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Y Horsmans

Publications and source records attributed to Y Horsmans.

At least 127 records · Page 7Linked to original sources
PubMed1992

Absence of CYP3A genetic polymorphism assessed by urinary excretion of 6 beta-hydroxycortisol in 102 healthy subjects on rifampicin.

A previous study has demonstrated that the urinary level of 6 beta-hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 beta-hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 beta-hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 beta-hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for cortisol 6 beta-hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme of this family.

17-Hydroxycorticosteroids↗
PubMed1991

Lecithin: cholesterol acyltransferase activity in familial hypercholesterolemia treated with simvastatin and simvastatin plus low-dose colestipol.

In 19 patients with heterozygous familial hypercholesterolemia (FH), the effects of simvastatin (S) 20 mg/d, 40 mg/d, and 40 mg/d plus low-dose colestipol (10 g/d) on plasma lipids, plasma lipoproteins, and plasma lecithin: cholesterol acyltransferase (LCAT) activity were investigated after an original dose-range escalation/descalation design. The drug regimen was changed every 8 weeks. A significant reduction in total cholesterol and LDL-cholesterol was observed, reaching 39% and 54% for the drug combination (week 28), and total apoprotein B and LDL-apoprotein B were reduced by 39% and 50%, respectively. Triglycerides were significantly lowered by S alone (up to 29% with 40 mg/d). HDL-cholesterol increased during therapy but the cholesterol content in HDL2-HDL3 fractions (isolated by ultracentrifugation) did not change significantly during the different steps. The ratio LDL-C/HDL-C fell by 57% at week 28. Plasma LCAT activity expressed as FER was significantly enhanced by S alone (+33%), and a further increase on drug combination regimen (+58%) was observed. This effect could be considered as a consequence of the increased fractional clearance of LDL-C. It tended to be sustained during the descalation part of the study. Biochemical adverse effects were scarce and transient. In conclusion, the combination therapy increased the plasma LCAT/FER activity without a preferential enhancement in HDL2-C concentration. This original design allowed to define the most appropriate individual cholesterol-lowering drug dosage in FH patients.

Adolescent↗
PubMed1991

Is there a link between debrisoquine oxidation phenotype and lung cancer susceptibility?

A link between debrisoquine oxidation phenotype and lung cancer susceptibility has been evoked by some authors but not confirmed by others. For this reason, we compared the frequency of debrisoquine poor metabolizer phenotype in 91 Belgian patients with lung cancer to that studied in 167 healthy Belgian subjects. No significant difference was observed in our study. These results do not support the existence of this link.

Adult↗
PubMed1991

Lack of effect by nifedipine on hepatic mixed function oxidase in man.

Nifedipine (NF), a calcium channel blocker, is often prescribed in association with other drugs. Therefore, it was interesting to know whether or not, nifedipine, which is metabolized by the cytochrome P-450NF, was able to induce or to inhibit in vivo the activity of the hepatic mixed function oxidase system. The study was conducted in ten young healthy male volunteers receiving 20 mg NF slow release bid for 15 days. Due to the small number of subjects, comparison of the NF pharmacokinetics at dose 1 and 26 failed to show a bimodality in the frequency distribution of its area under the plasma concentration-time curve (AUC 274.5 to 317.1 ng ml-1 h, NS). Hepatic microsomal autoinduction (t1/2 2.87 to 3.06 h, NS) was not found. No statistically significant effect was seen on the aminopyrine breath test and on the debrisoquine metabolic molar ratio performed before and at the end of the treatment. Unlike what has been suggested by in vitro studies, NF treatment did not modify significantly the urinary excretion of 6 beta-hydroxycortisol (318 to 265 micrograms/d, NS). After the last dose, the total oral clearance of NF was highly correlated with the metabolic clearance to 4-hydroxyantipyrine (r = 0.88; P = 0.005) but the other parameters of antipyrine biotransformation remained unchanged. We conclude that repeated nifedipine oral intake does not modify enzymatic activities of hepatic P-450 cytochromes involved in the biotransformation of antipyrine, aminopyrine, debrisoquine and cortisol.

Adult↗
PubMed1991

Reversible cholestasis with bile duct injury following azathioprine therapy. A case report.

A 67-year-old patient, with primary polymyositis and without previous evidence of liver disease, developed clinical and biochemical features of severe cholestasis 3 months after initiation of azathioprine therapy. Liver biopsy showed cholestasis with both cytological and architectural alterations of interlobular bile ducts. Azathioprine withdrawal resulted after 7 weeks in the resolution of clinical and biochemical abnormalities. It is believed that this is the first reported case of reversible azathioprine-induced cholestasis associated with histological evidence of bile duct injury.

