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G Valette

Publications and source records attributed to G Valette.

At least 19 recordsLinked to original sources
PubMed2002

Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands.

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.

Animals↗
PubMed2000

Simultaneous quantitation of the 5'-triphosphate metabolites of zidovudine, lamivudine, and stavudine in peripheral mononuclear blood cells of HIV infected patients by high-performance liquid chromatography tandem mass spectrometry.

A high-performance liquid chromatography (HPLC) method utilizing triple quadrupole mass spectrometry (MS) detection was developed and validated for the simultaneous measurement of the intracellular nucleoside 5'-triphosphate anabolites of zidovudine (ZDV-TP), lamivudine (3TC-TP), and stavudine (d4T-TP). These compounds were extracted from patient peripheral blood mononuclear cells (PBMCs) which are the sites of HIV replication and drug action. Ion-exchange solid phase extraction (SPE) followed by enzymatic digestion with alkaline phosphatase was utilized to yield the measurable nucleoside forms of the nucleotides. Reversed phase C-18 SPE with addition of a nucleoside internal standard, 3'-azido-2',3'-dideoxyuridine (AzdU) allowed for the indirect measurement of the original 5'-triphosphate concentration by HPLC/MS/MS. Quantitation was performed from calibration curves generated from authentic 5'-triphosphate standards spiked in PBMCs from healthy volunteers. Analytical range for the three 5'-triphosphates was equivalent to 50-45,000 pg. Mean interassay accuracies for 3TC-TP, d4T-TP, and ZDV-TP (n > 90) were 99.4%, 100.1%, and 108.0%, respectively. Mean interassay precisions (%C.V.) for 3TC-TP, d4T-TP, and ZDV-TP (n > 90) were 8.8%, 10.4%, and 8.2%, respectively. Recovery of the extraction method was 79.2%, 83.1%, and 98.3% for 3TC-TP, d4T-TP, and ZDV-TP, respectively. This method can be utilized to measure the intracellular 5'-triphosphate levels in HIV infected patients receiving antiretroviral therapy containing the nucleoside reverse transcriptase inhibitors 3TC, d4T, or ZDV.

Anti-HIV Agents↗
PubMed1999

Quantitation of intracellular triphosphate of emtricitabine in peripheral blood mononuclear cells from human immunodeficiency virus-infected patients.

An analytical methodology combining solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) was developed to quantitate the intracellular active 5'-triphosphate (TP) of beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (emtricitabine) (FTC) in human peripheral blood mononuclear cells (PBMCs). The FTC nucleotides, including 5'-mono-, di-, and triphosphates, were successively resolved on an anion-exchange SPE cartridge by applying a gradient of potassium chloride. The FTC-TP was subsequently digested to release the parent nucleoside that was finally analyzed by HPLC with UV detection (HPLC-UV). Validation of the methodology was performed by using PBMCs from healthy donors exposed to an isotopic solution of [(3)H]FTC with known specific activity, leading to the formation of intracellular FTC-TP that was quantitated by an anion-exchange HPLC method with radioactive detection. These levels of FTC-TP served as reference values and were used to validate the data obtained by HPLC-UV. The assay had a limit of quantitation of 4. 0 pmol of FTC-TP (amount on column from approximately 10(7) cells). Intra-assay precision (coefficient of variation percentage of repeated measurement) and accuracy (percentage deviation of the nominal reference value), estimated by using quality control samples at 16.2, 60.7, and 121.5 pmol, ranged from 1.3 to 3.3% and -1.0 to 4. 8%, respectively. Interassay precision and accuracy varied from 3.0 to 10.2% and from 2.5 to 6.7%, respectively. This methodology was successfully applied to the determination of FTC-TP in PBMCs of patients infected with human immunodeficiency virus after oral administration of various dosing regimens of FTC monotherapy.

Administration, Oral↗
PubMed1998

Comparison of the disposition of ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] in Caco-2 monolayers.

