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1.
Biol Pharm Bull ; 36(7): 1208-15, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23811571

RESUMEN

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Compuestos de Bifenilo/farmacología , Pirimidinas/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Tetrazoles/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Sitios de Unión , Compuestos de Bifenilo/uso terapéutico , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Técnicas In Vitro , Masculino , Estructura Molecular , Unión Proteica , Pirimidinas/uso terapéutico , Conejos , Ratas , Ratas Sprague-Dawley , Tetrazoles/uso terapéutico , Vasoconstricción/efectos de los fármacos
2.
Am J Cardiovasc Drugs ; 11(5): 335-46, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21910510

RESUMEN

BACKGROUND AND OBJECTIVES: Fimasartan (BR-A-657) is a novel, non-peptide angiotensin II receptor antagonist with a selective type I receptor blockade effect. Two first-in-human studies investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of fimasartan. METHODS: Fasted single oral tablet doses of fimasartan 20-480 mg or placebo were administered to 40 healthy male subjects (aged 19-54 years) in a double-blind, randomized, sequential-group design. Subjects receiving fimasartan 240 mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360 mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20-55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses. RESULTS: Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360 mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24-30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240 mg in the fed state. Urinary excretion of fimasartan was very low (1.74-2.51%), suggesting non-renal elimination. CONCLUSION: Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20-480 mg, a fed single oral dose of 240 mg, and fasted repeated oral doses of 120 and 360 mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients with hypertension.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/farmacocinética , Interacciones Alimento-Droga , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Tetrazoles/efectos adversos , Tetrazoles/farmacocinética , Administración Oral , Adulto , Angiotensina I/sangre , Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/orina , Antihipertensivos/efectos adversos , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/orina , Presión Sanguínea/efectos de los fármacos , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Humanos , Absorción Intestinal , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pirimidinas/sangre , Pirimidinas/orina , Renina/sangre , Tetrazoles/sangre , Tetrazoles/orina , Adulto Joven
3.
Biomed Chromatogr ; 25(11): 1208-14, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21268050

RESUMEN

Fimasartan, 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H tetrazol -5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (BR-A-657), is a novel angiotensin II receptor blocker exhibiting potent and selective AT1 receptor blocking activity. This study reports the liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of fimasartan and its active metabolite, BR-A-557, in rat plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification, accuracy, precision and stability. The multiple reaction monitoring was based on the transition of m/z 502.1 → 207.1 for fimasartan, 486.2 → 207.1 for BR-A-557 and 526.1 → 207.1 for BR-A-563 (internal standard). The assay utilized a simple precipitation procedure with acetonitrile and isocratic elution. The LLOQ was 0.2 ng/mL for fimasartan and BR-A-557 using 50 µL plasma samples. The assay was linear over a concentration range from 0.2 to 500 ng/mL for fimasartan and BR-A-557, with correlation coefficients >0.9995. The intra- and inter-day assay accuracies were 93.6-108.0 and 90.8-101.4% for fimasartan and 102.2-107.1 and 99.6-103.3% for BR-A-557, respectively. The intra- and inter-day precision were 2.4-4.4 and 3.0-13.4% for fimasartan and 3.1-5.2 and 2.8-9.8% for BR-A-557, respectively. The developed assay may be used to study the metabolism and mechanistic pharmacokinetics of fimasartan in future studies.


Asunto(s)
Antihipertensivos/sangre , Compuestos de Bifenilo/sangre , Cromatografía Liquida/métodos , Pirimidinas/sangre , Espectrometría de Masas en Tándem/métodos , Tetrazoles/sangre , Animales , Antihipertensivos/química , Compuestos de Bifenilo/química , Modelos Lineales , Masculino , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tetrazoles/química
4.
Protein Expr Purif ; 68(2): 137-45, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19595770

RESUMEN

A long-lasting recombinant human albumin-linker-erythropoietin (EPO) is a human albumin gene fused to the N-terminal of EPO with a (GGSGG)(n)-repeated linker inserted between albumin and EPO. Albumin-EPO fusion genes were co-transfected with the dhfr gene. Albumin-EPO fusion protein has three kinds of sub-types (IALE, AD2LE, AD1LE). Albumin-EPO fusion protein was quantified with human EPO ELISA. The in vitro efficacy of albumin-EPO fusion protein was estimated using F-36E cell, and in vivo efficacy of albumin-EPO fusion protein was estimated using normocythemic mice (B6D2F1). We also determined the in vivo half-life in a Sprague-Dawley rat. A PLA program analysis result demonstrated that the albumin-EPO fusion protein IALE is about 7.8-fold more potent than rHuEPO in increasing the hematocrit of normal mice.


