Suchergebnisse

In development regions, the management of environmental quality and the regional planning of water supply and the disposal of residuals are closely related to the form of intraregional population distribution. In this paper a hierarchical programming model is presented of the optimum intraregional population distribution in relation to environmental quality and the economic cost of water supply and the disposal of residuals. The model is applied to the specific case of a suburban region of the Tōkyō Metropolitan Region. The results show that the higher-order objective of environmental quality regulates the spatial allocation of disposal-of-residuals activities, and the lower-order objective of economic cost determines the form of intraregional population distribution.

BackgroundRilpivirine (TMC‐278) is a second‐generation NNRTI that is highly potent against both wild‐type and drug‐resistant HIV‐1 strains. The quantification of rilpivirine in human plasma is important to support clinical studies and determine pharmacokinetic parameters of rilpivirine. Until now there has been a methodological report for the determination of rilpivirine using LC‐MS/MS. However, the MS‐MS detector needs to be delicately set and it is expensive. To bypass these difficulties, we aimed to develop more conventional procedures for determining rilpivirine plasma concentration by LC‐MS method.MethodsA Waters Alliance 2695 HPLC and a Micromass ZQ‐2000 MS, controlled with MassLynx version 4.0 software, were used for detection. Our method involves rapid liquid‐liquid drug extraction from plasma and use of gradient elution on a reversed‐phase C18 column. The mobile phase comprised 0.1 mM EDTA in 0.1% acetic acid (65%), acetonitrile (15%), and methanol (20%). Quantitative analysis detected rilpivirine at m/z 367, and the internal standard, at m/z 313, all in the form of ions.ResultsThe established LC‐MS method was validated by estimating the precision and accuracy for inter‐ and intraday analysis in the concentration range of 18–715 ng/ml. The calibration curve was linear in this range. Average accuracy ranged from 100.0 to 100.6%. Relative standard deviations of both inter‐ and intraday assays were less than 3.3%. Recovery of rilpivirine was more than 82.0%.ConclusionsOur newly developed LC‐MS method achieves the same level of reproducibility and accuracy as the LC‐MS/MS method. Our method provides a conventional, accurate and precise way to determine rilpivirine in human plasma. This method can be used in routine clinical application for HIV‐1 infected patients, and permits management of drug interactions and toxicity for rilpivirine.

BackgroundDarunavir, a second‐generation protease inihibitor, is used with a low boosting dose of ritonavir to improve its clinical efficacy. The boosting dose of ritonavir acts as an inhibitor of CYP3A4, thereby increasing darunavir bioavailability. Recently, ritonavir tablet has been on sale in place of soft capsule. However, pharmacokinetic study of darunavir by changing ritonavir form is still not clear. In this study, we aimed to compare with plasma darunavir concentrations by switching ritinavir soft capsule to tablet in Japanese HIV‐1 infected patients.MethodsWe analyzed 34 Japanese HIV‐1 infected patients (32 males: 2 females) recruited at the National Hospital Organization Nagoya Medical Center. All patients had been administered with 800/100 mg darunavir/ritonavir once daily in combination with other antiretrovirals. Plasma darunavir concentrations were determined by an HPLC method. A pared t‐test was used to compare with their concentrations by switching from ritonavir soft capsule to tablet.ResultsThe mean of age, body weight, and duration of antiretroviral therapy for 34 patients were 41.9 (range: 24–62) years, 66.3 (range: 51.4–90.0) kg, and 436 (range: 182–739) days, respectively. The mean±SD darunavir concentration was 3.44±1.78 µg/ml when ritonavir soft capsule was co‐administered. After switching to ritonavir tablet, the mean±SD darunavir concentration was 3.30±2.02 µg/ml. Statistical difference was not found in plasma trough darunavir concentration between ritonavir soft capsule and tablet (P=0.826). On the other hand, the mean of viral load was 78 copies/ml when ritonavir soft capsule was administered. After switching to ritonavir tablet, the mean viral load was 33 copies/ml.ConclusionRecruited all patients have been sustained an ndetectable viral load (less than 40 copies/ml) after switching to ritonavir tablet. In this study, switching to ritonavir tablet had no significant difference on plasma darunavir concentrations in Japanese HIV‐1 infected patients.

BackgroundRaltegravir is metabolized by glucuronidation via UGT1A1. Among the genetic polymorphisms of UGT1A1, the *6, *27 and *28 alleles are associated with reduced levels of UGT1A1. In particular, the *28 allele accounts for most of the UGT1A1 polymorphisms, and the level of UGT1A1 activity has been the focus of most studies. On the other hand, among Asians, the *6 and *27 alleles are more commonly found in comparison with white populations. In this study, we aimed to clarify the contribution of UGT1A1 polymorphisms (*6, *27) to plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.Materials & MethodsWe analyzed the presence of genotypic variants (*6, *27 and *28) among the 74 patients recruited at the National Hospital Organization Nagoya Medical Center. Genotyping of *6 and *27 in UGT1A1 was performed using the TaqMan drug metabolism genotyping assay. Genotyping of *28 in UGT1A1 was performed using the primers described by Ehmer et al. Plasma raltegravir concentrations were determined by a LC‐MS method.ResultsAmong the 74 patients, the UGT1A1 genotype in 3 patients (two male, one female) was *6 homozygote. Heterozygous variants were found in 20 patients for *6, and in 14 patients for *28, while all of the patients were found to carry wild‐type sequences at the position corresponding to the *27 allele. The male *6 homozygote patient had modestly higher plasma raltegravir concentration (0.53 µg/ml) than other patients who were wild type (0.12 µg/ml) or heterozygous (0.16 µg/ml) for the *6 polymorphism. The other two UGT1A1*6 homozygote patients had a lower plasma raltegravir concentration (0.03 and 0.05 µg/ml). On the other hand, plasma raltegravir concentrations were 0.12 µg/ml (*6−/− *28−/−; n=37), 0.11 µg/ml (*6−/− *28−/+; n=14), 0.16 µg/ml (*6−/+ *28−/−; n=20). There were no statistically significant differences in the plasma raltegravir concentrations between patients carrying wild‐type alleles and those heterozygous for *6 or *28.ConclusionsPatients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild‐type allele. In this study, we showed that heterozygosity for the reduced‐function *6 and *28 alleles had no significant effect on plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.