RESUMO
Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Animais , Antiasmáticos/síntese química , Antiasmáticos/metabolismo , Antiasmáticos/toxicidade , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/toxicidade , Ligação Competitiva , Temperatura Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Ácidos Cicloexanocarboxílicos/síntese química , Ácidos Cicloexanocarboxílicos/metabolismo , Ácidos Cicloexanocarboxílicos/toxicidade , Cães , Ácido Gástrico/metabolismo , Cobaias , Humanos , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nitrilas , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/toxicidade , Pirrolidinonas/síntese química , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacologia , Pirrolidinonas/toxicidade , Coelhos , Proteínas Recombinantes/antagonistas & inibidores , Rolipram , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vômito/induzido quimicamenteRESUMO
Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.
Assuntos
Proteínas do Sistema Complemento/fisiologia , Interleucina-2/farmacologia , Pulmão/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Indometacina/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Complemento/metabolismo , Proteínas Recombinantes/metabolismo , Tromboxano B2/metabolismo , Timidina/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10(5)-10(6) U/rat (n = 7-9) dose-dependently elevated lung water content (27 +/- 1%, P less than 0.01), myeloperoxidase activity (+84 +/- 23%, P less than 0.05), and serum thromboxane B2 (990 +/- 70%, P less than 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-alpha, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P less than 0.05) and thromboxane B2 production (P less than 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18 +/- 16%, P less than 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy.
