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1.
Talanta ; 162: 604-611, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-27837878

ABSTRACT

A wide variety of medical devices (MDs) used in hospitals are made of flexible plasticized polyvinylchloride (PVC). Different plasticizers are present in variable amounts in the PVC matrix of the devices and can leach out into the infused solutions and may enter into contact with the patients. The ARMED1 project aims to assess the migration of these plasticizers from medical devices and therefore the level of exposure in patients. For the first task of the project, eight methods were developed to directly detect and quantify the plasticizers in the PVC matrix of the MDs. We compared the overall performances of the analytical methods using standardized and validated criteria in order to provide the scientific community with the guidance and the technical specifications of each method for the intended application. We have shown that routine rapid screening could be performed directly on the MDs using the FTIR technique, with cost-effective analyses. LC techniques may also be used, but with limits and only with individual quantification of the main plasticizers expected in the PVC matrix. GC techniques, especially GC-MS, are both more specific and more sensitive than other techniques. NMR is a robust and specific technique to precisely discriminate all plasticizers in a MD but is limited by its cost and its low ability to detect and quantify plasticizer contamination, e.g. by DEHP. All these results have been confirmed by a real test, called the " blind test " carried out on 10 MD samples.

2.
Int J Pharm ; 515(1-2): 774-787, 2016 Dec 30.
Article in English | MEDLINE | ID: mdl-27826027

ABSTRACT

The objective of this study was to evaluate five commercial ready-to-use transdermal vehicles (Phytobase®, Lipovan®, Pentravan®, Pentravan® Plus and Pluronic Lecithin Organogel (PLO)), for the compounding of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) and their administration in combination to treat chemotherapy-induced nausea and vomiting (CINV) at the hospital. Drugs were individually formulated in these vehicles and in mixture in Pentravan® Plus using different penetration enhancers. Quality control of the forms has demonstrated that formulation process was mastered and convenient for the hospital (time required: 20min). Diffusion experiments through synthetic membranes and pig ear epidermis performed using Franz-type diffusion cells, have shown that the release and permeation process were greater for ondansetron than for dexamethasone and aprepitant, with a release step not limiting. As permeation of aprepitant was too low, it was discarded of the study. When ondansetron and dexamethasone were compounded in combination in Pentravan® Plus, the most efficient vehicle, a permeation decrease was observed. Finally, the use of tween 20 instead of EtOH as chemical enhancer has led to 2-fold factor increase in the flux of dexamethasone, resulting in fluxes convenient for transdermal administration of ondansetron to a child, but insufficient for an adult and for dexamethasone.


Subject(s)
Antiemetics/chemistry , Antineoplastic Agents/adverse effects , Lecithins/chemistry , Nausea/drug therapy , Pharmaceutical Vehicles/chemistry , Vomiting/drug therapy , Administration, Cutaneous , Animals , Antiemetics/administration & dosage , Aprepitant , Chemistry, Pharmaceutical/methods , Dexamethasone/chemistry , Drug Carriers/chemistry , Humans , Morpholines/chemistry , Nausea/chemically induced , Ondansetron/chemistry , Swine , Vomiting/chemically induced
3.
Talanta ; 120: 274-82, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24468370

ABSTRACT

This work was dedicated to the development of a simple and direct multivariate UV spectrophotometric method for the simultaneous determination of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) in a new organogel formulation developed for their simultaneous transdermal administration. This method that does not require separation of the drugs and sophisticated instrument will permit to control quality of this new transdermal form both during the optimization step and for a further routine control of this preparation at the pharmacy department of the hospital. Hence, a partial least squares regression model using the spectral data record from 260 to 288 nm and 5 components, has firstly been validated thanks to the evaluation of the REP% (under 7.9%) and secondly using an accuracy profile approach (acceptance limit of ±10%). Thereby, the method allows the quantitation of the drugs in the ranges (5-15 mg L(-1)), (4-8 mg L(-1)) and (20-50 mg L(-1)) for ondansetron, dexamethasone and aprepitant, respectively. An HPLC/UV reference method has also been developed. Optimal separation (2.52