Asunto(s)
Clonación Molecular/métodos , Eritropoyetina/metabolismo , Proteínas Recombinantes de Fusión/biosíntesis , Albúmina Sérica/biosíntesis , Análisis de Varianza , Animales , Western Blotting , Células CHO , Recuento de Células , Línea Celular Tumoral , Cromatografía en Gel , Cricetinae , Cricetulus , Eritropoyetina/química , Eritropoyetina/genética , Semivida , Humanos , Ratones , Reacción en Cadena de la Polimerasa , Ratas , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes , Reticulocitos , Albúmina Sérica/química , Albúmina Sérica/genética
5.
J Microbiol Biotechnol ; 17(4): 611-5, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18051272

RESUMEN

The purpose of this study was to evaluate the immunogenicity and safety of Salmonella Typhi Vi capsular polysaccharide vaccine (Vi vaccine) in Korea. The immunogenicity of a single dose of Vi vaccine was evaluated in 157 subjects (75 children and 82 adults) before and at 1, 6, and 12 months after vaccination. Immunogenicity was measured with a passive hemagglutination assay (PHA), quantified as geometric mean titers (GMTs) and seroconversion rates. The safety of the vaccine was investigated by determining adverse reactions occurring within 4 h, 3 days, and 1 month after injection. The seroconversion rate for children and adults 1 month after vaccination was 96.92% and 89.02%, respectively. In the case of children, the GMTs of Vi antibodies before vaccination were 5.87 +/- 1.34 and 142.59 +/- 2.39 at one month after vaccination. For adults, the GMTs before and one month after vaccination were 5.58 +/- 1.28 and 58.56 +/- 3.67, respectively. Vi antibodies persisted for as long as 6 and 12 months after vaccination. All adverse reactions in adults and children were minor and did not require treatment. The Vi CPS vaccine was safe and immunogenic in adults and children older than 5 years.


Asunto(s)
Polisacáridos Bacterianos/inmunología , Vacunas Tifoides-Paratifoides/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antibacterianos/sangre , Niño , Preescolar , Femenino , Humanos , Inmunización , Masculino , Persona de Mediana Edad , Polisacáridos Bacterianos/efectos adversos , Vigilancia de Productos Comercializados , Vacunas Tifoides-Paratifoides/efectos adversos
6.
Protein Expr Purif ; 51(2): 293-302, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17079164

RESUMEN

Human cytotoxic T-lymphocyte antigen 4-immunoglobulin (hCTLA4I g) fusion protein, a novel immunosuppressive agent, was expressed in transgenic rice cell suspension culture and its characteristics and in vitro activities were investigated. The expression vector pMYN409 was constructed to express hCTLA4I g under the control of rice alpha-amylase 3D (RAmy3D) promoter. Transgenic calli were prepared by particle bombardment mediated transformation and were screened for hCTLA4I g expression using ELISA. Under the induction condition by sugar starvation, suspension-cultured rice cells secreted hCTLA4I g into the media up to 31.4 mg/L in flask culture. The rice-derived hCTLA4Ig (hCTLA4IgP) was purified from the culture media with affinity chromatography using protein A and compared with CHO-derived hCTLA4Ig (hCTLA4IgM). Recombinant hCTLA4IgP has molecular weight of approximately 50 kDa on SDS-PAGE under reducing condition, which is a little different from that of hCTLA4IgM probably due to the difference of carbohydrate chain structures. Purified hCTLA4IgP was biologically active and was confirmed to suppress T-cell proliferation.


Asunto(s)
Inmunoconjugados/metabolismo , Inmunosupresores/metabolismo , Abatacept , Animales , Southern Blotting , Células Cultivadas , Humanos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Oryza/citología , Oryza/metabolismo , Plantas Modificadas Genéticamente , alfa-Amilasas/genética
7.
Biotechnol Lett ; 28(24): 2039-48, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17072529

RESUMEN

The avidity for CD80Ig/CD86Ig and the in vitro immunosuppressive effect of recombinant human cytotoxic T lymphocyte-associated antigen 4-immunoglobulin, produced by transgenic rice cell suspension cultures (hCTLA4Ig(P)) with CHO-derived recombinant hCTLA4Ig (hCTLA4Ig(M)), were measured. Surface plasmon resonance (SPR) was used for kinetic binding analysis: hCTLA4Ig(P) and hCTLA4Ig(M) had higher avidity for CD80Ig/CD86Ig than for CD28Ig, and the avidity for CD80Ig/CD86Ig was similar. hCTLA4Ig(P) and hCTLA4Ig(M) had similar in vitro immunosuppressive activity against the expression of T cell-derived cytokines, such as IL-2, IL-4, and IFN-gamma, but did not suppress the expression of macrophage-derived cytokines, including TNF-alpha and IL-1beta, as well as NO. Thus the immunosuppressive mechanism of hCTLA4Ig(P) is also T cell-specific and it could therefore be used as an immunosuppressive agent with an equivalent potency to that of hCTLA4Ig(M).


Asunto(s)
Inmunoconjugados/genética , Inmunoconjugados/metabolismo , Oryza/genética , Oryza/metabolismo , Ingeniería de Proteínas/métodos , Abatacept , Animales , Afinidad de Anticuerpos , Células CHO , Técnicas de Cultivo de Célula , Células Cultivadas , Cricetinae , Cricetulus , Estudios de Factibilidad , Regulación de la Expresión Génica de las Plantas , Humanos , Ratones , Óxido Nítrico/metabolismo , Planticuerpos/genética , Plantas Modificadas Genéticamente , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
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