PURPOSE: To evaluate the potential of several bis-ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) to enhance the oral absorption of PMEA. METHODS: Caco-2 monolayers were used to estimate intestinal transport and metabolism of the bis(pivaloyloxymethyl)-ester [bis(POM)-] and a series of bis(S-acyl-2-thioethyl)-esters [bis(SATE)-] of PMEA. An LC-MS method was used for the identification of unknown metabolites which were formed from the SATE-esters. RESULTS: During transport across Caco-2 monolayers, all esters were extensively degraded as could be concluded from the appearance of the mono-ester and free PMEA in apical as well as basolateral compartments. Incubation of SATE-esters with the monolayers resulted in the formation of two additional metabolites, which were identified as 2-thioethyl-PMEA and its dimerisation product. All ester prodrugs resulted in enhanced transepithelial transport of total PMEA (i.e. the bis-esters and their corresponding metabolites, including PMEA), but significant differences could be observed between the various esters. Transport of total PMEA ranged from 0.4 +/- 0.1% for the bis[S(methyl) ATE]-ester to 15.3 +/- 0.9% for the more lipophilic bis[S(phenyl)ATE]-PMEA. A relationship between total transport of the esters and their lipophilicity (as estimated by their octanol/water partition coefficient) was established (r2 = 0.87). Incubation of prodrug esters with homogenates from Caco-2 cells showed large differences in susceptibility of the compounds to esterases, the half-lives of the bis-esters varying from 4.3 +/- 0.3 min for the bis[S(phenyl)ATE]-PMEA to 41.5 +/- 0.8 min for its methyl analogue. In addition, intracellularly formed PMEA was observed to be further converted by the cells to the diphosphorylated PMEA (PMEApp). CONCLUSIONS: Several SATE-esters of PMEA can be considered as potential alternatives to bis(POM)-PMEA, due to enhanced epithelial transport, sufficient chemical and enzymatic stability and adequate release of PMEA. Toxicological studies as well as in vivo experiments are required in order to further explore the potential of those SATE-esters as prodrugs for oral delivery of PMEA.

Adenine↗
PubMed1996

Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases.

Adenylyl Cyclases↗
PubMed1996

Decomposition pathways and in vitro HIV inhibitory effects of isoddA pronucleotides: toward a rational approach for intracellular delivery of nucleoside 5'-monophosphates.

The decomposition pathways and kinetics in various biological media and the in vitro anti-HIV-1 and anti-HIV-2 activities of four derivatives of the 5'-mononucleotide of isoddA incorporating carboxylate esterase-labile transient phosphate protecting groups are reported and compared: namely, two mononucleoside aryl phosphoramidate derivatives 1a,b and two mononucleoside phosphotriester derivatives incorporating two S-acyl-2-thioethyl groups 2a,b. All four compounds show better antiviral activity, compared to the parent nucleoside analog isoddA. The results highlight that both types of compounds act as pronucleotides, i.e. they exert their antiviral effect via intracellular delivery of the 5'-mononucleotide of isoddA. The results may give insights for the design of new more efficient pronucleotides.

Cell Line↗
PubMed1995

SR 120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist.

An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the pressor response of [Leu31,Pro34]NPY (5 micrograms/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y1 receptor antagonist yet described. It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y1 receptors.

Adenylyl Cyclases↗
PubMed1993

Biochemical and pharmacological properties of SR 27388, a dual antioxidant and PAF receptor antagonist.

SR 27388 (N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl[4-(3,5-di(tert- butyl)-4-hydroxylphenyl)thiazol-2-yl]amine) is a potent and competitive antagonist of the binding of [3H]PAF to its receptor on rabbit platelets exhibiting an equilibrium inhibition constant for PAF binding of 10.5 +/- 1.2 nM (n = 3). SR 27388 potently inhibited PAF-induced aggregation of rabbit platelets in vitro (IC50 = 65 +/- 12 nM) (n = 4). In this respect, SR 27388 was as potent as the triazolothienodiazepine WEB-2086 against PAF-induced aggregation of rabbit platelets and had no effect on the action of other platelet aggregating agents. SR 27388 prevented in a dose-dependent manner the formation of thiobarbituric acid reactive substances during membrane peroxidation (IC50 = 0.7 microM) and inhibited reduction of the stable 1,1-diphenyl-2-picrylhydrazyl radical, indicating that the antioxidant potency of SR 27388 was due to an efficient radical scavenging activity. SR 27388 displayed marked in vitro inhibition of zymosan-induced oxidative burst in human monuclear cells (IC50 = 3 microM). In vivo, SR 27388 protected mice from 100 micrograms/kg PAF-induced death with an ED50 value of 500 micrograms/kg, when given i.v., 5 min before PAF challenge or p.o. (ED50 = 800 micrograms/kg) when given 1 h before PAF administration. Similarly, i.v. or oral doses of SR 27388 afforded in mice complete protection against endotoxin-induced lethality (ED50 values were 250 micrograms/kg and 1.3 mg/kg, respectively). Neither BHT, vitamin E nor catechin exhibited significant protection against PAF- or endotoxin-induced death. In ovalbumin-presensitized rabbits, SR 27388 premixed with the allergen inhibited in a dose-dependent manner allergen-induced oedema formation in the skin (ED50 = 0.1 mumol/site). After an i.v. administration of 10 mg/kg, SR 27388 significantly protected mice against alloxan-induced diabetes. These results show that SR 27388 is a potent and orally active dual PAF receptor antagonist and antioxidant.

