溶剂型止惊退热药物直肠给药的动物与临床研究
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摘要
第 一 部 分
溶剂型直肠退热药物的筛选
目的:为成功配制起效快、疗效好、作用较持久的儿科溶剂型直肠止惊退热混合药物，筛选一种最适宜的配方退热药。
方法:对儿科常用的扑热息痛、布洛芬、酮洛芬三种退热剂，分别进行其溶液制剂口服和直肠给药的对比研究：（1）药效学的比较研究：Wistar大鼠共64只，随机分为正常对照组、酵母对照组、口服给药组、直肠给药组，以10％酵母悬液按10ml/kg剂量背部皮下注射制成发热模型。确认体温增高（酵母注射后3小时）后给退热药。给药前及给药后每小时测肛温，连续监测8小时；（2）药动学的比较研究：大白兔共48只，随机分为直肠给药组和口服给药组。给药前及给药后5、15、30、60、90、120、180、240、300、360分钟取血，采用高效液相色谱法（HPLC）测定血药浓度，比较各药Tlag、Tmax、Cmax、AUC等药动学参数。
结果:（1）扑热息痛直肠给药后Tlag、Tmax比口服显著延长，Cmax仅为口服的42.20%，与口服的相对生物利用度仅为60.09％，降温明显比口服差，且维持时间显著短于口服，仅在给药后1小时有显著降温；（2）布洛芬、酮洛芬直肠给药后的Tlag、Tmax与口服比无显著性差异，
Cmax比口服低约30％，而与口服的相对生物利用度都达到80％以上，其降温虽然比口服稍差，但无显著性差异。无论口服或直肠给药，都在给药后1小时就明显降温，并至少维持8小时；（3）与布洛芬、酮洛芬相比，经直肠给药，扑热息痛的Tlag、Tmax明显延长，与口服比较的相对生物利用度低，退热疗效差且维持时间短。而布洛芬和酮洛芬各指标间无显著性差异。
结论:（1）扑热息痛溶液直肠给药比口服吸收延迟且不完全，变异性大，退热疗效差，维持时间短；（2）布洛芬溶液和酮洛芬溶液直肠给药后吸收快而完全，退热疗效好，维持时间长，与口服比没有显著性差异；（3）无论从药效学还是药代动力学评价，其溶液经直肠给药，布洛芬和酮洛芬都比扑热息痛具有显著优越性；（4）结合本研究结果与临床长期用药的不良反应，确认布洛芬应是进一步研制小儿直肠止惊退热混合制剂的基本成分。
关键词:扑热息痛;布洛芬;酮洛芬;溶液;直肠给药
【Objective】To select an ideal soluble antipyretic administered rectally for a further study to produce a powerful mixed formulation of antipyretic and anticonvulsant.
【Methods】There were three antipyretics, including acetaminophen, ibuprofen and ketoprofen, which are common used by pediatrician, to be studied comparatively for their pharmacokinetics and pharmacodynamics of each drug with rectal and oral administration. (1)Comparison of pharmacodynamics: 64 Wistar rats were randomly assigned to the following four groups: normal control group; yeast-treated control group; oral administration group and rectal administration group. Rats were injected at dorsal site subcutaneously with a dose of 10ml/kg of 10% yeast suspension. The antipyretics were used respectively after three hours as
increased body temperature had been presented in all experimental rats. Rectal temperatures were taken before and every one hour after dosing in 8 hours. (2)Comparison of pharmacokinetics: 48 rabbits were randomly divided into oral administration group and rectal administration group. Blood samples were taken just before and 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 minutes after dosing and all samples were assayed by HPLC. All of pharmacokinetic parametes in every group, such as blood concentration at each time point and Tlag、Tmax、Cmax、AUC, were collected and analysed comparativly.
【Results】(1)Paracetamol: The Tlag and Tmax of paracetamol, when administered rectally, were significantly longer than that when administer- ed orally, the Cmax for rectal administration was only 42.0% of that for oral administration, and the relative bioavailability of the rectal administration, compared with the oral administration, was 60.1%. Its antipyretic effect after rectal administration was significantly weaker and shorter lasting than that after oral administration and the fever reduction was observed only in the first hour after dosing. (2)Ibuprofen and ketoprofen: Their Tlag and Tmax for oral and rectal administation were not significantly different. When administered rectally, the Cmax was 30% lower than that of oral administration, but the AUC was about 80% of that obtained after oral administration. Remarkable fever reduction had been observed since the
first hour after dosing and lasted for eight hours either orally or rectally administered. The antipyretic efficacy for oral administration seemed to be potenter than that for rectal administration, but the difference was not significant statistically. (3)Compared with those for rectal ibuprofen and ketoprofen, the Tlag and Tmax for rectal paracetamol were significantly longer and the relative bioavailability was obviously lower. The antipyretic efficacy for rectal acetaminophen was more weaker and shorter lasting than those for rectal ibuprofen and ketoprofen which were not significant different.
