Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC_0–∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC_0–∞ of 41.2 μg · h/ml decreased on average by 14.3% (90% confidence interval [CI], −90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 μg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385.)     

Comparison of 1- and 2-day protocols for myocardial SPECT: a Monte Carlo study

BACKGROUND: Myocardial perfusion single-photon emission computed tomography (SPECT) is carried out by combining a rest and a stress study that are performed either on one day or two separate days. A problem when performing the two studies on 1 day is that the residual activity from the first study contributes to the activity measured in the second study. AIM: Our aim was to identify and evaluate trends in the quantification parameters of myocardial perfusion images as a function of separation time between rest and stress. METHODS: A digital phantom was used for the generation of heart images and a Monte Carlo-based scintillation camera program was used to simulate SPECT projection images. In our simulations, the rest images were normal and the stress images included lesions of different types and localization. Two programs for quantification of myocardial perfusion images were used to assess the different images in an automated and objective way. RESULTS: The summed difference scores observed with the 2-day protocol were 3 +/- 1 (mean +/- SD) higher for AutoQUANT and 2 +/- 1 higher for 4D-MSPECT compared with those observed with the 1-day protocol. The extent values were 2% points higher for the 2-day protocol compared with the 1-day protocol for both programs. CONCLUSIONS: There are differences in the quantitative assessment of perfusion defects depending on the type of protocol used. The contribution of residual activity is larger when a 1-day protocol is used compared with the 2-day protocol. The differences, although small, are of a magnitude that results in a clear shift in quantification parameters.     

Evaluation of Dose Distribution of Molecular Delivery After Blood-Brain Barrier Disruption by Focused Ultrasound with Treatment Planning

The permeability of the blood-brain barrier (BBB) can be enhanced by focused ultrasound (FUS) in localized regions with applications of ultrasound contrast agent (UCA). The purpose of this study was to evaluate the dose distribution of Evans blue (EB) in the targeted brain by sonication with treatment strategy. FUS exposure was applied with an ultrasound frequency of 1 MHz, a 5% duty cycle and a repetition frequency of 1 Hz. Single sonication with two doses of UCA and two sonications at the same location or an interval of 3 mm to induce BBB disruption for assessing dose distribution. The permeability of the BBB was measured quantitatively based on EB extravasation. Gadolinium deposition was monitored by contrast enhanced MR imaging for dose distribution of the focal plane. Hematoxylin and eosin staining was performed for histologic observation. No significant difference was found for EB in the focal regions between the single sonication with UCA at a dose of 300 μL/kg and repeated sonication with UCA at a lower dose of 150 μL/kg. There was a sharper dose distribution in the brain with repeated sonication at the same location, compared with the brain receiving two sonications at an interval of 3 mm. Compared with a single sonication with UCA at a dose of 150 μL/kg, the histologic evaluation of the sonicated regions indicated that more erythrocytes were seen in the brain treated with single sonication at a higher dose of 300 μL/kg or repeated sonication at a dose of 150 μL/kg. This study demonstrated that the dose distribution of molecular delivery could be regulated by sonication with treatment planning.     

Evaluation of the uncertainty in the spectral band adjustment factor (SBAF) for cross-calibration using Monte Carlo simulation

Cross-calibration is one of the various methods applied for Earth Observation Satellites sensor calibration. In the cross-calibration procedure, one sensor is calibrated against another sensor, in which the radiometric calibration is better known, via near-simultaneous imaging of a common ground target. One of the most important steps during the cross-calibration is the Spectral Band Adjustment Factor (SBAF) assessment. The SBAF is used to compensate the differences in the spectral responses of the sensors, avoiding large uncertainties in cross-calibration results. The investigation described in this work focussed on the evaluation of the SBAF’s inherent uncertainties using Monte Carlo Simulation method. Basically, the Monte Carlo approach is based on calculating multiple integral by random sampling. The SBAFs were developed for analogous Landsat 8 Operational Land Imager and CBERS 4 Multispectral Camera spectral bands. The Hyperion hyperspectral sensor on-board Earth Observing-1 was utilized to understand the spectral profile of the target and to derive the SBAF. This study was performed over two pseudo invariant calibration sites: Algodones Dunes and Libya-4. The spectral uncertainty of the SBAFs using Monte Carlo was found to be within 0.01–1.79%. The results suggested that the uncertainty of the SBAFs is dependent on the correlation between the input variables: the higher the correlation, the lowest is the SBAF uncertainty.     

Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation

Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem.     

开胸肺癌根治术与完全胸腔镜下肺癌根治术治疗早期非小细胞肺癌的效果比较

目的比较开胸肺癌根治术与完全胸腔镜下肺癌根治术治疗早期非小细胞肺癌的效果。方法选取2013年2月~2015年10月我院收治的93例早期非小细胞肺癌患者,分为试验组47例和对照组46例。试验组给予完全胸腔镜下肺癌根治术治疗,对照组给予开胸肺癌根治术治疗。结果试验组术中出血量、第1d胸腔引流量少于对照组,其住院时间短于对照组,2组手术情况差异有统计学意义(P0.05);试验组术后分钟通气量(MV)与一秒用力呼气容积(FEV1)水平均高于对照组,2组术后MV、FEV1差异有统计学意义(P0.05)。结论完全胸腔镜下肺癌根治术治疗早期非小细胞肺癌的效果优于开胸肺癌根治术。     

Monte Carlo simulation for evaluation of the efficacy of carbapenems and new quinolones against ESBL-producing Escherichia coli

Extended-spectrum β-lactamase (ESBL)-producing bacteria are known to be resistant to penicillins, cephalosporins, and monobactams because of their substrate specificity, and these bacteria are sensitive only to a narrow range of antimicrobial agents. The present study was undertaken to evaluate the efficacy of carbapenems and the new quinolones against ESBL-producing Escherichia coli, using a Monte Carlo simulation based on the pharmacokinetic/pharmacodynamic (PK/PD) theory. The time above MIC (TAM, %) served as the PK/PD parameter for carbapenems, with the target level set at 40%. The AUC/MIC served as the PK/PD parameter for the new quinolones, with the target level set at more than 125. In the analysis of drug sensitivity, the MIC50 of all carbapenems other than imipenem was low (0.03 μg/ml), while the MIC50 of the new quinolones was higher (1–2 μg/ml). The probability of achieving the PK/PD target with carba penems after two doses at the usual dose level, as determined by the Monte Carlo simulation, was high for each of the carbapenems tested (99.0% for biapenem, 99.60% for meropenem, and 95.03% for doripenem), except for imipenem. Among the new quinolones, the highest probability of achieving the PK/PD target was obtained with pazufloxacin (42.90%). Thus, the results of the present study have revealed that carbapenems are effective at the regular dose and can be used as the first-choice antibiotics for ESBL-producing E. coli because the resistance ratios for carbapenems are low compared to those of the new quinolones.     

痰热清注射液联合抗生素对肺癌化疗后合并肺部感染的治疗价值评析

目的研究痰热清注射液联合抗生素对肺癌化疗后合并肺部感染的治疗价值。方法选取我院2014年2月~2015年11月肺癌化疗后合并肺部感染患者80例。按照治疗方法分为常规组和痰热清组各40例。常规组单纯采用抗生素进行治疗,痰热清组采用痰热清注射液联合抗生素进行治疗。比较两组患者感染缓解率,体温复常时间、咳嗽、肺部干湿性啰音消失时间,用药前和用药12天患者生活质量评分、卡氏评分。结果痰热清组相较于常规组感染缓解率更高(P0.05);痰热清组相较于常规组体温复常时间、咳嗽、肺部干湿性啰音消失时间更短(P0.05);用药前两组生活质量评分、卡氏评分相似(P0.05);用药12天痰热清组相较于常规组生活质量评分、卡氏评分改善更显著(P0.05)。结论痰热清注射液联合抗生素对肺癌化疗后合并肺部感染的治疗价值高,可有效缓解患者感染症状和体征,加速临床症状和体征消退,改善患者健康水平和生活质量,值得推广。     

