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Raymond Ardaillou

Publications and source records attributed to Raymond Ardaillou.

14 recordsLinked to original sources
PubMed2006

[Pharmacogenetics and pharmacogenomics].

Genetic polymorphisms can lead to drug adverse effects because certain allelic variants of genes that encode enzymes, targets or carriers involved in drug metabolism, are associated with an increase or a loss of function. Drug metabolism takes place essentially in the liver and is regulated by phase I enzymes (including several cytochrome P450 isoenzymes), the role of which is to make drug metabolites more polar by hydroxylation, and by phase II enzymes that catalyse conjugation reactions. Cytochromes P450 isoenzymes control 80% of oxidative reactions, owing to their low substrate specificity. The most extensively studied polymorphisms are those of CYP2D6 and CYP2C9, which are frequent and affect the metabolism of many drugs. For example, several CYP2C9 gene variants are associated with lower activity of the corresponding enzyme, potentially leading to drug overdose. Thiopurine methyl transferase and UDP-glucuronyl transferase are phase II enzymes that conjugate respectively 6-mercaptopurine metabolites with a methyl radical and metabolites of irinotecan (an anti-tumour drug) with a glucuronyl radical. Mutations in the corresponding genes can, through a loss of function, lead to excessively high levels of active metabolites, with a risk of bone marrow aplasia. The action of vitamin K antagonists is influenced by polymorphisms of vitamine K epoxyde reductase, the target molecule of vitamin K. A mutation in the methylene tetrahydrofolate reductase gene diminishes the folate pool and thereby increases the effects of methotrexate, a folic acid antagonist. Resistance to the anti-platelet effect of aspirin can be due to polymorphisms that affect other platelet aggregation pathways. Genotyping results must be confirmed by phenotyping, which examines the rate of transformation of a drug into its metabolites and shows whether the increase or decrease in this rate is linked to a specific polymorphism. Somatic mutations in malignant tumours can modify the response to anticancer drugs, and should therefore be taken into account. The National Academy of Medicine recommends:--development of genomic analyses for frequent polymorphisms in patients warranting treatment with drugs that have severe adverse effects;--collection of DNA samples from patients participating in drug trials in order to examine the possible relation between adverse effects and gene polymorphisms;--creation of biological resource centers in hospitals for the storage and analysis of tissue specimens.

Genotype↗
PubMed2004

[Threshold].

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Threshold Limit Values↗
PubMed2004

[Prevention and screening of chronic renal failure].

Chronic renal failure represents a major problem of public health. Incidence for patients arrived at the terminal stage of the disease is in France 126.4/million inhabitants and the cost of medical care reaches 2 % of the expenses of the National Health Insurance. The progression of the disease is divided into 5 stages that are defined by the level of creatinine clearance from the stage of renal diseases with a normal renal function (clearance>90 ml/min) to the terminal stage (clearance <15 ml/min). Prevalence of patients at this ultimate stage is around 50,000. Prevalence for the totality of patients with a renal disease is evaluated between 2 and 3 millions. Renal diseases must be screened because they are silent and because an early pre-dialysis nephrological care allows renal replacement therapy to be delayed and the number of cardiovascular accidents to be diminished. Screening must be performed in the high-risk populations, essentially patients with diabetes, hypertension, coronary ischemia, renal tract diseases and all subjects treated with drugs toxic for the kidneys. Screening in the total population seems inadequate because of a high cost to benefit ratio. Screening is based on testing for the presence of proteinuria, quantifying the number of formed elements and plasma creatinine determination, the latter allowing, together with age and weight, glomerular filtration rate to be evaluated according to Cockcroft's formula. Prevention of renal diseases in the whole population necessitates the same life style as that recommended for prevention of cardiac and metabolic diseases. In the high-risk populations, one must control glycemia, blood pressure and cholesterol plasma level. In patients that have been already screened, renal function decay has to be slowed down by blocking the renin angiotensin system with converting enzyme inhibitors, controlling plasma cholesterol with statins and diminishing dietary proteins. In the light of these various data, the National Academy of medicine recommends: 1 - in the field of public health, to extend to the whole country the registries containing data on patients with terminal chronic renal failure, to support the creation of medical networks for the screening of renal diseases, to vaccine the patients against hepatitis B, flue and pneumococcal infections and to verify whether a low birth weight is associated with a greater risk of renal diseases in adulthood; 2 - in the field of teaching and research, to stop the decrease in the number of nephrologists, to promote research in genetics, to evaluate the efficacy of antifibrosis drugs and the possible renal toxicity of all new drugs.

