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Biomedical subjects

Yves Horsmans

Publications and source records attributed to Yves Horsmans.

At least 37 records · Page 2Linked to original sources
PubMed2005

CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population.

The genetically polymorphic cytochrome P450 2C9 (CYP2C9) metabolizes many important drugs. Among them, phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and p-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 h. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH [defined as urinary volumex(S)-p-HPPH urinary concentration] and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), both markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in the genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra test). Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, analysis of variance (ANOVA) and P<0.0001, Kruskal-Wallis test, respectively) and decreased in the order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8 and CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r=0.08, P=0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r=0.21, P=0.001 and r=0.25, P<0.001, respectively). Furthermore, significant relation was found between urinary excretion of (R)-p-HPPH and CYP2C9 genotype (P=0.035) and levels significantly increased in the genotype order: CYP2C9*1/*9, CYP2C9*1/*1, CYP2C9*9/*11, CYP2C9*1/*8 and CYP2C9*1/*5 (P<0.001, Jonckheere-Terpstra test). In summary, the present study demonstrates that, in a Black population, CYP2C9*5, *6, *8 and *11 variants, but not CYP2C9*9, are associated with a decreased phenytoin metabolism. The data also confirm the limited contribution of MDR1 gene to inter-individual phenytoin pharmacokinetic variation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Alfentanil-induced miosis clearance as a liver CYP3A4 and 3A5 activity measure in healthy volunteers: improvement of experimental conditions.

The aims of this study were to demonstrate the correlation between alfentanil-induced miosis evaluation and alfentanil pharmacokinetics (PK) as a CYP3A4 and 3A5 activity probe in volunteers and to explain the variability in pupilar response and in alfentanil PK. In ambient light, the miosis kinetic parameters were significantly correlated with PK (CLs: r = 0.9, P = .00; AUCs: r = 0.8, P = .01). In dark, a similar correlation was observed between miosis and alfentanil clearances (r = 0.85, P = .03). In 6 volunteers, the sigmoid E(max) model was applicable (average E(max) = 2.5 +/- 0.7 mm, gamma = 2.5 +/- 1.6 and EC(50) = 76.8 +/- 22.3 ng/mL), and in 3, the simple E(max) model was applicable (average E(max) = 2.8 +/- 0.3 mm and EC(50) = 19.9 +/- 8.5 ng/mL). There was a large interindividual variability in PK parameters (coefficient of variation = 19.7%-31.2%). Free drug fraction concentrations were negatively correlated with plasma alpha(1)-AGP (r = -0.9, P = .04) and albumin levels (r = -0.94, P = .02). Alfentanil-induced miosis clearance as a noninvasive CYP3A4 and 3A5 activity measure can be done in both ambient and dark conditions. Drug free fraction may be responsible for large intersubject variability in alfentanil PK.

Adult↗
PubMed2004

Identification and functional analysis of two rare allelic variants of the thiopurine S-methyltransferase gene, TPMT*16 and TPMT*19.

Human thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. TPMT is genetically polymorphic and is associated with large interindividual variations in thiopurine drug toxicity and therapeutic efficacy. During routine genotyping of patients with Crohn's disease, one novel missense mutation, 365A>C (TPMT*19, Lys(122)Thr), and a recently described missense mutation, 488G>A (TPMT*16, Arg(163)His), were identified in a Caucasian and a Moroccan patient, respectively. Using a heterologous yeast expression system, kinetic parameters (K(m) and V(max)) of the two variants with respect to 6-thioguanine S-methylation were determined and compared with those obtained with the wild-type enzyme. The Lys(122)Thr exchange did not significantly decrease the intrinsic clearance value (V(max)/K(m)) of the variant enzyme. In contrast, the Arg(163)His substitution significantly decreased the intrinsic clearance value by three-fold. The Arg(163) is located in a highly conserved region of the human TPMT protein and, as such, the Arg(163)His substitution is expected to result in a marked reduction of enzyme activity, as confirmed by the in vitro data. Phenotyping by measurement of red blood cell TPMT activity indicated that the patient heterozygous for the Lys(122)Thr mutation had normal TPMT activity, whereas the patient heterozygous for the Arg(163)His mutation was an intermediate methylator, which demonstrated a positive correlation between TPMT phenotyping and the in vitro data. The identification of a novel non-functional allele of the TPMT gene improves our knowledge of the genetic basis of interindividual variability in TPMT activity. These data further enhance the efficiency of genotyping methods to predict patients at risk of an inadequate response to thiopurine therapy.

Alleles↗
PubMed2004

Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation.

