bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition by carbapenem antibiotic imipenem of intestinal absorption of valproic acid in rats
Authors: Torii Mayumi , Takiguchi Yoshiharu , Saito Fumiko , Izumi Miyako , Yokota Masayuki 
Published: July 2003

Abstract
The concomitant use of carbapenem antibiotics with valproic acid has been prohibited because panipenem induced a decrease in plasma concentration of valproic acid in epileptic patients during valproic acid therapy. To clarify the possible mechanism of the carbapenem-valproic acid interaction, we investigated the effect of imipenem on the pharmacokinetic behaviour of valproic acid in rats. Co-administration of imipenem (30 mg kg−1, i.v.) induced a decrease in the peak plasma concentration of valproic acid after oral administration. However, the imipenem-induced decrease in plasma concentrations of valproic acid was not observed within 60 min after intravenous injection of valproic acid. By utilizing in-situ vascular and luminal perfused small intestine, it was confirmed that absorption of valproic acid from the luminal to the vascular perfusate was decreased in the presence of imipenem (0.5 mM) in the vascular perfusate. The everted gut sac method was used to determine the effect of imipenem on active transport of valproic acid. The accumulation of valproic acid on the serosal side of the intestinal sac against the concentration gradient was reduced by lactic acid that inhibits the carrier-mediated transport of valproic acid across the intestinal brush-border membrane. However, imipenem did not affect the active transport of valproic acid. Therefore, the inhibition by imipenem of valproic acid absorption may be caused by a mechanism different from that of lactic acid. In conclusion, imipenem inhibits the intestinal absorption of valproic acid, which contributes to the decrease in plasma concentration of valproic acid after oral administration.
Synthesis of potential aldose reductase inhibitors based on minimal pharmacophore requirements
Authors: Schlitzer Martin , Rodriguez Labaniel , Kador Peter F 
Published: July 2003

Abstract
A series of 17 compounds were synthesized based on the premise that the minimal pharmacophore for aldose reductase inhibition requires the presence of both an aryl group and polar group connected by a linking structure. Three groups of compounds were synthesized, the first possessing an aniline-4-(2′-6′-methylbenzothiazole) or 2-aminobenzothiazole group as the aryl group, the second possessing a 2-naphthyl as the aryl group and the third possessing either a 4-(2-phenylthiazole) or 2-(5-2′-nitrophenylfuran) as the aryl group. In all three of these groups the carboxylate or its methyl ester are linked to the aryl group through various lengths of methylene carbons and amide or cinnamide groups. Optimal activity was observed when the carboxylic group was separated from the aryl group by a linking structure of five atoms in length. Both a double bond and an amide moiety are well tolerated in the linking structure.
Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility
Authors: Mahfouz Nadia M , Hassan Maha A 
Published: July 2003

Abstract
A series of amino acid esters (3a-e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37°C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t12, 4–16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutes to metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t12 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2–10 was investigated. The results indicated that 3a showed marked stability at pH 2–6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.
Solid phase synthesis of sulphonamides: novel ligands of 5-HT6 receptors
Authors: Renault J , Fabis F , Dauphin F , Lebranchu M , Roch M Le , Butt S , Uriac P , Rault S 
Published: July 2003

Abstract
Using solid phase synthesis techniques, we have rapidly obtained a series of eight aryl sulphonamides derived from putrescine. These conjugates with various aryl groups were evaluated for their affinity towards 5-HT6 receptors in man. This evaluation revealed the interest of two compounds which present the same activity level, in the submicromolar range, as two reference derivatives. The most potent will be considered as a new lead for further investigations.
Effect on insulin release of compounds structurally related to the potassium-channel opener 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73): introduction of heteroatoms on the 3-alkylamino side chain of the benzothiadiazine 1,1-dioxide ring
Authors: Boverie S , Antoine M-H , de Tullio P , Somers F , Becker B , Sebille S , Lebrun P , Pirotte B 
Published: July 2003

