RESUMEN
PURPOSE: Irinotecan (CPT-11) is a camptothecin derivative whose potent anti-tumor activity depends on the rapid formation of an in vivo active metabolite, SN38 (7-ethyl-10-hydroxycamptothecin). CPT-11 combine with other agents are often the treatment of choice for patients with advanced or metastatic colorectal cancer (CRC). This study evaluates the cytotoxic mechanism of a novel CPT-11 derivative, ZBH-1207 in CRC cells in vitro. METHODS: The anti-proliferation effect of ZBH-1207 on tumor cells was assessed by MTT assay. The inhibition of TOP1, the alteration of cell cycle and apoptosis, and the expression of caspase-3 and PARP in CRC cells induced by ZBH-1207 were detected by DNA relaxation assay, flow cytometry, and Western blot, respectively. RESULTS: ZBH-1207 significantly inhibits the proliferation of seven tumor cell lines and retains the activity of TOP1 as compared with CPT-11. Treatment with ZBH-1207 results in more apparent cell cycle arrests and apoptosis of CRC cells than that of CPT-11 and SN38. Accordingly, up-regulation of active caspase-3 and PARP expression were relatively higher in ZBH-1207 group than that in CPT-11 and SN38 group. CONCLUSION: ZBH-1207 has higher cytotoxicity than CPT-11/SN38 in CRC cells. Its molecular mechanism involves apoptosis signaling pathway.
Asunto(s)
Antineoplásicos Fitogénicos , Neoplasias del Colon , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Irinotecán/farmacología , Irinotecán/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.
Asunto(s)
Ácidos y Sales Biliares/administración & dosificación , Ácidos Grasos/administración & dosificación , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/administración & dosificación , Hígado/efectos de los fármacos , Animales , Ácidos y Sales Biliares/química , Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ácidos Grasos/química , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/etiología , Hiperlipidemias/patología , Hipolipemiantes/química , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Lisina/química , Ratones , Triglicéridos/sangreRESUMEN
'Biased' ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent µ-opioid-receptor (µOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable ß-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased µOR agonists for treating pain.
Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Receptores Opioides mu/agonistas , Analgésicos Opioides/química , Línea Celular , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Estructura Molecular , Unión Proteica , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , beta-Arrestinas/metabolismoRESUMEN
BACKGROUND: Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. METHODS: The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. RESULTS: Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. CONCLUSION: Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.
Asunto(s)
Benzodioxoles/uso terapéutico , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Microglía/efectos de los fármacos , Mielitis , Propilaminas/uso terapéutico , Animales , Benzodioxoles/química , Proteínas de Unión al Calcio/metabolismo , Línea Celular Transformada , Neuropatías Diabéticas/inducido químicamente , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Clorhidrato de Duloxetina/uso terapéutico , Conducta Exploratoria/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Hipoglucemiantes/química , Lipopolisacáridos/farmacología , Locomoción/efectos de los fármacos , Proteínas de Microfilamentos/metabolismo , Mielitis/tratamiento farmacológico , Mielitis/etiología , Mielitis/patología , Propilaminas/química , Ratas , Estreptozocina/toxicidadRESUMEN
A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.
Asunto(s)
Compuestos Aza/sangre , Compuestos Aza/farmacocinética , Cromatografía Liquida/métodos , Glicolatos/sangre , Glicolatos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Compuestos Aza/administración & dosificación , Disponibilidad Biológica , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/sangre , Antagonistas Colinérgicos/farmacocinética , Perros , Glicolatos/administración & dosificación , Masculino , Técnica de Dilución de Radioisótopos , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
CPT-11 (irinotecan) is a derivative of camptothecin which is a natural product derived from the Chinese tree Camptotheca acuminta and widely used in antitumor therapy. Here, the in vitro anti-tumor activity and associated mechanisms of a novel derivative of camptothecin, ZBH-1205, were investigated in a panel of 9 human tumor cell lines, as well as in HEK 293 and SK-OV-3/DPP, a multi-drug resistant (MDR) cell line, and compared to CPT-11 and 7-ethyl-10-hydroxy-camptothecin (SN38). Comparisons between the different compounds were made on the basis of IC50 values as determined by the MTT assay, and flow cytometry was used to evaluate cell cycle progression, apoptosis, and the levels of pro- and active caspase-3 among different treatment groups. Interaction between the molecules and topoisomerase-1 (Topo-1)-DNA complexes was detected by a DNA relaxation assay. Our results demonstrated that IC50 values for ZBH-1205 ranged from 0.0009 µmol/L to 2.5671 µmol/L, which were consistently lower than IC50 values of CPT-11 or SN38 in the panel of cell lines, including SK-OV-3/DPP. Furthermore, ZBH-1205 was more effective than CPT-11 or SN38 at stabilizing Topo-1-DNA complexes and inducing tumor cell apoptosis. Therefore, ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials.
