布洛芬-安定混合溶液直肠给药的动物和临床研究

Animal and clinical studies on rectal administration of a mixed solution of ibuprofen and diazepam

目的探讨布洛芬安定混合溶液(IBU DZP)经直肠给药的实效性和安全性。方法(1)动物实验:观察IBU DZP直肠给药后在兔体内的药动学、对戊四氮诱发的大鼠实验性惊厥发作的止惊疗效、对酵母诱导的大鼠发热退热疗效,以及对直肠黏膜的刺激性;(2)临床观察:该混合溶液直肠给药后在儿童体内的初步药动学研究。结果(1)动物实验:IBU DZP中的IBU和DZP均能经直肠迅速吸收,在兔体内分别约(11.7±1.2)min和(9.4±2.7)min达到峰值。IBU DZP混合液能快速有效地抑制戊四氮诱发的大鼠惊厥发作和死亡,有效降低酵母诱发的大鼠发热。该混合液连续多次直肠给药后对大鼠直肠黏膜没有明显刺激作用。(2)临床观察:IBU DZP混合液经儿童直肠给药后,IBU和DZP分别约在用药后30min和15min达峰值血药浓度[分别为(57.8±7.9)mg/L和(450.1±158.7)μg/L],且在用药后5min血药浓度就分别达到(41.4±5.5)mg/L和(321.8±53.9)μg/L,均远远超过最低有效血药浓度。结论直肠注入IBU DZP溶液是一种简便、安全、快速、有效的给药途径,对发热性惊厥的现场抢救和预防有实用价值。

Objective Seizure is a common emergency in children with complicated pathogeny. Seizures are usually caused by complicated etiology and fever and febrile seizure are the commonest causes. Repeated and permanent seizures can damage the brain. So it is important to take active and effective measures to control seizure and high fever. Because most seizures and fever take place at home or out of hospital and it is difficult to administer drugs intravenously, it is important to explore an easy, safe, quick and effective way to control and prevent both seizure and fever. The present study aimed to explore the efficacy and safety of rectal administration of mixed ibuprofen and diazepam (IBU-DZP) solution.Methods (1)Animal study on the pharmacokinetics in rabbits and pharmacodynamics in rats after rectal administration with the mixed solution and on the irritability of the mixed solution to rectum. (2) Clinical study: Pharmacokinetics of the mixed solution in children after rectal administration were investigated.Results (1)Animal study :IBU and DZP were both rapidly Absorbed from rectum with a peak blood level of (11.7±1.2)min and (9.4±2.7)min in rabbits, respectivly. The mixed solution could effectively prevent the severity of seizures induced by pentetrazole and significantly suppressed fever induced by yeast. There were no remarkable pathological changes in rectal tissues after repeated rectal administration of the mixed solution. (2) Clinical study: IBU and DZP rapidly reached their peak blood levels at about 30 min and 15 min respectively after rectal administration to the children. The peak values were (57.8±7.9)mg/L and( 450.1±158.7)μg/L, respectively. In fact, both of them reached levels that were much higher than their therapeutic levels in serum just at 5 min after administration, their blood levels were(41.4±5.5)mg/L and(321.8±53.9)μg/L, respectively. Conclusions IBU-DZP mixed solution administered rectally is an easy, safe, quick and effective way to control and prevent both seizure and fever.