Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation

Background  Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates.
Aim  To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response.
Methods  Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C).
Results  Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR.
Conclusions  Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log₁₀ drop in HCV-RNA at week 24.     

Longitudinal effects of hepatitis C virus treatment on hepatic mitochondrial dysfunction assessed by C-methionine breath test

Background  Hepatitis C virus (HCV) infection is characterized by remarkable levels of oxidative stress induced by virus interactions with hepatic mitochondria.
Aim  To examine hepatic mitochondrial function in HCV-infected patients assessed by a non-invasive ¹³C-methionine breath test (MeBT) and to explore longitudinal effects of antiviral treatment.
Methods  Twenty-one patients with chronic hepatitis C undergoing antiviral treatment with pegIFNα and ribavirin and 20 healthy controls were studied. MeBT was performed at baseline, week 12, end-of-treatment and after 24 weeks of follow-up in all patients with early virological response ( n  = 15).
Results  Twelve patients achieved sustained virological response (SVR); three patients relapsed for HCV-RNA replication. Cumulative percentage ¹³C-exhalation (cPDR_1.5h) was significantly decreased in HCV-infected individuals compared to controls irrespective of genotype and fibrosis stage ( P  < 0.001). Antiviral treatment induced a further decay in cPDR_1.5h ( P  < 0.01). After treatment cessation, ¹³C-exhalation returned at least to baseline values in all patients. SVR was even associated with a mean cPDR_1.5h increase of 70% compared to baseline.
Conclusions  Hepatitis C virus infection and antiviral treatment synergistically impair hepatic mitochondrial function, which may return to normal after sustained virus elimination. MeBT may be a valuable diagnostic instrument for monitoring hepatic mitochondrial function in particular in patients with mitochondrial comorbidities.     

Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alpha-2a plus ribavirin

Background  The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.
Aim  To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naïve patients with HCV genotype 1 infection enrolled in a large expanded access programme.
Methods  Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.
Results  Mean ribavirin exposure in week 0–12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P  < 0.001; SVR, 45% vs. 54%, respectively, P  = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received ( P  < 0.001 for both).
Conclusions  Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.     

Stereoselective interaction between piroxicam and acenocoumarol

1 An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.
2 Eight healthy male volunteers received an oral dose of 4  mg rac -acenocoumarol on days 1 and 8, plus 40  mg piroxicam orally 2  h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24  h interval.
3 The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: C _max+28.0% (s.d.23.8), P <0.05; AUC(0,  24  h)+47.2% (21.5), P <0.005; and t _1/2+38.0% (34.5), P <0.01. A concomitant decrease of CL/ F was observed: −30.8% (10.0), P <0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: C _max: +9.5% (s.d.36.6), AUC(0,  24  h): +15.4% (23.4), t _1/2: +19.9% (42.0), and CL/ F: −9.8% (20.5). V/F remained unchanged for both enantiomers.
4 Piroxicam plasma AUC(0,  24  h) correlated closely with R- and Sacenocoumarol AUCs on day 1 ( r =0.901, P <0.005 and r =0.797, P <0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol ( r =0.903, P <0.001) and S-acenocoumarol ( r =0.711, P <0.05).
5 Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.     

Clinical trial: extended treatment duration of peginterferon-alpha2b plus ribavirin for 72 and 96 weeks in hepatitis C genotype 1-infected late responders

Background  The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood.
Aim  To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment.
Methods  A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 μg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12–48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response.
Results  Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; P  =   0.080] and group C (OR, 17.748; P  =   0.025).
Conclusion  Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.     

Safety, tolerability, and efficacy of pegylated-interferon alfa-2a plus ribavirin in HCV-related decompensated cirrhotics

Background  Pretransplantation clearance of hepatitis C virus (HCV)-RNA reduces the risk of HCV recurrence after transplantation. Furthermore, a sustained virological response could reduce disease progression and slow clinical deterioration in nontransplanted patients.
Aim  To evaluate the safety, tolerability and efficacy of pegylated-interferon (PEG-IFN) alfa-2a plus ribavirin therapy in HCV-related decompensated cirrhotics.
Methods  Twenty HCV-related decompensated cirrhotics (44–67 years, 12 males, six Child–Pugh score A, 14 Child–Pugh score B, all with genotype 1b) were enrolled into the study. Treatment with PEG-IFN alfa-2a (135 μg, once a week) plus ribavirin (1000–1200 mg/day) was commenced. A 48-week treatment was planned in patients who had early virological response.
Results  Treatment was stopped in 8 (40%) patients. The remaining 12 (60%) patients completed 48 weeks of therapy; nine (45%) of them obtained end-of-therapy virological response and six (30%) of them obtained sustained virological response. Living donor liver transplantation was performed in three (15%) patients. Eight (40%) and six (30%) patients needed to reduce PEG-IFN alfa-2a and ribavirin dosages, respectively. No patient died during the follow-up period.
Conclusion  PEG-IFN alfa-2a plus ribavirin therapy is safe, tolerable and efficacious in selected HCV-related decompensated cirrhotics.     