Asunto(s)
Antineoplásicos/química , Camptotecina/análogos & derivados , Camptotecina/química , Apoptosis , Camptotheca/química , Caspasa 3/metabolismo , Ciclo Celular , Línea Celular Tumoral , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Concentración 50 Inhibidora , Irinotecán , Células K562 , Cinética , Extractos VegetalesRESUMEN
Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.
Asunto(s)
Antidepresivos , Benzodioxoles/farmacología , Monoaminas Biogénicas/metabolismo , Norepinefrina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina , Serotonina/metabolismo , Tiofenos/farmacología , Animales , Benzodioxoles/administración & dosificación , Encéfalo/metabolismo , Hipotermia/inducido químicamente , Masculino , Ratones Endogámicos ICR , Ratas Sprague-Dawley , Reserpina , Tiofenos/administración & dosificación , Yohimbina/toxicidadRESUMEN
AIM: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. METHODS: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. RESULTS: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. CONCLUSION: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Benzodioxoles/uso terapéutico , Fibromialgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Propilaminas/uso terapéutico , Neuropatía Ciática/tratamiento farmacológico , Inhibidores de Captación de Serotonina y Norepinefrina/uso terapéutico , Analgésicos no Narcóticos/administración & dosificación , Animales , Benzodioxoles/administración & dosificación , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos , Estructura Molecular , Dimensión del Dolor , Propilaminas/administración & dosificación , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificaciónRESUMEN
The herb-derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (p.o.) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, p.o.), glycyrrhizin (15 mg/kg, intraperitoneal [i.p.]), or oxymatrine (60 mg/kg, p.o.). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration-time curve (AUC0-t ) and the peak plasma concentration (Cmax ) of ribavirin and ribavirin base by 31.2-44.5% and 48.9-50.0%, respectively. Glycyrrhizin significantly decreased the Cmax and AUC0-t of both ribavirin and its metabolite by 35.3-37.6% and 38.6-39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and Cmax . Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the Cmax (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine.
Asunto(s)
Alcaloides/farmacología , Ácido Glicirrínico/farmacología , Quinolizinas/farmacología , Ribavirina/farmacocinética , Silimarina/farmacología , Alcaloides/administración & dosificación , Animales , Área Bajo la Curva , Interacciones Farmacológicas , Ácido Glicirrínico/administración & dosificación , Interacciones de Hierba-Droga , Masculino , Quinolizinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Ribavirina/administración & dosificación , Silimarina/administración & dosificaciónRESUMEN
The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Analgésicos/síntesis química , Analgésicos/farmacología , Indoles/química , Amidas/química , Analgésicos/química , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacologíaRESUMEN
Three series of apigenin derivatives have been prepared by coupling the carboxyl alkyl group to 4'-, 5- or 7-hydroxyl groups of apigenin respectively. Preliminary biological evaluation in vitro revealed that xanthine oxidase inhibitory activity was improved by modifications at 4'-position and decreased by similar modifications at 5-, 7-positions while α-glucosidase inhibitory activity was maintained by modifications at 5-, 7-positions but lost by modifications at 4'-position. Administration (ip) of 7e markedly lowered serum uric acid levels in potassium oxonate induced hyperuricemic mouse model and administration (p.o.) of 11d or 11e effectively suppressed the elevation of serum glucose in the oral sucrose tolerance test in mice, while apigenin were not significantly effective in both tests.