【Conclusions】(1)When administered rectally, the absorption of paracetamol was delayed and incomplete and irregular, and the antipyretic effect was more weaker and shorter lasting than that for oral administrtion. (2)The rectal absorption of ibuprofen and ketoprofen were rapid and complete which were comparable with that of oral dosing. Potent fever reduction and long lasting antipyretic efficacy were well demonstrated both after oral and after rectal administration with ibuprofen and ketoprofen. (3)For rectal administration, ibuprofen and ketoprofen were superior to paracetamol on their pharmacokinetics or pharmacodynamics. (4)Ibuprofen would be an ideal antipyretic drug to consist of a powerful mixed formulation with anticonvulsant according to the result as above and much less side effects of ibuprofen comparing with others.
【Key words】paracetamol; ibuprofen; ketoprofen; solution; rectal administration
溶剂型直肠退热药物的筛选
目的:为成功配制起效快、疗效好、作用较持久的儿科溶剂型直肠止惊退热混合药物，筛选一种最适宜的配方退热药。
方法:对儿科常用的扑热息痛、布洛芬、酮洛芬三种退热剂，分别进行其溶液制剂口服和直肠给药的对比研究：（1）药效学的比较研究：Wistar大鼠共64只，随机分为正常对照组、酵母对照组、口服给药组、直肠给药组，以10％酵母悬液按10ml/kg剂量背部皮下注射制成发热模型。确认体温增高（酵母注射后3小时）后给退热药。给药前及给药后每小时测肛温，连续监测8小时；（2）药动学的比较研究：大白兔共48只，随机分为直肠给药组和口服给药组。给药前及给药后5、15、30、60、90、120、180、240、300、360分钟取血，采用高效液相色谱法（HPLC）测定血药浓度，比较各药Tlag、Tmax、Cmax、AUC等药动学参数。
结果:（1）扑热息痛直肠给药后Tlag、Tmax比口服显著延长，Cmax仅为口服的42.20%，与口服的相对生物利用度仅为60.09％，降温明显比口服差，且维持时间显著短于口服，仅在给药后1小时有显著降温；（2）布洛芬、酮洛芬直肠给药后的Tlag、Tmax与口服比无显著性差异，
Cmax比口服低约30％，而与口服的相对生物利用度都达到80％以上，其降温虽然比口服稍差，但无显著性差异。无论口服或直肠给药，都在给药后1小时就明显降温，并至少维持8小时；（3）与布洛芬、酮洛芬相比，经直肠给药，扑热息痛的Tlag、Tmax明显延长，与口服比较的相对生物利用度低，退热疗效差且维持时间短。而布洛芬和酮洛芬各指标间无显著性差异。
结论:（1）扑热息痛溶液直肠给药比口服吸收延迟且不完全，变异性大，退热疗效差，维持时间短；（2）布洛芬溶液和酮洛芬溶液直肠给药后吸收快而完全，退热疗效好，维持时间长，与口服比没有显著性差异；（3）无论从药效学还是药代动力学评价，其溶液经直肠给药，布洛芬和酮洛芬都比扑热息痛具有显著优越性；（4）结合本研究结果与临床长期用药的不良反应，确认布洛芬应是进一步研制小儿直肠止惊退热混合制剂的基本成分。
关键词:扑热息痛;布洛芬;酮洛芬;溶液;直肠给药
【Objective】To select an ideal soluble antipyretic administered rectally for a further study to produce a powerful mixed formulation of antipyretic and anticonvulsant.