Peginterferon alfa-2a/ribavirin in hepatitis C virus patients nontolerant or nonresponsive to peginterferon alfa-2b/ribavirin

Background  Peginterferon alfa-2a/ribavirin treatment resulted in fewer incidences of depression and flu-like symptoms than that of standard interferon/ribavirin, whereas peginterferon alfa-2b/ribavirin and standard interferon/ribavirin treatment resulted in similar incidences of these adverse events (AEs).
Aim  To assess the efficacy and safety of peginterferon alfa-2a/ribavirin in genotype 1-infected patients treated for up to 12 weeks with peginterferon alfa-2b/ribavirin but not achieving early virologic response (EVR) (non-EVR) or nontolerant (NT) because of depression, fatigue, flu-like symptoms, or injection-site reactions.
Methods  Nontolerants were treated for an additional 36 weeks and non-EVRs for an additional 60 weeks with peginterferon alfa-2a (180 μg/week)/ribavirin (1000/1200 mg/day). Patients with detectable HCV RNA after 12 weeks were discontinued.
Results  Of 25 NTs, 23 (92%) were HCV-RNA negative after 12 weeks on peginterferon alfa-2a/ribavirin and 14 (56%) achieved sustained virologic response. Of 32 non-EVRs to peginterferon alfa-2b/ribavirin, four (13%) achieved EVR with peginterferon alfa-2a/ribavirin and one (3%) achieved sustained virologic response. Four non-EVRs and 0 NTs were withdrawn for AEs; 26 (81%) and 24 (96%), respectively, completed peginterferon alfa-2a/ribavirin treatment or were withdrawn for insufficient response at week 12. In NTs, depression, fatigue, flu-like symptoms, and injection-site reactions declined during treatment.
Conclusion  Most patients who did not tolerate peginterferon alfa-2b/ribavirin because of AEs, and who completed the full 36-week course of peginterferon alfa-2a/ribavirin treatment, achieved sustained virologic response.     

A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product

Aims The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration ( C _max ) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.
Methods Limited sampling models (LSM) were developed for CBZ and CBZE following 200–800  mg single oral dose and 400–800  mg twice daily dose for 14 days of a sustained-release product (CBZ-SR) to estimate AUC and C _max. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48  h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state C _min (plasma concentration obtained 5  min before the last CBZ-SR dose).
Results The model provided good estimates of AUC and C _max for CBZ and CBZE. The bias and the precision of the predicted AUC and C _max for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.
Conclusions The method described here may be used to estimate AUC and C _max for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial

Backgroud  The impact of virologic response on hepatic function has not been previously defined.
Aim  To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) ± ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR).
Methods  Participants ( n  = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24-¹³C]cholate, galactose and ^99mTc-sulfur colloid were administered intravenously; [2,2,4,2-²H]cholate, [1-¹³C]methionine, caffeine and antipyrine were administered orally. Clearances ( Cl ), breath ¹³CO₂, monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured.
Results  Rates of SVR were 18–26% in patients with good function by QLFTs, but ≤6% in patients with poor function. Hepatic metabolism, measured by caffeine k _elim ( P  = 0.02), antipyrine k _elim ( P  = 0.05) and antipyrine Cl ( P  = 0.02) and the portal circulation, measured by cholate Cl _oral ( P  = 0.0002) and cholate shunt ( P  = 0.0003) and PHM ( P  = 0.03) improved after SVR.
Conclusion  Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM.     

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

(−)-Timolol is a more potent antagonist of the positive inotropic effects of (−)-adrenaline than of those of (−)-noradrenaline in human atrium

1 The affinity of (−)-timolol for β₁- and β₂-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol were measured.
2 The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93±0.09 for (−)-adrenaline, 0.97±0.09 for (−)-noradrenaline].
3 The inotropic effects of (−)-adrenaline were antagonized significantly more by each concentration of (−)-timolol than those of (−)-noradrenaline. K _B-values (-log m) were 10.10±0.09 against (−)-adrenaline and 9.43±0.07 against (−)-noradrenaline ( P <0.001).
4 Blocking kinetics of (−)-timolol for the β-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times K _B of (−)-timolol were approximately 30  min for both (−)-adrenaline and (−)-noradrenaline; offset times were similar.
5 It is concluded that (−)-timolol has a higher affinity for the β₂-adrenoceptor than for the β₁-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β₂-adrenoceptor hypersensitivity induced by cardiac β₁-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.     