Azathioprine↗
PubMed1991

Nilutamide inhibits mephenytoin 4-hydroxylation in untreated male rats and in human liver microsomes.

1. The effects of nilutamide (an anti-androgen with a hydantoin moiety) on the 4-hydroxylation of mephenytoin were studied in rat liver microsomes. Nilutamide, at a concentration expected in human liver (100 microM) during prolonged administration of nilutamide, inhibited by 40% mephenytoin (0.3 mM) 4-hydroxylase activity in liver microsomes from untreated male rats, but not in microsomes from untreated female rats, or in microsomes from dexamethasone-treated male or female rats. 2. Administration to male rats of nilutamide, in doses (20 mg/kg i.p. twice daily) known to reproduce plasma concentrations observed in human therapeutics, decreased by 60% the 24 h urinary excretion of 4-hydroxymephenytoin after administration of mephenytoin (15 mg/kg oral). 3. Nilutamide (100 microM) markedly inhibited mephenytoin 4-hydroxylase activity in human liver microsomes. Inhibition kinetics were consistent with mixed inhibition. It is concluded that nilutamide inhibits mephenytoin 4-hydroxylase activity in untreated male rats and in human liver microsomes. It is suggested that inhibition is likely to occur in vivo in humans receiving therapeutic doses of nilutamide.

Androgen Antagonists↗
PubMed1991

[Atrium-related hepatitis. Report of four cases].

Four patients developed acute hepatitis after receiving Atrium, an association of phenobarbital, febarbamate and difebarbomate, for the treatment of tremor or for the prevention of alcohol withdrawal symptoms. Hepatitis occurred 1 to 3 months after treatment. Asthenia was the unique clinical manifestation. Marked increase in serum aminotransferases and gamma-glutamyltranspeptidase levels were the main biological features. Histological examination showed liver cell necrosis in two cases, prominent in the centrolobular area in one case. There was no case of hepatic failure. Atrium withdrawal was followed by complete recovery within 6 to 12 weeks. The mechanism of Atrium hepatotoxicity remains unknown.

Aged↗
PubMed1991

Pharmacogenetics of human erythrocyte thiopurine methyltransferase activity in a French population.

1. A genetic polymorphism in human erythrocyte thiopurine methyltransferase activity (RBC TPMT) resulting in a trimodal phenotypic distribution has been demonstrated both in a North American population and in British children. 2. We studied whether such a polymorphism may be also present in a white French population by testing RBC TPMT activity in 303 randomly selected blood donors. 3. We found a large inter-individual variation in RBC TPMT activity which ranged from 2 to 40 nmol ml-1 packed RBC h-1, with a mean value of 15.4 +/- 7.0 nmol ml-1 packed RBC h-1. The enzyme activity was not significantly influenced by the sex and age of the subjects. 4. In our population sample, we found no subject with undetectable enzyme activity. However, the probit plot of the log RBC TPMT activity showed a highly significant change in slope at a TPMT activity of 7.5 nmol ml-1 packed RBC h-1. Thirty four subjects (11% of our population) had TPMT activities below 7.5 nmol ml-1 packed RBC h-1. 5. These data are consistent with the view that the genetic polymorphism of TPMT activity described in populations from North America and the United Kingdom is also present in a French population, with about 89% of subjects exhibiting a high activity and 11% an intermediate activity.

Adult↗
PubMed1990

Biochemical changes and morphological alterations of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor).

Simvastatin is a potent competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) which is the rate-limiting enzyme of cholesterol synthesis. In guinea-pigs, administration of a high oral dose of simvastatin (125 mg/kg/day at the beginning of the study) during 18 days had a major hepatotoxic effect whereas a lower oral dose (30 mg/kg/day) did not seem to cause any liver damage. A significant reduction in microsomal Cyt P 450 content was only observed on a high dose of simvastatin whereas HMG CoA reductase activity was reduced in the group with the low simvastatin dose. The hepatic microsomal aminopyrine N-demethylase activity remained unchanged in all groups. The liver lesion was hepatocellular necrosis accompanied in some animals by a biliary duct proliferation. It was associated with a 10-fold elevation in serum aspartate and alanine aminotransferase activities, as well as a great reduction in daily food intake and body weight (28%). The hepatotoxicity of simvastatin could result from the low basal content of HMG-CoA reductase in guinea-pig liver, the prolonged inhibition of mevalonate synthesis and probably, from the absence of HMG-CoA reductase enzyme de novo synthesis.

