帮助药物入脑的一些办法

一、在用注射类抗癌药前半小时先输甘露醇

甘露醇能短暂打开血脑屏障几个小时，来看一个前瞻性随机对照临床试验：

《甘露醇对非小细胞肺癌脑转移患者脑部顺铂浓度的影响》

“60例ⅢB和Ⅳ期非小细胞肺癌(NSCLC)脑转移患者,随机分为A、B、C 3组。”

“Ａ 组于化疗开始前 ３０ ｍｉｎ 应 用 ２０％甘露醇（华润双鹤药业股份有限公司，生产批号： Ｈ１１０２０８６１）２５０ｍＬ快 速 静 滴，然 后 给 予 ＤＤＰ 静 脉
化疗（２０ｍｇ／ｍ２静 滴）；Ｂ 组 于 化 疗 开 始 前２ｈ应 用 ２０％甘露醇治疗；Ｃ 组仅给予 ＤＤＰ化疗。”

“3组脑脊液DDP浓度分别为:A组(2.82±1.46)mg/L,B组(1.24±1.11)mg/L,C组(1.03±0.92)mg/L,各组比较差异有统计学意义(P<0.05)。”

“无进展生存期3组情况:A组(11.46±4.35)个月、B组(9.29±4.61)个月和C组(7.39±3.12)个月,生存期分别为A组(18.75±5.63)个月、B组(16.82±3.73)个月和C组(13.09±4.24)个月,各组比较差异有统计学意义(P<0.05)。”

“3组不良反应发生率分别为63.5%、65.2%和64.3%,组比较差异无统计学意义(P>0.05)。”


二、大剂量用他莫昔芬

P-gp蛋白是主要的耐药蛋白，也是血脑屏障上的主要外排蛋白。抗癌药物大部分是p-gp蛋白的底物，是它们透过血脑屏障的主要阻碍。

抑制p-gp可帮助p-gp底物药物入脑。

治疗乳腺癌的内分泌药他莫昔芬有抑制p-gp的作用，但是治疗乳腺癌的常规剂量却体现不出抑制p-gp的疗效。

要抑制p-gp，他莫昔芬要用多大的剂量？人体是否能耐受？

来看这个前瞻性随机对照临床试验：

《Efficacy of tamoxifen in combination with docetaxel in patients with advanced non-small-cell lung cancer pretreated with platinum-based chemotherapy 》

多西他赛联合或者不联合大剂量的他莫昔芬治疗120名非小细胞肺癌患者；这里把大剂量的他莫昔芬当p-gp抑制剂用。“120 patients were entered into the trial and randomized by a computer system into the two treatment groups (the TXT and TXT + TAM groups) in a 1 : 1 ratio ”

多西他赛 ：“75 mg/m2 intravenously on day 1,repeated every 3 weeks.”，按照说明书常规剂量用。

他莫昔芬：“ 80 mg orally three times daily 3 days before TXT chemotherapy and continued for 7 days.”试验组的这个剂量远远超过了他莫昔芬治疗乳腺癌时的“每次10-20毫克，每天两次”说明书常规剂量。

疗效方面，联用大剂量他莫昔芬，对ORR、DCR、PFS、OS的改善，均有显著的统计学意义：

1、“The ORR and DCR in the TXT + TAM group were significantly higher than those in the TXT
group (36.7 vs. 15.0% for ORR, P =0.007; 85.0 vs. 68.3% for DCR, P =0.031). Two (3.3%) patients in the TXT + TAM group achieved CR, whereas none of the patients in the TXT groups did. ”

2、“After a median follow-up time of 10.4 months (range: 1.1–24.0 months), the median PFS and OS was 7.6 and 11.6 months in the TXT + TAM group and 6.4 and 9.1 months in the TXT group, respectively. There were statistically significant differences in the median PFS and OS between the two treatment groups (P =0.032 for median PFS and P= 0.030 for median OS, respectively)”

不良反应方面，联用大剂量他莫昔芬，不良反应的增加不明显，不良反应也都在能耐受的范围内：

1、“The overall incidence of treatment-related ADRs was similar across both arms (83.4 vs. 78.3% for the TXT +TAM group vs.the TXT group, P=0.901). ”

2、“There were no drug-related ADRs of grade 4 or higher in either treatment group.”

3、“However, these ADRs were mild (grades 1 and 2) and did not require any medical intervention or discontinuation of treatment.”


大剂量他莫昔芬抑制p-gp方面：

1、“IHC analysis performed on the second biopsy specimen found that of the original 46
patients with P-gp expression in the TXT + TAM group, 17 out of 46 (37.0%) patients had negative P-gp expression, indicating that P-gp reversal was achieved in these patients”

3、“Nevertheless, in the TXT group, none of the original 52 patients with P-gp expression achieved P-gp reversal following the treatment”


抑制p-gp后带来的益处：

“patients achieving P-gp reversal had a median PFS and OS of 12.0 months (95% CI: 7.6–16.4 months) and 14.9 months (95% CI: 8.0–21.8 months), which were significantly greater than those of nonreversal patients (PFS: 5.9 months, 95% CI: 4.8–7.0 months, P =0.035;
OS: 7.5 months, 95% CI: 5.6–9.4 months, P =0.022). In addition, we carried out a subgroup analysis using a Cox proportional hazard model to determine the association between survival advantage and each demographic, clinical, and pathological variable. The results showed that treatment with TXT + TAM resulted in a substantial survival advantage in the subgroup of patients with positive P-gp expression (hazard ratio: 0.68, 95% CI: 0.37–1.17)”

他莫昔芬的主要副作用有 血栓、子宫内膜增厚、骨质流失容易骨转和骨折

防治血栓可以正常吃 黄芩苷、绿原酸、大蒜素这些保肝消炎抗凝的药；女性长期用他莫昔芬可以装个曼月乐避孕装置来自动削薄子宫内膜；骨流失的问题可以通过日常吃汇仁肾宝、补骨脂、骨碎补、淫羊藿等益肾补骨药来防治。

我在《西地那非与他莫昔芬更配》一文里讲过 ，西地那非能提高他莫昔芬的药效，减轻他莫昔芬的副作用，两个是很好的配伍药对。依据《Strategies for overcoming the blood–brain barrier for the treatment of brain metastases》等论文所述，西地那非这些pde5抑制剂，能扩张血管，加强药物入脑。在动物试验里，西地那非与曲妥珠联用，将曲妥珠的入脑量提高了2倍左右。因此在要强化药物入脑时，可以用上他莫昔芬+西地那非这一药对。



三、联用冰片、苏合香等传统的芳香开窍药

《冰片对癫痫患者血清及脑脊液卡马西平药物浓度的作用》

“方法采用高效液相色谱法测定癫痫患者合用冰片前后血清及脑脊液卡马西平的药物浓度,观察冰片对其药物浓度的影响”

“合用冰片后平均血清卡马西平药物浓度由原来6.06μg/ml上升到6.21μg/ml,脑脊液平均卡马西平药物浓度由1.24μg/ml上升到1.32μg/ml,脑脊液/血清药物浓度比由20.5%提高到21.2%。”

口服抗癌药的脑转患者，可以联用雷允上的灵宝护心丹这个中成药。灵宝护心丹的主要成分是麝香、蟾酥、牛黄、冰片、红参、三七、琥珀、丹参、苏合香油等，有很多芳香开窍药的成分。

用注射类抗癌药的患者，可以联用醒脑静注射液。醒脑静注射液的主要成分有麝香、郁金、冰片、栀子等，有很多芳香开窍药。