A Study Identifying the Medical Regions : An Analysis by Hierarchical Clustering Using Inter-districtional Transfer Rate

1)千葉県医療実態調査の資料により,「市町村内受診率」「地区間移動率」「隣接市町村間の患者相互移動数」「移動指数」を求め,患者の流れの傾向を検討した。つぎに「地区間移動率」による階層的クラスター分析を実施し,千葉県における実態医療圏を求め,計画医療圏のあり方について検討した。2)一般入院の市町村内受診率は全県で57.8%であり,人口当たりの病院数等の医療供給指標と強い相関を認めた。市町村間の相互依存を示す地区間移動率は,鉄道路線と関連を認めた。隣接する市町村間の移動を検討した結果,「辺縁効果」「勾配効果」の存在が示唆された。移動指数は,男性・生産年齢・入院医療・悪性腫瘍と精神疾患で大きい傾向を認めた。地区別でも格差を認め特に印旛郡,山武郡等で大きかった。3)患者の相互移動で表した地区間の結び付きの指標である地区間移動率を用いた階層的クラスター分析によって実態医療圏を求めた。4)求めた実態医療圏を計画医療圏として用いる上では地域特性はほぼ均質であるが,行政圏域や商圏とは一部で違いを認めた。圏域間の変動については近郊医療圏での人口集中や郡部での広域化が問題と思われた。5)医療圏間で医療需給の指標は地域特性を示す社会経済的指標よりも変動係数が大きく,潜在的医療需要を示すと思われる老年人口割合や粗死亡率よりも顕在化した需要である入院患者数の方が変動が大きかった。また医療圏内受診率は千葉市圏を除いて70%以下にとどまった。医療の質的量的充実が医療計画上の課題と思われた。6)地区間移動率およびそれを用いた階層的クラスター分析は実態医療圏解析の有効な方法と考えられる。To determine the regions for health plann

Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

ABSTRACT Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated Plasmodium falciparum malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither in vitro parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships

Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: A randomized clinical trial

Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia. Methods: Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days. Results: 143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/μL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/μL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×109/L) by Day 14 and resulted in the arm being halted early. Conclusion: There is no pharmacodynamic benefit of increasing the daily dose of AS (4mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy

Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance

ABSTRACT Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC 50 ] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pf mdr1 ) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure

A Simplified Liquid Chromatography-Mass Spectrometry Assay for Artesunate and Dihydroartemisinin, Its Metabolite, in Human Plasma

Artesunate (AS) is a potent antimalarial that is used worldwide for the treatment of malaria. A simple method with a total run time of 12 min was developed and validated for the quantification of AS and dihydroartemisinin (DHA), its active metabolite, in human (heparinized) plasma based on one-step protein precipitation in acetonitrile using artemisinin (ARN) as an internal standard, followed by liquid chromatography with a single quadrupole mass spectrometry system connected to a C18 column. Peak area ratio responses were fitted to the 2nd-order curve type, polynomial equation with weighting (1/concentration) over a quantification range between 3.20/5.33–3,000/5,000 nM (1.23/1.52–1153/1422 ng/mL) of AS/DHA showing linearity with very good correlation (r2 > 0.999). Single ion recordings of 5 µL injections of plasma extracts allowed for limits of detection of 1.02 nM (0.39 ng/mL) for AS and 0.44 nM (0.13 ng/mL) for DHA. The inter-assay and intra-assay accuracy and precision of the method was very good with an inaccuracy of ±12.4% and coefficients of variation of ≤10.7% at all tested concentrations. The recovery of the analytes from plasma was ≥95%. Other commonly used antimalarials including mefloquine, quinine, and chloroquine, did not interfere with the analysis. Post-preparative tests over 24 h in an autosampler (10 °C) showed that the DHA response was only 2.1% of AS from auto-hydrolysis, and β-DHA was the major, stable epimer that was used for quantification of DHA. In contrast, α-DHA increased steadily up to 600%. Artesunate and DHA in plasma were stable through three freeze/thaw cycles for up to 6 h at room temperature and up to one year at -80 °C

Nonisotopic, Semiautomated Plasmodium falciparum Bioassay for Measurement of Antimalarial Drug Levels in Serum or Plasma

A simple, nonisotopic, semiautomated bioassay for the measurement of antimalarial drug levels in plasma or serum based on the quantitation of histidine-rich protein II in malaria culture is presented. The assay requires only small sample volumes and was found to be highly sensitive and reproducible. The results closely paralleled those obtained with isotopic bioassays (R = 0.988, P < 0.001) and high-performance liquid chromatography-electrochemical detection (R = 0.978, P < 0.001)