Animals↗
PubMed1991

Biochemical and pharmacological activities of SR 27417, a highly potent, long-acting platelet-activating factor receptor antagonist.

SR 27417 [N-(2-dimethylamino ethyl)-N-(3-pyridinyl methyl)[4- (2,4,6-triisopropylphenyl) thiazol-2-yl]amine] is the first member of a newly developed platelet-activating factor (PAF) antagonist series. It is a highly potent, competitive and selective antagonist of the binding of [3H]PAF to its receptor in rabbit platelets. It exhibits an equilibrium inhibition constant for PAF binding of 57 pM, a value that is at least 5-fold lower than that of unlabeled PAF itself. SR 27417 potently inhibited PAF-induced aggregation of rabbit and human platelets in vitro (IC50 = 0.10 and 0.50 nM, respectively) but had no effect on the action of other platelet-aggregating agents. In comparison with the triazolothienodiazepine WEB-2086, SR 27417 was 470 and 70 times more potent against PAF-induced aggregation of rabbit and human platelets, respectively. SR 27417 displayed marked in vitro inhibition of PAF-induced oxidative burst in guinea pig macrophages (IC50 = 32 nM). In an in vivo model, it protected mice from 100 micrograms/kg PAF-induced death when given i.v. (ED50 = 7.5 micrograms/kg) 5 min before PAF challenge or p.o. (ED50 = 45 micrograms/kg) 3 hr before PAF administration. SR 27417 inhibited PAF-induced death in mice with an impressive p.o. or i.v. duration of action of 30 to 48 hr. In anesthetized guinea pigs, SR 27417 inhibited i.v. and p.o. 100 ng/kg PAF-induced bronchoconstriction (ED50 = 14 and 140 micrograms/kg, respectively), hemoconcentration (ED50 = 20 and 270 micrograms/kg, respectively), thrombocytopenia (ED50 = 30 and 240 micrograms/kg, respectively) and leukopenia (ED50 = 0.1 and 1.5 mg/kg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effect of sodium 2-chloropropionate on glucagon secretion in the rat.

We have previously shown that, in alloxan-diabetic dogs, the adjunction of sodium 2-chloropropionate (2-CP) with insulin injections resulted in a reduction of both hyperglycemia and hyperglucagonemia. The present studies were designed to more closely examine the glucagon-lowering effect of 2-CP. We investigated whether 2-CP was able to reduce elevated glucagon secretion both in vivo in streptozocin (STZ)-diabetic rats, and in vitro in the isolated, perfused rat pancreas. 2-CP (1 mmol/kg or 108 mg/kg) was given during 2 mo through esophageal tube to diabetic rats deprived of exogenous insulin. The drug induced a significant reduction of hyperglucagonemia (P less than 0.05) of blood lactate and alanine levels (P less than 0.02) and of plasma triglyceride levels (P less than 0.001). Furthermore, 2-CP markedly decreased glucosuria (P less than 0.005). In the isolated rat pancreas perfused with 2.8 mmol/L glucose, the continuous perfusion of 2-CP (1 mmol/L) starting before an infusion of arginine or alanine (5 mmol/L) considerably reduced the hypersecretion of glucagon evoked by these amino acids (P less than 0.001). These experiments show that sodium 2-chloropropionate can reduce glucagon hypersecretion in the diabetic rat not only in vivo, but acts also directly in vitro on the isolated, perfused pancreas of normal rats.

Alanine↗
PubMed1984

Hypocholesterolaemic effect of fenugreek seeds in dogs.

Fractions of fenugreek seed were added to the diet of normal or diabetic hypercholesterolaemic dogs for 8 days. The effects on levels of blood glucose, plasma glucagon and plasma cholesterol were investigated. The lipid extract had no effect. The defatted fraction which is rich in fibres (53.9%) and contains 4.8% of steroid saponins significantly lowered basal blood glucose (P less than 0.02), plasma glucagon (P less than 0.01) and plasma cholesterol (P less than 0.02) levels in normal dogs. The addition of this fraction to the food of diabetic hypercholesterolaemic dogs caused a decrease of cholesterolaemia (P less than 0.02) and reduced hyperglycaemia. In conclusion, the defatted portion of fenugreek seed induces a hypocholesterolaemic effect.

Amino Acids↗
PubMed1984

Effects of fenugreek seeds on endocrine pancreatic secretions in dogs.

