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.     

Entecavir: a review of its use in the treatment of chronic hepatitis B in patients with decompensated liver disease

The oral deoxyguanosine nucleoside analogue entecavir (Baraclude?) has potent activity against hepatitis B virus (HBV) and a high genetic barrier to resistance. This article reviews the clinical efficacy and tolerability of entecavir in the treatment of chronic hepatitis B in patients with decompensated liver disease, as well as summarizing its pharmacological properties. Entecavir 1?mg/day was more effective than adefovir dipivoxil 10?mg/day in the treatment of patients with chronic hepatitis B and decompensated liver disease, according to the results of a randomized, open-label, multicentre trial. Patients were either nucleos(t)ide naive or lamivudine experienced. The reduction from baseline in HBV DNA levels at week 24 (primary endpoint) was significantly greater with entecavir than with adefovir dipivoxil. The proportion of patients with HBV DNA levels of <300 copies/mL was also significantly greater with entecavir than with adefovir dipivoxil at weeks 24, 48 and 96, as was the proportion of patients with ALT normalization. Entecavir 0.5 or 1?mg/day, tenofovir disoproxil fumarate 300?mg/day and a fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate 200?mg/300?mg per day were effective in the treatment of chronic hepatitis B in patients with decompensated liver disease, according to the 48-week analysis of a randomized, double-blind, multicentre trial, primarily designed to examine tolerability endpoints. In this trial, over one-third of patients had received previous therapy with lamivudine for ≥6 months. The efficacy of entecavir in treatment-naive patients with HBV-related decompensated cirrhosis did not significantly differ from that seen in patients with chronic hepatitis B or compensated cirrhosis (compensated group), according to the results of a prospective, nonrandomized study. After 6 or 12 months of entecavir treatment, there were no significant differences between the decompensated and compensated groups in virological, biochemical or serological endpoints. In patients with decompensated cirrhosis, significant improvements from baseline in liver function were seen after 12 months of entecavir therapy. Oral entecavir was generally well tolerated in patients with chronic hepatitis B and decompensated liver disease, with most of the reported treatment-emergent adverse events consistent with decompensated liver disease. In the trial primarily designed to examine tolerability endpoints, there was no significant difference between patients receiving entecavir and those receiving tenofovir disoproxil fumarate with or without emtricitabine in terms of the proportion of patients experiencing tolerability failure or the proportion of patients with confirmed increases in serum creatinine levels of ≥0.5?mg/dL above baseline or confirmed serum phosphorus levels of <2.0?mg/dL at week 48 (co-primary endpoints). It has been suggested that the risk of lactic acidosis associated with oral nucleos(t)ide analogue therapy is increased in patients with highly impaired liver function. However, only one case of lactic acidosis was reported among entecavir recipients across two clinical trials in patients with chronic hepatitis B and decompensated liver disease. Moreover, small studies found that the risk of lactic acidosis was not increased in patients with chronic hepatitis B and decompensated liver disease who received entecavir, compared with patients with non-HBV decompensated liver disease. In conclusion, entecavir is a valuable agent for the first-line treatment of chronic hepatitis B in patients with decompensated liver disease.     

The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease.

1. Serum and salivary concentrations of caffeine (1,3,7-trimethylxanthine) and its dimethylxanthine metabolites were measured in 10 healthy control subjects and in 19 patients with cirrhosis, for up to 96 h following a 400 mg oral caffeine load. 2. Serum and salivary caffeine concentrations correlated significantly (r = 0.954; P less than 0.001) and no significant differences were observed in the pharmacokinetic data derived from the respective concentration-time curves. 3. In the control subjects, basal salivary caffeine concentrations did not exceed 0.4 mg l-1. The median (range) basal salivary caffeine concentrations in patients with compensated cirrhosis (n = 10), 0.2 (0-0.7) mg l-1 and decompensated cirrhosis (n = 9), 0.7 (0-5.8) mg l-1, were not significantly different from control values, although three patients with decompensated cirrhosis had basal salivary caffeine values above 2.0 mg l-1. 4. In the patients with compensated cirrhosis, the median peak salivary caffeine concentration, 10.9 (8.2-16.5) mg l-1 was significantly greater than in controls, 7.1 (4.7-11.8) mg l-1 (P less than 0.01) and the median apparent volume of distribution was significantly reduced, 0.38 (0.19-0.49) vs 0.41 (0.23-0.63) l kg-1 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term pharmacokinetics of doxorubicin HCl stealth liposomes in patients after polychemotherapy with vinorelbine, cyclophosphamide and prednisone (CCVP).

