Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients

Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C_avg) and clinical response and between the free C_avg/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P = 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P = 0.014), and pathogen (yeast/mold, P < 0.001). The C_avg for 72% of the patients was 0.5 to 5.0 μg/ml, with the maximum response rate (74%) at 3.0 to 4.0 μg/ml. The C_avg showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C_avg < 0.5 μg/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C_avg ≥ 5.0 μg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C_avg/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C_avg. Patients with higher free C_avg/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.     

Highly Variable Plasma Concentrations of Voriconazole in Pediatric Hematopoietic Stem Cell Transplantation Patients

Invasive fungal infections are of great concern in pediatric hematopoietic stem cell transplantation (HSCT) recipients. Voriconazole is usually the drug of first choice for treating or preventing invasive aspergillosis. Optimum trough levels (C_troughs) are between 1 and 5 mg/liter. It is unclear whether these levels are reached with currently advised pediatric dosing schedules. Between 2007 and 2011, 11 patients <2 years of age, 31 between 2 and 12 years, and 20 between 12 and 20 years were (prophylactically or therapeutically) treated with voriconazole in the HSCT unit of UMC Utrecht. For children <2 years of age, the dosage recommended for 2 to 12 years was used. In 34% of children who started with the recommended dose, an adequate C_trough was reached irrespective of age or administration route. After therapeutic drug monitoring (TDM)-based dose adjustments, adequate C_troughs were reached in 80% of the patients at median doses of 31.5 (age, <2 years), 16 (age, 2 to 12 years), and 9.4 mg/kg of body weight/day (age, >12 years) (P = 0.034). The intrapatient variability in C_trough ranged between 1 and 238%. Voriconazole was discontinued in six patients due to toxicity. These patients had a median C_trough of 0.5 mg/liter at the initial dose (ranging from 0.5 to 2.6 mg/liter), and a medium maximal concentration of 4 mg/liter was reached. Inter- and intrapatient variability is a major concern in voriconazole treatment and necessitates therapeutic drug monitoring of dosing, especially in young children.     

Relationship between Trough Plasma and Epithelial Lining Fluid Concentrations of Voriconazole in Lung Transplant Recipients

Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r² = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients.     

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.     

Simultaneous Determination of Voriconazole and Posaconazole Concentrations in Human Plasma by High-Performance Liquid Chromatography

