Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment.

OBJECTIVE: We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use. METHODS: In this open-label, single-dose, case-control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score, 7-9) and 8 demographically matched healthy control subjects received a single oral 2-mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding. RESULTS: The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% higher area under the blood concentration-time curve (AUC) (245 +/- 91 versus 114 +/- 45 ng. h/ml) and 84% prolonged half-life (79 +/- 42 versus 43 +/- 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (C(max)) and time to reach C(max) (t(max)). Protein binding was similar in the two groups (73.8% +/- 3.6% versus 73.5% +/- 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed. CONCLUSIONS: The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.     

Pharmacokinetics of ornidazole in patients with acute viral hepatitis, alcoholic cirrhosis, and extrahepatic cholestasis

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was investigated after intravenous injection in 3 groups of 10 patients with different hepatic diseases: hepatitis, noncholestatic cirrhosis and extrahepatic cholestasis. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 [alpha-(chloromethyl)-2-hydroxymethyl-5-nitroimidazole-1-ethanol] and M4 [3-(2-methyl-5-nitroimidazole 1-yl)-1,2-propane diol] were measured by HPLC assay. As a consequence of a decreased clearance (26% to 48%), the half-life and MRT are increased in all patients by 19% to 38% when compared with healthy volunteers. No clear difference could be established between the different groups. The volume of distribution remains the same in all patients and controls except those suffering from cancer. As previously shown in patients with severe liver cirrhosis, both metabolites accumulate in plasma as a result of decreased elimination; formation is no longer the rate-limiting step of their kinetics. This metabolite accumulation is in part due to decreased biliary excretion and to hepatocellular failure.     

Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function

Amprenavir (141W94) is extensively metabolized by P450 cytochromes, specifically, CYP3A4. Because hepatic insufficiency reduces P450-mediated metabolism, the concentrations in plasma of drugs metabolized through this pathway are often increased in subjects with liver disease. Following administration of a single, oral dose of 600 mg of amprenavir, pharmacokinetic parameters were determined for 10 subjects with severe cirrhosis, 10 subjects with moderate cirrhosis, and 10 healthy volunteers. Model-independent methods for determining the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(0-infinity)) showed an increase in amprenavir AUC(0-infinity) of 2.5-fold in the group with moderate cirrhosis and 4.5-fold in the group with severe cirrhosis compared with that in the control group of healthy volunteers (P < 0.05). AUC(0-infinity) was linearly related to the severity of liver disease, as assessed by the Child-Pugh score. Of the laboratory data used to calculate the Child-Pugh score, only the mean total bilirubin concentration showed a significant relationship with AUC(0-infinity). The relationship between the total bilirubin concentration and the AUC(0-infinity) of amprenavir was well characterized by a simple E(max) model, suggesting that the total bilirubin concentration may be a useful parameter for predicting the amprenavir AUC in subjects with hepatic insufficiency. Finally, the sera of cirrhotic subjects showed significant decreases in the levels of alpha(1)-acid glycoprotein, the primary plasma binding protein for amprenavir. On the basis of the results of this study, for an exposure equivalent to a clinical dose of 1,200 mg twice daily in subjects without cirrhosis, subjects with Child-Pugh scores of 5 to 8 should receive a twice-daily 450-mg dose of amprenavir, and subjects with Child-Pugh scores of 9 to 15 should receive a twice-daily 300-mg dose of amprenavir.     

Amprenavir and ritonavir plasma concentrations in HIV-infected patients treated with fosamprenavir/ritonavir with various degrees of liver impairment

OBJECTIVES: The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment. METHODS: HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC. RESULTS: Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003). CONCLUSIONS: On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.     

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.     

Xipamide disposition in liver cirrhosis

The pharmacokinetics of the sulfonamide-type diuretic xipamide was studied in patients with liver cirrhosis and ascites and compared with healthy control subjects. After oral administration of 40 mg xipamide, the diuretic was rapidly distributed in the blood and the ascites. The ratio of the area under the concentration-time curve (AUC) of plasma and ascitic fluid was 7:2, as was the protein content in the respective compartments. The AUC in plasma of cirrhotic patients was significantly greater than in control subjects (p less than 0.001). The most striking finding was the increase of the amount (Ae) of parent drug and main metabolite excreted into the urine (p less than 0.001). The renal clearance of xipamide was only moderately reduced in patients with liver cirrhosis. Both AUC and Ae were positively correlated to the plasma concentration of direct bilirubin of the patients (p less than 0.05). We concluded that nonrenal drug clearance in patients with liver cirrhosis was reduced as a result of the blockade of hepatobiliary excretion during cholestatic conditions.     