Aminopyrine N-Demethylase↗
PubMed1990

[Sensitivity and specificity of the determination of urinary catecholamines and their acid metabolites in the diagnosis of neuroblastoma in children].

A retrospective comparison of urinary excretion of norepinephrine, epinephrine, dopamine and/or their acidic metabolites, HVA and VMA, in 36 children with neuroblastoma versus 360 hospitalized children without neuroblastoma showed a sensibility of 72% and a specificity of 98% for HVA and 80% and 97% for VMA respectively. Consequently, the sensibilities and specificities of these 2 determinations confirm their useful purpose for the biochemical diagnosis of neuroblastoma in preference to the determinations of norepinephrine, epinephrine and dopamine.

Adolescent↗
PubMed1989

Influence of rifampicin, phenobarbital and cimetidine on mixed function monooxygenase in extensive and poor metabolizers of debrisoquine.

The effect of enzyme induction by rifampicin and phenobarbital and enzyme inhibition by cimetidine on the hepatic mixed-function monooxygenase (MFO) was investigated in 11 non-smokers, healthy male volunteers. Five were classified as extensive metabolizers (EM) of debrisoquine and 6 as poor metabolizers (PM). Rifampicin (600 mg/day), phenobarbital (100 mg/day) and cimetidine (1.2 g/day) were given for 8, 14 and 4 days, respectively. In PM on rifampicin, the debrisoquine metabolic ratio (MR) was significantly reduced, even reaching a value less than 12.6 in 2 subjects but on phenobarbital and cimetidine, the MR was not significantly modified. In PM on rifampicin and phenobarbital, the urinary excretion of 6 beta-hydroxycortisol was significantly enhanced but not in EM on these drugs. In both groups on cimetidine, salivary antipyrine half-life was lengthened and on rifampicin, it was shortened. In EM and PM on cimetidine, the total oral clearance of antipyrine was lowered but on rifampicin it was solely increased in PM. Regarding the metabolic clearance to the three main urinary antipyrine metabolites, that of norantipyrine (NORA) was significantly increased in PM on rifampicin. In PM on cimetidine, the metabolic clearance of NORA and hydroxymethylantipyrine (HMA) was reduced but in EM that of hydroxyantipyrine was additionally decreased. In PM on rifampicin, the induction of the hepatic mixed-function oxidase system, assessed by the urinary excretion of 6 beta-hydroxycortisol, the salivary antipyrine half-life and total oral clearance and the metabolic clearance of urinary NORA, were shown. On the other hand in PM, cimetidine, a probe drug used for inhibition of the MFO system, made it impossible to distinguish PM from EM.

Adult↗
PubMed1984

Role of dietary iron in maturation of rat small intestine at weaning.

The weanling process is characterized by the transition from a liquid diet poor in iron (rat milk) to a solid diet high in iron (chow pellets). To examine the effects of iron content of the weanling diet on terminal maturation of rat small intestine, suckling pups, nursed by iron-sufficient mothers, were weaned by day 16 onto a solid basal diet that was either deficient [low-iron diet (LID): 0.5 mg iron/100 g solid] or high [high-iron diet (HID) controls: 30 mg iron/100 g solid] in iron. The animals were studied during or at the end of the 4th postnatal wk. By day 17 rats weaned onto the LID exhibited an initial rise in jejunal sucrase activity as did their controls, but the activity plateau of the enzyme was reduced to a level 60% of the controls. On day 28 iron-deprived rats were anemic and showed significant decreases (P less than 0.01 compared with HID rats) in the activity of jejunal sucrase (-57%), neutral lactase (-83%), and maltase (-46%), whereas villus height, crypt depth, mucosal mass parameters, ileal acid beta-galactosidase activity, mucosal protein, and DNA synthesis rates were equivalent in LID and HID groups. The concentration of the secretory component, a glycoprotein synthesized by the intestinal crypt cell, was markedly depressed (P less than 0.01 vs. controls) in the jejunum (-54%) and ileum (-79%) of iron-deprived rats. When D-[1-14C]glucosamine was injected intraperitoneally, incorporation of the label into jejunal and ileal brush-border proteins was two to three times lower for iron-deficient rats than for controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of simvastatin and pravastatin on 6 beta-hydroxycortisol excretion, a potential marker of cytochrome P-450 3A.