A simple, sensitive, and selective high-performance liquid chromatographic method for the simultaneous determination of voriconazole and posaconazole concentrations in human plasma was developed and validated. Quantitative recovery following liquid-liquid extraction with diethyl ether was achieved. Linearity ranged from 0.10 to 20.0 μg/ml for voriconazole and from 0.05 to 10.0 μg/ml for posaconazole. The intra- and interday coefficients of variation were less than 8.5%, and the lower limits of quantitation were <0.05 μg/ml.Based on the increasing number of immunosuppressed patients, a rising incidence of Aspergillus infections has been observed (15, 18). Voriconazole (VRC) and posaconazole (PSC), two broad-spectrum triazole derivatives, are the recommended antimycotics for either the treatment or the prophylaxis of invasive Aspergillus infections (4, 8). Both inhibit the cytochrome P450-dependent 14α-lanosterol demethylase, which is responsible for the synthesis of ergosterol, a key compound in the fungal cell membrane (19). VRC shows nonlinear pharmacokinetics in adults and is metabolized in the liver by CYP2C19, CYP3A4, and CYP2C9, resulting in a high interindividual variability of plasma levels (5). In contrast, PSC underlies no phase I metabolism but inhibits CYP3A4 (21). Currently, PSC is only available as an oral solution, and resorption depends strongly on gastric pH and nutrition. In order to manage possible drug interactions, to balance interindividual pharmacokinetic variability, and to ensure an effective exposure to VRC and PSC, therapeutic drug monitoring is recommended (16).Several methods for quantitation of VRC or PSC in human plasma by high-performance liquid chromatography (HPLC) have been reported (3, 6, 7, 9-14, 17, 20). Up to now, only one HPLC assay has been published for their simultaneous determination (1). This assay uses complex compositions of extractant and eluent, as well as high volumes of eluent; requires a long period of sample preparation; and is of poor sensitivity. Therefore, the aim of this work was to develop a rapid, sensitive, and economical HPLC method for the simultaneous determination of VRC and PSC in human plasma samples.VRC was provided by Pfizer (New York, NY) and PSC by Schering-Plough (Kenilworth, NJ). The internal standard (IS) quinoxaline and bovine serum albumin (BSA) powder were obtained from Sigma-Aldrich (Steinheim, Germany). Stock solutions of VRC (50.0 μg/ml) and PSC (25.0 μg/ml) were prepared in methanol and were diluted for the preparation of six combined working solutions (for VRC, 0.25, 0.50, 1.0, 2.0, 5.0, and 10.0 μg/ml, and for PSC, 0.125, 0.25, 5.0, 1.0, 2.5, and 5.0 μg/ml) and three combined quality control (QC) samples (for VRC, 0.50, 2.0, and 5.0 μg/ml, and for PSC, 0.50, 2.5, and 5.0 μg/ml). The IS working solution was prepared in methanol (20.0 μg/ml). Each solution was stored at −20°C. For the preparation of plasma standard samples, BSA solutions (5%, wt/vol) were spiked with VRC, PSC, and IS (0.80 μg/ml) to obtain the above-mentioned concentrations.Five-hundred-microliter aliquots of BSA standards or plasma samples were mixed with 200 μl of 0.1 M sodium hydroxide (Merck, Darmstadt, Germany) in 10-ml glass tubes, IS (20 μl) was added, and the solutions were briefly vortexed. After the tubes were capped, samples were extracted twice with 3 ml of diethyl ether (Merck, Darmstadt, Germany) for 5 min, followed by centrifugation at 5,000 × g for 5 min. The organic layers were transferred into glass tubes and evaporated to dryness (37°C) under a gentle stream of nitrogen. The residue was dissolved with 250 μl of the mobile phase.The HPLC system (Beckman-Coulter, Krefeld, Germany) consisted of a 126 solvent pump, a 168 UV-VIS photodiode array detector, a 508 autosampler, and 32 Karat software. A ReproSil-Pur Basic C₁₈ column (150 mm by 2 mm by 5 μm) (Dr. Maisch GmbH, Ammerbuch, Germany) protected by a C₁₈ guard column (4 mm by 2 mm; Phenomenex, Aschaffenburg, Germany) was used. The mobile phase consisted of 0.09 M aqueous ammonium phosphate monobasic (Riedel-de-Haën, Seelze, Germany) and acetonitrile (Merck, Darmstadt, Germany) (50%:50%, vol/vol) (pH 5.3). The flow rate was 0.2 ml/min, detection was at 260 nm, and the injected volume was 50 μl.Representative HPLC chromatograms are shown in Fig. ​Fig.1.1. Retention times for VRC, PSC, and IS were approximately 4.90, 14.50, and 7.50 min. No interfering endogenous peaks were detectable in the blank sample.Open in a separate windowFIG. 1.Representative HPLC chromatograms (at 260 nm) of VRC, PSC, and IS in plasma samples. (A) Drug-free 5% BSA sample (blank). (B) Five-percent BSA sample spiked with VRC at 2.00 μg/ml, PSC at 2.50 μg/ml, and IS at 0.80 μg/ml. (C) Plasma sample obtained from a patient, with VRC concentration of 1.40 μg/ml. (D) Plasma sample obtained from a patient, with PSC concentration of 2.17 μg/ml.Linearity was evaluated over a concentration range of 0.10 to 20.0 μg/ml for VRC and 0.05 to 10.0 μg/ml for PSC. Using the ratios of observed peak heights for each analyte and IS, the calibration curves showed a correlation coefficient (r²) of 0.999 for all compounds. The limit of detection, defined as the lowest detectable concentration level resulting in a signal-to-noise ratio of three (2), was determined at 12.5 and 6.25 ng/ml for VRC and PSC, respectively. The lower limit of quantitation was established for both analytes at concentrations below 0.05 μg/ml, and the upper limits of quantitation were arbitrarily set at 50.0 and 25.0 μg/ml.The intraday accuracy and precision of the method were determined by measuring nine replicates of each QC concentration on the same day. For interday accuracy and precision, the procedure was repeated on seven days. The intraday precision values of VRC and PSC were 2.22 to 4.24% and 2.11 to 8.46%, respectively. The interday precision values of the corresponding compounds were below 4.0% and 5.9% (Table ​(Table1).1). The levels of recovery of analytes and IS were estimated by comparing the peak heights of extracted QC samples with those of unextracted standard solutions. The highest recovery values achieved were 94.4% for VRC, 101.3% for PSC, and 100.3% for IS.

TABLE 1.

