RESUMEN
Various features of the evolution of a few antimalarial drugs including amodiaquine, dihydrofolate-reductase inhibitors, and artemisinin are described. The mechanism of action of artemisinin is detailed to explain the information of the main metabolites and drug design of certain compounds. Structure-activity and structure-neurotoxicity relations are reported. A few examples of cyclic peroxycetal synthesis are given. Finally, trends in new and novel compounds are presented.
Asunto(s)
Antimaláricos/química , Artemisininas , Amodiaquina/química , Animales , Antimaláricos/síntesis química , Antimaláricos/toxicidad , Resistencia a Medicamentos , Medicamentos Herbarios Chinos , Antagonistas del Ácido Fólico/química , Plasmodium falciparum/efectos de los fármacos , Sesquiterpenos/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Pirrolidinas/síntesis química , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/síntesis química , Indicadores y ReactivosRESUMEN
The authors report a series of 1972 inguinal hernias treated between 1993 and 1997 by the insertion of a PARIETEX mesh via either a transabdominal-preperitoneal (TAPP) (1,290 procedures) or a totally extraperitoneal TEP approach (682 procedures). Pain scores were equivalent in both groups, while the hospital stay and time to return to normal activity was lower in the TEP group than in the TAPP group (p<0.001). In both groups, the average incidence of the total reported events (complications) was around 10% with no statistical difference. This ratio seemed to compare favorably to previously published reports. Chronic pain was extremely rare (0.6% and 0.7% in the TAPP and TEP groups, respectively). Whatever the approach was, sepsis was also very rare (1/1,526 laparoscopic procedures). These findings illustrate the local tolerance of the mesh. Recurrence rates were below 1% with no statistical difference between groups. This retrospective study demonstrates the clinically apparent local tolerance of this type of mesh. Prospective and long-term clinical results will be necessary to demonstrate that the optimized short-term tolerance of PARIETEX mesh will influence the long term functional results.
Asunto(s)
Materiales Biocompatibles , Colágeno , Hernia Inguinal/cirugía , Laparoscopía/métodos , Poliésteres , Implantación de Prótesis/instrumentación , Músculos Abdominales/cirugía , Humanos , Peritoneo/cirugía , Complicaciones Posoperatorias , Diseño de Prótesis , Estudios Retrospectivos , Prevención SecundariaRESUMEN
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.
Asunto(s)
Aminobutiratos/farmacología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Receptores de GABA-B/efectos de los fármacos , Aminobutiratos/síntesis química , Aminobutiratos/aislamiento & purificación , Animales , Baclofeno/metabolismo , Baclofeno/farmacología , Unión Competitiva , Diseño de Fármacos , Agonistas del GABA/síntesis química , Agonistas del GABA/aislamiento & purificación , Antagonistas del GABA/síntesis química , Antagonistas del GABA/aislamiento & purificación , Ligandos , Masculino , Estructura Molecular , Muscimol/metabolismo , Muscimol/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Unión Proteica , Ratas , Ratas Wistar , Receptores de GABA-B/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The GABAB receptor antagonist saclofen (3-amino-2-(4-chlorophenyl)propylsulphonic acid) has been resolved by chiral high-performance liquid chromatography. The enantiomer (R)-saclofen, but not (S)-saclofen, reversibly antagonised the (R,S)-baclofen-induced depression of cholinergic twitch contractions in the guinea-pig ileum with an apparent pA2 of 5.3. Also, 2-hydroxy-saclofen was resolved by the same method, its (S)-enantiomer yielding an apparent pA2 of 5.0. This method provides a convenient resolution of these antagonists.
Asunto(s)
Baclofeno/análogos & derivados , Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-B , Íleon/efectos de los fármacos , Animales , Baclofeno/farmacología , Cromatografía Líquida de Alta Presión , Cobayas , Íleon/fisiología , Técnicas In Vitro , EstereoisomerismoRESUMEN
Substituting a furan, a thiophene, a benzo[b]furan, a benzo[b]thiophene, or a quinoline ring for the p-chlorophenyl moiety of baclofen has led to GABAB ligands with different affinities depending on the nature of the heteroaromatic ring, and on the nature and position of its substituent. As steric effects cannot account for all the affinity variations, we have studied the lipophilic and electronic properties of baclofen and selected 3-heteroaromatic analogues, gaining insight into the structural features necessary for GABAB affinity. Centrifugal partition chromatography (CPC) has been used to measure octan-1-ol water distribution coefficients, while ab initio molecular orbital (MO) calculations were performed to study electronic properties.
