Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Lipopolisacáridos/toxicidad , Ratones , Óxido Nítrico Sintasa de Tipo II , Nitritos/orina , Factor de Necrosis Tumoral alfa/análisisAsunto(s)
Citocinas/biosíntesis , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Sepsis/metabolismo , Animales , Guanidinas/farmacología , Interleucina-1/biosíntesis , Interleucina-10/biosíntesis , Cinética , Lipopolisacáridos , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Sepsis/inducido químicamente , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Inflammatory mediator release is one of the body's responses to tissue injury and inflammation. These mediators, such as interleukin-1 beta (I1-1 beta), tumor necrosis factor (TNF-alpha), and products of arachidonic acid metabolism, are themselves proinflammatory. Purified human monocytes stimulated in vitro with E. coli-derived lipopolysaccharide (LPS) will release these key cytokines along with various other eicosanoid mediators. Monocytes incubated with LPS and the prostaglandin E-1 analog, misoprostol, released significantly lower levels of cytokines compared to monocytes incubated with LPS alone. Eicosanoid release was also affected by misoprostol. SC-46275, a more potent mucosal protective PGE1 analog, also altered the release of cytokines and eicosanoids from human monocytes. However SC-46275 inhibited I1-1 beta release with an IC50 value of 9 microM compared to 75 microM for misoprostol. SC-46275 and misoprostol both inhibited TNF-alpha release. These data suggest there is a potential immunomodulatory role for prostaglandin analogs in the therapeutic treatment of inflammatory diseases such as ulcerative colitis, Crohn's disease, and autoimmune inflammatory diseases of the central nervous system.
Asunto(s)
Alprostadil/análogos & derivados , Antiulcerosos/farmacología , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Misoprostol/farmacología , Monocitos Activados Asesinos/metabolismo , Prostaglandinas Sintéticas/farmacología , Alprostadil/farmacología , Antiinflamatorios no Esteroideos/farmacología , Dinoprostona/metabolismo , Humanos , Indoles/farmacología , Interleucina-1/metabolismo , Interleucina-4/farmacología , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Oxindoles , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In a previous study (Hardy et al. (1994) J. Biol. Chem. 269, 18535-18540), we observed that the manganese-based superoxide dismutase mimetic Mn(II)-dichloro(1,4,7,10,13-pentaazacyclopentadecane) (MnPAM) inhibited neutrophil-mediated cell injury in vitro. We have extended these studies with the low molecular weight superoxide dismutase mimic to evaluate the role of superoxide in neutrophil-mediated tissue injury in vivo. In a dose-dependent manner, MnPAM inhibited colonic tissue injury and neutrophil accumulation into the colonic tissue induced by the intracolonic instillation of dilute aqueous acetic acid in mice. Tissue injury was assessed by visual and histological analysis. Neutrophil infiltration was determined by tissue myeloperoxidase activity and confirmed by histological analysis. Two novel Mn(II) dichloro complexes of the carbon-substituted macrocycles 2-methyl-1,4,7,10,13-pentaazacyclopentadecane (MnMAM) and 2-(2-methylpropyl)-1,4,7,10,13-pentaazacyclopentadecane (MnBAM) effectively catalyzed the dismutation of superoxide with catalytic rate constants (kcat) of 3. 31 x 10(7) M-1 s-1 and 1.91 x 10(7) M-1 s-1, respectively, as determined by stopped-flow kinetic analysis at pH 8.1 and 21 degrees C. The superoxide dismutase mimetics MnMAM and MnBAM also attenuated dilute aqueous acetic acid-induced tissue injury and neutrophil infiltration into colonic tissue; however, two Mn(II) complexes that had little or no detectable SOD activity (kcat = 0.1 x 10(7) M-1 s-1), specifically the Mn(II) dichloro complexes of 1,4,7,10,13-pentaazacyclohexadecane and 1,4,7,11,14-pentaazacycloheptadecane, failed to inhibit the colonic tissue injury or infiltration of neutrophils in mice treated intracolonically with dilute aqueous acetic acid. These results are consistent with a proinflammatory role for superoxide in the mediation of neutrophil infiltration in vivo.
Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Compuestos Organometálicos/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Colitis/inmunología , Colitis/patología , Colon/patología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/metabolismo , Masculino , Manganeso , Ratones , Imitación Molecular , Neutrófilos/patología , Relación Estructura-Actividad , Superóxidos/metabolismoRESUMEN
Leukotriene B4 (LTB4) is a potent neutrophil activator and chemotaxin that is present in increased concentrations in the colonic tissue and rectal dialysates of acute ulcerative colitis patients. Cotton-top tamarins (CTTs) with confirmed active colitis were treated with the second generation LTB4 receptor antagonist, SC-53228 ((+)-(S)-7-[3-(2-cyclopropyl-methyl)-3-methoxy-4-[(methylamino) carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- propanoic acid), 20 mg/kg bodyweight by gavage, twice daily for 56 days. End points were body weights, stool consistency, colonic endoscopy, assay of inflammatory mediators, and haematology and clinical chemistry tests. LTB4 and prostaglandin E (PGE) values were measured in rectal dialysates at pretreatment, 28 day and 56 day time points. LTB4 concentrations were reduced from pretreatment mean (SEM) values of 37.3 (0.8) ng/ml to 3.7 (0.8) ng/ml (p < 0.001) and 2.3 (0.5) ng/ml (p < 0.01) at days 28 and 56, respectively. On the other hand, mucosal protective PGE values remained constant or slightly increased during SC-53228 treatment (pre: 6.9 (2.2) ng/ml; day 28: 6.7 (1.4) ng/ml; day 56: 9.9 (1.6) ng/ml). Furthermore, assessment of a panel of 35 clinical chemistry and haematology parameters throughout the treatment showed there were no significant untoward effects of drug treatment. Six CCTs finished the eight week treatment and five of six gained weight (ranging from 27-121 grams each) while one CTT lost weight (50 g). Stool condition improved in five of six animals while one of six remained unchanged. All CCTs showed dramatic improvement histologically, with no or only minimally active colitis after treatment. The histological changes plus significant weight gains and improvement of stool condition (quality of life parameters) after eight weeks of SC-53228 treatment were remarkable. Furthermore, in follow up biopsies seven months after treatment ceased, three of six CTTs had no active colitis. This is the first time afflicted CTTs have not had recurring colitic exacerbations after a treatment regimen was stopped. It is concluded that in colitic CTTs, SC-53228 has shown both an immediate and a long acting anticolitic activity. It is also concluded that reduced LTB4 concentrations during treatment inhibited neutrophil infiltration of the colonic tissue and this, coupled with the maintenance of mucosal protective prostaglandins, contributed to the dramatic anticolitic efficacy. The treatment was safe over eight weeks. A compound such as SC-53228 may be useful in the medical treatment of human inflammatory bowel disease.
Asunto(s)
Enfermedades Inflamatorias del Intestino/veterinaria , Leucotrieno B4/metabolismo , Enfermedades de los Monos/tratamiento farmacológico , Animales , Heces/química , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Intestino Grueso/química , Intestino Grueso/patología , Leucotrieno B4/análisis , Enfermedades de los Monos/metabolismo , SaguinusRESUMEN
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes ulcerative colitis and Crohn's disease. Leukotriene B4 is thought to be a prominent proinflammatory mediator in these diseases, in that leukotriene B4 levels are increased in the colonic mucosa of inflammatory bowel disease patients and there is increased polymorphonuclear leukocyte infiltration of these tissues. SC-53228 [(+)-(S)-7-[3-[2(-cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], a second generation LTB4 receptor antagonist, was evaluated for therapeutic efficacy in a rodent model of acute colonic inflammation induced by short chain organic acids, as well as for effects on rodent liver. When given intracolonically to mice, SC-53228 inhibited neutrophil infiltration, assessed by myeloperoxidase (MPO) levels, with an ED50 value of 9 +/- 1.2 mg/kg. When given by gavage, SC-53228 inhibited neutrophil influx in colitic mice with an ED50 value of 30 mg/kg. These results were also confirmed histologically. Furthermore, high dose oral SC-53228 treatment had no effect on liver cytochrome P-450 content, fatty acyl CoA oxidase or liver weight in rats and mice. Together, these data suggest that SC-53228 may be efficacious orally and locally, as well as safe for use in trials for the medical management of IBD.
