Hepatic findings in long-term clinical trials of ximelagatran.

OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.     

Incidence and prevalence of abnormal liver associated enzymes in patients with atrial fibrillation in a routine clinical care population

The prevalence of elevated liver enzymes has not been described in patients with atrial fibrillation (AF) who may be more likely to develop these abnormalities due to comorbidities and medications. As signals of liver injury lead to termination of drug development programs, an attempt to better define the background prevalence would aid in interpreting these elevations in the setting of exposure to a new drug. The aim of this study was to estimate the prevalence and incidence of alanine aminotransferase (ALT) elevations in a cohort with AF. METHODS: Retrospective cohort of patients with AF using the outpatient medical record of the University of Pennsylvania Health System (UPHS). Primary outcomes were prevalence and incidence of ALT elevations (>40 U/L). We also examined the prevalence of risk factors for ALT elevations. RESULTS: Liver enzymes were measured at least once in 1630 of 2151 patients (76%). The prevalence of ALT >40 U/L was 27.6% (95%CI 25.7-29.5%). The incidence of new ALT elevations was 14.5/100 person-years (95%CI 13.0-16.1) for ALT > 40 U/L and 2.1/100 person-years (95%CI 1.6-2.8) for ALT elevations above twice the upper limit of normal (ULN). New persistent ALT elevations above twice the ULN were identified in 0.2% of patients. CONCLUSION: Elevated ALT is common among patients with AF, although new and persistent elevation greater than twice the ULN is uncommon. In the setting of a new drug, these factors make it difficult to delineate drug-induced liver injury from incident elevations due to comorbidities.     

Background incidence of liver chemistry abnormalities in a clinical trial population without underlying liver disease

Background

The FDA has recently proposed pre-marketing liver chemistry subject stopping criteria. The study was undertaken to determine the background rates of liver chemistry abnormalities in clinical trial populations without underlying liver disease.

Methods

Data from 28 Phase II–IV trials in diseases with normal risk of underlying liver abnormalities were included. Information on 18,672 subjects, mean age of 44.3 years and 92.3% female was available. Prevalence and incidence of abnormal liver chemistries were calculated.

Results

At baseline, the overall prevalence of alanine aminotransferase (ALT) elevations of 3 x ULN (upper limit of normal) and 5 x ULN was 0.08% and 0.01%, respectively. The prevalence of liver chemistry abnormalities was similar at study entry and exit. Overall, elevated liver chemistry incidence rates per 10,000 person months were 6.5 (95% CI 4.8; 8.5) for ALT 3 x ULN, 2.6 (1.6; 4.0) for ALT 5 x ULN, 0.3 (0.03; 0.9) for ALT 8 x ULN, 0.09 (0.04; 0.2) for alkaline phosphatase (ALP) 2 x ULN, and 0 for combined ALT + bilirubin elevation.

Conclusion

Elevations of ALT (3 x ULN) and ALP (2 x ULN) are rare in clinical trial populations without underlying liver disease and can be considered a safety signal. No events of ALT 3 x ULN with concomitant bilirubin 1.5 x ULN were noted. These analyses create a liver chemistry evidence base in normal risk clinical trial populations.     

拉米夫定治疗慢性乙型肝炎4年的长期疗效

目的 :评估拉米夫定治疗乙型肝炎 4a的长期疗效和安全性 ,以及对病毒变异的发生率的影响。方法 :42 9例HBsAg,HBeAg阳性的慢性乙型肝炎 (慢乙肝 )病人 ,先按 3∶1随机双盲分成拉米夫定组和安慰剂组 ,治疗共 1 2wk ,以后所有病人均服拉米夫定 1 0 0mg·d-1,共 4a。结果 :治疗 1 2wk ,拉米夫定组HBVDNA累计阴转率 (<1 .6ng·L-1)为 92 .2 % ,安慰剂组仅为 1 4.1 % (P <0 .0 1 )。服药 4a后 ,血清HBVDNA仍持续降低。 4a结束时 ,HBeAg阴转率和HBeAg/抗HBe血清转换率为2 7.4%和 2 6.7%。此与治疗前ALT水平有显著关系。治疗前ALT基础值 >2×ULN(正常值上限 )和 >5×ULN者 ,4a时HBeAg阴转率和血清转换率均为 5 0 %和 67%。治疗前ALT增高的病人 ,4a治疗后 ,ALT的复常率为 67.0 % ,治疗前ALT正常的病人 ,83 .6%仍正常。 1 ,2 ,3和 4a的YMDD变异率分别为 1 2 .1 % ,49.7% ,70 .5 %和67.0 %。发生变异后 ,HBVDNA大多仍抑制 ,在基线以下少部分可回升。在YMDD变异病人 ,继续有HBeAg阴转和血清转换 ,分别为 2 0 %和1 5 .5 % ,低于非变异组病人。疗程中ALT增高 >5×ULN有 2 2例 ,其中变异者 1 5例 ,非变异者 7例 ,经处理后均缓解。在 4a治疗期间 ,不良反应2 4.8%。结论 :长期应用拉米夫定可持久抑制HBV复制和促进血清转     

Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity

BACKGROUND: Tacrine, an anticholinesterase used to treat Alzheimer's disease (AD), leads to an increase in serum alanine aminotransferase (ALT) levels. The factors determining individual susceptibility are largely unknown. The purpose of this study was to investigate genetic predisposition. METHODS: Rats were administered single dose tacrine (3-40 mg/kg). After 6 and 24 h, hepatic gene expression was determined using the affymetrix rat U34A microarray. On the basis of the gene expression data, the IL6 gene was identified as a potential candidate for tacrine transaminitis susceptibility. Sixty-nine patients with AD on tacrine with or without transaminitis were genotyped for 17 IL6 polymorphisms. RESULTS: Serum aspartate aminotransferase levels in rats increased after tacrine (40 mg/kg) administration. Forty-six and 29 genes showed significant upregulation at 6 and 24 h, respectively, after administration, including the IL-6-regulated acute phase response genes alpha2-macroglobulin, fibronectin and haptoglobin. Five of the 17 IL6 polymorphisms studied in AD patients showed an association (P<0.05) with transaminitis [ALT>2 x upper limit of normal (ULN)]. An association existed between maximum ALT and area under curve for ALT over 15 weeks and an intronic polymorphism (P<0.01) and a 3'-variable nucleotide tandem repeat (P<0.05). Multilocus haplotype analysis showed one haplotype (which included the -597A, -572G, -174G and variable nucleotide tandem repeat-D alleles) had a frequency of 0.1 in patients with ALT values >2 x ULN, whereas it was absent in patients with ALT less than 2 x ULN (P=0.0093, Pcorrected=0.049). CONCLUSION: The IL6 genotype may act as a predisposing factor for tacrine transaminitis. This, however, requires further confirmatory functional studies. The role of acute dosing rodent models in identifying candidate genes associated with drug-induced liver injury in man deserves further study.     

Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients

Combination of disease-modifying antirheumatic drugs (DMARDs) is increasingly used in the treatment of rheumatoid arthritis (RA) patients. Hepatotoxicity has been an important safety concern with DMARDs therapy. Though leflunomide (CAS 75706-12-6) has emerged as an effective oral DMARD, its use is associated with hepatotoxicity. Limited data is available regarding hepatotoxic risk when leflunomide is used in combination therapy in RA patients. An open-label, prospective study was conducted to evaluate the hepatotoxic risk after addition of leflunomide with other DMARDs in RA patients, who did not respond to their ongoing DMARD therapy. A total of 46 patients were enrolled and leflunomide was given as add-on therapy with earlier DMARDs. Biochemical parameters of serum aminotransferase levels (AST and ALT) were estimated at the baseline and then every month after addition of leflunomide. Study results showed that 13.0% patients developed > 1.5 to < 2 times upper limit of normal (ULN) elevation; 6.5% patients developed > 2 to < 3 times the ULN elevation and 2.2% patients developed > 3 times the ULN elevation. In 20% of the patients with hepatic enzyme elevations, enzyme levels returned to normal within 4-6 weeks after discontinuation of leflunomide therapy, whereas in 50% of patients the dose of leflunomide was reduced from 20 mg/day to 10 mg/day for normalization of enzymes levels. 30% of patients were continued with leflunomide without dose reduction. None of the patients showed clinical signs and symptoms of hepatotoxicity. Leflunomide therapy with other DMARDs requires strict monitoring of serum aminotransferases.     

Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (also known as statins) are associated with elevated transaminase levels in 1-3% of patients. Therapy with these drugs requires monitoring of alanine aminotransferase (ALT) levels because animal studies and premarketing clinical trials showed signs of hepatotoxicity that were primarily minor elevations of ALT. Nevertheless, postmarketing experience suggests that hepatotoxicity is rare, and that elevated ALT levels are reversible with continued therapy and probably are related to cholesterol lowering. Based on the low occurrence of ALT elevations and the lack of clinical evidence of hepatotoxicity, some clinicians are calling for a change in the current practice of monitoring liver function tests. We report, however, the case of a 71-year-old woman who was receiving atorvastatin and experienced elevated transaminase levels on two occasions, and developed pruritus on rechallenge with the drug. Thus, clinicians should be aware of asymptomatic elevations in liver function tests in patients receiving atorvastatin who do not have known risk factors for liver damage.     

Incidence and characterization of serum transaminases elevations in pegylated interferon and ribavirin treated patients with chronic hepatitis C

BACKGROUND: A virological response to pegylated-interferon and ribavirin is typically associated with a prompt fall in serum transaminases. For some patients, transaminases rise during treatment. AIM: To assess the frequency and define factors associated with elevations of serum transaminases. METHODS: A total of 169 treated patients were studied. Transaminase elevations were graded by WHO criteria - grade 0: no value > baseline, grade 1: 1-2x baseline, grade 2: 2.1-5x baseline, grade 3: >5x, grade 4: any rise with evidence of liver failure. Results 60/169 (35%) patients experienced transaminase elevations: 52 grade 1, 6 grade 2, 1 grade 3, 1 grade 4. Overall, end of treatment response and sustained virological response rates were 72% and 55%. Lower rates were observed in the grade 1 elevation group (63% and 40%) compared with patients with grade 0 (79% and 65%) and grade > or =2 elevations (85% and 71%). Grade 1 elevations tended to occur earlier during treatment than grade > or =2 elevations. Transaminase elevations were associated with greater pre-treatment body weight (P = 0.006), steatosis (P = 0.008) and poorer sustained virological response rates (P = 0.007). CONCLUSIONS: Transaminase elevations during treatment of chronic Hepatitis C virus with pegylated interferon and ribavirin are common but rarely severe. Mild rises may reflect ongoing viral activity in treatment non-responders. More significant rises are frequently observed despite a virological response, and may be because of an immuno-modulating effect of interferon in susceptible patients.     

Drug-induced liver injury.

Drug-induced liver injury is a frequent cause of hepatic dysfunction. Reliably establishing whether the liver disease was caused by a drug requires the exclusion of other plausible causes and the search for a clinical drug signature. The drug signature consists of the pattern of liver test abnormality, the duration of latency to symptomatic presentation, the presence or absence of immune-mediated hypersensitivity and the response to drug withdrawal.Determination of causality also includes an evaluation of individual susceptibility to drug-induced liver injury. This susceptibility is governed by both genetic and environmental factors. Components of the drug signature in conjunction with certain risk factors have been incorporated into formal scoring systems that are predictive of the likelihood of drug-induced liver injury. The most validated scoring system is the Roussel-Uclaf causality assessment method, which nonetheless retains certain imperfections.Mitigating the potential for drug-induced liver injury is achieved by the identification of toxicity signals during clinical trials and the monitoring of liver tests in clinical practice. There are three signals of liver toxicity in clinical trials: (i) a statistically significant doubling (or more) in the incidence of serum alanine aminotransferase (ALT) elevation >3 x the upper limit of normal (ULN); (ii) any incidence of serum ALT elevation >8-10 x ULN; and (iii) any incidence of serum ALT elevation >3 x ULN accompanied by a serum bilirubin elevation >2 x ULN. Monitoring of liver tests in clinical practice has shown unconvincing efficacy, but where a benefit-risk analysis would favour continued therapy, monthly monitoring may have some benefit compared with no monitoring at all.With rare exception, treatment of drug-induced liver injury is principally supportive. Drug toxicity is the most common cause of acute liver failure, defined as a prolonged prothrombin time (international normalised ratio > or =1.5) and any degree of mental alteration occurring <26 weeks after the onset of illness in a patient without pre-existing cirrhosis. A patient who meets these criteria must be evaluated for liver transplantation. The pathogenesis of drug-induced liver injury can be examined on the basis of the two principal patterns of injury. The hepatocellular pattern is characterised by a predominant rise in the level of transaminases and results from the demise of hepatocytes by means of either apoptosis or necrosis. The cholestatic pattern is characterised by a predominant rise of the serum alkaline phosphatase level and usually results from injury to the bile ductular cells either directly by the drug or its metabolite, or indirectly by an adaptive immune response.     