Apolipoprotein B-associated cholesterol is a determinant of treatment outcome in patients with chronic hepatitis C virus infection receiving anti-viral agents interferon-alpha and ribavirin

Background  Hepatitis C virus (HCV) co-opts very-low-density lipoprotein (VLDL) pathways for replication, secretion and entry into hepatocytes and associates with apolipoprotein B (apoB) in plasma. Each VLDL contains apoB-100 and variable amounts of apolipoproteins E and C, cholesterol and triglycerides.
Aim  To determine whether baseline lipid levels predicted treatment outcome.
Methods  Retrospective analysis was performed of 250 chronic hepatitis C (CHC) patients who had received anti-viral agents interferon-alpha and ribavirin; 165 had a sustained virological response (SVR). Pre- and post-treatment nonfasting lipid profiles were measured and non-high-density lipoprotein (non-HDL) cholesterol (i.e. apoB-associated) was calculated. Binary logistic regression analysis assessed factors independently associated with treatment outcome.
Results  There was an independent association between higher apoB-associated cholesterol (non-HDL-C) and increased odds of SVR (odds ratio 2.09, P  = 0.042). In multivariate analysis, non-HDL-C was significantly lower in HCV genotype 3 (g3) than genotype 1 ( P  = 0.007); this was reversible upon eradication of HCVg3 (pre-treatment non-HDL-C = 2.8 mmol/L, SVR = 3.6 mmol/L, P  < 0.001).
Conclusions  Higher apoB-associated cholesterol is positively associated with treatment outcome in CHC patients receiving anti-viral therapy, possibly due to competition between apoB-containing lipoproteins and infectious low-density HCV lipo-viral particles for hepatocyte entry via shared lipoprotein receptors.     

Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients

Background  Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis.
Aims  To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients.
Methods  A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 μg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively.
Results  Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 ( P  < 0.01). At treatment week 4, 34 patients had undetectable HCV-RNA, 10 with genotype 1/4 and 24 with genotype 2/3. Of RVR patients, 24 achieved SVR (70.5%), 6 and 18 with genotypes 1 and non-1. At the multivariate analysis, only EVR, genotypes 2 and 3, and adherence to full course and dosage of therapy retained their independent predictive power, with corresponding ORs of 25.5 (95% CI 3.0–217.3), 4.2 (95% CI 1.2–15.3) and 9.1 (95% CI 2.2–38.0), respectively.
Conclusion  In decompensated cirrhotic patients, anti-viral therapy with current regimens is feasible and associated with an overall SVR rate of 35.1%. Treatment ought to be pursued among patients who attain an EVR, and maintain a full course and dosage of therapy.     

Clinical trial: individualized treatment duration for hepatitis C virus genotype 1 with peginterferon-alpha 2a plus ribavirin

Background  Individualized treatment regimens, taking into account the heterogeneity of patients with chronic hepatitis C, are needed to improve treatment outcomes.
Aim  To investigate prospectively the period of undetectable viraemia required for a high rate of sustained virological response in patients with chronic hepatitis C genotype 1 and the relationship to early viral kinetics.
Methods  Forty-five chronic hepatitis C genotype 1 patients were given peginterferon-alpha 2a plus ribavirin. Viraemia and hepatocyte HCV-RNA levels were quantified using a TaqMan assay. Beyond the first time point of undetectable viraemia (<20 IU/mL) between baseline and treatment week 12, 32 of 45 (71%) patients were randomized to additional 12 weeks (G12); 24 weeks (G24) or 36 weeks therapy (G36). The remaining 13 patients received 48 weeks' treatment (G48).
Results  The sustained virological response rates were: G12 – five of 11 (45%); G24 – eight of 10 (80%); G36 – eight of 11 (73%); G48 – four of 13 (31%). The anti-viral efficacy (ε) and treatment-induced loss of infected hepatocytes ( M δ), were significantly higher in patients with early viral clearance. In G12, patients with sustained virological response had lower baseline viraemia than those who relapsed.
Conclusions  Early viraemia clearance is a better marker than baseline viral load and differentiates chronic hepatitis C genotype 1 with high or low probability of sustained virological response. In patients with viraemia clearance within 12 weeks of starting peg-interferon/ribavirin therapy, an additional period of undetectable viraemia of minimum 24 weeks is required for high sustained virological response.     

Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B

Background  Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics.
Aim  To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor.
Methods  A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method.
Results  A total of 31 patients were enrolled into the 10 mg ( n  = 10), 30 mg ( n  = 11) and 50 mg ( n  = 10) groups, respectively. At week 12, the median VL change was −3.2, −3.7 and −4.2 log₁₀ copies/mL (−0.64, −0.74 and −0.84 log₁₀ IU/mL) in the 10, 30 and 50 mg groups, respectively ( P  = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound.
Conclusion  Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

H2-receptor antagonists and antacids have an aggravating effect on Helicobacter pylori gastritis in duodenal ulcer patients

Background : Antacids, such as aluminium–magnesium hydroxide (AlMg(OH)₃), or H₂-receptor antagonists, such as ranitidine, are common drugs used for treating peptic ulcer disease and acid-related symptoms.
Methods : In a prospective double-blind controlled study, 174 patients were randomized to a 4-week course of treatment with either AlMg(OH)₃ (acid-binding capacity: 280 mval/day) or ranitidine 300 mg for active Helicobacter pylori -associated duodenal ulcers (as determined by histology and the urease test). Before and after treatment, two biopsy specimens each were obtained from the antrum and corpus, and the grade and activity of gastritis, as well as H. pylori density, were determined using a score ranging from 0 = none to 4 = severe.
Results : Pre- and post-treatment histology were available for 138 patients (AlMg(OH)₃: 67, ranitidine: 71). Treatment with AlMg(OH)₃ significantly increased the activity of corpus gastritis (Wilcoxon signed-rank: P  = 0.0014), while ranitidine treatment significantly increased both the grade and activity of corpus gastritis ( P  = 0.0002 and P  = 0.0001 respectively). In the antrum, both regimens provoked a significant increase in the frequency of intestinal metaplasia, but this may be a consequence of sampling error.
Conclusions : Ranitidine and AlMg(OH)₃ have an aggravating effect on H. pylori gastritis in duodenal ulcer patients. This should be considered a side-effect of the respective drugs and is more pronounced with ranitidine.     

Clinical trial: low plasma cholesterol and oxidative stress predict rapid virological response to standard therapy with peginterferon and ribavirin in HCV patients

Background  Rapid virological response (RVR) is the best predictor of sustained response to standard HCV treatment.
Aim  To evaluate predictive factors of RVR.
Methods  Sixty-five patients (mean age 52.6 ± 13.8; 37 genotype-1, and 28 genotypes-2/3) were consecutively treated with pegIFN-alpha2a or 2b once weekly plus daily ribavirin based on body weight for 24 or 48 weeks, according to genotype. RVR was defined as undetectable HCV-RNA at week 4.
Results  Twenty-seven percent of patients achieved RVR in genotypes 1 and 60.7% in genotypes 2/3 ( P  < 0.01). Rapid responders had higher mean serum baseline total and LDL-cholesterol levels ( P  < 0.01). RVR was 20.0% in the bottom tertile of total cholesterol and 63.6% in the top tertile ( P  < 0.01). HCV-RNA levels at week 4 were positively correlated with baseline serum insulin ( P  < 0.01), HOMA-IR ( P  < 0.01), body mass index ( P  < 0.05) and number of components of metabolic syndrome ( P  < 0.01) and negatively correlated with cholesterol levels ( P  < 0.05). At multivariate analysis, age, LDL-cholesterol, HCV genotype and serum 8-iso-PGF2alpha, a marker of oxidative stress, were independent predictors of RVR.
Conclusions  Our prospective study supports a role of low serum total and LDL-cholesterol and of oxidative stress as positive independent predictive factors of poor RVR in HCV patients.     

Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers

Aims To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in  healthy female volunteers.
Methods This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50  μg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16  days of every 12  h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48  h after each dose and for plasma ritonavir on Day 29 at 0 and 4  h postdose.
Results Statistically significant decreases in ethinyl oestradiol mean C _max (−32%) and mean AUC (−41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17  h to 13  h during concomitant ritonavir. No statistically significant change was noted in t _max. The ratios of means (95% confidence intervals) for C _max and AUC were 0.682 (0.612–0.758) and 0.595 (0.506–0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450  hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4  μg  ml⁻¹ were observed at 0 and 4  h postdose, respectively.
Conclusions Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.