Hepatic epithelioid haemangioendotheliomas (HEHEs) are rare, low-grade vascular tumours. Five adults with HEHEs and one adult with a vascular tumour showing combined features of haemangioma and haemangioendothelioma underwent liver transplantation. Two HEHE patients had extrahepatic metastases at the time of transplantation. Median survival time following diagnosis was 10.7 years (range 40 months to 195 months). One patient needed resection of a HEHE in the breast 13 years post-transplantation. All six patients are surviving free from disease 22 to 166 months after transplantation (median 77 months). One HEHE-patient who had been treated for 8 years for vertebral and cerebral localisations is free of disease without immunosuppression 56 months after transplantation. We can conclude that liver transplantation is a valuable treatment for hepatic haemangioendothelioma, even in cases of extrahepatic localisation of the disease.

Adult↗
PubMed2004

Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans.

UNLABELLED: Background and aim Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9*5, *6, *8, and *11 polymorphisms in vivo has not been investigated previously in humans. METHODS: A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9*1/*1 (n = 9), *1/*5 (n = 1), *1/*6 (n = 1), *1/*8 (n = 2), *1/*11 (n = 3), *5/*6 (n = 1), *5/*8 (n = 1), and *8/*11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. RESULTS: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9*1/*1, 14.6 for CYP2C9*1/*5, 4.2 for CYP2C9*1/*6, 188 for CYP2C9*5/*6, 11.6 for CYP2C9*5/*8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9*1/*8, 2.2 for CYP2C9*8/*11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9*1/*11. Compared with the CYP2C9*1/*1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9*5 allele carriers (CYP2C9*1/*5, CYP2C9*5/*8, and CYP2C9*5/*6 genotypes) (P =.01, Mann-Whitney) but was not different in CYP2C9*1/*8 (P =.16) and CYP2C9*1/*11 (P =.11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0-18). CONCLUSIONS: The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects.

Administration, Oral↗
PubMed2004

Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice.

BACKGROUND/AIMS: While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis. METHODS: Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed. RESULTS: MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression. CONCLUSIONS: Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Animals↗
PubMed2004

Molecular mechanisms of apoptosis in the liver of rats after portal branch ligation with and without retrorsine.

The mechanisms accounting for the atrophy of the portal blood-deprived liver lobes after portal branch ligation (PBL) are still unclear. The first aim of this study was to confirm the role of apoptosis in this process and to determine which apoptotic pathways are involved. The second aim of the study was to evaluate the effect of blocking compensatory hyperplasia of the nonligated lobes with retrorsine on the mechanisms of apoptosis in the ligated lobes. Mitochondrial Bax, Bcl-2 and Bcl-X(L), cytosolic cytochrome c, caspase-3, -8 and -9 activities and TNF-alpha levels were assessed in the liver of rats before and at various time points, ranging from 30 min to 7 days, after PBL. Caspase activities were also measured in rats pretreated with retrorsine. Both the mitochondrial and the death receptor-mediated pathways are activated in the ligated liver lobes after portal branch ligation. Caspase activation is inhibited by retrorsine pretreatment, resulting in fewer apoptotic bodies. Apoptosis accounts for the atrophy of the ligated lobes after PBL. It is inhibited by retrorsine, suggesting an attempt to reduce the loss of liver mass when hyperplasia of the nonligated lobes is impaired

Animals↗
PubMed2003

Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension.

PURPOSE: To determine the correlations between hemodynamic parameters of hepatic flow measured with magnetic resonance (MR) imaging and Doppler ultrasonography (US) and the severity of cirrhosis and portal hypertension. MATERIALS AND METHODS: Forty-six patients referred for measurements of portal venous pressure (three with normal liver, 12 with chronic hepatitis, and 31 with cirrhosis [10 with Child-Pugh class A cirrhosis; 13 with class B cirrhosis; and eight with class C cirrhosis]) were included in the study. Apparent liver perfusion, apparent arterial and portal perfusion, portal fraction, distribution volume, and mean transit time were measured with dynamic contrast material-enhanced MR imaging. Portal velocity, portal flow, congestion index, right hepatic artery resistance index, and modified hepatic index were measured with Doppler US. Results in patients with cirrhosis and those without cirrhosis were compared with the Wilcoxon rank sum test. Correlations were assessed with Spearman rank correlation coefficients. RESULTS: With MR imaging, all flow parameters except distribution volume were significantly different between patients with and those without cirrhosis (P <.05). There was a significant correlation between all flow parameters measured with MR imaging and portal pressure (P <.02). Apparent arterial (P =.024) and portal (P <.001) perfusion, portal fraction (P <.001), and mean transit time (P =.004) were correlated with Child-Pugh class. Flow parameters measured with Doppler US did not differ significantly between patients with and those without cirrhosis. Only right hepatic arterial resistance (P <.007) and portal flow (P <.043) were weakly (r < 0.7) correlated with portal pressure. No Doppler US parameter was correlated with Child-Pugh class. CONCLUSION: Hepatic flow parameters measured with MR imaging correlate with the severity of cirrhosis and portal hypertension. Doppler US parameters are only weakly correlated with portal pressure.