105例乙肝肝硬化内镜特点分析

目的了解乙型肝炎肝硬化内镜特点，准确预测判断上消化道出血的危险性，为临床诊治提供可靠依据。方法对该院收治的105例乙型肝炎肝硬化患者应用日本产Olympus GIF-XQ240电子内窥镜作胃十二指肠检查。结果食管胃底静脉曲张100例，其中食管静脉曲张(esophageal variceal，EV)82例，胃底静脉曲张(gastric variceal，GV)18例，EV并门脉高压性胃病(portal hypertensive gastropathy，PHG)64例，十二指肠球部溃疡(duodenal ulcer，DU)21例。结论食管静脉曲张是乙肝肝硬化最具有特征的内镜表现，门脉高压性胃病、十二指肠溃疡是乙型肝炎肝硬化门脉高压症的常见合并症。     

A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution

To determine the effect of omeprazole on peak serum concentrations (C(max)) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. C(max), time to C(max) (T(max)) and AUC(0-8) were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS.     

Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysis

We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC(0)--> infinity ) were 480 +/- 216 and 832 +/- 325 ngh/mL, maximum plasma concentrations (C(max)) were 310 +/- 187 and 481 +/- 185 ng/mL, and times required to reach the maximum concentration t(max) were 1.13 +/- 0.22 and 1.09 +/- 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC(0)--> infinity were 256 +/- 122 and 383 +/- 158 ngh/mL, C(max) values were 57 +/- 29 and 72.9 +/- 33.6 ng/mL and t(max) values were 4.28 +/- 1.45 and 4.05 +/- 01.22 h for 10 and 20 mg doses, respectively. The C(max) values of enalapril were approximately 10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r = -0.95 with P < 0.001 and r = -0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids.     

Red wine-cisapride interaction: comparison with grapefruit juice.

OBJECTIVES: Our objective was to compare the interactions of red wine and grapefruit juice with cisapride. METHODS: The oral pharmacokinetics of cisapride, its norcisapride metabolite, and electrocardiographic QTc interval were determined over a 24-hour period after administration of cisapride 10 mg with 250 mL grapefruit juice, red wine (cabernet sauvignon), or water in a randomized 3-way crossover study in 12 healthy men. RESULTS: The cisapride area under the concentration-time curve (AUC) and the maximum plasma drug concentration after single-dose administration (C(max)) with grapefruit juice were 151% (P <.01) and 168% (P <.001), respectively, of those with water. The increase in cisapride AUC and C(max) was variable among individuals; however, cisapride AUC and C(max) were enhanced by the same proportion. The time to reach maximum concentration after drug administration (t(max)) and the apparent elimination half-life (t((1/2)) for cisapride and the pharmacokinetics of norcisapride were not altered. Norcisapride/cisapride ratios were reduced. Cisapride AUC and C(max) with red wine were 115% (difference not statistically significant) and 107% (difference not statistically significant), respectively, of those with water. The cisapride t(max) was slightly longer. Cisapride t((1/2)) and norcisapride pharmacokinetics were not different. The norcisapride/cisapride ratio at cisapride C(max) was lower. One subject had a doubling in cisapride AUC and C(max) and a decrease in norcisapride/cisapride ratios with red wine and also had the largest interaction with grapefruit juice. QTc interval was unchanged in all treatment groups and individuals. CONCLUSIONS: A single glass of grapefruit juice produced an individual-dependent variable increase in the systemic availability of cisapride by inhibition of intestinal cytochrome P450 3A4 (CYP3A4) activity. The identical volume of red wine caused only minor changes in cisapride pharmacokinetics despite some inhibition of CYP3A4 in most individuals. However, even this amount of red wine may cause a marked interaction similar to that for grapefruit juice in individuals with a preexisting high intestinal CYP3A4 content.     

Development of an oral sustained release drug delivery system utilizing pH-dependent swelling of carboxyvinyl polymer.

