A limited sampling model to estimate exposure to lenalidomide in multiple myeloma patients.

BACKGROUND: The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration-time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy. METHODS: Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3-10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: The AUC0-24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0-24 of lenalidomide (AUC0-24 = 13.0 × C8h + 1305.0; r = 0.832). To enhance the correlation between the predicted and the actual AUC0-24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0-24. Predicting the AUC0-24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0-24 of lenalidomide [AUC0-24 = 37.1 × C0h + 6.4 × C4h - 32.1 × CCr + 3265.6; r = 0.842]. CONCLUSIONS: The AUC0-24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.

Safety and efficacy of low-dose liposomal amphotericin B as empirical antifungal therapy for patients with prolonged neutropenia.

BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

Successful treatment of necrotizing fasciitis in an upper extremity caused by Clostridium perfringens after bone marrow transplantation.

We report a 47-year-old man with acute leukemia who survived a severe case of necrotizing fasciitis caused by Clostridium perfringens involving his right upper extremity. On day 5 after stem cell transplantation, progressive local tissue necrosis led to septicemia and disseminated intravascular coagulation. Early diagnosis and prompt initiation of appropriate therapy, including surgical debridement and broad-spectrum antibiotics, were crucial. A recombinant thrombomodulin might have not only resolved the coagulation problem but also prevented multiple organ failure associated with the systemic inflammatory response.

False-positive human immunodeficiency virus antibody test and autoimmune hemolytic anemia in a patient with angioimmunoblastic T-cell lymphoma.

A 44-year-old woman was admitted with generalized lymphadenopathy, which was diagnosed as angioimmunoblastic T-cell lymphoma (AITL). The patient showed autoimmune hemolytic anemia (AIHA), polyclonal hypergammaglobulinemia and a high antinuclear antibody titer. Moreover, a human immunodeficiency virus (HIV)-1/2 screening test using the particle agglutination method was reactive. After chemotherapy for AITL, the AIHA was eliminated, and the false-positive HIV results were no longer detected. Autoimmunity associated with AITL is the likely cause of the cross-reaction with HIV and the AIHA. It is important to recognize that the cross-reaction with HIV can be a potential complication in AITL as well as AIHA.

Genomic organization and functional analysis of murine PKD2L1.

Mutations in genes that encode polycystins 1 or 2 cause polycystic kidney disease (PKD). Here, we report the genomic organization and functional expression of murine orthologue of human polycystin-2L1 (PKD2L1). The murine PKD2L1 gene comprises 15 exons in chromosome 19C3. Coexpression of PKD2L1 together with polycystin-1 (PKD1) resulted in the expression of PKD2L1 channels on the cell surface, whereas PKD2L1 expressed alone was retained within the endoplasmic reticulum (ER). This suggested that interaction between PKD1 and PKD2L1 is essential for PKD2L1 trafficking and channel formation. Deletion analysis at the cytoplasmic tail of PKD2L1 revealed that the coiled-coil domain was important for trafficking by PKD1. Mutagenesis within two newly identified ER retention signal-like amino acid sequences caused PKD2L1 to be expressed at the cell surface. This indicated that the coiled-coil domain was responsible for retaining PKD2L1 within the ER. Functional analysis of murine PKD2L1 expressed in HEK 293 cells was undertaken using calcium imaging. Coexpression of PKD1 and PKD2L1 resulted in the formation of functional cation channels that were opened by hypo-osmotic stimulation, whereas neither molecule formed functional channels when expressed alone. We conclude that PKD2L1 forms functional cation channels on the plasma membrane by interacting with PKD1. These findings raise the possibility that PKD2L1 represents the third genetic locus that is responsible for PKD.