甲状腺素治疗老年充血性心衰的临床观察

[目的]探讨小荆量甲状腺素片对老年充血性心力衰竭(CHF)的治疗效果.[方法]对比观察46例老年CHF患者及24例健康对照基础甲状腺激素水平,选择有甲状腺激素水平变化的CHF患者38例,随机分为观察组(18例)和治疗组(20例).观察组按常规治疗;治疗组在常规治疗的基础上加用左甲状腺素钠片,25 mg/d,观察4周,对比治疗前后两组的甲状腺素水平及心功能改善情况.[结果]CHF患者基础甲状腺激素水平低于正常,降低程度与心功能相关.治疗后观察组及治疗组甲状腺水平及心功能均有改善,治疗组改善更为明显.[结论]小剂量甲状腺素可用于老年CHF的治疗.     

短程大剂量米托蒽醌和阿糖胞苷治疗难治性和复发的急性白血病

初诊的急性白血病,化疗常可获得较高的缓解率,而难治性和复发的白血病治疗效果较差。本研究观察了大剂量米托蒽醌和中剂量阿糖胞苷治疗30例难治性或复发的白血病的效果。米托蒽醌静脉注射总剂量为40mg/m^2,阿糖胞苷剂量为每天1-1.5g/m^2,注射时间为3小时连续5天。26例病人获得完全缓解（缓解率为87%）,1例（3.3%）部分缓解,治疗过程中无病例死亡。平均获得完全缓解所需的时间为30天左右。平均无病生存和存活时间分别为3.5和6个月。主要副作用为造血系统受抑。结果显示短程大剂量米托蒽醌联合阿糖胞苷治疗难治性或复发的折血病可获得较高的缓解率,值得推广应用。     

Examining the effect of hydroxyl groups on the thermal properties of polybenzoxazines: using molecular design and Monte Carlo simulation

The influence of methylol and phenolic hydroxyl on the thermal properties of polybenzoxazines has been studied using two monofunctional benzoxazine monomers synthesized from para methylol-/ethyl- phenol, aniline and paraformaldehyde. The chemical structures of the synthesized monomers are confirmed by ¹H nuclear magnetic resonance (NMR), ¹³C NMR and Fourier transform infrared spectroscopy (FT-IR). Polymerizations are monitored by differential scanning calorimetry (DSC). The glass transition temperature (T_g) of each polybenzoxazine is measured by DSC as well as dynamic mechanical analysis (DMA), indicating the greatly increased T_gvia incorporation of methylol functionality into benzoxazine moiety. Monte Carlo simulations are also applied to further investigate the underlying structure-property relationship between intermolecular hydrogen-bonding network originating from different types of hydroxyl groups and thermal properties of polybenzoxazines. The agreement between the experimental and simulation results provide us with a fundamental understanding of the designing roles in highly thermally stable polybenzoxazines.

This article is the first report on understanding the structure-property relationship between molecular interactions and thermal properties of polybenzoxazines by Monte Carlo simulations.     

血液灌流与大剂量纳洛酮联合治疗阿维菌素中毒的临床研究

【目的】探讨血液灌流与大剂量纳洛酮联合治疗阿维菌素中毒的疗效。【方法】选取收治于本科的40例口服阿维茵素重度中毒患者,随机分为对照组与治疗组,两组病人均予以洗胃、补液、利尿、预防感染、吸痰,使用地塞米松、血液灌流等常规处理,治疗组在此基础应用大剂量纳洛酮治疗。观察两组患者治疗72h后疗效;意识恢复需要的时间;自主呼吸恢复平稳所需时间;血压恢复稳定需要的时间;治疗24h后动脉血乳酸清除率。【结果】对照组的病死率高于治疗组的病死率,但两组相比较差异无显著性（P〉0．05）;治疗组的总有效率高于对照组,两组的总有效率相比较差异具有显著性（P〈O．05）。治疗组在患者的神志转清时间,自主呼吸及血压恢复平稳时间上均明显短于对照组,且差异具有统计学意义（P〈0．05）。治疗组的24h乳酸清除率明显高于对照组,差异具有统计学意义（P〈0．05）。【结论】血液灌流联合大剂量纳洛酮可以更快的稳定患者的生命体征,改善组织的缺血缺氧状态,明显地提高了治疗的总有效率,降低了患者的病死率。     