Subject(s)
Antiemetics/analysis , Dexamethasone/analysis , Gels/chemistry , Morpholines/analysis , Ondansetron/analysis , Spectrophotometry, Ultraviolet/methods , Administration, Cutaneous , Antiemetics/administration & dosage , Aprepitant , Chromatography, High Pressure Liquid/methods , Dexamethasone/administration & dosage , Least-Squares Analysis , Limit of Detection , Morpholines/administration & dosage , Ondansetron/administration & dosage
4.
Int J Pharm ; 454(2): 712-9, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23707251

ABSTRACT

Taxanes, including paclitaxel, are anti-cancer drugs approved for the treatment of prostate cancer but which have limited clinical application due to their hydrophobicity, their low therapeutic index and the emergence of chemoresistance. These side effects may be avoided through the use of new drug delivery systems such as nanoparticles, and paclitaxel-loaded PLGA nanoparticles up to 200 nm in size have shown encouraging results. As it is known that size affects the tissular penetration and distribution of tumors via the enhanced permeability and retention effect, so nanoparticles smaller than 100 nm are potentially interesting vehicles for improving paclitaxel delivery and efficacy. In this work, new paclitaxel-loaded small PLGA nanoparticles, between 49 nm and 95 nm in size and with positive or negative surface charges, were prepared without detergent. They were stable in the presence of serum, and HPLC showed that high paclitaxel loading and stability were achieved. Intracellular uptake of these nanoparticles was studied in PC3 cells by flow cytometry. Confocal studies confirmed a high tubulin destructuration at very low dose with these nanoparticles. This study suggests that both positively and negatively charged paclitaxel-loaded small PLGA nanoparticles deliver this drug into PC3 cells, and that this nanoparticle mode of delivery highly improves paclitaxel efficiency by up to two log-increase. These results also highlight the importance of small nanoparticles for drug delivery in cancer applications and are extremely promising for in vivo studies.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Lactic Acid/chemistry , Nanoparticles/chemistry , Paclitaxel/chemistry , Polyglycolic Acid/chemistry , Antineoplastic Agents, Phytogenic/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Endocytosis , Humans , Lactic Acid/administration & dosage , Male , Nanoparticles/administration & dosage , Paclitaxel/administration & dosage , Particle Size , Polyglycolic Acid/administration & dosage , Polylactic Acid-Polyglycolic Acid Copolymer , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Surface Properties
5.
J Chromatogr A ; 1217(24): 3871-5, 2010 Jun 11.
Article in English | MEDLINE | ID: mdl-20451916

ABSTRACT

Stereospecific separations of seven Tic-hydantoin sigma-1 agonists were performed by both HPLC method using derivatized cellulose and amylose chiral stationary phases and capillary electrophoresis (CE) method using neutral and anionic cyclodextrins added in the background electrolyte (BGE). An optimal baseline separation (R(s)>3.3 with analysis times<25min) was readily obtained with all silica-based celluloses and amyloses using a normal-phase methodology. CE was used as an alternative technique to HPLC for the Tic-hydantoin derivatives separation. The enantiomers were fully resolved with highly sulfated beta-cyclodextrins at pH 2.5 (R(s)>1.5 with analysis times <11min). Both methods were validated in terms of linearity, detection and quantification limits. They were used to check the enantiomeric purity of the enantiomers.


Subject(s)
Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Hydantoins/chemistry , Tetrahydroisoquinolines/chemistry , Cyclodextrins/isolation & purification , Hydantoins/metabolism , Linear Models , Receptors, sigma/agonists , Receptors, sigma/metabolism , Reproducibility of Results , Sensitivity and Specificity , Stereoisomerism , Tetrahydroisoquinolines/metabolism , Sigma-1 Receptor
6.
J Chromatogr B Analyt Technol Biomed Life Sci ; 877(29): 3475-81, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19748325

ABSTRACT

Separations of the diastereoisomers of three nucleoside 5'-phosphotriester derivatives of Ara-C (tBuSATE, hydroxy tBuSATE and bishydroxy tBuSATE phenylphosphotriester derivatives; pronucleotides) were performed by HPLC using derivatized cellulose and amylose chiral stationary phases. An optimal baseline separation (Rs>1.5) was readily obtained with an amylose based chiral column (AD-H) used in normal phase mode. This stereospecific HPLC method has been associated to a solid phase extraction step using a C18 cartridge and an internal standard for the quantification of one nucleoside 5'-phosphotriester derivative in cell extracts. After optimization, this method was validated in terms of specificity, recovery, linearity, precision and accuracy and detection limit. It was applied to the determination of the apparent rate constants of disappearance and half-lives of each diastereoisomer. This enabled us to conclude that the enzymatic activity involved in the first step of the decomposition pathway of the hydroxyl tBuSATE phenylphosphotriester of Ara-C is stereoselective and is related to the nature of the pyrimidic base.