Intra- and interday accuracy and precision for the determination of voriconazole (VRC) and posaconazole (PSC) concentrations in spiked 5% BSA samples using HPLC

ESR—K与血浆纤维蛋白原水平的临床相关性探讨

目的探讨ESR-K与血浆纤维蛋白原水平的临床相关性及其意义。方法对445例无活动性炎症的男女性中老年成人检测ESR-K、血浆纤维蛋白原及红细胞压积，并作动态ESR分析。结果ESR-K值与血浆纤维蛋白原水平呈显著直线正相关(r=0.603,P<0.01)；按ESR-K水平分组显示ESR-K水平依次上升其血浆纤维蛋白原值及其阳性率呈阶梯增高，有非常显著意义(P<0.01)；动态ESR-K呈持续缓降、前/后期速降、持续速降型表现时，各组血浆纤维蛋白原水平及其阳性率依次增高，有非常显著意义(P<0.01)。     

Treatment of Tension-type Headache With Tizanidine Hydrochloride: Its Efficacy and Relationship to the Plasma MHPG Concentration

Seventy-eight patients with tension-type headache (TH) were treated with tizanidine hydrochloride (tizanidine). Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum free fatty acids (FFA) levels in these patients were determined before the treatment with tizanidine. Eighteen healthy volunteers composed the control group. Four weeks after the treatment with tizanidine 24 (31%) of 78 patients showed excellent improvement (excellent group); 28 (35%) showed moderate improvement (moderate group); 18 (23%) showed mild improvement (mild group); 7 (10%) showed no improvement and one (1%) showed worsening of her headache (no change and worsened group). The plasma MHPG levels in the excellent group were significantly higher than in the other groups, including the control group. The serum FFA levels in the excellent group were significantly higher than in the controls. In this study, 66% of the patients reported improvement in their headaches. Some patients with TH had high plasma MHPG levels and these patients in particular showed excellent improvement after the administration of tizanidine. Though there may be a placebo response to some extent, the clinical usefulness of tizanidine for TH seems to be excellent. Further study is necessary concerning the pharmacological effect of tizanidine and plasma MHPG levels in patients with TH.     

Plasma Morphine and Metabolite Concentrations Are Associated With Clinical Effects of Morphine in Cancer Patients

ContextMorphine is the opioid of choice for cancer-related pain, but for many patients the benefits of morphine are outweighed by its side effect profile. Morphine is metabolized to morphine-3-glucuronide and morphine-6-glucuronide; however, little is known about the contribution of these metabolites to analgesia and morphine-related side effects.ObjectivesWe investigated the association between plasma morphine and metabolite concentrations and the clinical effects of morphine in cancer patients.MethodsA prospective study was performed in cancer patients taking oral morphine for moderate-to-severe cancer pain. Subjects who responded well to morphine (responders) and subjects who failed to respond to morphine because of lack of analgesia and/or the presence of intolerable side effects (nonresponders/switchers) were recruited. Pain and toxicity scores were recorded and blood samples were analyzed for plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations.ResultsResults showed that 1) morphine responders have higher plasma morphine and metabolite concentrations compared with nonresponders, 2) lower pain scores are associated with higher plasma morphine and metabolite concentrations, 3) central side effects are associated with a higher metabolite:plasma morphine ratio, and 4) myoclonus is associated with extremely high concentrations of plasma morphine and metabolites.ConclusionThis study has shown that plasma morphine and metabolite concentrations are associated with the clinical effects of morphine therapy. These results are important because they demonstrate the relevance of measuring plasma metabolite concentrations in clinical trials and the potential for metabolite data to deepen our understanding of factors that influence an individual's response to morphine.     

Flunarizine Plasma Concentrations and Side Effects in Migraine Patients

Flunarizine plasma concentrations and side effects were evaluated in migraine patients during a 3 month course of prophylactic treatment. Plasma concentrations did not correlate with daily dose (in mg/kg). Mean flunarizine levels were higher in patients showing sleepiness or sedation. Weight gain was independent of plasma concentrations. Future clinical trials of flunarizine should be supported by drug monitoring in order to clarify the relationship between plasma levels and drug effects.     

