咖啡因对大鼠酮洛芬抗伤害感受作用的影响。

Effect of caffeine on antinociceptive action of ketoprofen in rats.

作者信息

Díaz-Reval M I, Ventura-Martínez R, Hernández-Delgadillo G P, Domínguez-Ramírez A M, López-Muñoz F J

机构信息

Departamento de Farmacología y Toxicología, Centro de Investigación y de Estudios Avanzados del I.P.N. (Cinvestav), Unidad Sur, Mexico City, Mexico.

出版信息

Arch Med Res. 2001 Jan-Feb;32(1):13-20. doi: 10.1016/s0188-4409(00)00268-x.

DOI:10.1016/s0188-4409(00)00268-x

PMID:11282174

Abstract

BACKGROUND

To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain.

METHODS

Antinociceptive activity was assayed using "ellipsis pain-induced functional impairment in the rat" (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations).

RESULTS

ASA (ED(50) 465.2 +/- 1.5 mg/kg), MOR (ED(50) 71.0 +/- 1.6 mg/kg), and KET (ED(50) 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 +/- 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effective dose (ED(50)) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED(50) of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF.

CONCLUSIONS

These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.

摘要

背景

为评估可能的协同抗伤害感受相互作用，在关节炎疼痛模型中确定了单独或联合给予酮洛芬（KET）和咖啡因（CAF）的抗伤害感受作用。

方法

使用“大鼠椭圆疼痛诱导功能障碍”（PIFIR模型）测定抗伤害感受活性。使用多条剂量反应曲线和时程评估抗伤害感受效力。将产生更大效应的联合用药的抗伤害感受作用与吗啡、乙酰水杨酸（ASA）或单独使用KET的最大抗伤害感受作用进行比较。给动物关节内注射（i.a.）0.05 mL尿酸以诱导伤害感受。每组6只大鼠口服给予ASA、吗啡（MOR）、KET、CAF或联合用药KET + CAF（24种组合）。

结果

单独使用ASA（半数有效剂量[ED(50)] 465.2±1.5 mg/kg）、MOR（ED(50) 71.0±1.6 mg/kg）和KET（ED(50) 7.2±1.4 mg/kg）可诱导剂量依赖性抗伤害感受，而单独使用CAF在测定剂量下无活性。9种组合显示出不同程度的增效作用（p <0.01），其余组合仅表现出KET的抗伤害感受作用。17.8 mg/kg CAF与1.0、1.8、3.2、5.6或10.0 mg/kg KET的组合产生最高的抗伤害感受增效作用。例如，单独使用KET（3.2 mg/kg）时抗伤害感受作用为125.6±21.4面积单位（au），但与CAF（17.8 mg/kg）联合使用时显示为309.5±10.3 au。单独使用KET的半数有效剂量（ED(50)）为7.2±1.4 mg/kg，而KET + CAF 17.8 mg/kg的ED(50)为0.4±0.6 mg/kg：存在CAF时KET的效力比无CAF时的镇痛药高约18倍。

结论

这些结果表明，CAF能够增强KET的镇痛作用，但仅在特定剂量组合下：10.——和17.8 mg/kg剂量的CAF能够增强KET的镇痛作用，最有效的药物组合是CAF 17.8 mg/kg + KET 3.2 mg/kg。镇痛药与CAF联合使用比单独使用镇痛药可产生更好的抗伤害感受作用。这一知识将有助于选择治疗上最有效的药物联合比例，同时降低每种药物的剂量。