T Clerc

Aix-Marseille Université, Marsiglia, Provence-Alpes-Côte d'Azur, France

Are you T Clerc?

Claim your profile

Publications (20)77.26 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 32(24).
  • [Show abstract] [Hide abstract]
    ABSTRACT: MTX-liposomes, prepared with a polymerised core (LSP), were administered in anaesthetised rats by pulmonary instillation versus free drug. No toxicological effects were macroscopically observed. After each time point: 15, 30, 60 and 90 min, animals were humanely killed and analyses of radio-signal were done. This approach allowed recovery of MTX or breakdown products within biological samples. Previously, kinetics of MTX cellular uptake was performed to identify the cytotoxic concentration of drug formulation for human macrophage. Flow cytometry was set-up to characterise liposomal uptake by ex vivo pulmonary macrophage. Cells were isolated by bronchioloalveolar washes from animals. Results have shown clear different pharmacokinetic parameters between free MTX and the liposomal form of MTX. Unlike classical liposomes, which are mainly taken up by the reticulo-endothelial system, LSP-MTX was not targeted to spleen or kidney. The route of administration could be an explanation of this phenomenon. In addition, LSP-MTX was more retained by the lung tissue. Moreover, free form of the drug reaches easily lymph node. This latest result should be taken into consideration for neoplasic disease and more specifically when lymph nodes are a way for pulmonary metastasis. Finally, LSP-MTX should be tested in physio-pathological model of lung cancer to evaluate the influence of the variation of liposomal formulation pharmacokinetic parameters on the drug efficacy.
    International Journal of Pharmaceutics 07/2005; 297(1-2):180-9. · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Liposomes have been prepared with a polymerised core. Drug release and gastrointestinal (GI) degradation of liposomes with this polymerised core was slightly less important than those of classical liposomes. Vincristine, 5-fluorouracil (5-FU), and methotrexate (MTX) have been incorporated into the liposomes, and studies carried out using the differentiated cell lines Caco-2 and TC7, and with 150 histologically normal sections of human colon. Encapsulation of the drugs in liposomes had variable effects, depending on the test system and the drug used. For 5-FU and MTX calculated to be in a therapeutic range, liposomal formulation enhanced drug permeation, but not for the other drugs tested. In the excised human colon model, the treatment history of the patients can affect bioavailability: pre-operative radiation increased the drug tissue uptake. Transmucosal transport of ions was modified by prior chemotherapy. These results should be taken into account in the design of oral anticancer treatments both at the level of nutritional and pharmacological considerations.
    International Journal of Pharmaceutics 08/2003; 260(1):23-38. · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Liposomes have been prepared with a polymerised core. Drug release and gastrointestinal (GI) degradation of liposomes with this polymerised core was slightly less important than those of classical liposomes. Vincristine, 5-fluorouracil (5-FU), and methotrexate (MTX) have been incorporated into the liposomes, and studies carried out using the differentiated cell lines Caco-2 and TC7, and with 150 histologically normal sections of human colon. Encapsulation of the drugs in liposomes had variable effects, depending on the test system and the drug used. For 5-FU and MTX calculated to be in a therapeutic range, liposomal formulation enhanced drug permeation, but not for the other drugs tested. In the excised human colon model, the treatment history of the patients can affect bioavailability: pre-operative radiation increased the drug tissue uptake. Transmucosal transport of ions was modified by prior chemotherapy. These results should be taken into account in the design of oral anticancer treatments both at the level of nutritional and pharmacological considerations.
    International Journal of Pharmaceutics 07/2003; · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper describes the first covalent synthesis of kappa-carrageenan-3'-azido-3'-deoxythymidine (AZT) conjugates. A succinate diester spacer was used to covalently couple AZT onto kappa-carrageenan, resulting in a tripartite prodrug. Two methods (UV and radioactive counting) are described and validated to determine the AZT loading onto the kappa-carrageenan carrier. This polymeric carrier, through its own intrinsic anti-HIV activity, is expected to act not only as a drug delivery agent but also as an anti-HIV agent. Synergism between the two drugs (kappa-carrageenan and AZT) was demonstrated when MT-4 cells were preincubated with the kappa-carrageenan-AZT conjugate prior to HIV-1-infection. A threshold of AZT loaded onto the kappa-carrageenan was required to achieve this synergistic effect. Such kappa-carrageenan-AZT conjugates could be of great therapeutic interest because these conjugates, which contain a low AZT concentration, present improved anti-HIV activities relative to free AZT. Moreover, kappa-carrageenan is a well-tolerated biopolymer, already used in the food industry.
