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Archive > Volume 10 Issue 2 > 2018,10(2):136-143. DOI:10.1016/j.chmed.2018.03.001 Prev Next

復方黃黛片方中單藥與君藥雄黃配伍后的毒性差異及潛在機制初探

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Synergistic Effect and Different Toxicities of Adjuvant Components of Realgar-Indigo naturalis Formula

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    摘要:
    復方黃黛片臨床用于治療急性早幼粒細胞白血病(APL)，取得良好療效，近期的一個多中心臨床試驗結(jié)果表明，在APL患者中，完全緩解率達到96.08%-100%。但因該片劑中含有已知毒性中藥-雄黃，其安全性問題受到廣泛關(guān)注。為探究復方黃黛片的毒性潛能，我們對復方黃黛片進行拆方研究，采用急性毒性試驗與亞慢性毒性試驗進行評價。試驗結(jié)果表明，當雄黃單用時，LD50為2756.73mg/kg(等效于23.6mg/kg的As2O3)，然而當雄黃與丹參合用時，LD50升高至7538.86mg/kg，與青黛合用時LD50降低至936.90mg/kg，提示雄黃與青黛合用時，毒性顯著增強，然而與丹參合用時，毒性顯著降低，這兩者配伍雄黃后毒性呈現(xiàn)出十分顯著的差異。在后續(xù)進行的亞慢性毒性試驗中，配伍毒性顯示出相同的趨勢，進一步驗證了這一結(jié)果。對潛在機制的初步探究表明，毒性差異產(chǎn)生的原因可能與以下幾點有關(guān)：青黛配伍雄黃毒性增強與青黛能增加雄黃中可溶性砷的溶出有關(guān)，體內(nèi)和體外層面均有影響，然而丹參對雄黃中可溶性砷的溶出沒有影響；從藥物代謝角度探究青黛與丹參對雄黃體內(nèi)命運的影響或許也能提供一合理的解釋，但在I相藥物代謝酶上，未發(fā)現(xiàn)明顯關(guān)聯(lián)，可能與II相代謝酶相關(guān)。

    Abstract:
    Objective Realgar-Indigo naturalis formula (RIF) is a well-known arsenic-containingpreparationthat is used to treat acute promyelocytic leukemia (APL) in China. In recent multicenter clinical trials, complete remission rates in APL patients have ranged from 96.08% to 100%. RIF has a satisfactory therapeutic effect, but its safety isa widespread concern, since the preparation contains arsenic, a wide-rangingand naturally occurring toxicant. In this study, in order to determine the toxic potential of RIF, acute toxicity and subchronic toxicity assayswere performed to evaluate the toxic potential of realgar and the adjuvant components of RIFin addition to realgar’s synergy with theseadjuvant components. Methods KM mice and Wistar rats were selected forthese experiments. To evaluate acute toxicity, the toxic effects of a single dose ofa gradient of concentrations of realgarwere firstly determined. Then, the toxic effects of combinations of gradient doses of realgar and fixed doses of I. naturalis and S. miltiorrhizawere evaluated.Results The results showed that when realgar was used alone, the LD50 was 2756.73 mg/kg (equivalent to 23.6mg/kg As2O3).However, theLD50dropped to 936.90 mg/kg when realgar was used with I. naturalis.By contrast, the LD50increased to 7538.86 mg/kg when realgar was used with S. miltiorrhiza. Hence, I. naturalis strengthened the toxicity of realgar, whereas S. miltiorrhizadisplayed the opposite effect. The subchronic toxicity assessment results revealed a trend that was consistent with acute toxicity.Changes in the levels of different valence states of arsenic were also taken into account.The test results of the effects of in vitro combinations of realgar and adjuvant components on soluble arsenic dissolution showed that I. naturalis increased the level of soluble arsenic in realgar extractsand I. naturalis suspensions when the realgar/I. naturalis ratio was 2, 1.5, and 1.0.However, S. miltiorrhizadid not affect it. Conclusion Based on the collective experimental results presented here, it can be concluded that the toxicity of RIF is the result of the soluble arsenic in realgar and that the I. naturalis and S. miltiorrhiza in the RIF exert completely opposite effects on the toxicity of realgar. This maybe an intelligent explanation for the compatibility of this formula, and this RIF study may therefore be viewed as a classic case of traditional Chinese medicine research on compatibility.

    關(guān)鍵詞:
    毒性潛能;雄黃;急性毒性;亞慢性毒性;砷價態(tài)

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