The concentration-time profiles of Doxorubicin (DOXO) from day 0 to day 21 after i.v. infusion of 25 or 30 mg/m2 doxorubicin HCI stealth liposomes (Caelyx) were investigated in 9 patients receiving combination polychemotherapy with cyclophosphamide, vinorelbine and prednisone. Peak serum concentrations occurred from 0.04 to 4.0 days after infusion (mean tmax = 1.79 +/- 1.55 d) with a mean cmax of 4,595 +/- 2,849 ng/ml. A total amount of 12.84 +/- 2.47 mg liposomal DOXO in the plasma volume (Vp = 2,794 + 537 ml) could be estimated at tmax (= 27 % of the mean dose of 47.6 mg). Stealth liposomes were eliminated slowly from the blood with a mean t 1/2el of 1.9 + 0.5 days (MRT was 4.6 + 2.5 days). AUClast values ranged from 8,070 to 33,446 ng/ml*d (mean 10,987 +/- 9,339 ng/ml*d). The low plasma clearance (Cltot = 4,681 +/- 2,835 ml/day) and the small volume of distribution (Vz = 11.7 +/- 6.31) suggested that stealth-liposomes were stable in the blood at least for 14 days. Polychemotherapy with Hyper-CCVP schedule did not alter the stability of stealth liposomes, but peak levels of DOXO seemed to be somewhat lower compared to regression analysis of literature data (cmax versus dosage range from 20 to 60 mg/m2). Due to clast occurring between day 12 to 18, no indices for an accumulation of the drug in the blood could be found, when liposomes were given every four weeks.     

Phase II study of an oxaliplatin/vinorelbine combination in patients with anthracycline- and taxane-pre-treated metastatic breast cancer

A phase II study was conducted to evaluate the safety and efficacy of an oxaliplatin (OXA)/vinorelbine (VNB) combination in metastatic breast cancer (MBC) patients pre-treated with anthracyclines and taxanes. Patients received OXA at 130 mg/m (2-h i.v.), day 1, and VNB days 1 and 8 at 24-26 mg/m repeated every 3 weeks. Forty-two patients (median age 54; 64% with liver metastasis, 67% taxane resistant/refractory and 38% anthracycline resistant/refractory) were treated. A median of 4 cycles of treatment was given per patient, with 31% receiving 6 or more. Eleven partial responses and 16 patients with stable disease (five lasting more than 4 months) in 41 eligible patients were seen, for an overall response rate of 26.8% (95% confidence interval 14.2-42.9). Median follow-up was 15.9 months (7.2-30.6), median time to progression was 3.4 months and estimated overall survival was 12.7 months (20 events). Thirty-three patients experienced (National Cancer Institute Common Toxicity Criteria version 2) grade 3-4 neutropenia (one case of febrile neutropenia) and three patients had severe constipation requiring hospitalization. Nine patients developed grade 3 OXA-specific neurotoxicity. There were no treatment-related deaths. We conclude that OXA 130 mg/m (day 1) and VNB 24 mg/m (day 1 and 8) combination given every 3 weeks is effective with a good safety profile in MBC patients previously treated with anthracyclines and taxanes.     