Abstract
7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.
Synthesis of diverse 4,5-dihydro-3(2H)-pyridazinones on Wang resin
Authors: Gouault N , Cupif J F , Picard S , Lecat A , David M 
Published: July 2003

Abstract
An efficient solid-phase synthesis of structurally diverse 4,5-dihydro-3(2H)-pyridazinones is described using readily available substituted 4-oxo-butanoic acids. Polymer-supported γ-keto-esters prepared from Wang resin reacted with several hydrazines to afford the corresponding hydrazones. A protocol developed in mild conditions without isolating the intermediate hydrazone led to pyridazinones in good yields after a cyclization cleavage approach. This successful strategy represents an attractive method for a rapid synthesis of heterocyclic libraries for biological evaluation.
Biostability and pharmacokinetics of LJP 920, an octameric Gal (α1–3) Gal conjugate for the inhibition of xenotransplantation rejection
Authors: Jia Lee , Linnik Matthew D , Jack Richard M , Yu Lin 
Published: July 2003

Abstract
Antibodies to an α-galactosyl saccharide structure present in human serum are associated with hyperacute rejection and delayed xenograft rejection after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl α1–3 galactose (Gal (α1–3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (α1–3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these antibodies. Herein we report on the stability of LJP 920 in biological media and its pharmacokinetic profile. Incubation of LJP 920 with mouse serum or liver microsomes at 37°C for 2 days showed no indication of degradation of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intravenous administration of LJP 920 to mice at the doses of 20 and 100 mg kg−1, LJP 920 serum concentration decreased rapidly, showing a biphasic pattern, with a distribution half-life of 3 min and an elimination half-life of more than 30 min, respectively. The serum-to-erythrocyte concentration ratio of LJP 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intravenous administration (100 mg kg−1). Both Cmax and AUC values increased in a dose-proportional manner. LJP 920 displayed a great distribution to well-perfused tissues. It was eliminated mainly through renal excretion in the unchanged form, which accounted for 23% of the total amount within 8 h of dosing.
Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man
Authors: Salphati Laurent , Childers Kelly , Pan Lin , Tsutsui Ken , Takahashi Lori 
Published: July 2003

Abstract
Prediction of the fraction of dose absorbed from the intestine (Fa) in man is essential in the early drug discovery stage. In-vitro assays in Caco-2 and MDCK cells are routinely used for that purpose, and their predictive value has been reported. However, in-situ techniques might provide a more accurate estimation of Fa. In this study, we evaluated a single-pass intestinal-perfusion (SPIP) method in the rat for its use in the prediction of absorption in man and compared it with a previous report using cell-based assays. Effective permeability coefficients (Peff) were determined in rats for 14 compounds, and ranged from 0.043 times 10−4 cm s−1 to 1.67 times 10−4 cms−1. These values strongly correlated (r2 = 0.88) with reported Peff values for man. In addition, the Spearman rank correlation coefficient calculated for in-situ-derived Peff and absorption in man was 0.92 while for the previously tested in-vitro Caco-2 and MDCK systems vs absorption in man, the correlation coefficients were 0.61 and 0.59, respectively. SPIP provided a better prediction of human absorption than the cell-based assays. This method, although time consuming, could be used as a secondary test for studying the mechanisms governing the absorption of new compounds, and for predicting more accurately the fraction absorbed in man.
Metabolism of sulphobromophthalein I: positional isomers of sulphobromophthalein monoglutathione conjugate
Authors: Sano Kazumi , Totsuka Yukari , Ikegami Yoji , Uesugi Takashi 
Published: July 2003