不育患者精子活力、精液粘稠度与精浆Zn、PSA含量关系研究

目的探讨不育患者精子活力、精液粘稠度与精浆Zn、PSA含量关系。方法采用精子自动分析仪进行精液参数分析,应用分光光度比色法检测精浆锌含量,采用酶标法检测精浆PSA含量。结果精子活力异常组精浆Zn、PSA含量明显低于活力正常组,两组比较差异显著(P<0·05);精液粘稠度增高组精浆Zn、PSA含量明显低于精液粘稠度正常组,两组比较差异亦有显著性(P<0·05)。结论精浆Zn、PSA含量与精子活力、精液粘稠度有密切关系。     

Relationship Between Ultrasonographic,Electromyographic, and Clinical Parameters in Adult Stroke Patients With Spastic Equinus: An Observational Study

Objective

To find more accurate indices that could affect decisions in spasticity treatment by investigating the relation between ultrasonographic, electromyographic, and clinical parameters of the gastrocnemius muscle in adults with spastic equinus after stroke.

Design

Observational study.

Setting

University hospitals.

Participants

Chronic patients with stroke with spastic equinus (N=43).

Interventions

Not applicable.

Main Outcome Measures

Ultrasonographic features were spastic gastrocnemius muscle echo intensity, muscle thickness, and posterior pennation angle of the gastrocnemius medialis (GM) and gastrocnemius lateralis (GL) in both legs. Electromyographic evaluation included compound muscle action potentials (CMAPs) recorded from the GM and GL of both legs. Clinical assessment of the spastic gastrocnemius muscle was performed with the Modified Ashworth Scale (MAS) and by measuring ankle dorsiflexion passive range of motion (PROM).

Results

Spastic muscle echo intensity was inversely associated with proximal (GM and GL: P=.002) and distal (GM and GL: P=.001) muscle thickness, pennation angle (GM: P< .001; GL: P=.01), CMAP (GM: P=.014; GL: P=.026), and ankle PROM (GM: P=.038; GL: P=.024). The pennation angle was directly associated with the proximal (GM and GL: P< .001) and distal (GM: P=.001; GL: P< .001) muscle thickness of the spastic gastrocnemius muscle. The MAS score was directly associated with muscle echo intensity (GM: P=.039; GL: P=.027) and inversely related to the pennation angle (GM and GL: P=.001) and proximal (GM: P=.016; GL: P=.009) and distal (GL: P=.006) muscle thickness of the spastic gastrocnemius.

Conclusions

Increased spastic muscle echo intensity was associated with reduced muscle thickness, posterior pennation angle, and CMAP amplitude in the gastrocnemius muscle. Building on previous evidence that these instrumental features are related to botulinum toxin response, these new findings may usefully inform spasticity treatment decisions.     

非霍奇金淋巴瘤患者血浆同型半胱氨酸水平的测定及意义

【目的】探讨非霍奇金淋巴瘤（NHL）患者血浆同型半胱氨酸（P—HCY）水平的测定及其临床意义。【方法】循环酶法检测42例NHL患者PHCY（NHL组）的水平,30例健康人（CON组）及16例淋巴结反应性增生（RH组）患者作对照,比较P—HCY水平与NHL患者各临床因素的关系。【结果】NHL组P—HCY浓度较CON组及RH组明显增高（P〈0．05）;P—HCY在低年龄组、低度恶性程度及Ⅰ＋Ⅱ期患者血浆中表达水平显著性低于高年龄组、高度恶性组及Ⅲ＋Ⅳ期组（P〈0．05）。血清乳酸脱氢酶（S-I,DH）浓度与P—HCY浓度呈正相关。【结论】NHL患者P—HCY的表达,对临床分期、病理恶性程度、肿瘤侵犯程度有一定指导意义;P—HCY和S-LDH的检测对NHL治疗反应的判断有一定价值,有望成为判断恶性淋巴瘤预后的新指标。     

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, −17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was −0.7% (interquartile range, −7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, −1.4 to 14.7%; P = 0.16 versus the full posterior parameter value) and the dose bias was −6.7% (interquartile range, −18.7 to 2.4%; P = 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, −13.1 to 18%; P = 0.32) and a dose bias of −3.5% (interquartile range, −18 to 14%; P = 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01976078","term_id":"NCT01976078"}}NCT01976078.)     