Metabolic and histological features of non-alcoholic fatty liver disease patients with different serum alanine aminotransferase levels

Background  Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in affluent countries. Serum alanine aminotransferase (ALT) level is commonly performed to monitor NAFLD patients, but its clinical relevance is unclear.
Aim  To evaluate the metabolic and histological features of NAFLD patients with different ALT levels.
Methods  A total of 173 consecutive patients with biopsy-proven NAFLD were studied. Patients with persistently normal ALT and those with abnormal ALT were compared.
Results  Patients with persistently normal ALT had lower steatosis grade than patients with abnormal ALT, but they had similar degree of lobular inflammation, ballooning and fibrosis. Among 19 patients with ALT below 0.5 times the upper limit of normal (ULN) at the time of liver biopsies, 8 (42%) and 3 (16%) had steatohepatitis and significant fibrosis respectively. The within-patient coefficient of variance was similarly high in patients with simple steatosis and steatohepatitis (33.5). Age and glucose, but not ALT, were independent factors associated with significant fibrosis.
Discussion  Metabolic factors, but not ALT, are associated with histological severity. Patients with ALT < 0.5 × ULN may still have non-alcoholic steatohepatitis (NASH) and significant fibrosis. Evaluation of NAFLD patients should be based on metabolic risk factors, but not ALT level.     

A pre-marketing ALT signal predicts post-marketing liver safety

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an “ALT signal”. We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ? 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ? 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ? 3× ULN in treated versus placebo) was examined. An ALT signal of ? 1.2% was significantly associated with a post-marketing liver safety signal (p ? 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ? 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.     

Factors associated with the risk of liver enzyme elevation in patients with type 2 diabetes treated with a thiazolidinedione

STUDY OBJECTIVE: To characterize frequency of liver enzyme elevation in patients with type 2 diabetes mellitus receiving troglitazone. DESIGN: Retrospective study. SETTING: Hospital-affiliated medical center. PATIENTS: Two hundred ninety-one patients with type 2 diabetes mellitus. INTERVENTION: Data from patients with an average troglitazone exposure of 412.7 +/- 255.6 days were studied. MEASUREMENTS and MAIN RESULTS: Enzyme elevations more than 1.5 times the upper limit of normal (ULN) occurred in 17 patients (5.8%) and more than 3-fold elevations in 6 (2.1%). The relationship among enzyme elevation events, demographic factors, duration of troglitazone exposure, frequency of monitoring, and concurrent drugs (limited to glucose and lipid-lowering agents) was assessed by multiple logistic regression. Age was an independent predictor of risk (p=0.009), and concurrent insulin therapy approached statistical significance (p=0.051) for 1.5-fold ULN elevation in liver enzymes. Age and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were the only significant predictors of 3-fold ULN elevations (p=0.03 and p=0.04, respectively). CONCLUSION: Several factors appear to increase the risk of enzyme elevation events in patients treated with troglitazone.     

The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports

Aliment Pharmacol Ther 31 , 1337–1345

Summary

Background Drug‐induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. Aim To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. Methods Hepatotoxic drugs were identified from product labelling and classified in high‐medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (I_D) and placebo (I_C) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. Results The median I_C was 10/1000. The high‐medium‐risk drugs’ median I_D was significantly higher compared with low‐risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi‐squared test, absolute difference and odds ratio comparing I_D and I_C identified 35%, 51% and 77% of high‐medium‐risk drugs respectively. Less number of case reports were associated with low‐ than high‐medium‐risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (I_D vs. I_C) was the strongest predictor of published DILI case reports. Conclusion A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.     