Cost-Benefit Analysis↗
PubMed2003

AT1 receptor expression in glomeruli from NO-deficient rats.

Chronic inhibition of nitric oxide synthase promotes renin-dependent hypertension and renal injury. The present study examines how renal angiotensin II receptors are expressed in this model. N(G)-nitro-L-arginine methyl ester (L-NAME) was given orally to rats for 1 month and was associated or not with captopril during the 4 last days of the administration. 125I-[Sar1, Ile8]-Ang II binding, AT1)mRNA and cytosolic calcium were studied in isolated glomeruli from L-NAME and control rats and in cultured mesangial cells from normal rats. Renal injury was marked in rats receiving L-NAME. Type I angiotensin II (AT1) receptor number and mRNA expression were decreased (p < 0.05) in glomeruli isolated from L-NAME-treated rats compared with controls, unless they received captopril in combination. The low level of AT1 receptor expression was associated with an attenuated rise of cytosolic calcium in response to angiotensin II. Angiotensin-converting enzyme activity in glomeruli and angiotensin II concentration in renal cortex were increased (p < 0.05) in rats receiving L-NAME alone, whereas aminopeptidase A activity was not modified. To better discriminate between the direct and indirect effects of nitric oxide deficiency, rat mesangial cells were exposed or not for 24 h to S-nitroso-N-acetyl penicillamine, a nitric oxide donor. Angiotensin II binding, AT1 mRNA expression and calcium response to angiotensin II were decreased in presence of the nitric oxide donor (p < 0.01). These results suggest that the decrease of AT1 receptor expression after 1 month of L-NAME treatment does not depend on a direct effect of nitric oxide deficiency but results from the high local angiotensin II concentration due to the stimulated angiotensin-converting enzyme activity. They also show that the renin-angiotensin dependence of this model of hypertension does not result from the overexpression of AT1 receptors.

Administration, Oral↗
PubMed2003

[Prostate cancer screening using prostate-specific antigen (PSA) determinations in plasma. National Academy of Medicine].

Prostate cancer is the most frequent cancer in man above 50 years. There is an increase in its incidence due to the longer life of the population. Prostate cancer is a slowly progressing disease. If life expectation is smaller than 10 years, the risk of death from another cause is greater than that from cancer whereas it is the opposite in younger patients. Therefore, screening of the disease by rectal examination and prostatic specific antigen (PSA) assay is necessary, confirmation being obtained by prostate biopsy. Total prostatectomy and radiotherapy can cure the disease or inhibit its progression. Plasma PSA is a general marker of prostate lesions. It is easy to measure and the cost of the assay is acceptable; but its specificity and its sensitivity remain too low. In order to improve these two parameters, it has been proposed to follow PSA kinetics and to measure the ratio free PSA/total PSA. Taken together, these data lead us to recommend, in agreement with the French Association of Urology, that a PSA assay be proposed and a rectal examination be performed every year by a general practitioner in men between 50 and 75 years and from 45 years in case of familial history. If an anomaly is found, the patient must take advice from an urologist who will decide which examinations and which treatment are to be proposed. Moreover, studies are necessary to compare the principal treatments in the long term, to precise the distribution with age of plasma PSA in the population and to improve the specificity and the sensitivity of the screening test.

Adenocarcinoma↗
PubMed2001

Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta.

Hypertension is frequently associated with the development of renal vascular fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta.

Angiotensin II↗