大剂量低频率重组人促红细胞生成素治疗肾性贫血临床观察

[目的]观察大剂量低频率重组人促红细胞生成素(rhEPO)治疗肾性贫血的临床疗效及安全性.[方法]对60例确诊为慢性肾衰竭合并肾性贫血的维持性血透患者,随机分为大剂量低频率rhEPO治疗组与小剂量高频率rhEPO对照组,治疗组应用10000U rhEPO每周1次皮下注射,对照组应用3000U rhEPO每周3次皮下注射,分别观察治疗前及用药后4周、8周及12周患者血红蛋白(Hb)、红细胞压积(Hct)、血清铁蛋白(SF)、转铁蛋白饱和度(TSAT)的变化以及药物不良反应.[结果]治疗组与对照组治疗12周后患者Hb、Hct、SF、TSAT均较治疗前有升高( P <0.01),且治疗组治疗4、8周后患者Hb、Hct水平升高更明显,贫血伴随症状得到明显纠正,与对照组比较有统计学意义( P <0.05).[结论]大剂量低频率rhEPO能快速改善肾性贫血患者贫血情况、不良反应低、安全性良好.     

经阴道超声与宫腔镜评价不孕者宫腔因素的比较

目的 以宫腔镜为金标准，评估经阴道超声在诊断不孕患者宫腔异常中的意义。 方法 对在我院不孕门诊进行阴道超声、宫腔镜检查的171例患者资料进行回顾性分析。 结果 经宫腔镜检查发现异常宫腔99例（99／171，57．9％），包括：子宫内膜息肉42例（42．4％），宫腔粘连18例（18．2％），子宫内膜薄13例（13．1％），子宫内膜增生12例（12．1％），子宫内膜炎症8例（8．1％），子宫内膜息肉样增生6例（6．1％）。以宫腔镜为金标准，经阴道超声检查的敏感度及特异度分别为81．8％（81／99）、88．9oA（64／72）。其中超声诊断子宫内膜息肉的敏感度及特异度为83．3％（35／42）、98．4％（127／129）；诊断宫腔粘连的敏感度及特异度为66．7％（12／18）、100％；诊断子宫内膜增生、子宫内膜炎症敏感度及特异度分别为75％（8／12）、100％；87．5％（7／8）、100％。 结论 经阴道超声可作为是否行官腔镜检查的初筛方法，对有特殊病史如自然流产史、体外受精胚胎移植（in vitro fertilization，IVF-ET）失败的患者提倡常规官腔镜检查，二者的有机结合有益于发现潜在的不孕病因。     

MVP,NP方案治疗非小细胞肺癌疗效比较

目的 观察抗肿瘤药物丝裂霉素（ＭＭＣ）、西艾克（ＶＤＳ）和顺铂（ＰＤＤ）组成了ＭＶＰ方案和若维本（ＮＶＢ）顺铂（ＰＤＤ）组成的ＮＰ方案治疗晚期非小细胞肺癌的近期儿和毒性反应。方法 治疗晚期非小细胞肺癌１２３例,用ＭＶＰ方案治疗７２例,用ＮＰ方案治疗５１例,比较毒副反应及疗效。结果 有效率ＭＶＰ组为４３．５％,ＮＰ组为４９．０％,两组比较有效率相近（Ｘ＾２＝０．４３ Ｐ〉０．０５）。毒副反应主要为骨