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1.
Anal Chim Acta ; 661(2): 167-72, 2010 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-20113731

RESUMEN

Simvastatin (SS) is an effective cholesterol-lowering medicine, and is hydrolyzed to simvastatin acid (SSA) after oral administration. Due to SS and SSA inter-conversion and its pH and temperature dependence, SS and SSA quantitation is analytically challenging. Here we report a high-throughput salting-out assisted liquid/liquid extraction (SALLE) method with acetonitrile and mass spectrometry compatible salts for simultaneous LC-MS/MS analysis of SS and SSA. The sample preparation of a 96-well plate using SALLE was completed within 20 min, and the SALLE extract was diluted and injected into an LC-MS/MS system with a cycle time of 2.0 min/sample. The seamless interface of SALLE and LC-MS eliminated drying down step and thus potential sample exposure to room or higher temperature. The stability of SS and SSA in various concentration ratios in plasma was evaluated at room and low (4 degrees C) temperature and the low temperature (4 degrees C) was found necessary to maintain sample integrity. The short sample preparation time along with controlled temperature (2-4 degrees C) and acidity (pH 4.5) throughout sample preparation minimized the conversion of SS-->SSA to < or = 0.10% and the conversion of SSA-->SS to 0.00% The method was validated with a lower limit of quantitation (LLOQ) of 0.094 ng mL(-1) for both SS and SSA and a sample volume of 100 microL. The method was used for a bioequivalence study with 4048 samples. Incurred sample reproducibility (ISR) analysis of 362 samples from the study exceeded ISR requirement with 99% re-analysis results within 100+/-20% of the original analysis results.


Asunto(s)
Acetonitrilos/química , Análisis Químico de la Sangre/métodos , Fraccionamiento Químico/métodos , Ensayos Analíticos de Alto Rendimiento , Sales (Química)/química , Simvastatina/análogos & derivados , Simvastatina/sangre , Métodos Analíticos de la Preparación de la Muestra , Calibración , Fenómenos Químicos , Cromatografía Liquida , Estabilidad de Medicamentos , Humanos , Reproducibilidad de los Resultados , Simvastatina/química , Simvastatina/aislamiento & purificación , Simvastatina/farmacocinética , Temperatura , Equivalencia Terapéutica , Factores de Tiempo
2.
Bioorg Med Chem Lett ; 16(7): 1934-7, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16439127

RESUMEN

In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.


Asunto(s)
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Disponibilidad Biológica , Antagonistas de Dopamina/síntesis química , Humanos , Microsomas Hepáticos/metabolismo , Pirimidinonas/síntesis química , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 16(3): 658-62, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16271293

RESUMEN

The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.


Asunto(s)
Benzazepinas/síntesis química , Antagonistas de Dopamina/síntesis química , Quinolonas/síntesis química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Modelos Moleculares , Estructura Molecular , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad
5.
J Cardiovasc Pharmacol ; 46(2): 232-40, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16044036

RESUMEN

The pharmacological profile of the novel dihydropyridine K channel opener (KCO), (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), is described in numerous in vitro assays. Furthermore, the cardiovascular effects of A-325100 are characterized in both the anesthetized and conscious dog. In vitro, A-325100 selectively activated KATP currents and potently relaxed vascular smooth muscle (IC50 between 7.69x10 M and 7.78x10 M), an effect that was abolished by glyburide. Moreover, A-325100 did not interact with L-type Ca2+ channels at concentrations up to 30 microM. In anesthetized dogs A-325100 produced a dose-dependent reduction in systemic vascular resistance and mean arterial pressure concomitant with dose-dependent increases in dP/dtmax and heart rate. In conscious telemetry-instrumented dogs oral administration of A-325100 produced a similar response profile, including dose-dependent reductions in MAP and increases in heart rate and dP/dtmax. When concentration-dependent changes in MAP, heart rate, and dP/dtmax were compared relative to circulating plasma concentrations, A-325100 produced similar effects in both the anesthetized and conscious dog. In conclusion, the present study provides the first pharmacological description of the novel and selective tricyclic dihydropyridine KCO, A-325100. When studied in vivo, A-325100 produced similar concentration-dependent cardiovascular effects in both models consistent with its mode of action and independent of route of administration. Thus, these data demonstrate that the hemodynamic effects of vasoactive compounds, such as KCOs, can be effectively profiled in both the conscious and anesthetized dog.


