活菌药物的量效关系
发布时间：2022-09-23
活菌药物的量效关系
常秀娟、王薇、杜瑶、刘洋洋、李平
1 活菌产品（益生菌）的机制和药代特性与常规化药等有所不同
活菌药物的量效关系与小分子药物存在明显的差异。
小分子药物发挥药理学效应的基础一般是通过血液到达靶器官，在一定剂量范围内，药物的效应与靶部位的浓度成正相关，从而呈现较好的量效关系，而这个剂量范围一般会在2-5倍，不会跨越2个数量级以上。
活菌药物口服后不入血，发挥药理学效应的基础一般是通过与肠道的接触以及定植，并且活菌在消化道可能会死亡（如经胃酸）、繁殖及代谢，导致肠道内的活菌数量与实际给予的活菌数量不同。其后在一定剂量范围内通过影响肠道黏膜的免疫调节细胞（如树突细胞、巨噬细胞、NK细胞等）影响固有免疫系统[1-4]，介导调节剂（如细胞因子、趋化因子）的分泌效应发挥免疫效应[5-6]，或与体内多种肠道菌群发生协同或促进作用[7]，或通过一些代谢成分（如短链脂肪酸、膜蛋白、外膜囊泡等）发挥作用[8-9]。由于这些特性，它的量效关系通常在较宽的数量级范围（如10倍~1000倍）进行考察。
2 以膳食补充剂出现的益生菌产品，剂量多是一个范围
国际益生菌和益生元科学协会（ISAPP）益生菌应用指南[10]中提出：目前多数研究提出益生菌的推荐量为108～1011CFU/d。世界胃肠病学组织益生菌与益生元指南（World Gastroenterology Organization Global Guidelines• Probiotics and Prebiotics，2017）提出[11]：添加益生菌的产品所需剂量根据菌株和产品而有很大差异，大部分菌株的推荐摄入量是108~1011CFU/d，少数菌株推荐摄入量106~107 CFU/d。其他指南也有类似看法。
3 关于活菌计数与剂量控制
鉴于微生物计数的方法学偏差较大，而活菌数（稳定性）受储运、配制等的影响较大，所以对于一个研究系统中，对目的菌的活菌计数进行系统的方法学研究形成SOP，对稳定性进行了系统的考察，是评估量效关系的基础。
4 活菌产品的量效关系研究
使用检索词“probiotics+high dose+mice或human”检索的文献中，采用2个及以上剂量开展的药效研究（包括动物与人体）共89个，对其进行汇总和分析，可以看到：
（1）其中57篇研究只报道了2个剂量组研究，由于2个剂量的研究数据不能反映出量效关系的整体趋势，在此不做分析。
（2）实际上，3个及以上剂量组的研究结果更值得关注（上述89个里有32篇），存在着几种类型：常规的量效关系型、倒U型及其他。（见表1）。值得注意的是，即使是这里的剂量依赖性，也存在低、中剂量间差异不明显。
从药效学研究本身来说，上述几种剂量关系类型都是客观存在并合理的。研究逻辑本身，是先进行大范围的剂量探索，再选择合适的剂量范围进行更细致的量效研究。前述的大部分文献报道（2个剂量组研究），往往是将更小范围的量效结果展示出来。
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