Realgar/Indigo naturalis

<h2 id="composition">Composition</h2>
WHO data indicates that the medication is provided in units of 270 mg of the mixture, 30 mg of which is tetraarsenic tetrasulfide (As4S4).<a class="footnote-ref" id="fnref:14" href="#fn:14">14</a> The 2004 Chinese patent for this medication indicates that it contains 12-18% realgar (90-95% As4S4), 25-42% Indigo naturalis, 36-46% Salvia miltiorrhiza root (separately water-extracted), and 12-18% Pseudostellaria heterophylla root.<a class="footnote-ref" id="fnref:15" href="#fn:15">15</a>

<h2 id="pharmacology">Pharmacology</h2>
The basic action of this medication is similar to <a href="/facts/Arsenic_trioxide/YhlrDAg7">arsenic trioxide</a> in that the arsenic component triggers degradation of the PML-RARα oncoprotein, by shifting the protein out of the <a href="/facts/Nucleoplasm/PNGpzgCK">nucleoplasm</a> onto the <a href="/facts/Nuclear_matrix/cAEsB6nd">nuclear matrix</a>. Arsenic also encourages <a href="/facts/Ubiquitination/hpulmU3m">ubiquitination</a> of the oncoprotein, together making it a target for the <a href="/facts/Proteosome/8vTtg2MI">proteosome</a>. Wang et al. 2008 suggests that the addition of indirubin and tanshinone IIA enhances the action of arsenic by <a href="/facts/Synergy/lfcwWuAc">synergy</a>; these components cannot move the protein on their own.<a class="footnote-ref" id="fnref:16" href="#fn:16">16</a>
The pharmokinetics are similar to IV arsenic trioxide.<a class="footnote-ref" id="fnref:17" href="#fn:17">17</a>

<h2 id="society-and-culture">Society and culture</h2>
<h3>History</h3>
A combination of indigo with realgar, named Qīnghuáng sǎn, is known in old <a href="/facts/Traditional_Chinese_medicine/51rSRXua">traditional Chinese medicine</a> (TCM) literature. In the 1960s, Zhōu Ǎixiáng of China Academy of Chinese Medical Sciences Xiyuan Hospital tried the combination on leukemia with some results. In the 1980s, Huáng Shìlín of Shenyang Theatre Military Hospital came up with the current formulation, again justifying it only using TCM theory.<a class="footnote-ref" id="fnref:18" href="#fn:18">18</a><a class="footnote-ref" id="fnref:19" href="#fn:19">19</a> It is unclear whether Huáng was aware of <a href="/facts/Zhang_Tingdong/6aKy1wMI">Zhang Tingdong</a>'s work on arsenic trioxide in the 1970s.
In 1995, the medication was approved within the <a href="/facts/People%2527s_Liberation_Army/nr4YlS9J">People's Liberation Army</a> health system. It was allowed to start formal clinical trial in 2002, patented in 2004, then approved for the general Chinese market in 2009. It entered the Chinese treatment guide for APL in 2014 as an alternative to injected arsenic. The patent was initially held by Tiankang Pharmaceuticals, an unprofitable spin-off of an electrics company. In 2015, Yifan Biotech acquired all of Tiankang Pharmaceuticals and started heavier promotion of the drug.<a class="footnote-ref" id="fnref:20" href="#fn:20">20</a>

<h3>Ethnopharmacology</h3>
The medication is approved in China as a <a href="/facts/Chinese_patent_medicine/m6vzHazU">Chinese patent medicine</a>. A medication being approved as such means that it would have to conform to some form of TCM theory, and that its indication is commonly written both in modern medicine language and in the folk-medical language of TCM. In the case of RIF, the approved Chinese package insert states the following as indication:

<blockquote>
Clears away <a href="/facts/Traditional_Chinese_medicine/51rSRXua">heat</a> and detoxifies, replenishes <a href="/facts/Qi/cMj34xNM">qi</a> and produces blood. Used for the initial treatment of acute promyelocytic leukemia.<a class="footnote-ref" id="fnref:21" href="#fn:21">21</a>

</blockquote>
The four ingredients are also said to conform to a rule called 君臣佐使 "sovereign, minister, aide, and agent [zh]", in which each TCM formula consists of a small number of "sovereign drugs" with the three other classes serving as supporting forces. In this case, realgar is considered the "sovereign", Salvia miltiorrhiza the "minister", and the rest the "agents". The synergy reported by Wang et al. (2008) is reported in domestic media as scientific validation of this aspect of TCM theory.<a class="footnote-ref" id="fnref:22" href="#fn:22">22</a>