Asunto(s)
Benzamidas/farmacología , Benzopiranos/farmacología , Colitis/patología , Hígado/efectos de los fármacos , Receptores de Leucotrieno B4/antagonistas & inhibidores , Acil-CoA Oxidasa , Animales , Colitis/enzimología , Colon/enzimología , Sistema Enzimático del Citocromo P-450/metabolismo , Gemfibrozilo/farmacología , Hígado/anatomía & histología , Hígado/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos/efectos de los fármacos , Oxidorreductasas/metabolismo , Peroxidasa/metabolismo , Fenobarbital/farmacología , Ratas , Ratas Sprague-DawleyAsunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Granulocitos/efectos de los fármacos , Leucotrieno B4/análogos & derivados , Piel/citología , Animales , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/farmacología , Benzopiranos/farmacología , Biomarcadores , Granulocitos/enzimología , Cobayas , Leucotrieno B4/farmacología , Masculino , Peroxidasa/metabolismo , Piel/efectos de los fármacos , Piel/enzimologíaAsunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacocinética , Benzamidas/metabolismo , Benzamidas/farmacocinética , Benzopiranos/metabolismo , Benzopiranos/farmacocinética , Receptores de Leucotrieno B4/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Disponibilidad Biológica , Perros , Cobayas , Inyecciones Intravenosas , Macaca fascicularis , Macaca mulatta , Masculino , Ratas , Especificidad de la EspecieRESUMEN
To establish a direct link between IL-8 and inflammation in vivo, we first isolated the gene encoding rhesus macaque IL-8. The open reading frame directs the translation of a 101 amino acid (aa) precursor, which is 94% identical to human IL-8. Rhesus IL-8 was expressed in bacteria and purified to homogeneity with ion-exchange chromatography. Pure rhesus IL-8 was biologically active as measured by its ability to bind specifically to either rhesus (Kd = 0.5 nM) or human (Kd = 2 nM) IL-8 receptors and to promote in vitro chemotaxis of rhesus (EC50 = 2 nM) or human neutrophils (EC50 = 4 nM). Moreover, a mouse monoclonal antibody, DM/C7, which neutralizes human IL-8 activity, also recognized and neutralized (IC50 = 0.5-3.0 microgram/ml) rhesus IL-8 in vitro. Systemic administration of DM/C7 completely inhibited the dermal inflammation of rhesus ears induced by the external application of phorbol myristoyl acetate. These observations reveal that rhesus IL-8 is structurally and functionally similar to human IL-8 and suggests that IL-8 plays a prominent role in a primate model of inflammation.
