Realgar/Indigo naturalis

Realgar/Indigo naturalis (RIF), also known as Compound Huangdai (复方黄黛), is a medication used to treat acute promyelocytic leukemia. Effectiveness appears similar to arsenic trioxide. It is generally used together with all-trans-retinoic acid (ATRA). It is taken by mouth.

Side effects may include abdominal pain and rash. It is made up of a combination of realgar (tetra-arsenic tetra-sulfide), Indigo naturalis, root of Salvia miltiorrhiza, and root of Pseudostellaria heterophylla. It works by breaking down the cancer protein retinoic acid receptor alpha. The main active ingredients according to NCI are tetraarsenic tetrasulfide (realgar), indirubin (from the indigo) and tanshinone IIA (from the Salvia).

Realgar-Indigo naturalis was developed in the 1980s and approved for medical use in China in 2009. It is on the World Health Organization's List of Essential Medicines. It is made in China and was originally a herbal remedy. It is not approved in either the United States or Europe. A year of treatment costs 60,000 Chinese yuan, as of 2017.

Composition
WHO data indicates that the medication is provided in units of 270 mg of the mixture, 30 mg of which is tetraarsenic tetrasulfide (As4S4). 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.

Pharmacology
The basic action of this medication is similar to arsenic trioxide in that the arsenic component triggers degradation of the PML-RARα oncoprotein, by shifting the protein out of the nucleoplasm onto the nuclear matrix. Arsenic also encourages ubiquitination of the oncoprotein, together making it a target for the proteosome. Wang et al. 2008 suggests that the addition of indirubin and tanshinone IIA enhances the action of arsenic by synergy; these components cannot move the protein on their own.

The pharmokinetics are similar to IV arsenic trioxide.

History
A combination of indigo with realgar, named Qīnghuáng sǎn, is known in old traditional Chinese medicine (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. It is unclear whether Huáng was aware of Zhang Tingdong's work on arsenic trioxide in the 1970s.

In 1995, the medication was approved within the People's Liberation Army 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.