白血病患者血浆白细胞介素18的水平及其临床意义

本研究探讨白血病患者血浆白细胞介素 18(IL 18)水平与白血病发病、预后及治疗的相关临床意义。采用酶联免疫吸附测定法 ,对 3 7例白血病患者在初诊时及化疗后 2周分别采集静脉血 ,测定其血浆IL 18水平 ,以18名献血员为正常对照组。结果显示 ,白血病患者血浆IL 18水平治疗前略高于正常水平 ,但差异无显著性。其中急性淋巴细胞白血病患者血浆IL 18水平升高显著 (173 2 7± 3 4 2 4pg/ml) ,慢性粒细胞性白血病患者IL 18水平 (111.82± 50 .56pg/ml)低于正常对照组 (13 5.82± 47.0 0pg/ml)。化疗后 ,白血病各组患者血浆IL 18水平均明显低于正常对照组 (P <0 0 0 1)。结论 :白血病患者血浆IL 18水平是不均一性的 ,而其化疗后血浆IL 18水平均明显减低。这一点预示着白血病患者化疗后的免疫功能低下与其血浆IL 18水平下降 ,以致其相关联的一系列细胞因子的相应减少有关     

急性脑梗死患者血浆同型半胱氨酸水平及临床意义

目的：探讨不同年龄段急性脑梗死患者血浆同型半胱氨酸（Hcy）水平及临床意义。方法：将538例急性脑梗死患者按年龄分为A组（年龄40~49岁）、B组（年龄50~59岁）、C组（年龄60~69岁）、D组（年龄70~79岁）和E组（年龄80~89岁）。分析各年龄段患者血浆Hcy水平、伴随疾病与急性脑梗死的发病关系。结果：各年龄段脑梗死患者血浆Hcy水平均高于对照组 A组和E组血浆Hcy水平明显高于C组,差异有统计学意义,P〈0.05。结论：血浆Hcy水平的升高与各年龄段急性脑梗死发病均有关,与40~49岁和80~89岁的患者关系更密切。     

急性脑梗死患者血浆溶血磷脂酸水平的临床意义及厄贝沙坦对其影响

目的:探讨急性脑梗死早期血浆溶血磷脂酸(LPA)水平变化的临床意义及厄贝沙坦对其影响。方法:急性脑梗死患者100例为病例组,随机分为厄贝沙坦亚组和常规亚组各50例,厄贝沙坦亚组给予厄贝沙坦+阿司匹林,常规亚组给予阿司匹林,连续治疗14 d。分别检测病例组治疗前后血浆LPA浓度,进行神经功能缺损程度评分,分析其与梗死部位、大小、病因、病情的相关性,并另选择50例健康体检者为对照组。结果:急性脑梗死患者血浆LPA急性期升高,和对照组比较有显著性差异(P0.01)。大梗死灶患者血浆LPA浓度较小梗死灶者高(P0.01);重型患者血浆LPA浓度高于轻型患者(P0.01);不同病因的脑梗死患者血清LPA水平均高于对照组,分别为心源性大动脉型其他类型小动脉型对照组(P0.05)。厄贝沙坦亚组和常规亚组治疗后LPA和神经功能缺损评分较治疗前显著降低(P0.01),治疗后与常规亚组比较,厄贝沙坦亚组的LPA含量和神经功能缺损评分降低更为明显(P0.01)。结论:血浆LPA浓度与梗死大小、部位、病因、病情严重程度相关,可作为脑梗死的预警因子。厄贝沙坦能显著降低急性脑梗死患者血浆LPA含量,对缺血性脑血管病的防治具有重要的临床应用价值。     

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.     

慢性心力衰竭患者血浆D-二聚体与LVEF检测及意义

[目的]通过定量检测慢性心力衰竭患者血浆D-二聚体水平,探讨慢性心力衰竭与高凝状态的关系,为慢性心力衰竭抗凝治疗提供理论依据.[方法]应用散射免疫比浊法分别定量检测慢性心力衰竭患者（心功能Ⅱ～Ⅳ级）组（n=60）和健康对照组（n=30）血浆D-二聚体含量;应用彩色多普勒超声心动图测定慢性心力衰竭患者左心室射血分数（LVEF）;并对心衰患者组按心衰程度、LVEF不同进行分组,分别比较各亚组组间血浆D-二聚体水平,并对结果进行统计学分析.[结果]①慢性心力衰竭患者组血浆D-二聚体含量较健康对照组明显升高,两组比较有显著性差异（P〈0.01）;②随心衰程度加重,D-二聚体水平明显升高,不同心衰程度患者组间比较有显著性差异（P〈0.01）;③随LVEF值降低,D-二聚体水平无明显升高,各不同射血分数（EF）水平患者组间比较无显著性差异（P〉0.05）,两者无明显相关性（r=-0.215,P=0.098）.[结论]①慢性心力衰竭患者体内存在高凝状态;②随心衰程度加重,高凝状态更为严重;③慢性心力衰竭患者左心室射血分数与高凝状态无明显相关性.