Abstract
Three positional isomers of sulphobromophthalein glutathione monoconjugate (BSP-mGSH) were detected using a paired-ion HPLC method that employs triethylamine phosphate (TEA-H3PO4) as a pairing agent. To confirm that these compounds were glutathione (GSH) conjugates, sulphobromophthalein (BSP) was incubated with a four-fold volume of GSH under alkaline ammonium hydroxide. At least 6 metabolites (3 di-GSH conjugates and 3 isomers of mono-GSH conjugates) were produced under these conditions. The three mono-GSH conjugates were each purified and identified as compounds with a molecular weight of 1020 according to FAB mass spectrometry results. Positional isomers of BSP-GSH were provisionally distinguished via the addition of the symbols α, β and δ to the end of each abbreviation, to reflect the amount of isomers present. Thus, the isomer present in the largest quantity was termed BSP-mGSH(α), the second most abundant isomer was termed BSP-mGSH(β) and the third was termed BSP-mGSH(δ). Interestingly, a species difference was recognized in that rat cytosol GSH S-transferase (GST) primarily produced BSP-mGSH(α), whereas guinea-pig cytosol generated BSP-mGSH(δ), BSP-mGSH(α) and BSP-mGSH(β) equally and rabbit cytosol mainly produced BSP-mGSH(β).
Designing multidrug-resistance modulators circumventing the reverse pH gradient in tumours
Authors: Castaing Madeleine , Loiseau Alain , Dani Michele 
Published: July 2003

Abstract
Multidrug-resistant tumours often exhibit a reverse pH gradient (acid outside), as they have an acid extracellular pH (pHe) and a neutral alkaline intracellular pH (pHi). This study was designed to test the hypothesis that the ability of lipophilic drugs to mediate multidrug resistance (MDR) reversal by interacting with the membrane phospholipids may be correlated with pH in resistant tumours. The permeation properties of five MDR modulators were therefore studied at 37°C by quantifying their ability to induce the leakage of Sulfan blue through unilamellar anionic liposomes, over the range pH 6.5–7.7, and in the absence of any membrane potential (pHe = pHi). The dye leakage induced by two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was found to significantly increase with the pH of the medium (P &lt; 0.001), whereas that induced by a non-ionic detergent (Triton X-100) showed almost no pH-dependent variations. This process was a cooperative one (0.8 &lt; Hill coefficient &lt; 8.5) and the permeation doses inducing 50% dye leakage (PD50) ranged from 1.6 to 36.0 mM. The permeation ability of the MDR modulators (log(1/PD50)) significantly increased with their octanol-buffer distributions (logD) (slope = 0.35 ± 0.06; y intercept = 1.65 ± 0.14; P &lt; 0.0001) and significantly decreased with their net electric charge (z) (slope = −0.48 ± 0.07; y intercept = 2.85 ± 0.08; P &lt; 0.0001). A highly significant multiple correlation was found to exist between the variations of log(1/PD50) with those of logD and z (dlog(1/PD50)/dlogD = 0.21 ± 0.05; dlog(1/PD50)/dz = −0.34 ± 0.07; y intercept = 2.27 ± 0.17; P &lt; 0.000001). The results provide evidence that in resistant tumours (acid pHe and neutral alkaline pHi), the MDR reversal might be enhanced by favourable drug-membrane interactions if the modulators are designed in the form of highly lipophilic (logP ≅ 4) mono-basic drugs with a near neutral pKa (pKa ≅ 7–8).
Apoptosis induced by doxorubicin and cinchonine in P388 multidrug-resistant cells
Authors: Furusawa Shinobu , Nakano Shinya , Wu Jianghong , Sakaguchi Shuhei , Takayanagi Motoaki , Sasaki Ken-Ichi , Satoh Susumu 
Published: July 2003