Asunto(s)
Baclofeno/análogos & derivados , Baclofeno/química , Agonistas del GABA/química , Baclofeno/farmacología , Conformación Molecular , Receptores de GABA-B/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
The depression of the amplitude of extracellularly recorded monosynaptic excitatory field potentials in the lumbar spinal cord of pentobarbitone anaesthetised rats and cats by three thienyl derivatives of GABA: 4-amino-3-(2-thienyl)-butanoic acid; 4-amino-3-(2-thienyl-5-methyl)-butanoic acid and 4-amino-3-(2-thienyl-5-chloro)-butanoic acid was reversibly blocked by the (-)-baclofen antagonist 3-aminopropyl-diethoxymethyl-phosphinic acid (CGP 35348). These compounds, of which the most potent, the 5-chloro derivative, was weaker than (-)-baclofen, thus activate baclofen receptors in the cat and rat spinal cord.
Asunto(s)
Baclofeno/farmacología , Médula Espinal/efectos de los fármacos , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/farmacología , Animales , Gatos , Electroforesis , Potenciales Evocados/efectos de los fármacos , Antagonistas de Receptores de GABA-A , Compuestos Organofosforados/farmacología , Ratas , Ratas Wistar , Receptores de GABA/efectos de los fármacos , Receptores de GABA-B/efectos de los fármacosRESUMEN
In the guinea-pig isolated ileum, beta-(2-thienyl)-gamma-aminobutyric acid (BTG; 100-500 microM) reversibly and competitively (pA2 = 4.3 +/- 0.1) antagonised the baclofen-induced (5-100 microM) depression of cholinergic twitch contractions, but not that to adenosine or morphine. By contrast, in rat neocortical slice preparations, BTG (100-500 microM) acted as an agonist, abolishing the frequency and amplitude of spontaneous discharges, sensitive to 2-hydroxysaclofen (100-500 microM). BTG exhibits differential actions at GABAB receptors in brain and periphery.
Asunto(s)
Antagonistas del GABA , Receptores de GABA-A/efectos de los fármacos , Tiofenos/farmacología , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Relación Dosis-Respuesta a Droga , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
In guinea-pig isolated ileal preparations, the 5-methylthien-2-yl (5d), 5-bromothien-2-yl (5f) and 5-chlorothien-2-yl (5h) analogs of baclofen depressed twitch responses to field stimulation in a dose-dependent manner. These actions were reversibly and competitively antagonised by 2-hydroxysaclofen but not by naloxone, phentolamine, propranolol or theophylline. The relative potencies (EC50 values) were baclofen (10 microM) greater than 5h (40 microM) greater than 5d (80 microM) greater than 5f (120 microM). These analogs represent a novel class of specific GABAB receptor agonists which, like baclofen, should readily enter the brain.
Asunto(s)
Baclofeno/análogos & derivados , Músculo Liso/efectos de los fármacos , Animales , Baclofeno/farmacología , Relación Dosis-Respuesta a Droga , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacosRESUMEN
Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids. 4-Amino-3-(5-methyl-2-thienyl)butyric acid (5d) and 4-amino-3-(5-chloro-2-thienyl)butyric acid (5h) are potent and specific ligands for GABAB receptor. The IC50 values for the displacement of (R)-(-)-[3H]baclofen are 1.34 and 0.61 microM for 5d and 5h, respectively, as compared to 0.33 microM for baclofen.
Asunto(s)
Furanos/síntesis química , Receptores de GABA-A/metabolismo , Tiofenos/síntesis química , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Baclofeno/metabolismo , Unión Competitiva , Encéfalo/metabolismo , Fenómenos Químicos , Química , Furanos/metabolismo , Estructura Molecular , Muscimol/metabolismo , Ratas , Membranas Sinápticas/metabolismo , Tiofenos/metabolismo , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Several oximes, hydrazones and dichloroacétamides were synthesized. The antiparasitic properties of these compounds were evaluated in vitro against two Protozoaires Entamoeba histolytica and Trichomonas vaginalis.
Asunto(s)
Acetamidas/farmacología , Antiprotozoarios/síntesis química , Hidrazonas/síntesis química , Oximas/síntesis química , Animales , Antiprotozoarios/farmacología , Entamoeba histolytica/efectos de los fármacos , Hidrazonas/farmacología , Oximas/farmacología , Trichomonas vaginalis/efectos de los fármacosRESUMEN
In this study, eight new 1-(2-benzoxazolinone-6-yl)-2-(4-arylpiperazine-1-yl)ethanol and -propanol derivatives have been prepared. Their structures have been elucidated by IR- and 1H-NMR-spectra and by elementary analysis. The analgesic activities of these compounds, using modified Koster's test have been investigated. 1-(5-Chloro-3-methyl-2-benzoxazolone-6-yl)-2-[4-(2-methoxyphenyl)p iperazine-1- yl]ethanol has been found more active than O-acetyl-salicylic acid, respectively.
