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.
Huan-Hua Xu a, b, Zeng-Chun Ma a, b, Qiao-Li Shic, Shi-Han Yangb, La Jiangb, Xiang-Mei Chend, Yue Gao a, b*. Synergistic Effect and Different Toxicities of Adjuvant Components of Realgar-Indigo naturalis Formula[J]. Chinese Herbal Medicines (CHM),2018,10(2):136-143