The influence of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, simvastatin and pravastatin, on the level of urinary 6 beta-hydroxycortisol/17-hydroxycorticosteroids (6 beta-OHC/17-OHCS) ratio was determined in two groups of normolipidemic Caucasian subjects (n = 18 and n = 14, respectively). The 6 beta-OHC/17-OHCS ratio increased significantly after simvastatin administration (20 mg day-1 for 17 days) (P = 0.0125) whereas no modification was observed after pravastatin administration (20 mg day-1 during 17 days). As the level of 6 beta-OHC/17-OHCS ratio is a function of cytochrome P-450 3A activity, these results suggest that in Caucasian subjects, simvastatin but not pravastatin could be a weak inducer of cytochrome P-450 3A. This contrasting effect could be related to the major pharmacological differences existing between these two drugs.

17-Hydroxycorticosteroids↗
PubMedDate not supplied

Inflammatory pseudotumor of the liver: MRI with mangafodipir trisodium.

Inflammatory pseudotumor of the liver is a rare benign mass that is often misdiagnosed as hepatocellular carcinoma at preoperative imaging. We report a case of inflammatory pseudotumor of the liver with special emphasis on the appearance at MRI after administration of mangafodipir trisodium. On T1-weighted images the lesion was slightly hypointense relative to the liver, and on T2-weighted images it was isointense with a hyperintense capsule. No tumor enhancement was seen on T1-weighted images after administration of mangafodipir trisodium. MRI with mangafodipir trisodium might help to distinguish inflammatory pseudotumor of the liver from hepatocellular carcinoma.

Adult↗
PubMedDate not supplied

Focal nodular hyperplasia: natural course observed with CT and MRI.

PURPOSE: The purpose of this work was to assess the natural course of biopsy-proven focal nodular hyperplasia (FNH). METHOD: Eighteen biopsy-proven FNHs in 14 patients (12 women and 2 men) who were followed for at least 6 months with CT and/or MRI were included in the study. The volume of the lesions was calculated twice by two observers using the summation of areas method. Intra- and interobserver variability was assessed by intraclass correlation coefficients. Longitudinal data analysis was performed with generalized estimating equations. RESULTS: The volume of FNH was stable in 6 cases, decreased in 10 cases, and increased in 2 cases. Intra- and interobserver variability in size measurements was 5-10%. Intraclass correlation coefficients were >0.992. Longitudinal data analysis showed that there was a general trend of lesion regression. CONCLUSION: Long-term follow-up and objective measurements performed in patients with biopsy-proven lesions show that the natural course of FNH is variable. In particular, lesion regression is not rare.

Adolescent↗
PubMedDate not supplied

High 6-thioguanine nucleotide levels and low thiopurine methyltransferase activity in patients with lupus erythematosus treated with azathioprine.

Azathioprine (AZA) is characterized by a high interindividual variability in bioavailability and metabolism. AZA is converted into 6-thioguanine nucleotides (6-TGN) to which the immune modifier activity is attributed. The 6-TGN levels are known to be affected by the activity of the key enzyme, thiopurine methyltransferase (TPMT), which is under genetic dependence. The authors measured a significantly lower TPMT activity in 53 women with systemic lupus erythematosus (SLE) (12.2 +/- 2.4 pmol/h/ml RBC; P < 0.01) when compared with 30 healthy control participants (13.15 +/- 3.1 pmol/h/ml RBC) but not with 28 patients with other dysimmune diseases (non-SLE; 13.0 +/- 3.0 pmol/h/ml RBC; P = 0.10). To evaluate the impact of TPMT activity on the concentrations of AZA metabolites, we measured the TPMT activity and 6-TGN levels in a subgroup of 26 patients in remission and treated with a stable dose of AZA (mean value: 1.9 +/- 0.5 mg/kg/day) for at least six months (n = 13 with SLE and n = 13 with other dysimmune diseases, ie, non-SLE). In such a subgroup, no correlation between 6-TGN levels and TPMT activity was observed. However, patients with SLE presented lower TPMT activity and higher 6-TGN levels (215 +/- 123 versus 140 +/- 75 pmol/8 x 10(8) RBC in non-SLE patients; P < 0.04). It must be noted that transient increase in 6-methylmercaptopurine levels (6-MMP), a putative toxic metabolite (up to 21.7 nmol/8 x 10(8) RBC), was more frequently observed in the non-SLE group (P < 0.01). Even if a relationship was observed between low TPMT activity and 6-TGN levels in SLE, its clinical impact appears to be limited as far as regular hematologic controls are performed.

Azathioprine↗