Analysis of severe hepatic events associated with nevirapine-containing regimens: CD4+ T-cell count and gender in hepatitis C seropositive and seronegative patients.

BACKGROUND: Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of > or =250/mm(3) or men with CD4+ T-cell counts of > or =400/mm(3), i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients co-infected with hepatitis C virus (HCV). METHODS: Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade > or =III hepatotoxicity (i.e. > or =5 x upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients. RESULTS: Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade > or =III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p < 0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p = 0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome. CONCLUSIONS: Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of > or =400/mm(3) or females with CD4+ T-cell counts of > or =250/mm(3).     

Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus

STUDY OBJECTIVE: To evaluate the effectiveness and hepatotoxicity of statins in patients who are seropositive for hepatitis C virus (HCV). DESIGN: Retrospective review of a registry of patients with HCV. SETTING: Veterans Affairs Medical Center. PATIENTS: One hundred forty-six male patients who were seropositive for HCV and had received statin therapy between January 1, 1995, and September 9, 2003. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were collected for each patient; lipid and alanine aminotransferase (ALT) levels at baseline (within 6 mo of starting a statin), at 3 and 6 months after starting a statin, and at long-term follow-up (mean 22 mo) were also recorded. The primary efficacy end point was a significant decrease from baseline to long-term follow-up low-density lipoprotein cholesterol (LDL) level; the primary safety end point was a significant increase from baseline in ALT level. The mean change in LDL level was a reduction of 22% (p<0.01). No significant increases in ALT levels were observed; only one patient discontinued therapy due to ALT level elevations greater than 3 times the upper limit of normal. CONCLUSION: In men seropositive for HCV, statins were effective in reducing LDL levels and did not result in significant increases in ALT levels from baseline. Thus, statin therapy should be considered for patients with HCV who are at risk for coronary heart disease and do not have significantly elevated serum transaminase levels at baseline.     

多项无创模型指数诊断慢性乙型肝炎肝纤维化的价值比较

目的分析无创模型指数对慢性乙型肝炎肝纤维化的诊断价值。方法未曾接受抗病毒治疗的1038例慢性乙型肝炎患者,均接受肝活检,并检测血液、B超等指标。计算天冬氨酸转氨酶与血小板比值(APRI)、4因子肝纤维化指数(FIB-4)、γ-谷氨酰转肽酶与血小板计数比值(GPR)、S指数(S)、年龄-脾脏/血小板比值(ASPRI)、年龄-血小板指数(API)及FV等不同无创模型指数,并利用受试者工作特征(ROC)曲线下面积(AUROC)分析不同无创模型指数对肝纤维化的诊断价值。结果诊断肝纤维化(F2~3):FIB-4在谷丙转氨酶(ALT)<参考值上限(ULN)时价值最好,AUROC为0.795,但在ALT>5ULN时AUROC明显下降(Z=2.442,P<0.05);ASPRI、S、GPR、FV在2ULN≤ALT≤5ULN时价值最好,AUROC分别为0.809、0.828、0.830、0.873。诊断早期肝硬化(F4):API、FIB-4、GPR、S、ASPRI、FV的AUROC在不同的ALT水平时均>0.800,其中,在不同ALT水平下,ASPRI和FV的AUROC分别为0.898和0.900、0.892和0.928、0.887和0.920、0.895和0.918,均具有较高的诊断价值。结论ASPRI、S、GPR、FIB-4、FV诊断肝纤维化和肝硬化均有价值,ASPRI、FV诊断早期肝硬化价值较高,FIB-4诊断肝纤维化的价值受ALT水平影响较大。     

Sustained virological response rates and health-related quality of life after interferon and ribavirin therapy in patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels

BACKGROUND: Few studies have evaluated interferon and ribavirin therapy in hepatitis C virus-infected patients with persistently normal alanine aminotransferase (ALT) levels. AIM: To determine the efficacy and safety of combination therapy in this population, and to evaluate the impact of treatment on health-related quality of life. METHODS: Forty-six hepatitis C virus-infected patients with persistently normal ALT levels and 92 matched subjects with elevated ALT levels were treated with interferon-alpha2b plus ribavirin for up to 48 weeks. Health-related quality of life was measured prior to therapy and 24 weeks after completion of treatment using the Hepatitis Quality of Life Questionnaire. RESULTS: Overall, 32.6% of patients with normal ALT levels and 28.3% of those with elevated ALT levels had undetectable hepatitis C virus RNA at 24 weeks after completion of treatment (P = 0.60). Three patients in the normal ALT group had mild transient ALT elevations during therapy. Compared with baseline, treatment was associated with significant improvements in nearly all domains of health-related quality of life in both groups of patients. CONCLUSIONS: In hepatitis C virus-infected patients with persistently normal ALT levels, interferon-alpha and ribavirin therapy is efficacious, safe, and associated with significant improvements in health-related quality of life.     

Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.     

Lamivudine. A review of its therapeutic potential in chronic hepatitis B.

Lamivudine is a deoxycytidine analogue that is active against hepatitis B virus (HBV). In patients with chronic hepatitis B, lamivudine profoundly suppresses HBV replication. Clinically significant improvements in liver histology and biochemical parameters were obtained with lamivudine in double-blind, randomised, trials in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B and compensated liver disease. After 52 weeks of treatment, relative to placebo (< or = 25%), significantly more Chinese (56%) or Western patients (52%) treated with lamivudine 100 mg/day had reductions of > or = 2 or more points in Knodell necro-inflammatory scores. Moreover, significantly fewer lamivudine 100 mg/day than placebo recipients had progressive fibrosis in liver biopsies (< or = 5 vs > or = 15%) and fewer lamivudine- than placebo-treated patients progressed to cirrhosis (1.8 vs 7.1%). More lamivudine 100 mg/day than placebo recipients acquired antibodies to HBeAg after 52 weeks (16 vs 4% in Chinese patients and 17 vs 6% in Western patients). ALT levels normalised in significantly more lamivudine than placebo recipients enrolled in these trials. In HBeAg-negative, HBV DNA positive patients with compensated liver disease enrolled in a double-blind, randomised study, HBV DNA levels were suppressed to below the limit of detection (< 2.5 pg/ml) and ALT levels normalised in 63% and 6% of patients treated with lamivudine 100 mg/day or placebo for 24 weeks. Clinically significant improvements in liver histology were obtained in 60% of patients treated with lamivudine for 52 weeks in this study. Lamivudine 100 mg/day for 52 weeks produced similar or significantly greater improvements in liver histology and ALT levels than 24 weeks' treatment with lamivudine plus interferon-alpha. In liver transplant candidates with chronic hepatitis B and end-stage liver disease, lamivudine 100 mg/day alone, or in combination with hepatitis B immune globulin, generally suppressed HBV replication and appeared to protect the grafted liver from reinfection. Lamivudine 100 mg/day suppressed viral replication and improved liver histology in liver transplant recipients with recurrent or de novo chronic hepatitis B. Lamivudine 300 or 600 mg/day reduced HBV replication in HIV-positive patients. The incidence of adverse events in patients with chronic hepatitis B and compensated liver disease treated with lamivudine 100 mg/day or placebo for 52 to 68 weeks was similar. 3.1- to 10-fold increases in ALT over baseline occurred in 13% of patients during treatment with lamivudine 100 mg/day or placebo for 52 weeks. Post-treatment ALT elevations were more common in lamivudine than placebo recipients; however, these generally resolved spontaneously; < or = 1.5% of lamivudine- or placebo-treated patients experienced hepatic decompensation. CONCLUSION: Lamivudine inhibits HBV replication, reduces hepatic necro-inflammatory activity and the progression of fibrosis in patients with chronic hepatitis B, ongoing viral replication and compensated liver disease including HBeAg-negative patients. The drug also suppresses viral replication in liver transplant recipients and HIV-positive patients. Thus, lamivudine is potentially useful in a wide range of patients with chronic hepatitis B and ongoing viral replication.     

The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

BACKGROUND AND PURPOSE

Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo.

EXPERIMENTAL APPROACH

Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model.

KEY RESULTS

Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes.

CONCLUSIONS AND IMPLICATION

Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed.