 mg per day) (23 patients) or no ketoconazole (20 patients). The main end points were the dose of cyclosporine required and the incidence of cardiac rejection and infection. RESULTS Ketoconazole reduced the dose of cyclosporine needed to maintain target levels by 62 percent at one week and by 80 percent at one year. The cost savings per patient (in U.S. dollars, inclusive of the cost of ketoconazole) was about

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation

5,200 in the first year and about

Urinary nitrate excretion is a noninvasive indicator of acute cardiac allograft rejection and nitric oxide production in the rat

3,920 in each subsequent year. The mean (+/- SD) rate of rejection in the first month was lower in the ketoconazole group than in the controls (4.2 +/- 0.8 vs 5.7 +/- 1.0 episodes per 100 patient-days, P < 0.001), and the average number of days to the first rejection was higher (30 +/- 29 vs. 15 +/- 8, P = 0.03). In the first year, 22 percent of the ketoconazole group required cytolytic therapy, as compared with 35 percent of the controls, and 9 percent of the ketoconazole group required total lymphoid irradiation, as compared with 15 percent of the controls (P = 0.07). The incidence of infection was lower in ketoconazole-treated patients than in controls in the second month (1.4 +/- 0.5 vs. 2.8 +/- 0.7 episodes per 100 patient-days, P < 0.001) and in the third month (0.8 +/- 0.3 vs. 2.3 +/- 0.6 episodes per 100 patient days, P < 0.001). Transient, asymptomatic cholestasis was observed in the ketoconazole group. CONCLUSIONS After cardiac transplantation, ketoconazole greatly reduced the need for cyclosporine, resulting in substantial cost savings. Ketoconazole also reduced the rates of rejection and infection, without persistent toxic effects. We now use ketoconazole routinely in cardiac-transplant recipients.

A prospective randomized study of prophylactic OKT3 versus equine antithymocyte globulin after heart transplantation--increased morbidity with OKT3.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.

Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.

Cytokine induction of calcium-independent nitric oxide synthase is associated with production of large amounts of nitric oxide (NO). NO is a free radical that is rapidly degraded to nitrite and nitrate. Measurement of plasma and urinary nitrate is an indirect marker of NO production and previous studies have demonstrated that plasma nitrate rises with allograft rejection. The purpose of this study was to examine the temporal relationship between the rise in urinary nitrate excretion and the onset of graft rejection, and to determine the effect of conventional immunosuppression on nitrate excretion. The heterotropic model of cardiac transplantation in the rat was used, with Brown-Norway to Lewis allografts and Lewis to Lewis isograft controls. Twenty-four-hour urine specimens were collected before and after transplantation. Urinary nitrate excretion was measured by gas chromatography/mass spectrometry. Each group was treated with (1) no immunosuppression, (2) dexamethasone (3 mg/kg), or (3) CsA (10 mg/kg) on days 0, 1, and 2. Time to rejection for untreated allografts was 5.1 +/- 0.1 days, extending to 8.4 +/- 0.5 and 9.6 +/- 0.4 days with dexamethasone and CsA treatment, respectively. There was a significant rise in nitrate excretion on days 4, 7, and 9 for control, dexamethasone-treated, and CsA-treated allografts, respectively, preceding evidence of rejection. Untreated allograft rejection was associated with a peak in nitrate excretion 8 times that of basal excretion by isografts. Treatment of the allografts with dexamethasone and CsA significantly attenuated peak nitrate excretion compared with untreated allografts with a only a 2- to 3-fold rise preceding rejection. Results indicate that allograft rejection is associated with a dramatic increase in peak urinary nitrate excretion that is attenuated by standard immunosuppressive therapy. An increase in nitrate excretion precedes evidence of graft rejection, and may serve as a noninvasive marker of graft rejection.

PAPAVERIVE ABOLISHES ENDOTHELIUM-DEPENDENT DILATATION OF HUMAN INTERNAL MAMMARY ARTERIES IN VITRO

The aim of this study was to compare the efficacy and toxicity of prophylactic OKT3 and equine antithymo-cyte globulin when each drug was administered for a similar duration after heart transplantation. Forty-one patients (35 males, 6 females; mean age 46±2 years) were randomized to receive either OKT3 for 10 days (20 patients) commencing within 24–48 hr of transplantation or ATGAM for 8 days (21 patients) commencing on the day of transplantation. All patients were maintained on triple-agent immunosuppression with prednisolone, azathioprine, and cyclosporine. The two groups were well matched with respect to age, sex distribution, pretransplant cardiac diagnosis, and donor heart ischemic time. Mean duration of follow-up was 14 months (range 9–19 months): Actuarial survival at 12 months was 83±9 in the OKT3 group and 81±9 in the ATG group (P=NS). Mean time to first cardiac rejection was 33±8 days in the OKT3 group compared with 27± 5 days in the ATG group (P=NS). Linearized rejection rate did not differ between the two groups at any time point up to 12 months posttransplant. Viral infections were significantly more common in the OKT3 group: 1.6±0.3 vs. 0.8±0.2 infections per patient (P<0.05). Adverse reactions were more common in patients who received OKT3 prophylaxis and included three patients who developed acute respiratory distress, two of whom required assisted ventilation. In conclusion, prophylactic OKT3 and ATGAM result in comparable rejection rates and survival when administered for a similar duration after cardiac transplantation. OKT3, however, is associated with increased morbidity due to a higher incidence of adverse reactions and of viral infections.

Successful treatment of life-threatening acute reperfusion injury after lung transplantation with inhaled nitric oxide

BACKGROUND Two important processes in the preservation of the function of donor hearts are the maintenance of ATP-sensitive potassium channel activity during myocardial ischemia and the scavenging of reactive oxygen species formed during reperfusion. The aim of this study was to compare the effect of three protocols on the preservation of hemodynamic function in isolated rat hearts after hypothermic storage. These protocols were: (1) pretreatment of the heart with a potassium channel opener (200 microM pinacidil); (2) storage of the heart in an aspartate-enriched extracellular cardioplegic solution containing the lazaroid antioxidant, U74500A (30 microM); and (3) a combination of protocols 1 and 2. METHODS Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, coronary and aortic flow, and cardiac output were performed. Hearts (n=6 in each group) were then randomized to protocols 1-3, untreated controls, or vehicle-treated controls. Hearts were stored in extracellular-based preservation solution for 12 hr at 2-3 degrees C, remounted on the perfusion apparatus, and stabilized as before; hemodynamic measurements were then repeated. RESULTS Recovery of hemodynamic function was enhanced by pinacidil pretreatment or incorporation of lazaroid in the storage solution, but the combination of these two treatments produced the best results. CONCLUSIONS Combined pharmacological activation of ATP-sensitive potassium channels before cardioplegia and the addition of U74500A to the preservation solution is associated with significantly enhanced hemodynamic function in the isolated rat heart after 12 hr of hypothermic storage. These data suggest a novel use for these agents in the transplantation context.

Initial steroid-free versus steroid-based maintenance therapy and steroid withdrawal after heart transplantation: two views of the steroid question.

1. The purpose of the present study was to examine the effects of papaverine‐HCl, administered into the lumen of the human internal mammary artery (IMA) during harvesting of this vessel, on vascular reactivity in vitro and to specifically test the hypothesis that intraluminal administration of papaverine‐HCl impairs endothelium‐dependent vasodilation.