Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing.
Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304. (+info)
Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation.
BACKGROUND: Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. METHODS AND RESULTS: Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic = 30.7%, standard = 33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic = 29%, standard = 39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of > or = 4 (P=0.03). CONCLUSIONS: An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes. (+info)
Pharmaceutical calculations instruction and assessment in US colleges and schools of pharmacy.
OBJECTIVE: To characterize the current strategies used in the instruction and assessment of pharmaceutical calculations content through the administration of a nationwide survey. METHODS: Instructors of pharmaceutical calculations were invited to complete a 34-item questionnaire designed to gather information on course logistics, content delivery, covered topics, homework, examinations, and retention measures. RESULTS: Seventy-two colleges and schools responded to the survey. Exactly half of the respondents indicated that they had a standalone pharmaceutical calculations course, while the other half indicated this material was integrated into other coursework. An average of 24.8 hours was devoted to calculations topics. A minimum passing examination score of 70% was reported by 53% of programs. Knowledge retention was formally measured in 16% of programs, while 27% responded that they did not measure retention. CONCLUSION: This survey provided the first assessment of the strategies used to teach and assess pharmaceutical calculations content. Further work is needed to determine the optimal teaching and assessment strategies for pharmaceutical calculations, as well as optimal methods of evaluating and promoting retention of this material. (+info)
Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly.
Thiotepa/cyclophosphamide/TBI as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients aged 50 years and over.
OBJECTIVE: To reduce the relapse rate for hematological malignancies after allogeneic hematopoietic stem cell transplantation, we employed a myeloablative regimen comprising thiotepa 400 mg/m(2), cyclophosphamide 3,600 mg/m(2) and total body irradiation 10 Gy. MATERIALS AND METHODS: Subjects comprised 17 patients (median age, 53 years; range, 50-56 years) with hematological malignancies who received allogeneic hematopoietic stem cell transplantation from HLA-identical related (n=6), HLA-mismatched family (n=2) or unrelated donors (n=9). Prophylaxis of acute graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine (n=4) or short-term methotrexate and tacrolimus (n=13). RESULTS: No grade IV regimen-related toxicities as determined by Bearman's criteria were encountered. Acute grade II-IV GVHD developed in 7 patients, with chronic GVHD in 11 patients. With a median follow-up of 39 months, 3 years survival rate after transplantation was 59%. Two patients died due to infection by 100 days after transplantation. Only 1 patient with Philadelphia-positive acute lymphoblastic leukemia experienced relapse. Eight patients died of non-leukemic causes (sepsis, n=2; liver dysfunction, n=2; idiopathic interstitial pneumonia, n=1; bacterial pneumonia, n=1; bronchiolitis obliterans resulting from chronic GVHD, n=1; and disseminated infection with varicella zoster virus, n=1). CONCLUSIONS: This regimen was tolerable, but a large trial is warranted to confirm the efficacy of this conditioning. (+info)
Daily insulin requirement of children and adolescents with type 1 diabetes: effect of age, gender, body mass index and mode of therapy.
Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer.