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1.
Transplant Proc ; 51(6): 2081-2098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399186

RESUMO

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of 5 G protein-coupled receptors (S1P1 to S1P5). Among these, S1P1 is a major regulator of lymphocyte trafficking. Fingolimod, whose active metabolite, fingolimod phosphate, acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating lymphocyte trafficking via downregulation of S1P1 expression on lymphocytes. Here, we describe the pharmacologic profile of a novel S1P1 agonist, ASP1126. ASP1126 preferentially activated S1P1 compared to S1P3 in rat and human guanosine-5'-(γ-thio)-triphosphate (GTPγS) assays. Oral single administration of ASP1126 decreased the number of peripheral lymphocytes and repeated dosing showed a cumulative effect on lymphopenia in both rats and monkeys. ASP1126 prolonged allograft survival in a rat heterotopic heart transplantation model in combination with a subtherapeutic dose of tacrolimus that was independent of drug-drug interactions. In addition, in nonhuman primate (NHP) renal transplantation, pretreatment with ASP1126 reduced not only the number of naive T cells and central memory T cells but also effector memory T cells in the peripheral blood, all of which could contribute to acute graft rejection and prolonged allograft survival in combination with tacrolimus. Further, we confirmed that ASP1126 has a broad ranging safety margin with respect to its effect on lung weight in rats and bradycardia in NHPs, which were the adverse events found in clinical studies of fingolimod. ASP1126 with improved safety profile has the potential to be an adjunct therapy in combination with tacrolimus in clinical transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Aloenxertos/efeitos dos fármacos , Aloenxertos/metabolismo , Animais , Bradicardia/induzido quimicamente , Sinergismo Farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Ratos , Esfingosina/agonistas , Tacrolimo/farmacologia , Transplante Homólogo/métodos
2.
PLoS One ; 9(10): e110819, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25347187

RESUMO

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1-S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.


Assuntos
Benzimidazóis/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Cloridrato de Fingolimode , Frequência Cardíaca/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Propilenoglicóis/farmacologia , Ratos , Esfingosina/análogos & derivados , Esfingosina/farmacologia
3.
Bioorg Med Chem ; 22(13): 3478-87, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24837158

RESUMO

Herein, we describe the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives. Among them, the quinuclidin-4-yl thiazolylcarbamate derivative ASP9133 was identified as a promising long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action in a rat model than tiotropium bromide.


Assuntos
Carbamatos/farmacologia , Quinuclidinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/química , Relação Dose-Resposta a Droga , Masculino , Modelos Moleculares , Estrutura Molecular , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
Immunology ; 134(4): 386-97, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22043861

RESUMO

α1,3-Galactosyltransferase gene-knockout pigs transgenic for porcine cytotoxic T-lymphocyte antigen 4 immunoglobulin (pCTLA4-Ig) have been produced to reduce T-cell-mediated rejection following xenotransplantation. The level of soluble pCTLA4-Ig in their blood was greatly in excess of the therapeutic level in patients, rendering the pigs immune-incompetent. Soluble pCTLA4-Ig produced by these transgenic pigs was evaluated for binding to porcine and human (h) B7 molecules, and for its inhibitory effect on allogeneic and xenogeneic human T-cell responses. Porcine CTLA4-Ig-expressing peripheral blood mononuclear cells (PBMCs) and aortic endothelial cells (AECs) were evaluated for their direct inhibitory effect on hCD4+ T-cell responses. Soluble pCTLA4-Ig and purified hCTLA4-Ig showed similar binding to pB7 molecules, but pCTLA4-Ig showed significantly less binding to hB7 molecules. The pCTLA4-Ig and hCTLA4-Ig inhibited the response of hCD4+ T cells to pAECs equally, but pCTLA4-Ig was less successful in inhibiting the human allogeneic response. The hCD4+ T-cell response to PBMCs from pCTLA4-Ig pigs was significantly lower than that of non-pCTLA4-Ig pigs. Although pCTLA4-Ig was detected in the cytoplasm of pCTLA4-Ig-expressing pAECs, only a minimal level of soluble pCTLA4-Ig was detected in the supernatant during culture, and pCTLA4-Ig-expressing pAECs did not inhibit the xenogeneic direct human T-cell response. High-level tissue-specific production of pCTLA4-Ig may be required for sufficient immunosuppression for organ or cell (e.g., islets) transplantation.


Assuntos
Antígenos B7/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Citotoxicidade Imunológica , Terapia de Imunossupressão , Linfócitos T Citotóxicos/imunologia , Animais , Animais Geneticamente Modificados , Antígenos CD4/imunologia , Células Cultivadas , Técnicas de Cocultura , Humanos , Suínos/genética , Imunologia de Transplantes , Transplante Heterólogo , Transplante Homólogo
5.
J Pharmacol Sci ; 115(3): 374-82, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21358117

RESUMO

The aim of the current study was to characterize comparatively the binding of muscarinic receptor in the lung of rats intratracheally administered anticholinergic agents (tiotropium, ipratropium, glycopyrrolate) used clinically to treat chronic obstructive pulmonary disease (COPD) and asthma. Binding parameters of [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) were determined in tissues (lung, bladder, submaxillary gland) of rats intratracheally administered tiotropium, ipratropium, and glycopyrrolate. The in vitro binding affinity of tiotropium for the receptors was 10-11-fold higher than those of ipratropium and glycopyrrolate. Intratracheal administration of tiotropium (0.6-6.4 nmol/kg) caused sustained (lasting at least 24 h) increase in the apparent dissociation constant (K(d)) for [(3)H]NMS binding in rat lung compared with the control value. Concomitantly, there was a long-lasting decrease in the maximal number of binding sites (B(max)) for [(3)H]NMS. Similary, ipratropium and glycopyrrolate at 7.3 and 7.5 nmol/kg, respectively, brought about a significant increase in K(d) for [(3)H]NMS binding. The effect by ipratropium was observed at 2 h but not 12 h, and that by glycopyrrolate lasted for 24 h. Both agents had little influence on the muscarinic receptors in the bladder and submaxillary gland. The present study provides the first evidence that tiotropium, ipratropium, and glycopyrrolate administered intratracheally in rats selectively bound muscarinic receptors of the lung, and tiotropium and glycopyrrolate had a much longer-lasting effect than ipratropium.


Assuntos
Glicopirrolato/metabolismo , Ipratrópio/metabolismo , Pulmão/metabolismo , Antagonistas Muscarínicos/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptores Muscarínicos/metabolismo , Derivados da Escopolamina/metabolismo , Animais , Sítios de Ligação , Broncodilatadores/administração & dosagem , Broncodilatadores/metabolismo , Broncodilatadores/farmacologia , Glicopirrolato/farmacologia , Coração/fisiologia , Ipratrópio/farmacologia , Pulmão/fisiopatologia , Masculino , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos , Ratos Sprague-Dawley , Derivados da Escopolamina/farmacocinética , Glândula Submandibular/metabolismo , Brometo de Tiotrópio , Traqueia/efeitos dos fármacos , Bexiga Urinária/metabolismo
6.
Eur J Pharmacol ; 515(1-3): 169-78, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15894307

RESUMO

The effects of tacrolimus on murine acute lung injury were tested, especially in comparison to dexamethasone. Acute lung injury was induced by intratracheal instillation of bleomycin. Oral tacrolimus significantly improved survival rates of bleomycin-exposed mice, while cyclosporin A or dexamethasone did not. After instillation of bleomycin (day 0), a migration of neutrophils into alveolar spaces peaked on day 3, with concomitant increases of chemokines. On day 6, marked morphological changes in the lungs were observed. All these changes were significantly inhibited by tacrolimus. Furthermore, DNA ladder and immunohistochemical analyses of lungs showed that apoptosis of lung cells appeared on day 6 and was abolished only by the treatment of tacrolimus. These results suggest that both anti-inflammatory and anti-apoptotic action of tacrolimus contribute to improvement of bleomycin-induced acute lung injury.


Assuntos
Imunossupressores/farmacologia , Pneumopatias/prevenção & controle , Tacrolimo/farmacologia , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Bleomicina , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Quimiocinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Imunossupressores/uso terapêutico , Marcação In Situ das Extremidades Cortadas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/induzido quimicamente , Pneumopatias/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Taxa de Sobrevida , Tacrolimo/uso terapêutico
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