Asunto(s)
Dihidropiridinas/farmacología , Hemodinámica/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Canales de Potasio/metabolismo , Pironas/farmacología , Adenosina Trifosfato/metabolismo , Anestesia , Animales , Aorta Torácica/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Dihidropiridinas/sangre , Perros , Relación Dosis-Respuesta a Droga , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Ligandos , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Técnicas de Placa-Clamp , Vena Porta/efectos de los fármacos , Pironas/sangre , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiología
6.
J Med Chem ; 47(12): 3163-79, 2004 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-15163196

RESUMEN

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.


Asunto(s)
Adenosina Trifosfato/fisiología , Óxidos S-Cíclicos/síntesis química , Canales de Potasio/efectos de los fármacos , Quinolonas/síntesis química , Vejiga Urinaria/efectos de los fármacos , Animales , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Estimulación Eléctrica , Cobayas , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Potenciales de la Membrana , Contracción Muscular/efectos de los fármacos , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Quinolonas/química , Quinolonas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Porcinos , Vejiga Urinaria/citología , Vejiga Urinaria/fisiología , Urodinámica/efectos de los fármacos
7.
Life Sci ; 72(17): 1931-41, 2003 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-12597992

RESUMEN

Symptoms of urinary frequency and urgency secondary to benign prostatic obstruction are common in elderly men. In many patients, these symptoms correspond to the urodynamic finding of involuntary detrusor contractions during filling cystometry (i.e., detrusor instability). Spontaneous non-voiding contractions during filling can be modeled in animals by subchronic, partial urethral obstruction. However, many investigators remove the obstructive ligature a few days prior to cystometrical evaluation (which may not be an ideal representation of the clinical situation where obstruction is still present), and all perform cystometry within 3 days post-bladder catheterization surgery (i.e., while considerable wound healing is present). In the current study, we evaluated the effects, after oral dosing, of three structurally diverse ATP-sensitive potassium channel openers (KCOs) on spontaneous contractions secondary to obstruction in rats with an intact obstructive ligature at the time of testing and 2 weeks post-bladder catheterization. ZD6169, WAY-133537 and a novel dihydropyridine KCO, A-278637, all significantly decreased spontaneous bladder contractions at 30 min post-dosing (p.o.). However, only ZD6169 (10 micromol/kg) and A-278637 (3 micromol/kg) attenuated such bladder contractions at doses that did not concurrently, significantly affect mean arterial blood pressure and heart rate. These data confirm the efficacy of KCOs to inhibit unstable contractions in obstructed rats, and they further demonstrate the positive effect of a novel, bladder-selective KCO, A-278637, in an animal model with potentially less artifact than in previous such models.


Asunto(s)
Músculo Liso/efectos de los fármacos , Canales de Potasio/agonistas , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Vejiga Urinaria/efectos de los fármacos , Transportadoras de Casetes de Unión a ATP , Amidas/farmacología , Animales , Benzofenonas/farmacología , Presión Sanguínea/efectos de los fármacos , Óxidos S-Cíclicos/farmacología , Ciclobutanos/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Canales KATP , Masculino , Contracción Muscular/efectos de los fármacos , Nitrilos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Plasma/metabolismo , Canales de Potasio de Rectificación Interna , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Telemetría
8.
Neurourol Urodyn ; 22(2): 147-55, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12579633

RESUMEN

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Cresoles/farmacología , Óxidos N-Cíclicos/farmacología , Antagonistas Muscarínicos/farmacología , Oxazinas/farmacología , Fenilpropanolamina , Canales de Potasio/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Animales , Benzoxazinas , Cromakalim/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Activación del Canal Iónico/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Parasimpatolíticos/farmacología , Sus scrofa , Tartrato de Tolterodina , Vejiga Urinaria/fisiología , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Urodinámica/efectos de los fármacos
9.
Oecologia ; 43(3): 317-328, 1979 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28309888

RESUMEN

The mangrove tree crab (Aratus pisonii) is a key member of the arboreal arthropod community of the red mangrove (Rhizophora mangle) swamps of south Florida. Its ecological roles include primary herbivory, predation, and export of biomass and energy in the form of offspring and frass. Although the larval stage is planktonic, distribution of adults and Aratus leaf damage are patchy.

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