RESUMO
RATIONALE: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. OBJECTIVE: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. METHODS: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. RESULTS: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. CONCLUSIONS: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.
Assuntos
Alérgenos/administração & dosagem , Antiasmáticos/administração & dosagem , Asma , Broncoconstrição/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-2/antagonistas & inibidores , Administração por Inalação , Adulto , Antiasmáticos/farmacocinética , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Asma/fisiopatologia , Testes de Provocação Brônquica/métodos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Fluxo Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Escarro/citologia , Escarro/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Despite their proven efficacy in the treatment and prevention of asthma exacerbations, current inhaled corticosteroids carry safety concerns, especially adrenal suppression. Ciclesonide (hydrofluoroalkane propellant) is a novel inhaled corticosteroid with few, if any, clinical adverse events. OBJECTIVE: To evaluate the potential effects of ciclesonide therapy on the dynamic cortisol response to sequential low- and high-dose cosyntropin stimulation in adults with mild-to-moderate persistent asthma. METHODS: This was a double-blind, randomized, placebo-controlled, 12-week study in adults with mild-to-moderate asthma. One hundred sixty-four patients were randomized and treated; 148 patients completed the study. Fluticasone propionate (chlorofluorocarbon propellant) was used as an active comparator. The doses administered were 320 microg of ciclesonide once daily, 320 microg of ciclesonide twice daily, and 440 microg of fluticasone propionate twice daily, all doses ex-actuator. RESULTS: For both ciclesonide groups, changes in mean low- and high-dose peak serum cortisol levels and in 24-hour urinary free cortisol levels corrected for creatinine were small vs baseline and comparable with placebo. For the fluticasone propionate group, significant reductions vs placebo in serum cortisol levels in response to high-dose cosyntropin stimulation and in 24-hour urinary free cortisol levels were observed. Oral candidiasis rates were 2.5% for 320-microg/d ciclesonide, 2.4% for 640-microg/d ciclesonide, and 22.0% for 880-microg/d fluticasone propionate. CONCLUSIONS: These findings confirm the safety of ciclesonide therapy, demonstrating that at doses up to 640 microg/d, the drug does not affect sensitive markers of adrenal function.
Assuntos
Androstadienos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Pregnenodionas/uso terapêutico , Adolescente , Adulto , Idoso , Androstadienos/efeitos adversos , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Asma/fisiopatologia , Cosintropina/uso terapêutico , Método Duplo-Cego , Feminino , Fluticasona , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Sistema Hipófise-Suprarrenal/fisiopatologia , Pregnenodionas/efeitos adversosRESUMO
Novel substituted 2-anilino- and 2-cycloalkylaminoquinoxalines have been found to be useful and selective inhibitors of PDGF-R autophosphorylation. Replacement of an anilino-substituent with substituted cyclohexylamino- or norbornylamino substituents led to significant improvements in the pharmacokinetic profile of these analogues.
Assuntos
Quinoxalinas/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Angioplastia Coronária com Balão/efeitos adversos , Aorta/citologia , Divisão Celular/efeitos dos fármacos , Reestenose Coronária/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
Assuntos
Quinoxalinas/síntese química , Quinoxalinas/farmacocinética , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Divisão Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Colágeno/biossíntese , Sistema Enzimático do Citocromo P-450/biossíntese , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinoxalinas/farmacologia , Ratos , Relação Estrutura-Atividade , SuínosRESUMO
Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFbetar-TK with a K(i) value of 56 +/- 14 nM. TKI963 also inhibited PDGF-dependent events in human aortic SMCs (e.g., in situ PDGFr autophosphorylation, mitogenesis, chemotaxis, and collagen production with median inhibitory concentration values of approximately 300 nM) without affecting the activity of a series of membrane receptor tyrosine kinases and intracellular serine/threonine kinases. In vivo, stent-induced restenosis in the swine coronary artery was reduced by oral administration of TKI963 (1.25, 2.5, and 5 mg/kg BID, for 28 days). Late lumen cross-sectional area (CSA) loss, plaque CSA growth, and plaque volume in the stent determined by IVUS were dose-relatedly decreased (33-62% at 1.25 mg/kg BID to 66-92% at 5 mg/kg BID, depending on the parameter) compared with controls. TKI963 treatment of =1 week following stent placement had no effect on the prevention of restenosis. TKI963, a selective, orally bioavailable inhibitor of the PDGFr-TK, dose-relatedly reduced stent-induced restenosis and did so by inhibiting PDGF-dependent activities that occur as late events following stent placement.