Abstract
Acquired drug resistance is a major factor in the failure of doxorubicin-based cancer chemotherapy. We determined the ability of cinchonine to reverse doxorubicin drug resistance in a doxorubicin-resistant leukaemia cell line (mouse P388/DOX). A non-cytotoxic concentration of cinchonine (10 μM) increased the sensitivity to doxorubicin of multidrug-resistant P388/DOX cells and significantly enhanced the doxorubicin-induced apoptosis and DNA fragmentation in resistant cells, but had no effect in parent cells. Time-course studies demonstrated that DNA fragmentation was present 24 h after incubation with doxorubicin and cinchonine, indicating that DNA degradation was a preceding event. In cultured cells, cinchonine increased the intracellular accumulation of doxorubicin in the resistant cells in a dose-dependent manner. Using flow cytometry to measure the inhibition of the P-glycoprotein (P-gp) dependent efflux of rhodamine 123, cinchonine was found to be considerably more effective than quinine. The results with cinchonine suggest that there may be quinine derivatives with a similar capacity to inhibit drug transport by P-gp. Additionally, the G2/M phase cell population in resistant cells is increased by doxorubicin/cinchonine treatment. Exposure of resistant cells to 1 μM doxorubicin and 10 μM cinchonine resulted in the expression of Fas (APO-1/CD95) in cells after 6 h. These studies demonstrate that the cell killing effects of doxorubicin and cinchonine in resistant cells are mediated, at least in part, by the induction of apoptosis.
Cisapride raises the bioavailability of paracetamol by inhibiting its glucuronidation in man
Authors: Itoh Hiroki , Nagano Toshiaki , Takeyama Masaharu 
Published: July 2003

Abstract
The effect of cisapride on plasma concentrations of paracetamol was investigated with respect to hepatic metabolism. Paracetamol (1 g) together with cisapride (7.5 mg) or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and its glucuronide and sulfate conjugates were measured by HPLC. The pharmacokinetic variables were calculated from the plasma concentration-time curves of each volunteer. The area under the plasma paracetamol concentration-time curve from 0 to 180 min (mean ± s.d.) increased from 1875.0 ± 112.8 μg min mL−1 (placebo coadministration) to 2238.8 ± 125.8 μg min mL−1 (cisapride coadministration) (P &lt; 0.01). The mean maximum plasma paracetamol concentration (18.2 μg mL−1) with placebo was reached 30 min after administration, whereas mean maximum plasma paracetamol concentration (21.2 μg mL−1) with cisapride occurred 45 min after administration. The plasma paracetamol concentrations with cisapride were significantly greater at 45 to 120 min after administration compared with placebo. Plasma paracetamol glucuronide conjugate concentrations with cisapride were decreased at 15 to 60 min compared with placebo (P &lt; 0.05), whereas plasma paracetamol sulfate conjugate concentrations did not change significantly. Hence the coadministration of paracetamol with cisapride reduced plasma paracetamol glucuronide concentrations and increased plasma paracetamol concentrations, presumably due to inhibition of paracetamol metabolism via paracetamol glucuronyltransferase. Thus, care is necessary when paracetamol and cisapride are coadministered.
Synthesis and pharmacological evaluation of 5-dialkylaminomethyl-2-amino-2-oxazolines as H1-antagonists
Authors: Bosc J J , Jarry C , Martinez B , Molimard M 
Published: July 2003

Abstract
New 5-dialkylaminomethyl-2-amino-2-oxazolines have been synthezised in two steps from the corresponding dialkylamines. They were evaluated in-vitro as H1-antagonists. Compounds 1c, 1d and 1j significantly antagonized histamine-induced contraction of guinea-pig trachea with a rightward shift of the concentration-response curve to histamine. Compound 1f, 5-[(4-benzyl-1-piperidinyl)methyl]-2-amino-2-oxazoline, induced an increase in acetylcholine Emax (the maximal response to acetylcholine 10−3 M) and a shift to the left of the concentration-response curve. The lack of effect of this compound on histamine-induced contraction rules out a non-selective potentiation of the contraction mechanisms. Preliminary structure-activity results were reported partly based on physicochemical results.
A flexible approach to the design of new potent substance P receptor ligands
Authors: Millet R , Goossens L , Bertrand-Caumont K , Goossens J-F , Houssin R , Hénichart J-P 
Published: July 2003