The components of fenugreek seeds were separated and analyzed to determine which fraction of the seed had hypoglycemic activity. These fractions were administered orally to normal or diabetic dogs for 8 days. The effect on blood glucose and pancreatic hormones was studied in normal dogs. The lipid extract had no effect; the defatted fraction (50.2% fibers: gum 17.7%, hemicellulose 22%, cellulose 8.3%, lignin 2.2%) lowered basal blood glucose level, plasma glucagon and somatostatin levels and reduced the orally induced hyperglycemia. The addition of this fraction to the insulin treatment resulted in a decrease of hyperglycemia and glycosuria in diabetic dogs. The results indicate that the defatted part is responsible for the antidiabetic action. However, the present study does not permit one to know whether the effects are caused by an unknown pharmacological compound or by the gastrointestinal action of fibers.

Animals↗
PubMed1982

Effects of chronic administration of sodium 2 chloropropionate in normal and diabetic dogs.

Pancreatic hormonal and metabolic responses to chronic administration of sodium 2 chloropropionate (2 CP) were investigated in conscious dogs. We subcutaneously administered 2 CP daily for 7 days at the dose of 0.58 mmol/kg (62.5 mg/kg) in normal dogs and those rendered diabetic by injection of alloxan (0.24 mmol/kg, i.v.). In the normal dogs, the chronic administration of 2 CP provoked a decrease in blood lactate and pyruvate but not in blood glucose concentrations. Urinary oxalate was not increased by the daily injection of 2 CP. Blood ketone body concentrations progressively increased after the third day of treatment. At the same time, plasma cholesterol slowly decreased. The 2 CP chronic administration did not change the plasma somatostatin, glucagon, and insulin levels. In the alloxan-diabetic dogs, treated with insulin alone, blood glucose, ketone body concentrations, and plasma somatostatin and glucagon levels were elevated. The adjunction of 2 CP with insulin injections resulted in a fall in blood lactate and pyruvate levels and a progressive decrease of blood glucose concentrations. Blood ketone bodies, which were already high at the start, were not affected when 2 CP was combined with insulin. The hypersomatostatinemia was not decreased, whereas the hyperglucagonemia was considerably reduced. So, I/G ratio, which was strongly decreased with insulin alone, progressively returned to normal values. As to urinary compounds, 2 CP induced a marked decrease in glucosuria and did not change the elevated urinary beta hydroxybutyrate levels. In conclusion, these findings show that the adjunction of sodium 2 chloropropionate to insulin in diabetic dogs results in a reduction of hyperglycemia and hyperglucagonemia.

Animals↗
PubMed1981

[Toxic effect of the combination of propranolol and phenformin combination in anesthetized dogs].

Phenformin (20 mg/kg subcutaneously) as well as propranolol (0.3 mg/kg. i.v.) induced an increase in blood lactate level in the normal anesthetized log; with phenformin a slight decrease in the arterial pH was noted. The combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg. i.v.) induced a more rapid increase in lactate level, a slight reduction of arterial pH and led to the death of the animals in all cases. After a chronic treatment by phenformin (20 mg/kg daily orally during 7 days, the administration of phenformin (20 mg/kg subcutaneously) induced lactic acidosis in 3 out of the 8 animals and death within 150 minutes. In the animals pretreated by phenformin, the combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg i.v.) caused the death of all the animals without the occurrence of lactic acidosis. These results point to the possible toxicity of the propranolol-phenformin combination.

Anesthesia↗
PubMed1981

Sodium 2-chloropropionate: its effects on experimental hyperlactatemia in the dog.

The effects of sodium 2-chloropropionate (2-CP), an activator of pyruvate dehydrogenase were studied on normal dogs. Two sets of experiments were performed: 1) 2-CP was administered to conscious dogs by gastric intubation at 1.16 mmol/kg b.wt. The drug induced a decrease in blood lactate and pyruvate levels but did not produce any significant change in blood glucose, blood beta-hydroxybutyrate or acetoacetate levels. 2) 2-CP given i.v. (1.16 mmol/kg b.wt. during 20 min) rapidly reduced the experimental hyperlactatemia induced by continuous infusion of epinephrine (1.5 microgram/kg . min) or fructose (0.5 g/kg . hr). Considering the metabolic side effects induced by dichloroacetate, another activator of pyruvate dehydrogenase, we suggest that use of 2-CP rather than dichloroacetate might be of interest, particularly in the treatment of hyperlactatemia or lactic acidosis.

Anesthesia↗
PubMed1980

Different effects of hypothermia on insulin and glucagon secretion from the isolated perfused rat pancreas.

Two series of experiments with the isolated perfused rat pancreas were performed in parallel. The conditions differed only with respect to temperature, which was 37.5 degrees C in one series and 28 degrees C in the other. The lowering of the temperature decreased insulin secretion induced by glucose as well as the insulin response to tolbutamide and acetylcholine. Unlike insulin, glucagon secretion was not significantly modified by hypothermia. Our results suggest that the mechanisms involved in glucagon and insulin secretion are different.

Acetylcholine↗