Adolescent↗
PubMed2003

Glycogenosis storage type I diseases and evolutive adenomatosis: an indication for liver transplantation.

We report on two cases of type I glycogen storage disease (GSD) complicated by malignant tumors. A 23-year-old man had GSD Ia with adenomatosis. He underwent transplantation for rapidly growing and radiologically changing adenomata. At histological examination, one adenoma had become a hepatocellular carcinoma. A 22-year-old, HBV-infected woman had GSD type Ib with adenomatosis. At follow-up, several tumors showed changing morphological characteristics. Pre-transplant laparotomy confirmed the presence of a metastatic cholangiocarcinoma. Liver transplantation should be considered in GSD type I patients with adenomatosis, especially when tumor characteristics change. Regular detailed Doppler ultrasound and magnetic nuclear resonance screening during childhood and adolescence are, therefore, mandatory in order for the timing of transplantation to be optimized.

Adenoma, Liver Cell↗
PubMed2003

Cytochrome P4502E1 (CYP2E1) expression in peripheral blood lymphocytes: evaluation in hepatitis C and diabetes.

OBJECTIVE: Cytochrome P4502E1 (CYP2E1) is expressed in human peripheral blood lymphocytes (PBLs), and previous reports have suggested the possibility of using this readily available tissue as a reporter of CYP2E1 status. To further explore the relevance of this approach we assessed CYP2E1 expression in PBLs in two contrasting conditions, chronic hepatitis C and insulin-dependent diabetes (IDD), illustrating an organ and a systemic disease, respectively. METHODS: Total RNA was isolated from extracted PBLs (hepatitis C patients + IDD) and by percutaneous needle biopsy (hepatitis C patients only). Gene expression for CYP2E1 was determined by real-time reverse-transcription polymerase chain reaction. Histological changes in liver tissue were assessed according to Ludwig's criteria. RESULTS: In patients with chronic hepatitis C a clear relationship was found between CYP2E1 expression in the liver and the progression of hepatic disease (both lobular inflammation and fibrosis indices), and observed variations were consistent with the preferential distribution of CYP2E1 in the lobular zone. No effect of the liver disease was, however, found at the PBL level. A statistically significant increase in mean CYP2E1 expression level was observed in the lymphocytes from poorly controlled IDD subjects compared to controls. CONCLUSIONS: Taken together, our data indicate that the measurement of CYP2E1 expression in PBLs is not useful in liver diseases. However, in a systemic condition (IDD) this measurement can be proposed for monitoring the CYP2E1 induction in a relatively noninvasive manner. This tool should therefore be further validated in clinical field or experimental studies for CYP2E1 phenotyping purposes.

Case-Control Studies↗
PubMed2003

Capillarization of the sinusoids in liver fibrosis: noninvasive assessment with contrast-enhanced MRI in the rabbit.

Sinusoidal capillarization induces microcirculatory changes in liver cirrhosis and fibrosis. The purpose of this study was to assess whether contrast-enhanced MRI can be used to demonstrate the effects of sinusoidal capillarization in liver fibrosis. Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA), and two high-molecular-weight contrast agents of 6.47 kDa and 52 kDa (P792 and P717) was performed in rabbits with liver fibrosis induced by cholesterol and diethylstilbestrol. The hepatic distribution volume accessible to the high-molecular-weight agents decreased in the rabbits with liver fibrosis (P792: 7.8% +/- 1.7% vs. 10.1% +/- 1.8% in normal rabbits, P =.038; P717: 6.2% +/- 2.1% vs. 9.7% +/- 1.6% in normal rabbits, P =.007), whereas the hepatic mean transit time (MTT) of the low-molecular-weight agent was increased (15.9 +/- 8.0 s vs. 8.8 +/- 2.6 s in normal rabbits, P =.015). In rabbits with liver fibrosis, the clearance of indocyanine green (ICG) was correlated with the volume accessible to the high-molecular-weight agents (P792: r = 0.810, P =.015; P717: r = 0.857, P =.007). The collagen content of the liver was inversely correlated with the distribution volume of P717 (r = -.833, P =.010) and with the ICG clearance (r = -.810, P =.015). It was concluded that the microcirculatory changes induced by sinusoidal capillarization in liver fibrosis can be demonstrated noninvasively with MRI.

