背景:横纹肌溶解症诱导的急性肾损伤(RIAKI)可中断体能训练并增加受伤战士的死亡率。提高法律性能的药物咖啡因和布洛芬,会导致肾损伤,被服务成员广泛使用。咖啡因或布洛芬是否会影响RIAKI尚不清楚。西司他丁治疗最近被确定为预防RIAKI损伤的实验性治疗。为了确定RIAKI治疗中潜在的相互作用因素,我们检验了咖啡因和布洛芬使RIAKI恶化并干扰治疗的假设.
方法:在小鼠中,通过甘油肌内注射诱导RIAKI。同时,小鼠接受咖啡因(3mg/kg),布洛芬(10mg/kg),或车辆。第二个队列接受了容量复苏(PlasmaLyte,20mL/kg)除咖啡因或布洛芬外。在第三组中,西司他丁(200mg/kg)与药物和甘油给药同时给药。肾小球滤过率(GFR),血尿素氮(BUN),尿量(UOP),肾脏病理学,24小时后对肾损伤分子1的肾免疫荧光进行定量。
结果:咖啡因并没有使RIAKI恶化;尽管服用咖啡因会适度增加BUN,24小时GFR,UOP,和肾组织病理学相似,咖啡因处理,和咖啡因+PlasmaLyte处理的小鼠。布洛芬给药大大恶化了RIAKI(GFR14.3±19.5vs.577.4±454.6微升/分钟/100克对照,UOP0.5±0.4布洛芬治疗的小鼠与对照2.7±1.7mL/24h,和BUN264±201在布洛芬治疗的小鼠与对照组为66±21mg/dL,P<0.05);PlasmaLyte治疗并未逆转这种作用。有或没有PlasmaLyte的西司他丁都不能逆转布洛芬在RIAKI中的有害作用。
结论:咖啡因不会使RIAKI恶化。广泛使用的性能增强药物布洛芬极大地恶化了小鼠的RIAKI。包括向标准复苏中添加西司他丁的RIAKI的标准或实验治疗在布洛芬加重的RIAKI小鼠中是无效的。这些发现可能对RIAKI的当前治疗和新疗法的转化研究具有临床意义。
Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown.
Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment.
In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort,
cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours.
Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect.
Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI.
Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of
cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.