Asunto(s)
Apigenina/química , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/química , Xantina Oxidasa/antagonistas & inhibidores , alfa-Glucosidasas/química , Animales , Apigenina/metabolismo , Apigenina/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Flavonoides/química , Prueba de Tolerancia a la Glucosa , Inhibidores de Glicósido Hidrolasas/metabolismo , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Hiperuricemia/inducido químicamente , Hiperuricemia/tratamiento farmacológico , Hipoglucemiantes/metabolismo , Hipoglucemiantes/uso terapéutico , Infusiones Parenterales , Ratones , Unión Proteica , Relación Estructura-Actividad , Ácido Úrico/sangre , Xantina Oxidasa/metabolismo , alfa-Glucosidasas/metabolismoRESUMEN
In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
Asunto(s)
Camptotecina/análogos & derivados , Profármacos/síntesis química , Profármacos/farmacología , Animales , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacología , Camptotecina/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Estabilidad de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Irinotecán , Ratones Desnudos , Profármacos/química , Profármacos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel phenoxyalkylcarboxylic acid derivatives based on the natural scaffolds, flavonoids, or resveratrol were designed, synthesized, and evaluated for hypolipidaemic activity. Among the compounds, 30b lowered the triglycerides by 48.5% (P < 0.05) and total cholesterol by 44.2% (P < 0.05), respectively, and was more effective than the reference drug fenofibric acid in a Triton WR-1339-induced hyperlipidaemic mice model orally (300 mg/kg body weight). 30b also showed 59.4% triglycerides lowering in an alloxan-induced diabetic mice model orally (150 mg/kg body weight). Receptor docking studies revealed that compound 30b could interact with the amino acid residues in the ligand-binding domain essential for the activation of the PPARα. The results indicate that resveratrol should be a better scaffold to derive a new class of hypolipidaemic agents in comparison with a flavonoid scaffold.
Asunto(s)
Ácidos Carboxílicos/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/síntesis química , Hipolipemiantes/farmacología , Animales , Colesterol/metabolismo , Fenofibrato/análogos & derivados , Fenofibrato/toxicidad , Flavonoides/química , Hiperlipidemias/inducido químicamente , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Polietilenglicoles/toxicidad , Resveratrol , Estilbenos/química , Tensoactivos/toxicidad , Triglicéridos/metabolismoRESUMEN
A rapid and sensitive LC-MS/MS method for the quantification of fenofibric acid in rat plasma was developed and validated. Plasma samples were prepared by liquid-liquid extraction with a mixture of N-hexane-dichloromethane-isopropanol (100:50:5, v/v/v). Isocratic chromatographic separation was performed on a reversed-phase Discovery C(18) column (2.1 × 50 mm, 5 µm). The mobile phase was methanol-water-formic (75:25:0.25, v/v/v). Detection of fenofibric acid and the internal standard (IS) diclofenac acid was achieved by ESI MS/MS in the negative ion mode using m/z 317 â m/z 213 and m/z 294 â m/z 250 transitions, respectively. The method was linear from 0.005 to 1.250 µg/mL when 100 µL plasma was analyzed. The lower limit of quantification was 0.005 µg/mL. The intra- and inter-day precision values were below 8.2%, and accuracy ranged from -0.9 to 2.1% in all quality control samples. The recovery was 90.3-94.7% and 83.3% for fenofibric acid and IS, respectively. Total run time for each sample analysis was 2.5 min. The validated method was successfully applied to a pharmacokinetic study in six rats after oral administration of fenofibrate, the ester prodrug of fenofibric acid (equivalent to fenofibric acid 5 mg/kg). The method permits laboratory scientists with access to the appropriate instrumentation to perform rapid fenofibric acid determination.
Asunto(s)
Anticolesterolemiantes/sangre , Fenofibrato/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Liquida/métodos , Fenofibrato/sangre , Modelos Lineales , Extracción Líquido-Líquido/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Sensibilidad y EspecificidadRESUMEN
In the title compound, C(15)H(25)ClN(5)O(4)P, the r.m.s. deviation for the purine ring system is 0.0165â Å. The coordination about the P atom is a distorted tetrahedron [O=P-O angles = 116.70â (6) and 109.87â (6)°]. In the crystal, molecules are linked by N-Hâ¯O hydrogen bonds, generating a three-dimensional network.
RESUMEN
In the crystal of the title compound, C(11)H(16)N(2)O(4)S, molecules are linked via pairs of N-Hâ¯N hydrogen bonds to form inversion dimers. The dimers are linked by a weak C-Hâ¯O interaction to form chains propagating along direction [100].