Animals↗
PubMed2003

Expression and DNA-binding activity of signal transducer and activator of transcription 3 in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans.

In rats, activation of the cytokine-inducible transcription factor signal transducer and activator of transcription 3 (Stat3) is impaired in the liver after ethanol administration. The aim was to examine Stat3 expression, localization, and activity in alcoholic liver disease (ALD) in humans. Explanted livers of ALD patients were compared to normal and primary biliary cirrhosis livers. Protein expression, DNA-binding, and subcellular localization of Stat3 was examined by Western blotting, electrophoretic mobility shift assays, and immunohistochemistry; and interleukin-6, Stat3, and suppressor of cytokine signaling (SOCS)-3 mRNA expression by quantitative polymerase chain reaction. Stat3 proteins increased markedly in ALD, mainly in hepatocyte and proliferating biliary epithelial cell nuclei. In contrast to normal and primary biliary cirrhosis livers where Stat3 DNA-binding occurred normally, no Stat3 DNA-binding complexes were observed in ALD, although the tyrosine and serine phosphorylation of Stat3 was not altered. Elevated interleukin-6 mRNA was found in ALD whereas Stat3 and suppressor of cytokine signaling-3 mRNA levels were decreased. Although end-stage ALD is characterized by up-regulation of Stat3 proteins, this transcription factor appears to be functionally inactive. Furthermore, decreased transcription of the Stat3 gene in ALD might also affect cytoplasmic reserves of inactivated Stat3 in the long term. Impaired activation and restoration of Stat3 might thus contribute to the development of cell damage leading to liver cirrhosis in ALD.

Acute-Phase Proteins↗
PubMed2003

Retrorsine: a kinetic study of its influence on rat liver regeneration in the portal branch ligation model.

BACKGROUND: Retrorsine, a naturally occurring pyrrolizidine alkaloid, impairs liver regeneration after partial hepatectomy by mechanisms that are still unclear. AIM: The aim of the study was to clarify the influence of retrorsine on cell cycle progression in the regenerating liver lobes of rats after portal branch ligation (PBL). METHODS: Liver weight, protein and DNA contents, DNA synthesis (5'-bromodeoxyuridine (BrdU) incorporation) and cellular levels of Cyclin E, CDK-2, CDK-4 and proliferating cell nuclear antigen (PCNA) were assessed before and 24, 48, 72 and 168 h after PBL. RESULTS: Before surgery, higher levels of cyclin E, CDK-2, CDK-4 and PCNA as well as BrdU incorporation were found in the liver of retrorsine-treated rats than in untreated rats. Liver weight gain, protein and DNA synthesis as well as induction of cell cycle related proteins were all strongly impaired by retrorsine in the regenerating lobes after PBL. CONCLUSIONS: In conclusion, retrorsine impairs liver regeneration in the PBL model not only by an S or G2/M phase block, but also by a block located before the G1/S transition of the cell cycle.

Animals↗
PubMed2003

Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats.

BACKGROUND/AIMS: Pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood. Cytochrome P450 2E1 (CYP 2E1), cytokines, oxidative stress and activation of hepatic stellate cells seem to play a role in this process. The aim was to determine the potential implication of these factors in the progression from uncomplicated steatosis to steatohepatitis with progressive fibrosis. METHODS: Animals were fed a standard diet, a 5% orotic acid-diet (OA) developing hepatic steatosis, or the methionine-choline deficient (MCD) diet inducing steatohepatitis for 2 and 6 weeks. Lipid peroxidation, CYP 2E1 expression and activity, expression of UCP-2, interleukin (IL)-6, transforming growth factor (TGF)beta1, KLF6 mRNAs, and activation of hepatic stellate cells were examined by gas chromatography, high-performance liquid chromatography, Western blotting, quantitative polymerase chain reaction and immunohistochemistry. RESULTS: Lipid peroxidation increased in the MCD model whereas only minor changes occurred in the OA model. KLF6 and TGFbeta1 mRNAs were selectively up-regulated in MCD animals. Stellate cell activation, inflammation and collagen deposition only occurred in the MCD group. CYP 2E1 expression and activity increased in the OA group while both decreased in MCD animals. UCP-2 and IL-6 mRNA increased in both groups. CONCLUSIONS: In the context of steatosis, lipid peroxidation is associated with inflammation and stellate cell activation with concomitant increase in TGFbeta1 production, possibly through up-regulation of KLF6.

Actins↗
PubMed2003

Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations.

