第一型組織胺阻斷劑：Doxylamine與Pheniramine具有強效之皮下局部止痛效果

Hl Histamine Blocking Agents: Doxylamine and Pheniramine, Have a Potent Cutaneous Analgesic Effect in Rats

背景：第一型組織胺阻斷劑被廣泛地應用於治療過敏反應。這些藥物與胺類或酯類局部麻醉劑有相似的環狀結構。此外，他們也被證實有明顯的納離子通道阻斷活性。據此，我們假設H1組織胺阻斷劑有局部浸潤止痛效果，並以大鼠模式來評估之。材料與方法：實驗一，我們篩選八種第一型組織胺阻斷劑，將藥物皮下注射於大鼠背部皮膚，再由不知情的觀察者於注射部位給與六次Von Frey filament針刺刺激，六次針刺刺激皆無反應定義為百分之百最大可能效果。據此，選出兩種具局部止痛強效及最無皮膚毒性的H1組織胺阻斷劑（每組有六隻大鼠），進行後續的劑量反應曲線及作用時間的研究。實驗二，H1組織胺阻斷劑在表皮止痛強度以劑量反應曲線及ED75時間反應曲線，並與兩種現有的局部麻醉藥lidocaine及bupivacaine比較。在實驗三，我們評估比較這兩種H1組織胺阻斷劑與lidocaine及bupivacaine在ED25、ED50及ED75 的作用時間。結果：在等當量基礎下，doxylamine及pheniramine比其他的H1組織胺阻斷劑，具有較強且最低皮膚毒性的局部止痛效果。經由比較劑量反應曲線及ED75的時間作用曲線。我們發現藥效強度的排序是：bupivacaine > doxylamine ≒ lidocaine > pheniramine。作用時間依序是：doxylamine > pheniramine ≒ bupivacaine > lidocaine。結論：在第一型組織胺阻斷劑中，doxylamine及pheniramine有最強的表皮浸潤止痛效果。他們的藥效強度比bupivacaine為弱但與lidocaine類似。除此之外，doxylamine有最長的作用時間。

Background: Histamine-1 (H1) antihistamines are widely used for the treatment of allergic diseases. These drugs have a similar aromatic ring and amine structure with that of local anesthetics, and proved having a prominent sodium channel blocking activity. Therefore, we performed a dose-response study to test the local analgesic effects ofH1 antihistamines in a rat model.　Material and methods: In study 1, eight H1 antihistamines were subcutaneous injected to the shaved dorsal skin to screen the local analgesic effect in S.D. rats (6 rats in each group). The inhibition of the cutaneous trunci muscle reflex to pinpricks with No. 15 Von Frey filament was quantitatively evaluated. No response to six pinpricks was defined as 100% maximum possible effect. Two of the most potent H1 antihistamines were then chosen in study 2 for further dose-response studies, and compared with two clinically used local anesthetics: lidocaine and bupivacaine. Moreover, in study 3, we compared the antinociceptive duration of test drugs at ED25、ED50 and ED75 doses.　Result: On an equimolar basis, we found doxylamine and pheniramine possessed potent local analgesic effect. The rank of potency was as following rank: bupivacaine > doxylamine ≒ lidocaine > pheniramine. The ranking of anesthetic durations were: doxylamine > pheniramine ≒ bupivacaine > lidocaine　Conclusion: Both doxylamine and pheniramine are potent infiltrative analgesics. The potencies are weaker than that of bupivacaine but similar to that of lidocaine. Moreover, doxylamine had a long duration of drug effect.