Subject(s)
Chromatography, High Pressure Liquid/methods , Cytarabine/chemistry , Cytarabine/isolation & purification , Esters/chemistry , Esters/isolation & purification , Solid Phase Extraction/methods , Kinetics , Molecular Structure , Stereoisomerism
7.
Article in English | MEDLINE | ID: mdl-18773872

ABSTRACT

Separations of five diastereoisomers of nucleoside phosphoramidate derivatives (pronucleotides) were performed by both HPLC method using derivatized cellulose and amylose chiral stationary phases and CE method using anionic cyclodextrins added in the background electrolyte (BGE). An optimal baseline separation (Rs > 1.5) was readily obtained with all silica-based celluloses and amyloses using in a normal-phase methodology. Capillary electrophoresis was used as an alternative technique to HPLC for the separation of pronucleotides. The diastereoisomers were fully resolved with sulfated cyclodextrins at both BGE pH (2.5 and 6.2). Limits of detection and limits of quantification, calculated for both methods, are up to 200 times higher in CE separations than in HPLC separations. The analytical HPLC method was then applied in a preliminary study for the pronucleotide 1 quantification in cellular extract.


Subject(s)
Amides/isolation & purification , Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Nucleotides/isolation & purification , Phosphoric Acids/isolation & purification , Cell Line, Tumor , Humans , Prodrugs/isolation & purification , Uncertainty , Zidovudine/analogs & derivatives , Zidovudine/isolation & purification
8.
J Pharm Biomed Anal ; 46(5): 848-53, 2008 Apr 14.
Article in English | MEDLINE | ID: mdl-17367983

ABSTRACT

Analytical HPLC methods using derivatized amylose chiral stationary phases, Chiralpak AD-H and Chiralpak AS, were developed for the direct enantioseparation of eight substituted 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives with one stereogenic center. Baseline separation (Rs>1.5) was always achieved on amylose based Chiralpak AD-H column to the difference with Chiralpak AS. Using UV detection, a linear response was observed within a 180-420 micromol L(-1) concentration range (r2>0.991) for three racemic compounds 1, 3 and 4 with best pharmacological potentials; repeatability, limit of detection (LD) and quantification (LQ) were also determined: LD varied, for the solutes, from 0.36 to 2.56 micromol L(-1). Finally, the enantiopurity of these compounds was determined. Additionally, the effect of temperature variations upon isomer separations was investigated.


Subject(s)
Amylose/analogs & derivatives , Carbamates/chemistry , Chromatography, High Pressure Liquid , Phenylcarbamates/chemistry , Quinolines/isolation & purification , Receptor, Cannabinoid, CB2/agonists , Technology, Pharmaceutical/methods , Amylose/chemistry , Chromatography, High Pressure Liquid/standards , Molecular Structure , Quinolines/chemistry , Quinolines/pharmacology , Reproducibility of Results , Solvents/chemistry , Spectrophotometry, Ultraviolet , Stereoisomerism , Technology, Pharmaceutical/standards , Temperature
9.
Eur J Pharm Sci ; 31(3-4): 165-71, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17462870

ABSTRACT

Acidity constants of benzoxa-, benzothia- and benzoselena-zolinone derivatives were determined by capillary electrophoresis, potentiometry and spectrophotometry experiments. These three analytical techniques gave pK(a) results that were in good agreement. A convenient, accurate and precise method for the determination of pK(a) was developed to measure changes in acidity constants induced by heteroatom or 6-benzoyl substituted derivatives. pK(a) values were determined simultaneously for two compounds characterized by different electrophoretic mobility (micro(e)) and pK(a) value and in the presence of an analogous neutral marker.