A new oral sustained-release (SR) drug delivery system utilizing pH-dependent swelling of carboxyvinyl polymer (CP) has been proposed. This swelling polymer incorporation layer system, referred to as SPILA system, consists of core granules coated with a mixture of CP, water insoluble polymer, and water-soluble polymer (WP). Release profiles of metoprolol tartrate (ME) from SPILA system were pH dependent: drug release was slower in the medium of pH 1.2 than in the medium of pH 6.8 due to a coating layer with pH-dependent swelling polymer, CP. Lower C(max), longer T(max), longer MRT and higher AUC values were obtained following administration of SR granules based on SPILA system to beagle dogs compared with pH-independent SR granules having a coating layer without CP, while both SR granules provided similar in vitro release profiles. Moreover, using morphine hydrochloride (MO), in vitro and in vivo performances of the SPILA system were investigated. pH-dependency on the release profiles of MO from SPILA system was more evident when the amount of CP incorporated in SPILA system was increased. AUC and MRT values following administration of SR granules of MO with a coating layer containing 8% of CP to beagle dogs were 191 ng h/mL and 10.6 h respectively, while those following SR granules of MO with a coating layer containing 1% of CP to beagle dogs were 86.4 ng h/mL and 5.86 h, respectively. An important role of CP in the release-regulating layer of SPILA system for keeping the higher and more extended plasma levels of morphine free base was confirmed from the in vivo performance of SPILA system.     

美托洛尔联合厄贝沙坦对高血压性心脏病患者心功能、炎症因子水平的影响

目的 分析美托洛尔联合厄贝沙坦对高血压性心脏病患者心功能及炎症因子水平的影响。方法 选取本院收治的90例高血压性心脏病患者,按随机数字表法分为对照组（45例,美托洛尔）和观察组（45例,美托洛尔+厄贝沙坦）。比较两组治疗前、后的血压、血脂水平、超声心动图指标、炎症因子水平及不良反应发生情况。结果 治疗后,观察组的血压、血脂（DBP、SBP、TC、TG）水平、超声心动图指标（LVEF、IVST、LADD）、炎症因子（hs-CRP、IL-6、MMP-9）水平均优于对照组（P<0.05）。两组的不良反应总发生率比较,差异无统计学意义（P>0.05）。结论 美托洛尔联合厄贝沙坦治疗高血压性心脏病能有效改善患者的心功能,降低血压、血脂水平,控制炎症反应,且安全性较高。     

比较MR弹性成像及动态增强成像评价肝硬化食管胃底静脉曲张

目的 比较MR弹性成像（MRE）及动态增强成像（DCE-MRI）诊断肝硬化食管胃底静脉曲张（GEV）的价值。方法 收集接受MRE及DCE-MRI检查的肝硬化患者59例,记录血小板计数（PLT）,测量肝弹性值（HS）、脾弹性值（SS）和MR增强视觉分级相关指标;以内镜结果为金标准,采用ROC曲线下面积（AUC）比较相关指标诊断GEV的价值。结果 PLT、HS、SS及MR增强视觉分级与肝硬化GEV分级具有相关性（r_s=-0.317、0.436、0.682、0.703,P均<0.05）。诊断有无GEV时,SS的AUC略高于MR增强视觉分级、HS、PLT （AUC分别为0.880、0.795、0.744、0.635）,其中SS与PLT的AUC差异有统计学意义（P=0.002）;诊断中重度GEV时,MR增强视觉分级的AUC略高于SS、HS、PLT （AUC分别为0.893、0.816、0.713、0.665）,其中MR增强视觉分级与HS、PLT的AUC差异有统计学意义（P=0.018、0.002）。联合SS及MR增强视觉分级,鉴别诊断有无GEV及中重度GEV的敏感度分别为94.16%、96.83%。结论 MRE可有效预测GEV及其严重程度,与DCE-MRI效果相当。     

Pharmacokinetics of zidovudine in patients with liver cirrhosis

The pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 14 human immunodeficiency virus seronegative patients with liver cirrhosis. They were divided in three groups according to the severity of the liver disease quantitated by the Child-Pugh score. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. Findings were compared with those previously measured in six healthy volunteers. As a consequence of a marked drop in oral clearance (10 +/- 4 versus 38 +/- 15 ml/min/kg), zidovudine concentrations, half-life, and mean residence time were increased in patients with cirrhosis. No difference could be established between the three groups. The reason for such a decrease in oral clearance of zidovudine was the reduction in the GAZT formation clearance (236 +/- 73 versus 1540 +/- 540 ml/min); this led to a decrease in the AUC ratio of GAZT and zidovudine (1.3 +/- 0.6 versus 4.6 +/- 0.7), which was directly related to the severity of the cirrhosis. In patients, as in volunteers, formation of GAZT rate limits its elimination. To avoid important cumulation of zidovudine after repeated dosing in patients with acquired immunodeficiency syndrome who have hepatic impairment, a dosage adjustment could be proposed.     