Asunto(s)
Interleucina-8/aislamiento & purificación , Macaca mulatta/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Secuencia de Bases , Quimiotaxis de Leucocito/efectos de los fármacos , Cromatografía por Intercambio Iónico , Clonación Molecular , Edema/inducido químicamente , Edema/fisiopatología , Edema/prevención & control , Femenino , Genes , Humanos , Inflamación , Interleucina-8/antagonistas & inhibidores , Interleucina-8/genética , Interleucina-8/inmunología , Interleucina-8/farmacología , Macaca mulatta/genética , Mamíferos/genética , Datos de Secuencia Molecular , Neutrófilos/efectos de los fármacos , Sistemas de Lectura Abierta , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Granulocyte infiltration is a prominent feature of human psoriasis. Psoriatic lesional skin contains abnormally high amounts of immunoreactive leukotriene B4 (LTB4), a potent granulocyte chemotaxin in vivo and in vitro. SC-53228 [(+)-(S)-7-(3-}2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy}propoxy}-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], a second-generation LTB4 receptor antagonist, was tested topically and orally in phorbol ester-induced dermal inflammation in three species. Skin inflammation was induced by topical application of phorbol-12-myristate-13-acetate-(PMA/TPA) and assessed by ear thickness, levels of the neutrophil marker enzyme myeloperoxidase (MPO) and histological examination. In mice, SC-53228 inhibited inflammation with a topical ED50 value of 200 +/- 18 micrograms. When applied to guinea pigs, SC-53228 (100 micrograms) inhibited the MPO increase by 86%, while 1000 micrograms abrogated inflammation in rhesus macaques with no plasma accumulation of the drug. A 1% gel formulation was also efficacious in guinea pig PMA-induced epidermal inflammation. Furthermore, single oral dose administration to mice was efficacious (ED50 < 2.5 mg/kg) as was multidose administration to rhesus macaques. PMA-induced skin inflammation possesses some of the attributes of human psoriasis and an agent such as SC-53228 may have utility in the medical management of this condition.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Erupciones por Medicamentos/prevención & control , Edema/prevención & control , Psoriasis/tratamiento farmacológico , Receptores de Leucotrieno B4/antagonistas & inhibidores , Administración Cutánea , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/farmacología , Benzopiranos/farmacología , Modelos Animales de Enfermedad , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/inmunología , Evaluación Preclínica de Medicamentos , Oído Externo , Edema/inducido químicamente , Edema/inmunología , Femenino , Geles , Cobayas , Humanos , Masculino , Ratones , Peroxidasa/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzamidas/farmacología , Benzopiranos/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Ácidos Hidroxieicosatetraenoicos/farmacología , Leucotrieno B4/farmacología , Receptores de Leucotrieno B4/antagonistas & inhibidores , Piel/efectos de los fármacos , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Biomarcadores , Granulocitos/efectos de los fármacos , Cobayas , Ácidos Hidroxieicosatetraenoicos/administración & dosificación , Inyecciones Intradérmicas , Leucotrieno B4/administración & dosificación , Masculino , Potenciales de la Membrana/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Peroxidasa/análisis , Receptores de Leucotrieno B4/fisiología , Piel/inmunología , Piel/patologíaRESUMEN
Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.
Asunto(s)
Azoles/síntesis química , Azoles/farmacología , Benzopiranos/síntesis química , Benzopiranos/farmacología , Receptores de Leucotrieno B4/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Azoles/metabolismo , Benzopiranos/metabolismo , Factores Quimiotácticos/síntesis química , Factores Quimiotácticos/farmacología , Cobayas , Humanos , Ratones , Datos de Secuencia Molecular , N-Formilmetionina Leucil-Fenilalanina/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , Receptores de Leucotrieno B4/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
In the reverse passive Arthus reaction in mouse skin and immune injury of mouse dermal basement membrane, neutrophil (PMN) infiltration in mast cell deficient WBB6F1-W/Wv (W/Wv) mice was only 40% of that in WBB6F1-(+)/+ (+/+) mice that had a normal mast cell repertoire. An anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody (mAb) decreased PMN infiltration by 35-80% in +/+ but not W/Wv mice. In addition, an anti-human interleukin-8 (IL-8) MAb, DM/C7, inhibited PMN infiltration of the skin induced by either intradermal administration of recombinant human IL-1 beta or immune complex deposition. In both models of immune complex injury, DM/C7 reduced PMN infiltration by 40-60% in +/+ mice but not W/Wv mice. PMN infiltration and the sensitivity of this infiltration to anti-TNF-alpha or DM/C7 MAb in W/Wv mice whose mast cell population had been restored was indistinguishable from the influx observed in +/+ mice. These data suggest that TNF-alpha, IL-8, and mast cells play a fundamental role in PMN recruitment following immune complex injury.
Asunto(s)
Interleucina-8/farmacología , Mastocitos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Anticuerpos Monoclonales/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Reacción de Arthus , Quimiotaxis de Leucocito/efectos de los fármacos , Interleucina-1/inmunología , Interleucina-8/inmunología , Ratones , Ratones Mutantes , Proteínas Recombinantes , Piel/citología , Piel/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Reactive oxygen species have been implicated as mediators of inflammation in ulcerative colitis. Chemiluminescence is a reliable means of estimating reactive oxygen species in biological media. Increased reactive oxygen species values in the inflamed colonic mucosa in rats were seen by chemiluminescence. The aims of the study were to find out if chemiluminescence is raised in the colonic mucosa of patients with ulcerative colitis and correlates with disease activity, and to elucidate the sources of the chemiluminescence. It was found that reactive oxygen species, as measured by the chemiluminescence technique, are raised in inflamed colonic mucosa and correlates with symptom score, sigmoidoscopic score, disease activity, and activity of the neutrophil enzyme myeloperoxidase. Chemiluminescence was inhibited by a myeloperoxidase inhibitor (azide) and an H2O2 scavenger (catalase) but not by allopurinol, an inhibitor of the enzyme xanthine oxidase. Chemiluminescence was also inhibited by indomethacin, but this did not seem to be related to inhibition of cyclo-oxygenase. These findings suggest that a likely cellular source of reactive oxygen species in the inflamed colon of patients with ulcerative colitis is the neutrophil and that myeloperoxidase conversion of H2O2 to hypochlorous acid, contributes to the chemiluminescence signal and possibly, to the tissue injury. Neither cyclo-oxygenase nor lipoxygenase seem to play a part as sources for the chemiluminescence.
Asunto(s)
Colitis Ulcerosa/metabolismo , Colon/química , Mucosa Intestinal/química , Especies Reactivas de Oxígeno/análisis , Adulto , Anciano , Colitis Ulcerosa/enzimología , Femenino , Humanos , Peróxido de Hidrógeno/metabolismo , Mediciones Luminiscentes , Luminol , Masculino , Persona de Mediana Edad , Neutrófilos/enzimología , Peroxidasa/metabolismo , SigmoidoscopíaRESUMEN
Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has been implicated as a mediator in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 elicits a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-p ropyl-2H-1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist inhibited the chemotactic actions of LTB4 when coadministered into the dermal site and when given orally with ED50 values of 340 ng and 1.7 mg/kg, respectively. The second-generation LTB4 receptor antagonists SC-50605 (7-[3-[2(cyclopropylmethyl)-3-methoxy-4-(4-thiazolyl)phenoxy]propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) and SC-51146 (7-[3-[2(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl] phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid) inhibited LTB4-induced chemotaxis when coadministered with ED50 values of 70 ng and 32 ng, respectively, and when given intragastrically with ED50 values of 0.10 and 0.09 mg/kg, respectively. SC-41930, SC-50605, and SC-51146 had oral durations of action of 5.5, 15, and 21 h, respectively. These potent, LTB4 receptor antagonists may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, where LTB4 is implicated as an inflammatory mediator.
Asunto(s)
Benzamidas/farmacología , Benzopiranos/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Leucotrieno B4/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Piel/efectos de los fármacos , Tiazoles/farmacología , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Granulocitos/efectos de los fármacos , Cobayas , Inyecciones Intradérmicas , Masculino , Peroxidasa/análisis , Receptores de Leucotrieno B4 , Piel/citología , Tiazoles/administración & dosificaciónRESUMEN
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.
