MK-0524 is a potent, selective and orally active Prosglandin D(2) Receptor 1 (DP(1)) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5 mg/kg), the mean Cl(p) was approximately 2 and approximately 6 ml/min/kg, the T(1/2) was approximately 7 and approximately 13 h and the Vd(ss) was approximately 1 and approximately 5 L/kg, respectively. In monkeys dosed i.v. at 3 mg/kg, the corresponding values were 8 ml/min/kg, 3 h and 1 L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100 mg/kg), dogs (5 mg/kg) and monkeys (3 mg/kg), the absorption was rapid with the mean C(max) occurring between 1 and 4 h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.

Summary:Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (Po0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P ¼ 0.04) and cytogenetic risk group (P ¼ 0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.

Although basiliximab and rabbit anti-thymocyte globulin (ATG) are effective in delaying and reducing the incidence of acute rejection (AR) thus improving short-term graft survival, their impact on long-term graft survival has not been well established in renal transplant recipients. To evaluate the long-term efficacy after induction therapy with ATG/basiliximab in renal transplant recipients, we studied retrospectively 86 renal transplant recipients of living donor renal transplantation from 2003 to 2006; of them, 42 patients received induction with ATG three doses of 50 mg, 25 mg, 25 mg/day on 0, 1 and 2 post-operative days (POD) and 44 age-matched patients received induction with basiliximab (20 mg/day on 0 and 4 PODs). All the patients received tacrolimus, mycophenolate mofetil and corticosteroids as maintenance immunosuppressive therapy. Demographic characteristics were similar between both groups. Patient survival at 5 years was 90.5% in the ATG group and 84.1% in the basiliximab group, while graft survival was 83.4% and 77.3%, respectively. The incidence of acute rejection was 14.2% and 18.1% in the ATG and the basiliximab groups, respectively. The estimated mean glomerular filtration rates at 5 years post-transplantation was 52.1 mL/min and 49.1 mL/min and the mean serum creatinine levels were 1.55 ± 0.37 and 1.66 ± 0.51 mg/dL in the ATG and basiliximab groups, respectively. A low incidence of tuberculosis and cytomegalovirus (CMV) was observed in the ATG group. There were no significant differences between the two groups, and both induction regimens assured a safe and effective treatment and were associated with similar excellent long-term patient and graft survival.