AIMS: To investigate the distribution of cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) genotype frequencies in the Beninese and Belgian Caucasian populations. METHODS: Beninese (n = 111) and Belgian (n = 121) were genotyped for CYP2C9*2, *3, *4, *5, and *11 as well as for CYP2C19*2 and*3. RESULTS: The distribution of alleles was: CYP2C9*1: 95.5 vs. 82.2% (P < 0.001); CYP2C9*2: 0 vs. 10% (P < 0.001); CYP2C9*3: 0 vs. 7.4% (P < 0.01); CYP2C9*4: both 0%; CYP2C9*5: 1.8 vs. 0% (P = 0.05); and CYP2C9*11: 2.7 vs. 0.4% (P < 0.05). The frequencies of the CYP2C19*2 allele were 13 vs. 9.1%, respectively. CYP2C19*3 was not detected in either population. The 95% confidence intervals for the differences of frequencies of CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*11, CYP2C19*1, CYP2C19*2 and CYP2C19*3 between Belgian and Beninese were 7%, 19%; - 14%, - 6%; - 11%, - 4%; - 1%, 1%; 0%, 4%; 0%, 5%; - 10%, 2%; - 2%, 10%; - 1%; respectively. The distributions of CYP2C9 genotypes in the Beninese and Belgian individuals were: CYP2C9*1/*1: 91 vs. 67% (P < 0.00001); CYP2C9*1/*2: 0 vs. 18.2% (P < 0.0001); CYP2C9*1/*3: 0 vs. 11.6% (P < 0.001); CYP2C9*1/*5: 3.6 vs. 0% (P = 0.05); CYP2C9*1/*11: 5.4 vs. 0.8% (P = 0.05); CYP2C9*2/*3: 0 vs. 1.6% (NS); CYP2C9*3/*3: 0 vs. 0.8% (NS). The distributions of CYP2C19 genotypes between these ethnic groups were: CYP2C19*1/*1: 73.9 vs. 83.5% (NS); CYP2C19*1/*2: 26.1 vs. 14.9% (P < 0.05); CYP2C9*2/*2: 0 vs. 1.6% (NS). CONCLUSIONS: Differences of allele frequencies between Beninese and Belgian populations were statistically significant for CYP2C9*2, *3, *5 and *11, but not for CYP2C9*4 or for CYP2C19*2 and *3.

Adult↗
PubMed2003

A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C.

New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 mug of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P < or =.01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study.

Alanine Transaminase↗
PubMed2003

Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites.

BACKGROUND AND OBJECTIVES: Atomoxetine is a treatment for attention-deficit/hyperactivity disorder and is primarily eliminated via cytochrome P4502D6 (CYP2D6). The pharmacokinetics of atomoxetine and its primary metabolites were investigated in 10 adults with hepatic impairment (6 moderate, 4 severe) and 10 age- and sex-matched control subjects, all being genotyped as CYP2D6 extensive metabolizers. METHODS: A single oral 20-mg dose of atomoxetine was given. Multiple blood samples were collected for 48 hours in healthy subjects and for 120 hours in patients. Urine was collected up to 24 hours. Before atomoxetine administration (10-20 days), sorbitol clearance and debrisoquin (INN, debrisoquine) metabolic ratio were determined as markers of hepatic blood flow and CYP2D6 activity, respectively. RESULTS: The systemic clearance of atomoxetine was significantly reduced in those with hepatic impairment compared with controls, thereby resulting in increased exposure (area under the concentration-time curve from time 0 to infinity, 1.58 versus 0.85 microg. h(-1). mL(-1); P =.035) but no change in maximum concentration. Mean 4-hydroxyatomoxetine area under the concentration-time curve from time 0 to time t and maximum concentration were increased approximately 7-fold and 2-fold, respectively (P =.0001 and P =.0056, respectively). For the glucuronide conjugate of 4-hydroxyatomoxetine, the mean half-life was longer and the mean area under the concentration-time curve from time 0 to infinity and the maximum concentration were lower (P =.0028, P =.003, and P =.0001, respectively). The sorbitol clearance was lower and the debrisoquin metabolic ratio was higher, reflecting reduced hepatic blood flow and decreased CYP2D6 activity, respectively. Decreased atomoxetine clearance in patients with hepatic impairment was clearly correlated with decreased CYP2D6 activity and decreased hepatic blood flow. Mean atomoxetine plasma protein binding was lower in patients with hepatic impairment compared with controls (96.5% versus 98.7%, P =.0008). Atomoxetine was well tolerated in the 2 populations. CONCLUSION: For patients with attention-deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.

Administration, Oral↗