Disposition of enalapril in the perfused rat intestine-liver preparation: absorption, metabolism and first-pass effect

A new procedure, namely the in situ perfused rat intestine-liver preparation, was introduced to examine the roles of the intestine and the liver in the elimination of enalapril, a new angiotensin-converting enzyme inhibitor. The in situ perfused rat intestine preparation was used to determine the rate and extent of enalapril absorption after an-intraduodenal dose. In the former technique, enalapril in blood perfusate (10 ml/min) was delivered via the superior mesenteric artery into the once-through perfused rat intestine-liver preparation, with sampling effected in reservoir, portal vein and hepatic vein. The ease of sampling, proximal and distal to the intestine and liver, allowed the direct estimation of the extraction ratios by the intestine and the liver. The steady-state intestinal extraction ratio of enalapril was small (0.04 +/- 0.066) compared to that for the liver (0.74 +/- 0.06), indicating that the liver was responsible for most of the hydrolytic conversion of enalapril to its pharmacologically active diacid metabolite, enalaprilat. Moreover, no trend in the values of the extraction ratios by both organs was apparent among the input concentrations of enalapril (0.55, 2.6 and 13.3 microM) used. Portal venous plasma consisted mainly of enalapril and was devoid of enalaprilat, whereas both enalapril and enalaprilat were detected in bile and hepatic venous plasma. With the latter technique, an intraduodenal injection of a tracer dose of [14C]enalapril (0.14-0.39 mumol) was made close to the pyloric sphinctor, whereas the intestine preparation was recirculated (7.5 ml/min) with blank perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ACE inhibitor fosinopril on a 24-h profile of arterial pressure in hypertensive patients with obesity and hypercholesterolemia

AIM: To study effects of fosinopril on a 24-h profile of blood pressure (BP) in hypertensive patients with obesity and hypercholesterolemia. MATERIAL AND METHODS: A randomized comparative trial enrolled 96 patients aged 30-50 years with arterial hypertension (AH) of the first and second degree. The patients were randomized into 2 groups by age, gender, AH duration, office AP, body mass index, cholesterol level. The patients of group 1 received fosinopril (monopril) in a single daily dose 10 mg with further rise to 20 mg. The patients of group 2 were given metoprolol twice a day in a dose 25 mg with further rise to 75 mg. Examination of the patients was made before the treatment and after 16 weeks of therapy with fosinopril and metoprolol. RESULTS: A 16-week therapy with fosinopril resulted in lowering of office BP, mean day systolic, diastolic, pulse BP. The profile of SBP improved: the number of "dippers" with an adequate day profile of BP rose. Fosinopril significantly reduced left ventricular myocardial mass (LVMM) and myocardial mass index. Metoprolol had the same hypotensive action but had no effect on mean 24-h pulse and mean BP, LVMM, LVMM index. CONCLUSION: Fosinopril is more effective than metoprolol in relation to a 24-h profile of BP and LVMM reduction.     

肝硬化患者幽门螺杆菌感染及相关因素分析——附155例报告

目的;探讨肝硬化患者的幽门螺杆菌感染及相关因素的状况。方法：对１５５例确诊肝硬化并已行胃镜检查,Ｈｐ快速尿素酶试验的住院患者的Ｈｐ;感染状况及相关因素进行统计分析。结果;（１）Ｈｐ感染率随食管静脉曲线程度增加,肝功能恶化而降低;（２）Ｈｐ感染与肝硬化患者的年龄无关;（３）Ｈｐ感染与血白细胞总数,中性粒细胞与淋巴细胞比例及血氨变化无关;（４）Ｈｐ感染与肝硬化患者消化性溃疡的发生无关。结论：在肝硬化患     

Pharmacokinetics of Nisoldipine Coat--Core Formulation in Subjects with Liver Cirrhosis