Subject(s)
Benzothiazoles/chemistry , Benzoxazoles/chemistry , Organoselenium Compounds/chemistry , Oxazolidinones/chemistry , Acids/chemistry , Algorithms , Buffers , Electrophoresis, Capillary , Hydrogen-Ion Concentration , Molecular Structure , Potentiometry , Spectrophotometry, Ultraviolet
10.
J Chromatogr A ; 1132(1-2): 141-7, 2006 Nov 03.
Article in English | MEDLINE | ID: mdl-16965783

ABSTRACT

Compounds 1-4 are diastereoisomeric thymine derivatives of isochroman aromatic analogues of stavudine, an approved drug. Both capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) techniques were used to separate these species with high resolution and thus permit the determination of enantiomeric excess. Chiral selectivity was developed using anionic (highly sulfated) cyclodextrins as chiral selectors in CE and amylose, cellulose and cyclodextrin chiral stationary phases by HPLC. The HPLC method was found to be more efficient than the CE method and was applied, after validation (repeatability, limit of detection, limit of quantification) to follow and quantify the kinetics of a stereoselective esterification.


Subject(s)
Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Nucleosides/isolation & purification , Stavudine/isolation & purification , Molecular Structure , Nucleosides/chemistry , Reproducibility of Results , Stavudine/analogs & derivatives , Stavudine/chemistry , Stereoisomerism
11.
J Pharm Biomed Anal ; 42(2): 245-52, 2006 Sep 18.
Article in English | MEDLINE | ID: mdl-16806786

ABSTRACT

A stereospecific HPLC methodology has been developed for the diastereoisomeric resolution of a mononucleotide prodrug in cell extracts. This method involves the use of solid phase extraction on a C18 cartridge. Diastereoisomers and internal standard resolutions were performed on a cellulose based chiral column (Chiralcel OD-H) used in the normal phase mode. The method was validated in terms of specificity, recovery, linearity (diasteroisomers mixture concentration: 3-60 micromol L(-1)), precision and accuracy and detection limit (1.67 and 1.33 micromol L(-1) for first and second eluted diastereoisomer). This method was applied to the determination of the apparent rate constants of disappearance and half-lives of each stereoisomers. This permits to conclude to the stereoselectivity of the enzymatic activity involved in the decomposition pathway of 2.


Subject(s)
Chromatography, High Pressure Liquid/methods , Prodrugs/analysis , Zidovudine/analogs & derivatives , Zidovudine/analysis , Cell Line, Tumor , Humans , Kinetics , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Stereoisomerism
12.
Biomed Chromatogr ; 19(6): 415-25, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16037929

ABSTRACT

Analytical HPLC methods using derivatized cellulose and amylose chiral stationary phases used in normal and reversed-phase modes were developed for the diastereoisomeric separation of mononucleotide prodrugs (pronucleotides) of 3'-azido-2',3'-dideoxythymidine (AZT). The resolutions were performed with two silica-based celluloses using normal and reversed-phase methodologies: Tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H and Chiracel OD-RH) and Tris-methylbenzoate (Chiralcel OJ and OJ-R). Two amyloses phases, Tris-3,5-dimethylphenylcarbamate (Chiralpak AD) and Tris-(S)-1-phenylethylcarbamate (Chiralpak AS), were used in normal-phase mode. Additionally, we developed separation using two stationary phases with immobilized cyclodextrins in reversed-phase and polar-organic modes. The mobile phase and the chiral stationary phase were varied to achieve the best resolution. Different types and concentration of aliphatic alcohols, acetonitrile or water in the mobile phase were also tested for the different separation modes. An optimal baseline separation (Rs > 1.5) was readily obtained with all silica-based celluloses and amyloses using a normal-phase methodology. The different columns gave complementary results in term of resolution. Limits of detection and quantification were 0.12-0.20 and 0.40-0.67 microm, respectively. This analytical method was applied in a preliminary study for the pronucleotide 2 quantification in cellular extract.


