Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy.

STUDY OBJECTIVE: Because the incidence rate of renal impairment is 2-10% for patients treated with high-dose methotrexate and renal impairment develops in 0-12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination. DESIGN: Pooled analysis of efficacy data from four multicenter single-arm compassionate-use clinical trials using protocols from 1993 to 2007. PATIENTS: Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1 µmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement. MEASUREMENTS AND MAIN RESULTS: Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1 µmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20 years (range 5 weeks-84 years). Osteosarcoma (36%), non-Hodgkin lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7 µmol/L. At the first (median 15 minutes) through the last (median 40 hours) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. A total of 64% of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5 days after glucarpidase administration. CONCLUSION: Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients.

Clinical significance of cerebrovascular gas emboli during polidocanol endovenous ultra-low nitrogen microfoam ablation and correlation with magnetic resonance imaging in patients with right-to-left shunt.

BACKGROUND: Foam generated by manual agitation of liquid sclerosant with air or gas is routinely utilized to treat refluxing veins. Although generally well tolerated, serious neurological events have been reported. The composition and properties of the foam, including bubble size and gaseous components, may contribute to the potential for microcirculatory obstruction and cerebral ischemia. We tested an ultra-low nitrogen polidocanol endovenous microfoam with controlled bubble size and density and hypothesized that patients at risk due to the presence of middle cerebral artery (MCA) bubble emboli during microfoam injection would not demonstrate evidence of clinical or subclinical cerebral infarction. METHODS: Patients with great saphenous vein incompetence were treated with ultra-low nitrogen (≤ 0.8%) polidocanol endovenous microfoam injected under ultrasound guidance. Patients with right-to-left shunt were included to evaluate the safety of cerebral arterial bubbles. All patients with MCA emboli detected by transcranial Doppler during endovenous microfoam ablation received intensive surveillance for microinfarction, including brain magnetic resonance imaging and measurement of cardiac troponin-I. RESULTS: MCA bubble emboli were detected in 60 of 82 treated patients; 22 patients had no detectable emboli. Among patients with MCA bubbles detected, 49 (82%) had ≤ 15 bubbles. No patients developed magnetic resonance imaging abnormalities, neurological signs, or elevated cardiac troponin. CONCLUSIONS: Patients treated with foamed liquid sclerosants are commonly exposed to cerebrovascular gas bubbles. In this series of 60 high-risk patients with MCA bubble emboli during or after treatment with ultra-low nitrogen polidocanol endovenous microfoam, there was no evidence of cerebral or cardiac microinfarction. The results of this study cannot be generalized to foams compounded using bedside methodologies, since the composition of these foams is substantially different.

Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The current standard of care for patients with non-ST-segment elevation acute coronary syndromes (ACS) includes antithrombotic therapy with aspirin and heparin. Although emerging data suggest that low-molecular weight preparations offer distinct advantages over unfractionated heparin, limited information on patient-related factors that may influence dosing, safety, and efficacy is available. PURPOSE: The purpose of our study was the determination of the impact of patient age, sex, body weight, and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in patients with ACS. METHODS AND RESULTS: Patients enrolled in the TIMI 11A trial received a full complement of antiischemic therapy, aspirin, and enoxaparin (30 mg intravenously, followed by weight-adjusted doses of either 1 mg/kg or 1.25 mg/kg subcutaneously every 12 hours). Before and after the third and last doses, blood samples were obtained from 445 patients for measurement of anti-Xa activity. The mean apparent clearance, distribution volume, and plasma half-life were 0.733 L/h, 5.24 L, and 5 hours, respectively. Among a wide range of clinical and laboratory covariates, creatinine clearance emerged as the most influential factor on apparent clearance, area under the curve, and anti-Xa activity. Patients with marked renal impairment (creatinine clearance <40 mL/min) had higher trough and peak anti-Xa activity compared with those with normal renal function and were more likely to have major hemorrhagic events. CONCLUSION: The pharmacokinetic and pharmacodynamic profiles after enoxaparin administration are consistent across a broad range of patients with ACS. Dose adjustments or anti-Xa coagulation monitoring or both will be necessary rarely in routine clinical practice, with the exception of patients with severe renal insufficiency.