Reduced Susceptibility of Plasmodium Falciparum to Artesunate in Southern Myanmar.

Reduced Susceptibility of Plasmodium falciparum to Artesunate in Southern Myanmar.

PLoS One. 2013; 8(3): e57689
Kyaw MP, Nyunt MH, Chit K, Aye MM, Aye KH, Aye MM, Lindegardh N, Tarning J, Imwong M, Jacob CG, Rasmussen C, Perin J, Ringwald P, Nyunt MM

Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels.The median (range) parasite clearance half-life and time were 4.8 (2.1-9.7) and 60 (24-96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics.A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar.Australian New Zealand Clinical Trials Registry ACTRN12610000896077. HubMed – drug


Wee1 Inhibition by MK-1775 Leads to Tumor Inhibition and Enhances Efficacy of Gemcitabine in Human Sarcomas.

PLoS One. 2013; 8(3): e57523
Kreahling JM, Foroutan P, Reed D, Martinez G, Razabdouski T, Bui MM, Raghavan M, Letson D, Gillies RJ, Altiok S

Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10-20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible and new agents are needed. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by MK1775 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas. In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo both alone and in combination with gemcitabine, which is frequently used in the treatment of sarcomas. Our data demonstrate that MK1775 treatment as a single agent at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. Additionally, MK1775 significantly enhances the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status. In patient-derived bone and soft tissue sarcoma samples we showed that MK1775 alone and in combination with gemcitabine causes significant apoptotic cell death. Magnetic resonance imaging (MRI) and histopathologic studies showed that MK1775 induces significant cell death and terminal differentiation in a patient-derived xenograft mouse model of osteosarcoma in vivo. Our results together with the high safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients. HubMed – drug


A Trial-Based Cost-Effectiveness Analysis of Erlotinib Alone versus Platinum-Based Doublet Chemotherapy as First-Line Therapy for Eastern Asian Nonsquamous Non-Small-Cell Lung Cancer.

PLoS One. 2013; 8(3): e55917
Wang S, Peng L, Li J, Zeng X, Ouyang L, Tan C, Lu Q

Lung cancer, the most prevalent malignant cancer in the world, remains a serious threat to public health. Recently, a large number of studies have shown that an epidermoid growth factor receptor-tyrosine kinase inhibitor (EGFR TKI), Erlotinib, has significantly better efficacy and is better tolerated in advanced non-small cell lung cancer (NSCLC) patients with a positive EGFR gene mutation. However, access to this drug is severely limited in China due to its high acquisition cost. Therefore, we decided to conduct a study to compare cost-effectiveness between erlotinib monotherapy and carboplatin-gemcitabine (CG) combination therapy in patients with advanced EGFR mutation-positive NSCLC.A Markov model was developed from the perspective of the Chinese health care system to evaluate the cost-effectiveness of the two treatment strategies; this model was based on data from the OPTIMAL trial, which was undertaken at 22 centres in China. The 10-year quality-adjusted life years (QALYs), direct costs, and incremental cost-effectiveness ratio (ICER) were estimated. To allow for uncertainties within the parameters and to estimate the model robustness, one-way sensitivity analysis and probabilistic sensitivity analysis were performed.The median progression-free survival (PFS) obtained from Markov model was 13.2 months (13.1 months was reported in the trial) in the erlotinib group while and 4.64 months (4.6 months was reported in the trial) in the CG group. The QALYs were 1.4 years in the erlotinib group and 1.96 years in the CG group, indicating difference of 0.56 years. The ICER was most sensitive to the health utility of DP ranged from $ 58,584.57 to $ 336,404.2. At a threshold of $ 96,884, erlotinib had a 50%probability of being cost-effective.Erlotinib monotherapy is more cost-effective compared with platinum-based doublets chemotherapy as a first-line therapy for advanced EGFR mutation- positive NSCLC patients from within the Chinese health care system. HubMed – drug