    Journal of Medicinal Chemistry 04/2002; 45(6):1275-83. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper describes the first covalent synthesis of kappa-carrageenan-3'-azido-3'-deoxythymidine (AZT) conjugates. A succinate diester spacer was used to covalently couple AZT onto kappa-carrageenan, resulting in a tripartite prodrug. Two methods (UV and radioactive counting) are described and validated to determine the AZT loading onto the kappa-carrageenan carrier. This polymeric carrier, through its own intrinsic anti-HIV activity, is expected to act not only as a drug delivery agent but also as an anti-HIV agent. Synergism between the two drugs (kappa-carrageenan and AZT) was demonstrated when MT-4 cells were preincubated with the kappa-carrageenan-AZT conjugate prior to HIV-1-infection. A threshold of AZT loaded onto the kappa-carrageenan was required to achieve this synergistic effect. Such kappa-carrageenan-AZT conjugates could be of great therapeutic interest because these conjugates, which contain a low AZT concentration, present improved anti-HIV activities relative to free AZT. Moreover, kappa-carrageenan is a well-tolerated biopolymer, already used in the food industry.
    Journal of Medicinal Chemistry 03/2002; 45(6):1275. · 5.61 Impact Factor
  • Journal of Medicinal Chemistry - J MED CHEM. 01/2002; 45(6):1275-1283.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5'-O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotoxicity of AZT could be reduced with these 5'-O-carbonate prodrug series by delaying the 5'-O-glucuronidation of AZT, which is one of the major limitations of AZT.
    Journal of Medicinal Chemistry 09/2001; 44(18):3014-21. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5'-O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotoxicity of AZT could be reduced with these 5'-O-carbonate prodrug series by delaying the 5'-O-glucuronidation of AZT, which is one of the major limitations of AZT.
    Journal of Medicinal Chemistry 08/2001; 44(18):3014. · 5.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC(50)) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.
    Journal of Medicinal Chemistry 04/2001; 44(5):777-86. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC(50)) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.
    Journal of Medicinal Chemistry 03/2001; 44(5):777. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Synthetic glucocorticoids, such as dexamethasone, and diets enriched with unsaturated fatty acids have been shown to stimulate hepatic bile salt synthesis. This fact led us to investigate the effects of dexamethasone and linoleic acid supplementation on bile secretion. Cholesterol (Ch) and phospholipid secretions are bile acid dependent. Ch and phospholipid in bile are also highly bound to a small apoprotein, the anionic polypeptide factor (APF). In bile, APF may play a physiological role in stabilizing cholesterol:phospholipid vesicles and might also be important in the regulatory process of bile lipid secretion. In order to study the factors influencing bile secretion, the biliary secretion rates of bile lipids and APF were experimentally modulated in perfused rat liver (PRL) and HepG2 cells. As expected, dexamethasone induced an increase in the biliary secretion rate of bile salts (BS) in the two models (PRL: 34 up to 67 nmol/l/min/g liver; HepG2 cells: 234% vs. 100% in controls). The bile secretion rates for phospholipids (PRL: from 5 down to 1.5 nmol/l/min/g liver; HepG2 cells: 93 vs. 100% in controls) and APF (PRL: from 0.34 down to 0.12 microg/l/min/g liver; cells: 86 vs. 100% in controls) rapidly decreased independently from those of BS. The data from experimental cell models supplemented with linoleic acid indicated a correlation between the BS and APF levels (APF: 71 and 63%; BS: 161 and 197% vs. 100% in controls). The phospholipid level was regulated independently from that of APF and BS and increased (106 and 111% vs. 100% in controls), while Ch remained nevertheless unchanged. Our data showed that dexamethasone induced changes in bile and that linoleic acid clearly impaired the regulation exerted by the dexamethasone on bile lipids.
    Digestion 01/1999; 60(6):515-21. · 1.94 Impact Factor
  • Atherosclerosis 01/1997; 134(1):29-29. · 3.71 Impact Factor
  • Atherosclerosis 01/1997; 134(1):29-29. · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)-cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin. 2. The experiments were carried out for 20 h, each well contained 4.2 x 10(5)/cm2 Hep G2 cells or 0.5 x 10(5)/Cm2 human hepatocytes, 130 microM ursodeoxycholate, 0.68 microCi or 1.59 microCi unesterified human [14C]-LDL-cholesterol, crilvastatin or simvastatin at 0 or 50 microM (both cell types) or 300 microM (Hep-G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]-LDL-cholesterol taken by the two cell types, compared to control. 3. Crilvastatin 50 microM led to significantly higher quantities of [14C]-glyco-tauro-conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein. 4. Crilvastatin not only acts by stimulating LDL-cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL-cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments. 5. The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological-metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells.