Effect of Telenzepine,an M1-Selective Muscarinic Receptor Antagonist,in Patients with Nocturnal Asthma

Summary: Muscarinic M₁-receptor antagonists can prevent the induction of a long-lasting excitatory post-synaptic potential in autonomic ganglia. As the prolonged occupation of M₁-receptors is a possible protective mechanism against vagal overstimulation, M₁-antagonists might prove to be effective in preventing nocturnal wheeze. The aim of the present study was to investigate whether telenzepine, an M₁-selective muscarinic receptor antagonist, administered orally at different doses (1.5 mg, 3 mg, 5 mg) for one week, reduced airway obstruction in patients with nocturnal asthma in comparison with placebo. Peak expiratory flow rate (PEFR) difference between each study medication (arithmetic means from values on days 4, 5 and 6) and baseline at 6 a.m. and at midnight on day 5 did not differ significantly. Treatment with placebo nocte (at night, 9 p.m.), or telenzepine 1.5 mg nocte, telenzepine 3 mg nocte and telenzepine 5 mg nocte did not affect significantly the 24-h time course of PEFR. The results of this study indicate that the use of telenzepine via the oral route at a dose of up to 5 mg is not effective in preventing nocturnal asthma.     

Pharmacokinetics of famotidine in normal subjects and in patients with chronic liver disease

The pharmacokinetics of famotidine were studied in seven healthy control subjects and in 14 patients with cirrhosis, following single oral and intravenous 20-mg dose administration, and after seven daily doses of 40 mg. Following intravenous (i.v.) administration, the mean (range) total plasma clearance values were not significantly different in the patients with compensated cirrhosis (n = 7), 337 (241-576) ml/min or in the patients with decompensated cirrhosis (n = 7), 270 (120-408) ml/min compared with the control group, 370 (154-612) ml/min. The mean half-life in the compensated cirrhotics, 2.86 (1.87-4.98) h, was similar to that in the control group 2.91 (1.86-6.03) h, but it was insignificantly prolonged in the decompensated cirrhotics 3.35 (2.00-5.77) h. The mean, maximum, plasma famotidine concentrations after single oral doses were comparable between the groups but there was considerable inter-subject variability, with individual values ranging from 17 to 139 ng/ml. Peak plasma concentrations were reached within 2-3 h, although more variability was observed among patients with decompensated cirrhosis. The mean systemic availability of the drug, estimated from urinary recovery, was 0.39 (0.15-0.64) in the healthy controls, 0.35 (0.14-0.51) in the patients with compensated cirrhosis and 0.38 (0.13-0.77) in the patients with decompensated cirrhosis. No significant increases were observed in plasma trough famotidine concentrations following multiple oral dosing in any of the subjects, and the kinetic variables after the seventh dose were not significantly different from those following the single oral dose. No significant changes were observed in psychometric performance in control subjects or in patients between the pre-study day and day seven of the multiple oral dose phase.     

INCREASE IN SERUM TOTAL ANGIOTENSIN-CONVERTING ENZYME ACTIVITY WITH ENALAPRIL THERAPY IN HUMANS: A CONTROLLED TRIAL

1. In a controlled, randomized double-blind trial, 15 patients with essential hypertension were treated with enalapril 5-20 mg/day, or doxazosin 1-8 mg/day, during a 7 week dose titration phase. This was followed by 7 weeks of combined treatment with doxazosin and enalapril. 2. Blood was taken after a 2 week placebo run-in phase, and at 3 and 7 weeks in the single-agent and combined treatment phases, for measurement of plasma renin activity (PRA), plasma angiotensin II (AII), plasma aldosterone and serum free and total angiotensin-converting enzyme (ACE) activities. 3. Doxazosin had no effect on serum free or total ACE activities. 4. Enalapril reduced serum free ACE activity and increased serum total ACE activity, which at 7 weeks was significantly greater than in patients receiving doxazosin. 5. In those patients who received enalapril, 10 mg/day for 3 weeks and then 20 mg/day for 4 weeks (n = 12), with or without doxazosin, mean serum total ACE activity increased by 51%. PRA was also increased in this group, but there were no changes in plasma AII or aldosterone concentrations.     