Subject(s)
Chromatography, High Pressure Liquid/instrumentation , Nucleotides/isolation & purification , Prodrugs/isolation & purification , Zidovudine/analogs & derivatives , Amylose/analogs & derivatives , Benzoates , Carbamates , Cell Line, Tumor , Cellulose/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Dideoxynucleotides , Humans , Lymphocytes/chemistry , Lymphocytes/metabolism , Organophosphates/isolation & purification , Phenylcarbamates , Sensitivity and Specificity , Stereoisomerism , Zidovudine/chemistry , Zidovudine/isolation & purification , beta-Cyclodextrins
13.
J Chromatogr A ; 1034(1-2): 161-7, 2004 Apr 23.
Article in English | MEDLINE | ID: mdl-15116926

ABSTRACT

Compounds 1-4 are the four stereoisomers of a synthetic new potential antiviral agent (d4T analog) containing two chiral centers and a base (uracil). Both high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) techniques were used to separate and quantify enantiomers with high resolution. The determination of enantiomeric purity of the compounds was developed using both amylose chiral stationary phase by HPLC and anionic cyclodextrins (highly S-CD) as chiral selectors in CE. The HPLC method was found to be superior in sensitivity to the CE method.


Subject(s)
Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Reverse Transcriptase Inhibitors/isolation & purification , Stavudine/isolation & purification , Reproducibility of Results , Reverse Transcriptase Inhibitors/chemistry , Sensitivity and Specificity , Stavudine/analogs & derivatives , Stavudine/chemistry , Stereoisomerism
14.
J Chromatogr A ; 1035(1): 131-6, 2004 Apr 30.
Article in English | MEDLINE | ID: mdl-15117082

ABSTRACT

Capillary electrophoresis (CE) was used as a method to determine the acidity constants of eight aromatase inhibitors. This method was validated by comparison of results obtained with a traditional method, UV spectroscopy, and additionally with computational calculations. We confirmed here, with our series of compounds, that capillary electrophoresis is an attractive method for pKa measurements which is based on migration time or mobilities of the ionic species over a range of pH values. The precision of pKa measurements of N-imidazole derivatives is useful to observe pKa shifts induced by chemical modifications introduced on adjacent aromatic rings such as heterocycle (benzoxa- or benzothiazolinone) or substituted benzyle. The knowledge of these pKa values is a great interest to predict migration of solutes and qualitative interactions with ionized cyclodextrines as chiral selectors in further enantioseparative CE studies.


Subject(s)
Aromatase Inhibitors , Enzyme Inhibitors/analysis , Imidazoles/chemistry , Buffers , Enzyme Inhibitors/pharmacology , Hydrogen-Ion Concentration , Imidazoles/pharmacology , Ions , Osmosis , Reproducibility of Results
15.
Chirality ; 13(4): 199-206, 2001 May 05.
Article in English | MEDLINE | ID: mdl-11284025

ABSTRACT

In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (+/-)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5 was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (-)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2.


Subject(s)
Receptors, Cell Surface/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Tetrahydronaphthalenes/isolation & purification , Tetrahydronaphthalenes/metabolism , Cell Line , Chromatography, High Pressure Liquid/methods , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Receptors, Melatonin , Stereoisomerism , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology
16.
Ann Pharm Fr ; 59(1): 40-50, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11223578

ABSTRACT

Some new N-substituted pyrrolidin-2-ones, cyclic analogs of baclofen and of 3-(5-methylbenzo[b]furan-2-yl)-gamma-aminobutyric acid, have been prepared starting from corresponding pyrrolidinones and characterized.


Subject(s)
Pyrrolidines/chemical synthesis , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/chemical synthesis , Indicators and Reagents
17.
J Chromatogr A ; 907(1-2): 101-13, 2001 Jan 12.
Article in English | MEDLINE | ID: mdl-11217017

ABSTRACT

Analytical HPLC methods using derivatized cellulose chiral stationary phases were developed for the direct separation of the stereoisomers of disubstituted tetralin derivatives with two chiral centers, new agonist and antagonist ligands for melatonin receptors. The separations were made using normal-phase methodology with a mobile phase consisting of n-hexane-alcohol (methanol, ethanol, 1-propanol or 2-propanol) in various proportions, and a silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). The effects of concentration of various aliphatic alcohols in the mobile phase were studied. A better separation was achieved on cellulose carbamate phase compared with the cellulose ester phase. The effects of structural features of the solutes on the discrimination between the stereoisomers were examined. Baseline separation (Rs>1.5) was easily obtained in many cases.