The pharmacokinetics of a controlled-release formulation (coat--core) of the calcium channel blocker nisoldipine was investigated in eight subjects with biopsy-proved liver cirrhosis and eight healthy subjects. In Stage I, subjects received a single 10-mg dose to determine if this dose would be safely tolerated in the subjects with cirrhosis. Because all subjects in both groups tolerated the dose without difficulty, all were continued to Stage II. In Stage II, subjects received a once-daily dose of 10-mg coat-core tablets for 7 days. Serial plasma samples were assayed for nisoldipine in both stages. The C(max) and AUC of nisoldipine were approximately fourfold to fivefold higher (p < 0.01) in subjects with cirrhosis as compared to healthy subjects; however, there was overlap in the range of pharmacokinetic parameters between the two groups. The accumulation factor following multiple dosing was similar in both groups. Results suggest that nisoldipine dose should be optimized by monitoring of a pharmacodynamic end point, such as effect on blood pressure. It is likely that dose requirements for patients with liver disease will be lower.     

Time to reach tacrolimus maximum blood concentration,mean residence time, and acute renal allograft rejection: an open-label, prospective, pharmacokinetic study in adult recipients

OBJECTIVES: The aims of this study were to determine whether disposition-related pharmacokinetic parameters such as T(max) and mean residence time (MRT) could be used as predictors of clinical efficacy of tacrolimus in renal transplant recipients, and to what extent these parameters would be influenced by clinical variables. METHODS: We previously demonstrated, in a prospective pharmacokinetic study in de novo renal allograft recipients, that patients who experienced early acute rejection did not differ from patients free from rejection in terms of tacrolimus pharmacokinetic exposure parameters (dose interval AUC, preadministration trough blood concentration, C(max), dose). However, recipients with acute rejection reached mean (SD) tacrolimus T(max) significantly faster than those who were free from rejection (0.96 [0.56] hour vs 1.77 [1.06] hours; P < 0.001). Taking into account that neither differences in tacrolimus steady-state clearance nor T(1/2) could explain this unusual finding, we used data from the previous study to calculate MRT from the concentration-time curves. RESULTS: As part of the previous study, 100 patients (59 male, 41 female; mean [SD] age, 51.4 [13.8] years;age range, 20-75 years) were enrolled in the study The calculated MRT was significantly shorter in recipients with acute allograft rejection (11.32 [031] hours vs 11.52 [028] hours; P = 0.02), just like T(max) was an independent risk factor for acute rejection in a multivariate logistic regression model (odds ratio, 0.092 [95% CI, 0.014-0.629]; P = 0.01). Analyzing the impact of demographic, transplantation-related, and biochemical variables on MRT, we found that increasing serum albumin and hematocrit concentrations were associated with a prolonged MRT (P < 0.05). Conversely, serum albumin and hematocrit concentrations were significantly lower in recipients with acute rejection (P < (101). CONCLUSIONS: In this selected population of de novo renal allograft recipients, a shorter tacrolimus T(max) and calculated MRT were associated with a higher incidence of early acute graft rejection. These findings suggest that a shorter transit time of tacrolimus in certain tissue compartments, rather than failure to obtain a maximum absolute tacrolimus blood concentration, might lead to inadequate immunosuppression early after transplantation.     

Role of Helicobacter pylori in cirrhotic patients with dyspepsia: a 13C-urea breath test study

The role ofHelicobacter pylori in dyspeptic, cirrhotic patients remains unclear. This prospective outpatient study, conducted to assess the relationship of gastroduodenal disease andH. pylori as determined by the (¹³C) urea breath test, enrolled 109 consecutive cirrhotic patients with dyspepsia. All patients underwent upper-gastrointestinal endoscopy, which revealed respective prevalences of peptic ulcer, gastric ulcer, and duodenal ulcer of 41.3%, 23.9%, and 22.9%;H. pylori infection was found in 52.3%. The rate of peptic ulcer disease in theH. pylori-positive (45.6%) and -negative (36.5%) groups was not significantly different; neither was the prevalence ofH. pylori in patients with or without portal hypertensive gastropathy and with or without esophageal varices. The relationship between peptic ulcer disease andH. pylori in dyspeptic patients with cirrhosis appears to be weak. Likewise, no significant relationship was evident betweenH. pylori and portal hypertensive gastropathy or esophageal varices. This organism may not be a major pathogenetic factor in gastroduodenal diseases in dyspeptic patients with cirrhosis.