血清学指标对肝硬化程度的预测分析

目的探讨不同程度肝硬化患者临床血清学指标,评价和判断在诊断中的应用价值。方法肝硬化代偿期和失代偿期患者各50例,对照组50例,对其相关血清学指标进行统计分析。结果失代偿期肝硬化总胆红素（TBIL）和丙氨酸氨基转移酶（ALT）分别为（69．5±7．0）μmol／L、（143．1±14．2）U／L,高于代偿期肝硬化[（44．6±5．8）Ixmol／L、（77．4±8．6）U／L,P〈0．05];两组均高于对照组（P〈0．05）;失代偿期肝硬化血清白蛋白（Alb）和胆碱酯酶（ChE）分别为（28．2±3．7）e,／L和（2024．39±211．40）U／L,均低于对照组（36．1±3．7）g／L、（6169．36±607．42）U／L和代偿期肝硬化[（34．7±4．3）g／L（3571．27±310．01）U／L]（P〈0．05）;代偿期肝硬化组ChE低于对照组（P〈0．05）。失代偿期肝硬化和代偿期肝硬化前白蛋白（PA）和腺苷脱氨酶（ADA）分别为（0．14±0．04）mg／I。、（16．17±1．94）U／L和（0．21±0．05）mg,／L、（34．20±3．29）U／L,差异有统计学意义（P〈0．05）。失代偿期肝硬化和代偿期肝硬化A／G分别为（0．64±0．29）和（I．06±0．30）,均低于对照组（1．51±0．21）（P〈0．05）,且失代偿期肝硬化低于代偿期肝硬化（P〈0．05）。失代偿期肝硬化Ⅳ型胶原（Ⅳ-c）和层黏连蛋白（LN）分别为（97．4±9．8）肛g／L和（205．7±20．1）斗g／I。,均高于代偿期肝硬化（68．7±7．5）斗g／L和（124．1±11．8）肛g／L和对照组[（52．3±6．1）U/L和（83．8±7．6）U/L],且代偿期肝硬化组高于对照组（P〈0．05）;失代偿期肝硬化透明质酸（HA）、HI型前胶原（PCⅢ）分别为（211．3±16．4）肛g,／L和（168．1±16．2）U/L,均高于对照组（51．2±5．3）Ixg／L和（79．1±8．0）斗∥L（P〈0．05）。结论丙氨酸氨基转移酶等几项血清学指标对于不同肝硬化程度临床诊断和预后判断有重要的参考价值。     

Pharmacokinetics and therapeutic effects of oltipraz after consecutive or intermittent oral administration in rats with liver cirrhosis induced by dimethylnitrosamine

Pharmacokinetics and therapeutic effects of oltipraz were evaluated after consecutive (once per day at 30 mg/kg/day for 7 and 14 days) or intermittent (once per week at 100 mg/kg/week for 1-3 weeks) oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. The AUC of oltipraz was significantly greater in cirrhotic rats than controls (890 compared with 270 microg . min/mL) due to impaired liver function in cirrhotic rats. However, the AUC values after consecutive 7 (421 compared with 753 microg . min/mL) and 14 (309 compared with 821 microg . min/mL) days oral administration of oltipraz in cirrhotic rats were significantly smaller than those in respective vehicle-treated cirrhotic rats. Moreover, the AUC values after intermittent 2 and 3 weeks in cirrhotic rats were also significantly smaller than that in 1 week vehicle-treated cirrhotic rats (2370 and 1690 compared with 4760 microg . min/mL). This could be due to induction of CYP isozymes and considerably greater numbers of normal liver cells in cirrhotic rats by oral administration of oltipraz. Improved liver function by oltipraz in cirrhotic rats was proved by liver microscopy; livers are free of significant fibrosis, although evidence of bridging necrosis is still present in many rats.     

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.     

Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure

Summary Plasma concentrations of canrenone and canrenoate were measured in 43 patients treated with spironolactone 50–400 mg/day, and in one patient treated with canrenoate-K 3×200 mg/day. The cumulation of canrenone and canrenoate was followed in 9 patients recovering from myocardial infarction, without congestive heart failure or cirrhosis, who received spironolactone 2×100 mg/day. The cumulation half-life was 1–4 days, which may partly explain the delayed clinical action of spironolactone. The plasma elimination half-life of canrenone and canrenoate in six of these patients lay between 13.5 and 24 h. After 10 doses it was unchanged in three patients and had decreased only slightly in three others. Steady state minimum plasma levels of canrenone and canrenoate were measured in 33 patients with congestive heart failure or cirrhosis who received spironolactone 50–400 mg/day for at least three weeks. There was up to 15 fold inter-individual variation in the plasma levels of canrenone amongst those receiving spironolactone 200 mg/day. No statistically significant correlation was found between steady state levels of canrenone and plasma creatinine or the results of bromsulphalein liver function tests. In one patient with severe congestive heart failure given canrenoate-K 3×200 mg/day, cumulation of canrenone and canrenoate occurred for seven days, followed by a gradual decline in their plasma levels until the eleventh day of therapy. A loading dose is recommended for initiation of spironolactone therapy.     

复方甘草酸苷对肝癌合并肝硬化患者术中肝功能的影响

目的:探讨复方甘草酸苷对肝癌合并肝硬化患者肝切除术中肝功能的影响。方法:55例肝癌并肝硬化患者随机分为A、B组,A组手术切皮前静脉滴注复方甘草酸苷(1ml/kg),B组给予等量的生理盐水;术后第1、3、6d抽取外周静脉血检测肝功能指标,并对结果进行统计学处理。结果:A、B组术后第1、3d各项肝功能指标均高于术前,且A组低于B组(P<0.05);术后第6d2组患者肝功指标下降,组间比较无显著性差异。结论:复方甘草酸苷用于肝癌并肝硬化患者肝切除术中有护肝效应。     

HBV慢性肝病尿酶活性检测的临床意义

目的探讨尿酶(LAP、NAG、GPDA)水平对HBV慢性肝病的临床意义。方法①将研究对象分为慢性肝炎组、代偿期肝炎肝硬化组、失代偿期肝炎肝硬化组以及正常对照组,测定其晨尿中LAP、NAG、GPDA水平的变化,分析各组间LAP、NAG、GPDA活性的差异;②根据肝功损害程度将所有研究对象分为轻度、中度和重度三组,比较三组间尿LAP、NAG、GPDA水平的差异;③根据HBV DNA复制的水平,将所有研究对象分为低度和高度复制两组,分析两组间尿LAP、NAG、GPDA水平的变化。结果①代偿期及失代偿期肝硬化尿NAG、LAP和GPDA水平均明显高于正常对照组及慢性肝炎组(P<0.05和P<0.01),肝硬化失代偿期尿NAG、LAP和GPDA水平均明显高于代偿期(P<0.05);②肝功损害程度与尿NAG、LAP和GPDA活性呈正相关(P<0.05和P<0.01);③HB VDNA高度复制组和低度复制组两组比较,尿NAG、LAP和GPDA水平无显著性差异(P>0.05)。结论尿LAP、NAG、GPDA活性测定可较灵敏地反映HBV慢性肝病出现的早期肾脏损害,并可间接判断慢性肝病肝功能的损害程度;尿酶(NAG、LAP和GPDA)活性与HBV DNA复制水平无明显相关性。     

The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.     

Effects of TJN-101, a lignan compound isolated from Schisandra fruits, on liver fibrosis and on liver regeneration after partial hepatectomy in rats with chronic liver injury induced by CCl4

TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. 1) Effect of TJN-101 on liver fibrosis was investigated in rats which were injected with CCl4 (1 ml/kg) subcutaneously twice a week for 12 weeks. TJN-101 was given orally at the dose of 10 or 30 mg/kg/day for 6 or 3 weeks beginning on the 6th or 9th week after the start of CCl4-intoxication, respectively. The elevations of serum transaminase activities and the increase of liver 4-hydroxyproline content were observed depending on the period of CCl4-intoxication. These changes were marked on the 9th and 12th weeks after. In the histopathological study, the degenerative fatty change on the 6th week after and the formation of pseudolobule caused by fibrosis proliferation on the 9th or 12th week after were mainly observed. When rats were treated with TJN-101, the abnormalities in biochemical parameters and the fibrosis proliferation caused by CCl4-intoxication were improved. 2) Chronic liver injury was induced by the treatment with CCl4 (1 ml/kg) subcutaneously twice a week for 10 weeks to investigate the effect of TJN-101 on liver regeneration after partial hepatectomy. TJN-101, which was given orally at the dose of 10, 30 or 100 mg/kg/day for 6 days from the 1st day after partial hepatectomy, dose-dependently increased the liver regeneration rate and improved the serum BSP retention rate. These results suggest that TJN-101 suppresses the fibrosis proliferation and accelerates both the liver regeneration and the recovery of liver function after partial hepatectomy in chronic liver injury.     

乙型肝炎肝硬化失代偿期抗病毒治疗疗效观察

目的观察核苷类药物治疗乙型肝炎肝硬化失代偿期的疗效。方法对96例乙型肝炎肝硬化失代偿期患者随机分组,所有患者在保肝对症治疗的基础上,分别给予拉米夫定（A组）100mg/d、阿德福韦酯（B组）10mg/d、恩替卡韦（C组）0.5mg/d口服,疗程为48周,同时设立保守治疗组（D组）,观察所有患者临床症状、体征、肝功能变化、凝血酶原时间活动度（PTA）、HBV-DNA定量、HBeAg阴转、HBeAg/HBeAb转换情况。结果通过抗病毒治疗,A、B、C三组患者无一例死亡,临床表现、体征、肝功能、PTA均有明显改善,HBeAg血清转换率三组分别为20%、8%、23%,三者统计学处理有显著差异（P〈0.05）,HBV-DNA阴转率三组分别为48%、28%、68.2%,组间比较有显著差异（P〈0.05）。D组疗效最差,死亡3例,抗病毒治疗组与保守治疗组疗效有显著差异（P〈0.01）。结论乙型肝炎肝硬化失代偿期患者应行抗病毒治疗,可首先选用拉米夫定或恩替卡韦,为防止应用拉米夫定病毒变异,可在病情好转后改用阿德福韦酯继续治疗。     

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.     

Effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits and cholesterol-fed rabbits

The aim of this study was to evaluate the effects of (+)-(E)-6S-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (HR780), a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on hypercholesterolemia in Watanabe heritable hyperlipidemic (WHHL) rabbits and rabbits fed a diet with 1% cholesterol, in comparison with the effects of simvastatin. Each drug was administered orally to WHHL rabbits for 24 weeks and to 1% cholesterol-fed rabbits for 10 weeks. In WHHL rabbits, HR780 at doses of 1, 2.5 and 5 mg/kg/day reduced the plasma total cholesterol level by 15, 24 and 20%, respectively. In contrast, simvastatin at 5 mg/kg/day lowered the level by 23%. In 1% cholesterol-fed rabbits, HR780 (1 and 2.5 mg/kg/day) was found to inhibit the increases in the plasma total cholesterol and phospholipid levels and liver cholesterol contents in a dose-dependent manner. Simvastatin (5 mg/kg/day) also inhibited their increase. Neither HR780 nor simvastatin increased the contents of cholesterol and total bile acid in the gallbladder bile. In conclusion, long-term treatment with HR780 reduced the plasma cholesterol level in WHHL rabbits and 1% cholesterol-fed rabbits, and decreased the liver cholesterol contents in 1% cholesterol-fed rabbits.     

Short report: effect of ranitidine on duodenal ulcer healing in patients with cirrhosis of the liver

The effect of ranitidine (300 mg daily) on the healing of acute duodenal ulcer was investigated in patients with and without cirrhosis of the liver. Of the 109 patients who entered the study, two patients from each group were excluded. Healing rates after 4 and 8 weeks were significantly different between patients with cirrhosis and controls (4- and 8-week healing rates in cirrhotics and non-cirrhotics: 49 and 69%, and 71 and 91%, respectively). This study demonstrates that duodenal ulcer healing is delayed in patients with cirrhosis.