磷酸二酯酶抑制剂brl61063、己酮茶碱和罗利普兰对内毒素休克小鼠模型的有益作用。

Circulatory shock Pub Date : 1994-12-01
A M Badger, D L Olivera, K M Esser
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引用次数: 0

摘要

研究了三种钙依赖性环腺苷3′5′-单磷酸(cAMP)依赖性磷酸二酯酶IV (PDE IV)抑制剂在体外和体内对脂多糖(LPS)诱导的肿瘤坏死因子(TNF)产生的影响,以及它们保护d -半乳糖胺(D-gal)致敏小鼠免受脂多糖诱导致死的能力。在体外,在lps刺激的小鼠腹腔巨噬细胞(PEM)上,BRL 61063(1,3-二(环丙基甲基)-8-氨基黄嘌呤)和罗利普拉姆(4-(3-环戊氧基-4-甲氧基苯基)-2-吡罗烷酮)具有相似的TNF抑制活性,IC50范围为0.1至0.5微米。己酮茶碱(PTX),(3,7-二甲基-1-(5-氧己基)黄嘌呤)的IC50 = 100微米时作用较弱。在体内,对LPS刺激的D-gal致敏小鼠血清TNF水平有一个等级效价。BRL 61063抑制TNF生成的ID50为0.1 mg/kg,罗利普兰为1 mg/kg, PTX为200 mg/kg。因此,在该模型中,BRL 61063降低TNF血清水平的效力是PTX的2000倍。有趣的是,TNF在LPS/D-gal模型中被认为具有核心致病作用,因为动物的生存与所有三种化合物血清TNF水平的降低直接相关。有人提出,TNF的强效抑制剂可能在TNF似乎在疾病发病机制中起作用的疾病状态中具有治疗活性。
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Beneficial effects of the phosphodiesterase inhibitors BRL 61063, pentoxifylline, and rolipram in a murine model of endotoxin shock.

Three inhibitors of calcium-dependent cyclic adenosine 3'5'-monophosphate (cAMP) dependent phosphodiesterase IV (PDE IV) were evaluated for their effects on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production in vitro and in vivo and for their ability to protect mice from LPS-induced lethality in D-galactosamine (D-gal) sensitized mice. In vitro, on LPS-stimulated murine peritoneal macrophages (PEM), BRL 61063 (1,3-di(cyclopropylmethyl)-8-aminoxanthine) and rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) had similar TNF inhibitory activity with an IC50 ranging from 0.1 to 0.5 microM. Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)xanthine) was less potent with an IC50 = 100 microM. In vivo, there was a rank order potency on serum TNF levels in LPS challenged D-gal sensitized mice. BRL 61063 inhibited TNF production with an ID50 of 0.1 mg/kg, rolipram at 1 mg/kg, and PTX at 200 mg/kg. Thus, BRL 61063 is 2,000 times more potent than PTX in reducing TNF serum levels in this model. Interestingly, TNF is implicated as having a central pathogenic role in the LPS/D-gal model, since survival of animals correlated directly with reduction of serum TNF levels for all three compounds tested. It is proposed that potent inhibitors of TNF may have therapeutic activity in disease states where TNF appears to play a role in the pathogenesis of the disease.

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