RESUMO
BACKGROUND AND PURPOSE: KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction. EXPERIMENTAL APPROACH: Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated. KEY RESULTS: KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge. CONCLUSIONS AND IMPLICATIONS: KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.
Assuntos
Obstrução das Vias Respiratórias/prevenção & controle , Antiasmáticos/farmacologia , Benzoatos/farmacologia , Broncoconstrição/efeitos dos fármacos , Antagonistas de Leucotrienos/farmacologia , Pulmão/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Antagonistas de Prostaglandina/farmacologia , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Hipersensibilidade Respiratória/prevenção & controle , Tiazóis/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Acetatos/farmacologia , Administração por Inalação , Administração Oral , Obstrução das Vias Respiratórias/induzido quimicamente , Obstrução das Vias Respiratórias/metabolismo , Obstrução das Vias Respiratórias/fisiopatologia , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/metabolismo , Benzoatos/administração & dosagem , Benzoatos/metabolismo , Benzoquinonas/farmacologia , Ciclopropanos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Cobaias , Ácidos Heptanoicos/farmacologia , Antagonistas de Leucotrienos/administração & dosagem , Antagonistas de Leucotrienos/metabolismo , Leucotrieno D4 , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Proteínas de Membrana/metabolismo , Ovalbumina , Antagonistas de Prostaglandina/administração & dosagem , Antagonistas de Prostaglandina/metabolismo , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/fisiopatologia , Sulfetos , Tiazóis/administração & dosagem , Tiazóis/metabolismo , Fatores de TempoRESUMO
Two Japanese women and one Japanese man, who had been taking the same germanium preparation, mainly containing inorganic germanium, as an elixir for health almost every day at 90 mg of germanium per day for 6 to 20 months, suffered from chronic renal failure. Histological examination of the kidney in one patient showed marked interstitial changes with vacuolar degeneration of the renal tubules. High germanium concentrations were found in hair and nails of the three patients, but no germanium was detected in hair or nails of normal persons. These results suggest that long-term use of a germanium preparation at high dosage can cause serious renal tubular damage and renal failure due to germanium toxicity.