Asunto(s)
Benzopiranos/farmacología , Colitis/tratamiento farmacológico , Dermatitis/tratamiento farmacológico , Leucotrieno B4/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Benzopiranos/administración & dosificación , Benzopiranos/síntesis química , Benzopiranos/metabolismo , Sitios de Unión , Degranulación de la Célula/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Modelos Animales de Enfermedad , Diseño de Fármacos , Cobayas , Técnicas In Vitro , Ratones , Receptores de Leucotrieno B4/metabolismo , Tiazoles/administración & dosificación , Tiazoles/síntesis química , Tiazoles/metabolismoRESUMEN
To evaluate anti-colitic efficacy, eight cotton-top tamarins (CTTs) with histologically confirmed persistent active colitis were given the anti-inflammatory agent SC-41930 (10 mg/kg BW by gavage BID) for eight weeks. Colonic endoscopy and biopsy observations, CBCs and clinical chemistries, and stool consistency were evaluated pre-, mid-, and posttreatment. Colitic activity was graded histologically from A1 (mild) to A5 (severe); results varied among the seven animals that completed the study: five improved, one worsened, and one was unchanged. Serum enzyme levels were significantly reduced with treatment. Stool condition remained puddly throughout treatment and body weights did not vary from pretreatment levels. However, SC-41930 produced histological evidence (reduced numbers of polymorphonuclear cells) of anti-colitic efficacy over an eight-week treatment period in CTTs with persistent active colitis. These results support the use of the CTT colitis model to evaluate efficacy of therapeutic agents and provide useful predictive information to aid in the medical management of human IBD.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Benzopiranos/uso terapéutico , Colitis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Benzopiranos/administración & dosificación , Peso Corporal/efectos de los fármacos , Colon/patología , Modelos Animales de Enfermedad , Leucotrieno B4/antagonistas & inhibidores , SaguinusRESUMEN
Use of the CTT model provides insight into the inflammatory mediator contribution in the pathogenesis of idiopathic colitis. To evaluate anti-colitic efficacy, the leukotriene B4 receptor antagonist and anti-inflammatory agent, SC-41930, was administered (10 mg/kg BW by gavage BID) for 8 weeks to CTTs with histologically confirmed persistent and defined active colitis. The inflammatory mediators LTB4, PGE2, TXB2, and PAF were assayed in colonic dialysate that was collected after 1 1/2 h from four CTTs pre-, mid-, and post-treatment, frozen at -70 degrees C, and analyzed by RIA after HPLC purification. LTB4 levels were lower at mid- and post-treatment and had little inter-animal variation post-treatment. PGE2 and PAF levels were elevated during SC-41930 treatment, but there was a trend towards lower thromboxane B2 levels. Reduced LTB4 (PMN degranulation and chemotaxis) and increased PGE2 (mucosal-protective effect) may, in part, explain the observed efficacy of SC-41930 in active tamarin colitis.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ácidos Araquidónicos/metabolismo , Benzopiranos/farmacología , Colitis/metabolismo , Colon/metabolismo , Factor de Activación Plaquetaria/metabolismo , Animales , Benzopiranos/administración & dosificación , Benzopiranos/uso terapéutico , Colitis/tratamiento farmacológico , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Leucotrieno B4/antagonistas & inhibidores , Leucotrieno B4/metabolismo , Radioinmunoensayo , Saguinus , Tromboxano B2/metabolismoRESUMEN
The mucosal protective prostaglandin analogs misoprostol, enisoprost, and SC-46275 (the 17E-18-cyclopentenyl analog of enisoprost) were tested in mouse and rat colitis induced by the intrarectal instillation of dilute acetic acid. Colitis was assessed by histology and colonic levels of myeloperoxidase (a neutrophil marker enzyme). When given as enemas 30 min ahead of colitis induction, 15(R)-15-methyl-PGE2 (arbaprostil) and 15(S)-15-methyl-PGE1 were inactive; however, misoprostol, enisoprost, and SC-46275 protected against colonic inflammation with ED50 values of 24, 12 and 1.3 micrograms/kg, respectively, in rats and 11, 5, and 1 micrograms/kg, respectively, in mice. These compounds may have utility in the medical management of human inflammatory bowel disease.