Asunto(s)
Analgésicos/síntesis química , Benzoxazoles/síntesis química , Piperazinas/síntesis química , 1-Propanol/síntesis química , 1-Propanol/farmacología , 1-Propanol/toxicidad , Analgésicos/farmacología , Analgésicos/toxicidad , Animales , Aspirina/farmacología , Benzoxazoles/farmacología , Benzoxazoles/toxicidad , Etanol/síntesis química , Etanol/farmacología , Etanol/toxicidad , Femenino , Espectroscopía de Resonancia Magnética , Ratones , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/fisiopatología , Oxidación-Reducción , Dimensión del Dolor , Piperazinas/farmacología , Piperazinas/toxicidad , Espectrofotometría InfrarrojaRESUMEN
The synthesis of vinylogous of 1,2-dithiole-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity) was tested with mice infected with Schistosoma mansoni. The reference compound was 4-methyl-5-(pyrazinyl)-1,2-dithiole-3-thione (oltipraz).
Asunto(s)
Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/síntesis química , Animales , Femenino , Hígado/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Esquistosomiasis/tratamiento farmacológico , Esquistosomiasis/parasitología , Esquistosomicidas/uso terapéuticoRESUMEN
Dosage of lactulose and determination of related sugars (lactose, fructose, galactose, épilactose) were undertaken by high performance liquid chromatography (HPLC). The present note described two modes of detection used simultaneously and compared: refractive index detector (RI) and multiwavelength ultraviolet detector (UV). HPLC is performed with an aminopropylsylil phase as stationary phase and an isocratic mobile phase containing acetonitrile and aqueous sodium phosphate. The results are outlined and discussed.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Lactulosa/química , Refractometría/métodos , Rayos UltravioletaRESUMEN
Two novel beta-(benzo[b]furan) analogues of baclofen (4-amino-3-benzo[b]furan-2-ylbutanoic acid, 9G, and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid, 9H) antagonised the baclofen-induced depression of twitch contractions in the guinea-pig isolated ileum (estimated apparent pA2 3.9 and 4.1 respectively); both 9G and 9H also antagonised in a dose-dependent manner the baclofen-induced reduction of repetitive paroxysmal discharges in rat neo-cortical slice preparations maintained in Mg2+-free Krebs solution. These benzofurans evidently represents a new class of GABAB-receptor antagonist.
Asunto(s)
Baclofeno/análogos & derivados , Benzofuranos/farmacología , Antagonistas de Receptores de GABA-A , Animales , Baclofeno/farmacología , Corteza Cerebral/efectos de los fármacos , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Magnesio/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Ratas , Ratas EndogámicasRESUMEN
When administered microelectrophoretically, 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (MBFG) reversibly reduced the presynaptic depression by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in muscle low-threshold afferent fibres of the cat as well as the postsynaptic depression by (-)-baclofen of the firing of these neurones. MBFG, as an antagonist of (-)-baclofen, may be useful in investigating the structure-activity relationships of central and peripheral baclofen receptors.
Asunto(s)
Baclofeno/farmacología , Benzofuranos/farmacología , Interneuronas/fisiología , Reflejo Monosináptico/efectos de los fármacos , Médula Espinal/fisiología , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Gatos , Estimulación Eléctrica , Interneuronas/efectos de los fármacos , Neuronas Aferentes/fisiología , Médula Espinal/efectos de los fármacos , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The synthesis of new arylpropenones derived from 1-methyl-5-nitro imidazole is described. The investigation of some antiprotozoal properties has shown that compounds with the groups 4-hydroxyphenyl, 4-chlorophenyl or thiophenyl have trichomonacidal activity similar to that of metronidazole.
Asunto(s)
Amebicidas/síntesis química , Antitricomonas/síntesis química , Nitroimidazoles/síntesis química , Animales , Fenómenos Químicos , Química , Entamoeba histolytica/efectos de los fármacos , Nitroimidazoles/farmacología , Trichomonas vaginalis/efectos de los fármacosRESUMEN
Syntheses are given for derivatives of the type: 2-amino-1-[(1-methyl-5-nitro-2-imidazolyl) methyleneimino] imidazole, of new hydrazones of 1-methyl-5-nitroimidazole-2-carboxaldehyde and also for semicarbazones and a hydrazone of 1-methyl-5-nitro-2-(4-formyl-styryl)imidazole.
Asunto(s)
Amebicidas/síntesis química , Antitricomonas/síntesis química , Nitroimidazoles/síntesis química , Animales , Fenómenos Químicos , Química , Entamoeba histolytica/efectos de los fármacos , Hidrazonas/síntesis química , Hidrazonas/farmacología , Nitroimidazoles/farmacología , Semicarbazonas/síntesis química , Semicarbazonas/farmacología , Trichomonas vaginalis/efectos de los fármacosRESUMEN
The synthesis of vinylogues of 1,2-dithiol-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity and, for the most interesting ones, on the egg-laying) was tested in mice with Schistosoma mansoni in comparison with oltipraz.