<h2 id="references">References</h2>

<ol>
<li id="fn:1">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></li>
<li id="fn:2">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></li>
<li id="fn:3">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></li>
<li id="fn:4">World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. <a href="/wiki/World_Health_Organization" target="_blank">/wiki/World_Health_Organization</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></li>
<li id="fn:5">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></li>
<li id="fn:6">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></li>
<li id="fn:7">"Realgar-Indigo naturalis formulation". National Cancer Institute. 2 February 2011. Retrieved 15 November 2019. <a href="https://www.cancer.gov/publications/dictionaries/cancer-drug/def/realgar-indigo-naturalis-formulation" target="_blank">https://www.cancer.gov/publications/dictionaries/cancer-drug/def/realgar-indigo-naturalis-formulation</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></li>
<li id="fn:8">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></li>
<li id="fn:9">Ghosh D, Smarta RB (2016). Pharmaceuticals to Nutraceuticals: A Shift in Disease Prevention. CRC Press. p. PT41. ISBN 9781315354934. <a href="9781315354934" target="_blank">9781315354934</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></li>
<li id="fn:10">World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. <a href="/wiki/World_Health_Organization" target="_blank">/wiki/World_Health_Organization</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></li>
<li id="fn:11">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></li>
<li id="fn:12">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></li>
<li id="fn:13">"亿帆医药(002019.SZ)" [Yifan Pharmaceuticals (002019.SZ)] (PDF). GF Securities. April 2017. Retrieved 23 January 2023. [non-medical; investment advice for economics and history] <a href="http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf" target="_blank">http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></li>
<li id="fn:14">"Realgar-indigo naturalis formulation". eEML - Electronic Essential Medicines List. <a href="https://list.essentialmeds.org/recommendations/1137" target="_blank">https://list.essentialmeds.org/recommendations/1137</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></li>
<li id="fn:15">CN 100393329C, Huang S, Wang X, "Chinese medicine preparation compound Huangdai tablet for treating leukemia and its jpreparing method", issued 11 June 2008, assigned to Anhui Province Tiankang Pharmaceutical Co., Ltd. and Chinese people's Liberation Army 210th hospital
 <a href="https://patents.google.com/patent/CN100393329C/en" target="_blank">https://patents.google.com/patent/CN100393329C/en</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></li>
<li id="fn:16">Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, et al. (March 2008). "Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 105 (12): 4826–4831. Bibcode:2008PNAS..105.4826W. doi:10.1073/pnas.0712365105. PMC 2290784. PMID 18344322. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290784" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290784</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></li>
<li id="fn:17">Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model list of ESSENTIAL MEDICINES for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019. <a href="https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf" target="_blank">https://web.archive.org/web/20220309054858/https://www.who.int/selection_medicines/committees/expert/22/applications/s8.2_arsenic.pdf</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></li>
<li id="fn:18">"亿帆医药(002019.SZ)" [Yifan Pharmaceuticals (002019.SZ)] (PDF). GF Securities. April 2017. Retrieved 23 January 2023. [non-medical; investment advice for economics and history] <a href="http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf" target="_blank">http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></li>
<li id="fn:19">Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, et al. (March 2008). "Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 105 (12): 4826–4831. Bibcode:2008PNAS..105.4826W. doi:10.1073/pnas.0712365105. PMC 2290784. PMID 18344322. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290784" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290784</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></li>
<li id="fn:20">"亿帆医药(002019.SZ)" [Yifan Pharmaceuticals (002019.SZ)] (PDF). GF Securities. April 2017. Retrieved 23 January 2023. [non-medical; investment advice for economics and history] <a href="http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf" target="_blank">http://xqdoc.imedao.com/15d5afe4dd8d1a13fdf94e85.pdf</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></li>
<li id="fn:21">"复方黄黛片说明书" (PDF). yifanyy.com. 1 December 2020. Retrieved 17 January 2025. <a href="https://www.yifanyy.com/upload/file/20221011/20221011094508_86674.pdf" target="_blank">https://www.yifanyy.com/upload/file/20221011/20221011094508_86674.pdf</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></li>
<li id="fn:22">"陈竺：白血病治疗是中药现代化契机" [Chen Li: Leukemia treatment is a key opportunity for TCM modernization]. cas.cn (in Chinese). Chinese Academy of Sciences. March 2009. – article describing the Chinese understanding of Wang et al. (2008). <a href="https://www.cas.cn/ys/gzdt/200903/t20090303_2302389.shtml" target="_blank">https://www.cas.cn/ys/gzdt/200903/t20090303_2302389.shtml</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></li>
</ol>

Realgar/Indigo naturalis open-in-new

Realgar/Indigo naturalis