【Methods】There were three antipyretics, including acetaminophen, ibuprofen and ketoprofen, which are common used by pediatrician, to be studied comparatively for their pharmacokinetics and pharmacodynamics of each drug with rectal and oral administration. (1)Comparison of pharmacodynamics: 64 Wistar rats were randomly assigned to the following four groups: normal control group; yeast-treated control group; oral administration group and rectal administration group. Rats were injected at dorsal site subcutaneously with a dose of 10ml/kg of 10% yeast suspension. The antipyretics were used respectively after three hours as
increased body temperature had been presented in all experimental rats. Rectal temperatures were taken before and every one hour after dosing in 8 hours. (2)Comparison of pharmacokinetics: 48 rabbits were randomly divided into oral administration group and rectal administration group. Blood samples were taken just before and 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 minutes after dosing and all samples were assayed by HPLC. All of pharmacokinetic parametes in every group, such as blood concentration at each time point and Tlag、Tmax、Cmax、AUC, were collected and analysed comparativly.
【Results】(1)Paracetamol: The Tlag and Tmax of paracetamol, when administered rectally, were significantly longer than that when administer- ed orally, the Cmax for rectal administration was only 42.0% of that for oral administration, and the relative bioavailability of the rectal administration, compared with the oral administration, was 60.1%. Its antipyretic effect after rectal administration was significantly weaker and shorter lasting than that after oral administration and the fever reduction was observed only in the first hour after dosing. (2)Ibuprofen and ketoprofen: Their Tlag and Tmax for oral and rectal administation were not significantly different. When administered rectally, the Cmax was 30% lower than that of oral administration, but the AUC was about 80% of that obtained after oral administration. Remarkable fever reduction had been observed since the
first hour after dosing and lasted for eight hours either orally or rectally administered. The antipyretic efficacy for oral administration seemed to be potenter than that for rectal administration, but the difference was not significant statistically. (3)Compared with those for rectal ibuprofen and ketoprofen, the Tlag and Tmax for rectal paracetamol were significantly longer and the relative bioavailability was obviously lower. The antipyretic efficacy for rectal acetaminophen was more weaker and shorter lasting than those for rectal ibuprofen and ketoprofen which were not significant different.
【Conclusions】(1)When administered rectally, the absorption of paracetamol was delayed and incomplete and irregular, and the antipyretic effect was more weaker and shorter lasting than that for oral administrtion. (2)The rectal absorption of ibuprofen and ketoprofen were rapid and complete which were comparable with that of oral dosing. Potent fever reduction and long lasting antipyretic efficacy were well demonstrated both after oral and after rectal administration with ibuprofen and ketoprofen. (3)For rectal administration, ibuprofen and ketoprofen were superior to paracetamol on their pharmacokinetics or pharmacodynamics. (4)Ibuprofen would be an ideal antipyretic drug to consist of a powerful mixed formulation with anticonvulsant according to the result as above and much less side effects of ibuprofen comparing with others.
【Key words】paracetamol; ibuprofen; ketoprofen; solution; rectal administration
引文
前 言
1． Berkovic SF, Scheffer IE. Febrile seizures:genetics and relationship to other epilepsy syndromes. Current Opinion in Neurology, 1998;11:129-134
2． Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus : a genetic disorder with heterogeneous clinical phenotypes. Brain,1997;120:479-490
3． 蒋莉，蔡方成。高热惊厥预后与防治的研究进展。中国实用儿科杂志，1999；14（1）：51-52
4． 蒋莉，蔡方成。氯硝基安定溶液直肠给药的动物实验与临床研究。中华儿科杂志，1997；35（4）：202-205