RESUMEN
A simple, specific, sensitive LC/MS/MS method for the quantitation of tenofovir (TFV) in monkey plasma was developed and validated. After the addition of adefovir as an internal standard (IS), methanol was used to produce a protein-free extract. Isocratic chromatographic separation was performed on a reverse-phase Discovery C(18) column (4.6×250 mm, 5 µm). The mobile phase consisted of methanol-water-formic acid (20 : 80 : 0.5, v/v/v). Detection of TFV and the IS was achieved with electrospray ionization (ESI)-MS/MS in the positive ion mode using 288/176 and 274/162 transitions, respectively. The analytical range was set at 0.005-1.250 µg/ml using a 200 µl plasma sample. The intra- and inter-day precision values were less than 11.4%, and accuracy ranged from 0.4 to 2.9% in all quality control samples. The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect, recovery, and stability. Due to the high polarity of TFV, the major challenge was to circumvent ion suppression when quantitating the plasma concentration of TFV using the LC/MS/MS method. To avoid ion suppression, sufficient chromatographic separation was the most effective means for the present purposes. Moreover, it was found that the reconstitution solvents of the dried residue had a significant impact on LC peak shapes. The validated method was successfully applied to a bioequivalence study in 6 monkeys after the oral administration of two ester prodrugs of TFV (equivalent to TFV 20 mg/kg). The method permits laboratory scientists with access to the appropriate instrumentation to perform rapid TFV determination.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/sangre , Organofosfonatos/sangre , Inhibidores de la Transcriptasa Inversa/sangre , Adenina/sangre , Adenina/química , Adenina/farmacocinética , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Estabilidad de Medicamentos , Semivida , Límite de Detección , Macaca mulatta , Masculino , Organofosfonatos/química , Organofosfonatos/farmacocinética , Profármacos/farmacocinética , Reproducibilidad de los Resultados , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Tenofovir , Equivalencia TerapéuticaRESUMEN
Background and Aims: Therapeutic drugs that are used to treat cholestatic liver disease are limited; however, the results of clinical trials on primary biliary cholangitis treatment targeting peroxisome proliferator-activated receptors (PPARs) are encouraging. In this study, we aimed to identify the effects of MBT1805, a novel balanced PPARα/γ/δ agonist, on cholestasis induced by α-naphthylisothiocyanate (ANIT) and elucidate the underlying mechanisms through untargeted and bile acid-targeted metabolomic analysis. Methods: Levels of serum biochemical indicators (transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin) and liver histopathology were analyzed to evaluate the therapeutic effects of MBT1805 on ANIT-induced cholestasis in C57BL/6 mice. Untargeted and bile acid-targeted metabolomic analysis of liver tissues was performed using ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MC/MC). qRT-PCR and Western blot analysis were carried out to measure the expression of key enzymes and transporters regulating bile acid synthesis, biotransformation, and transport. Results: MBT1805 significantly improved abnormal levels of liver biochemical indicators and gallbladder enlargement induced by ANIT. Histopathological analysis showed that MBT1805 effectively relieved ANIT-induced necrosis, vacuolation, and inflammatory infiltration. Untargeted metabolomic analysis identified 27 metabolites that were involved in the primary biliary acid biosynthesis pathway. In addition, bile acid-targeted metabolomics showed that MBT1805 could alleviate the abnormal bile acid content and composition induced by ANIT. Furthermore, qRT-PCR and Western blot results confirmed that MBT1805 could effectively regulate bile acid synthesis, biotransformation, and transport which helps relieve cholestasis. Conclusions: MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.
RESUMEN
In this paper, duloxetine was chosen as the lead compound. The pharmacophores with 5-HT(1A) antagonism activity were used to replace the naphthyl of duloxetine. A series of duloxetine derivatives had been designed and synthesized and whose structures were confirmed with elemental analysis, MS and H NMR. All synthesized compounds were tested by tail suspension test and forced swimming test in vivo. The test results revealed that most of the compounds have shown better activity than duloxetine at the same dosage. Some of them are worth to be studied further.
Asunto(s)
Antidepresivos/síntesis química , Tiofenos/síntesis química , Animales , Antidepresivos/química , Antidepresivos/farmacología , Clorhidrato de Duloxetina , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Relación Estructura-Actividad , Natación , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
G protein-biased mu-opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities inâ vivo and greater bias toward G protein signaling inâ vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-phenethylurea) and 7 j ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less ß-arrestin-2 recruitment.