    British Journal of Pharmacology 09/1996; 118(7):1862-8. · 5.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1. The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)-cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. 2. Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 microM taurocholate and 50 microM or 300 microM crilvastatin. 3. This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin-bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL-cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non-conjugated as well as tauro- and glyco-conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL-cholesterol by the liver.
    British Journal of Pharmacology 03/1995; 114(3):624-31. · 5.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this work was to determine the effect of exogenous unesterified cholesterol provided in either artificial liposomes or LDL on bile salt synthesis by isolated rat hepatocytes. Rates of de novo synthesis were determined in the presence of 300 or 600 microM taurocholate, 600 microM taurodehydrocholate, cholate, deoxycholate or chenodeoxycholate. There was no significant difference between the cholesterol uptake by hepatocytes when the degree of hydrophobicity of the bile salts changed (cholate vs deoxycholate or chenodeoxycholate). Compared to taurocholate, taurodehydrocholate lowered the hepatic incorporation of unesterified cholesterol for the first 60 minutes; compared to control, taurocholate stimulated the cholesterol incorporation for the first 20 minutes. A possible explanation for this finding would be an interaction between bile salts and exogenous cholesterol, depending on the kind of conjugated bile salt. Taurocholate increased the exchange of cholesterol between liposomes or LDL and hepatocyte membranes. It resulted in a significant increase of bile salt synthesis and secretion. This phenomenon was not observed with taurodehydrocholate.
    Life Sciences 02/1995; 56(4):277-86. · 2.56 Impact Factor
  • Atherosclerosis 01/1994; 109:318-319. · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this work was to evaluate biliary phosphatidylcholine (PC) secretion after intravenous infusion of high density lipoprotein (HDL)-[3H]phosphatidylcholine (HDL-[3H]PC) in rats and to study the effect of infusion of dehydrocholic and cholic acids, which, respectively, inhibit and stimulate biliary secretion of PC. The data obtained in this study showed that, in the basal state, HDL-PC accounted for 38% of biliary PC. Dehydrocholic acid infusion caused only a "residual" secretion of HDL-PC in the bile; however, cholic acid infusion stimulated the secretion of HDL-PC as well as PC from intrahepatic microsomes. The low level of radioactivity of HDL-PC in intrahepatic compartments suggests that HDL-PC taken up by the liver is predestined for the bile secretion. The correlation between the kinetics of bile secretion of HDL-cholesterol and HDL-[3H]PC suggests the importance of HDL-PC in reverse transport of cholesterol to the liver and its transport to the bile. The differences between the effects of dehydrocholic acid and cholic acid infusions can be explained by the differences in bile salts binding to the surface of HDL.
    The American journal of physiology 07/1993; 264(6 Pt 1):G1052-6. · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Crilvastatin is a drug from the pyrrolidone family that had been shown to induce non-competitive inhibition of rat hydroxymethylglutaryl-coenzyme A reductase activity in vitro. The aim of this study was to evaluate the activity of crilvastatin on the hepatic metabolism of cholesterol in rats. Crilvastatin increased low density lipoprotein (LDL)-cholesterol uptake by the liver more than high density lipoprotein (HDL) uptake, thus increasing by up 30% the clearance of excess plasma cholesterol. In normolipidemic rats, crilvastatin significantly enhanced acyl coenzyme A:cholesterol acyl transferase and cholesterol 7 alpha-hydroxylase activity. In rats with a previous high cholesterolemia, crilvastatin also enhanced cholesterol 7 alpha-hydroxylase activity and did not increase liver acyl coenzyme A:cholesterol acyl transferase activity. These findings suggest that a drug such as crilvastatin could have a hypocholesterolemic effect by a mechanism other than the sole inhibition of cholesterol synthesis, possibly by stimulating cholesterol and bile salt secretion via the biliary tract in previously hypercholesterolemic rats.
    European Journal of Pharmacology 05/1993; 235(1):59-68. · 2.59 Impact Factor

Publication Stats

108 Citations
77.26 Total Impact Points

Institutions

  • 2005
    • Aix-Marseille Université
      • Faculté de Médecine
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2003
    • Institut Paoli Calmettes
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 1993–1996
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Université de Montréal
      • Department of Nutrition
      Montréal, Quebec, Canada