5． 蒋莉，蔡方成，瞿平。氯硝基安定与安定溶液直肠给药用于惊厥急救的对照研究。中华儿科杂志，1998；36（10）：591-593
6． Knudsen FU. Febrile seizures : treatment and prognosis. Epilepsia, 2000;41(1):2-9
7． Gaudreault P, Guay J, Nicol O, et al. Pharmacokinetics and clinical efficacy of intrarectal solution of acetaminophen. Can J Anaesth, 1988;35(2):149-52
8． Avouac B, Teule M. Ketoprofen: the European experience. J Clin Pharmacol, 1988; 28:s2-s7
第 一 部 分
1．Knudsen FU. Febrile seizures : treatment and prognosis. Epilepsia, 2000;41(1):2-9
2．Gaudreault P, Guay J, Nicol O, et al. Pharmacokinetics and clinical efficacy of intrarectal solution of acetaminophen. Can J Anaesth, 1988;35(2):149-52
3． vouac B, Teule M. Ketoprofen: the European experience. J Clin Pharmacol, 1988; 28:s2-s7
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6． Ceserani R, Carboni L, Germini M, et al. Antipyretic and platelet antiaggregating effects of nimesulide. Drugs,1993;46(suppl 1):48-51
7．苗明三。实验动物和动物实验技术。北京，中国中医药出版社,1997;143-145
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23. Wilson JT, Don Brown R, Kearns, GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen antipyresis in children. J Pediatr, 1991;119 (5): 803-811
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25. Eller MG, Wright Ⅲ C, Della-Coletta AA. Absorption kinetics of rectally and orally administered ibuprofen. Biopharmaceutic ＆ Drug Disposition, 1989;10: 269-278
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第 二 部 分
蒋莉，蔡方成。氯硝基安定溶液直肠给药的动物实验与临床研究。中华儿科杂
1. 志，1997；35（4）：202-205
2. 蒋莉，蔡方成，瞿平。氯硝基安定与安定溶液直肠给药用于惊厥急救的对照研究。中华儿科杂志，1998；36（10）：591-593
3. 赵燕燕，李建恒，张秋燕。扑热息痛滴鼻剂的制剂学研究。中国药房，1998；9（3）：107-108
4. 苗明三。实验动物和动物实验技术。北京，中国中医药出版社，1997，191
5. 王丽，Ono J, Walson PD. 大鼠戊四氮点燃模型的建立。药学学报，1993；28：486-488
6. 周爱华。高效液相色谱法同时测定血液中安定、舒乐安定和氯硝基安定的浓度。临床检验杂志，2000；18（4）：223-224
7. Don Brown R, Wilson JT, Kearns GL, et al. Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. J Clin Pharmacol, 1992;32: 231-241
8. 蒋莉，蔡方成，瞿平。安定溶液直肠给药止惊药效的临床和实验研究。重庆医科大学学报，1998；23（1）：30-33
9. Cloyd JC, Lalonde RL, Beniak TE, et al. A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam. Epilepsia,1998;39(5):520-526
10. 宫崎正三等。图解药剂学。北京，中国医药科技出版社，1989，78
11. Carol B, Lindsley MD. Uses of nonsteroid anti-inflammatory drugs in pediatrics. AJDC,147:229-236
12. 陈伯銮。临床麻醉药理学。北京，人民卫生出版社。2000，221-223
Don Brown R, Kearns GL, Wilson JT. Integrated pharmacokinetic-pharmaco- dynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children.
13. Journal of Pharmacokinetics and Biopharmaceutics,1998;26(5):559-579
14. Wilson JT, Don Brown R, Kearns, GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen antipyresis in children. J Pediatr, 1991;119 (5): 803-811
15. Carolyne J, James P, Clayton C, et al. Plasma concentrations after high-dose(45 mg/kg) rectal acetaminophen in children. Can J Anaesth,1995;42(11):982-6
16. Eller MG, Wright Ⅲ C, Della-Coletta AA. Absorption kinetics of rectally and orally administered ibuprofen. Biopharmaceutics ＆ Drug Disposition, 1989; (10):269-278
1． Berkovic SF, Scheffer IE. Febrile seizures:genetics and relationship to other epilepsy syndromes. Current Opinion in Neurology, 1998;11:129-134
2． Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus : a genetic disorder with heterogeneous clinical phenotypes. Brain,1997;120:479-490
3． 蒋莉，蔡方成。高热惊厥预后与防治的研究进展。中国实用儿科杂志，1999；14（1）：51-52
4． 蒋莉，蔡方成。氯硝基安定溶液直肠给药的动物实验与临床研究。中华儿科杂志，1997；35（4）：202-205
5． 蒋莉，蔡方成，瞿平。氯硝基安定与安定溶液直肠给药用于惊厥急救的对照研究。中华儿科杂志，1998；36（10）：591-593
6． Knudsen FU. Febrile seizures : treatment and prognosis. Epilepsia, 2000;41(1):2-9
7． Gaudreault P, Guay J, Nicol O, et al. Pharmacokinetics and clinical efficacy of intrarectal solution of acetaminophen. Can J Anaesth, 1988;35(2):149-52
8． Avouac B, Teule M. Ketoprofen: the European experience. J Clin Pharmacol, 1988; 28:s2-s7
第 一 部 分
1．Knudsen FU. Febrile seizures : treatment and prognosis. Epilepsia, 2000;41(1):2-9
2．Gaudreault P, Guay J, Nicol O, et al. Pharmacokinetics and clinical efficacy of intrarectal solution of acetaminophen. Can J Anaesth, 1988;35(2):149-52
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