差之毫厘谬以千里：抗抑郁药阿米替林可预防肺部感染

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Elavil for Cystic Fibrosis?

Antidepressant Prevents CF Lung Infection in Mice; Correct Dosage Crucial

March 31, 2008 -- The antidepressantElavil prevents lung infection in mice with cystic fibrosis, but the dose must be exactly right to avoid harm.

The finding comes from researchers who may have found the key to why the genetic mutation that causes cystic fibrosis leads to the deadly lung-clogging infections that are the hallmark of the disease.

The cystic-fibrosis mutation disables a gene called CFTR (cystic fibrosis transmembrane conductance regulator). Researchers Erich Gulbins, MD, PhD, of Germany's University of Duisburg-Essen and colleagues now find that CFTR dysfunction upsets a delicate chemical balance in the lungs. This results in accumulation of a sticky lipid called ceramide.

As ceramide accumulates, it inflames the lung and kills lung cells. Debris from the dead cells piles up, giving a foothold to dangerous bacteria -- particularly the pseudomonas germs that plague people with cystic fibrosis.

Gulbins' team showed that this happens in mice lacking the CFTR gene. But they could prevent lung inflammation and pseudomonas infection by giving the animals Elavil.

Elavil is commonly used as an antidepressant. The drug works in cystic fibrosis by blocking an enzyme, Asm, that becomes overactive when CFTR isn't working properly.

\"Treatment of CFTR-deficient mice with [Elavil] ... normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection,\" Gulbins and colleagues report. \"Normalization of ceramide levels by [Elavil] may represent a new and important strategy to prevent bacterial infection in people with cystic fibrosis.\"

By blocking Asm, Elavil causes the body to make less ceramide. But Gulbins and colleagues warn that too little ceramide is dangerous. The sticky molecule helps remove bacteria from the airways. Mice with too little ceramide are unable to fight off lung infections.

\"Thus any future cystic fibrosis drug targeting the Asm must be carefully titrated to normalize ceramide levels in the lungs of people with cystic fibrosis, but not reduce ceramide concentrations below a critical cellular level that would impair the biological functions of ceramide,\" they note.

Gulbins and colleagues report their findings in the March 30 online edition of Nature Medicine.
阿米替林治疗囊性纤维化病

抗抑郁药物预防囊性纤维化病老鼠肺部感染：正确的剂量是关键
2008年3月31日----给囊性纤维化病的老鼠使用抗抑郁药物阿米替林能预防肺部感染，但是用量必须确切以免造成危害。
那些研究导致囊性纤维化病的基因突变为何会引起致死性的肺部阻塞性感染的研究者发现了以上现象。
囊性纤维化病基因突变是一个叫做CFTR（囊性纤维化跨膜通道调节因子）的基因丧失了功能。现在，德国Duisburg-Essen大学研究人员Erich Gulbins博士和他的同仁们发现CFTR的异常扰乱了肺部精细的化学物质平衡。这导致了称为神经酰胺的粘性脂质聚集。
神经酰胺的聚集激起了肺部炎症并杀死肺细胞。死亡细胞的残骸为危险细菌的入侵提供了立足点----特别是让囊性纤维化病患者深受其害的假单胞菌属病菌。
Gulbins的团队研究显示这些均发生在缺乏CFTR基因的老鼠身上。但是通过给予阿米替林能使老鼠发生肺部炎症和假单胞菌属感染。
阿米替林通常是作为抗抑郁药物使用。该药在囊性纤维化病的作用机理是抑制一种叫Asm的酶，Asm在CFTR异常时过度激活。
Gulbins和他的同仁们报道：“经（阿米替林）治疗CFTR基因异常的老鼠，肺部神经酰胺正常化，且阻止了所有的病理改变，包括对感染性疾病的易感性。通过应用（阿米替林）而使神经酰胺水平正常化，这可能是预防囊性纤维化病患者肺部感染的一种新的重要的方法。”
阿米替林通过抑制Asm使机体神经酰胺产生减少。但是Gulbins和他的同仁们同时警告神经酰胺过少也是危险的。这些粘附分子能够帮助清除气道的细菌。过少的神经酰胺不能消除肺部炎症。
他们写道：“这样将来任何一种作用于Asm酶靶点的治疗囊性纤维化病的药物必须小心谨慎地滴定到患者神经酰胺水平正常化为止，而不能降低到损害神经酰胺生物学功能的危险分子水平。”
Gulbins和他的同仁们的报告发表在3月30日的《Nature Medicine》网络版。

阿米替林还可以治疗胃炎