Abstract
The development of small-molecule antagonists of the substance-P-preferring tachykinin NK1 receptor offers an excellent opportunity to exploit these molecules as novel therapeutic agents in diverse pathologies such as depression, emesis or asthma. GR71251 has previously been identified as a potent and selective substance-P-receptor antagonist. We have therefore undertaken the synthesis of new pseudopeptidic analogues based on the C-terminal sequence of GR71251. The evaluation of binding affinities toward NK1 and NK2 receptors has enabled us to propose new selective NK1 ligands with high affinity. Structure-activity relationships showed that the Trp-OBzl(CF3)2 moiety is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a useful starting point for new substance P antagonists and represent an attractive lead series for further studies on the design of specific NK1 antagonists.
Antimalarial in-vivo activity of bis(9-amino-6-chloro-2-methoxyacridines)
Authors: Girault S , Delarue S , Grellier P , Berecibar A , Maes L , Quirijnen L , Lemiere P , Debreu-Fontaine M-A , Sergheraert C 
Published: July 2003

Abstract
In the fight against malaria, chemotherapy using bisacridines may represent an alternative method to overcoming chloroquine-resistance. Eight bis(9-amino-6-chloro-2-methoxyacri-dines), in which acridine moieties were linked by polyamines substituted with a side chain, were tested for their in-vivo activity upon mice infected by Plasmodium berghei. Three of the compounds revealed antimalarial activity but no relationship could be deduced from a comparison of in-vitro and in-vivo activities. N-alkylation of the central amino group generated toxicity and, therefore, only compounds N-acylated in this position can be selected as leads.
Spirohydantoins from D-ribose as new potent enzymatic inhibitors
Authors: Nguyen A , Villa P , Ronco G , Postel D 
Published: July 2003

Abstract
Anomeric spirohydantoin derivatives from monosaccharides are known for various biological properties. We describe herein the synthesis of the 3-spirohydantoin derivatives of D-allose and D-ribose. The key step is the stereoselective glyco-α-aminonitrile formation from ulose derivatives of D-glucose and D-xylose using titanium tetra-isopropoxide as a mild and efficient catalyst. Target compounds were synthesized from these intermediates. The glucidic moiety was partially or totally deprotected under acidic conditions. These new heterocyclic monosaccharidic derivatives are potent glycogen phosphorylase inhibitors.
Asymmetric synthesis of novel isoindolines: azasaccharide mimics as potential enzyme inhibitors
Authors: Ewing D F , Len C , Mackenzie G , Petit J P , Ronco G , Villa P 
Published: July 2003

Abstract
2′,3′-Dideoxy-2′,3′-didehydronucleosides and azasaccharides are known to possess antiviral activity. The synthesized 1-methoxyisoindoline system (10), which is related to the above nucleosides, is potentially stable in-vivo. The 1-methoxyisoindoline was synthesized from the achiral phthalaldehyde in 10 steps via an enantiomerically pure diol obtained by Sharpless asymmetric dihydroxylation. The new heterocyclic compound is an azosaccharide mimic which provides an access to a new series of nucleoside analogues with potential as antiretroviral agents (anti-HIV) and as glycosidase inhibitors.
Conformational analysis of tripeptide Ac-Lys-Pro-Val-NH2, COOH-terminal sequence of alpha-MSH
Authors: Chavatte Philippe , Yous Saïd , Lesieur Daniel , Hénichar Jean-Pierre 
Published: July 2003

Abstract
Alpha-melanocyte stimulating hormone (alpha-MSH) is an endogenous linear tridecapeptide which interacts with the melanocortin receptors (MC1-R to MC5-R) to mediate its biological effects. Antipyretic and anti-inflammatory activities of alpha-MSH are due to the COOH-terminal peptide sequence, Lys-Pro-Val (alpha-MSH[11–13]). This tripeptide might be useful as a therapeutic agent in the control of fever and inflammatory reactions. With this aim, a theoretical conformational study of the tripeptide has been carried out using molecular dynamics. The obtained conformational space has been classified into families according to the letter-code convention to partition the φ-ψ map. The lowest energy conformations of each family were used as templates to design six models of conformationally constrained non-peptide analogues.