Subject(s)
Cellulose/chemistry , Chromatography, High Pressure Liquid/methods , Naphthalenes/isolation & purification , Receptors, Cell Surface/drug effects , Receptors, Cytoplasmic and Nuclear/drug effects , Ligands , Naphthalenes/chemistry , Naphthalenes/pharmacology , Receptors, Cell Surface/agonists , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Melatonin , Stereoisomerism
18.
Therapie ; 54(5): 651-8, 1999.
Article in English | MEDLINE | ID: mdl-10667104

ABSTRACT

Baclofen (4-amino-3-(4-chlorophenyl)butyric acid) is the only selective agonist for GABA-B receptors. Its R-(-)-enantiomer is about 100 times more active than the S-(+)-enantiomer. In the search for new compounds that bind to GABA-B receptors, it is very important to clarify the structural requirements. The authors report the synthesis and separation of isomers of various 3-heteroaromatic (benzo[b]furan and thiophen) aminobutyric acids. The 4-amino-3-(7-methylbenzo[b]furan-2-yl)butanoic acid is a potent and specific ligand for GABA-B receptors, with an IC50 value of 5.4 microM for the displacement of [3H] GABA.


Subject(s)
Aminobutyrates/pharmacology , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , Receptors, GABA-B/drug effects , Aminobutyrates/chemical synthesis , Aminobutyrates/isolation & purification , Animals , Baclofen/metabolism , Baclofen/pharmacology , Binding, Competitive , Drug Design , GABA Agonists/chemical synthesis , GABA Agonists/isolation & purification , GABA Antagonists/chemical synthesis , GABA Antagonists/isolation & purification , Ligands , Male , Molecular Structure , Muscimol/metabolism , Muscimol/pharmacology , Nerve Tissue Proteins/drug effects , Protein Binding , Rats , Rats, Wistar , Receptors, GABA-B/metabolism , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/metabolism
19.
J Chromatogr A ; 824(1): 15-23, 1998 Oct 16.
Article in English | MEDLINE | ID: mdl-9818426

ABSTRACT

Analytical HPLC methods using derivatized cellulose chiral stationary phases were developed for the separation of the enantiomers of methoxy and ethyl tetrahydronaphthalenic derivatives, new agonist and antagonist ligands for melatonin receptors. The resolution were made using normal-phase methodology with a mobile phase consisting of n-hexane-alcohol (methanol, ethanol, 1-propanol or 2-propanol) in various percentage, and a silica-based cellulose tris-3,5-dimethyl-phenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). The mobile phase and the chiral stationary phase were varied to achieve the best resolution. The effects of concentration of alcohol, various aliphatic alcohols in the mobile phase were studied. The effects of substitution were analysed. Baseline separation (R(s) > 1.5) was easily obtained in many cases. The resolution results were complementary between the two columns.


Subject(s)
Chromatography, High Pressure Liquid/methods , Receptors, Cell Surface/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/isolation & purification , Cellulose , Ligands , Receptors, Melatonin , Silicon Dioxide , Spectrophotometry, Ultraviolet , Stereoisomerism , Tetrahydronaphthalenes/metabolism
20.
Can J Physiol Pharmacol ; 76(7-8): 798-801, 1998.
Article in English | MEDLINE | ID: mdl-10030461

ABSTRACT

(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABA(B) receptor agonist baclofen, has been evaluated for pharmacological activity on GABA(B) receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 microM) reversibly antagonized the (R,S)-baclofen induced depression of cholinergic twitch contractions in the guinea-pig ileum and shifted the concentration-response curve for baclofen to the right, in a parallel manner, giving an apparent pA2 value of 3.7+/-0.3. Likewise, 7-MBFG (300 and 500 microM) reversibly blocked the baclofen-induced suppression of spontaneous discharges, in rat neocortical slices maintained in Mg2+ -free Krebs medium, and caused a rightward, parallel shift of the baclofen concentration-response curve, giving an apparent pA2 value of 4.1+/-0.1. The compound 7-MBFG belongs to a novel, new class of antagonist at central and peripheral GABA(B) receptors, in which the antagonist properties reside in the pseudo-aromatic character of their 3-benzo[b]furan-2-yl substituents, and might provide useful leads for further development of GABA(B) receptor ligands.


Subject(s)
Benzofurans/pharmacology , Butyrates/pharmacology , GABA Antagonists/pharmacology , GABA-B Receptor Antagonists , Ileum/drug effects , Muscle Contraction/drug effects , Neocortex/drug effects , Animals , Baclofen/pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Male , Muscle, Smooth/drug effects , Rats , Rats, Sprague-Dawley
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