Xun Gu Feng

Aristolochic acid injury is cumulative-dose dependent and irreversible. Aristolactam-DNA adducts persist in renal and urothelial tissue for decades, and cancers have appeared many years after exposure ceased. Combining A. mollissima with any other Aristolochiaceae drug simply adds to the same lifetime dose. A. mollissima is at the high end of the genus for aristolochic acid I: 123.659-600.260 µg/g against 6.734-17.256 µg/g in A. debilis in a single comparative UPLC-QTOF-MS/MS study. That study also found that A. cinnabarina, a further Aristolochia drug, carries a considerably higher total aristolochic acid load than either A. mollissima or A. debilis, so a lower figure for one species is no reassurance about another. Asarum species carry aristolochic acid analogues and aristolactam I as well. Where a species or a batch has not been assayed, that silence must be read as an unmeasured exposure and not as a clean result: absence of an assay is not evidence of absence, and the aristolochic acid content of this genus varies by species, by plant part and by geographic origin.

Aristolochic acid nephropathy is a rapidly progressive hypocellular interstitial fibrosis with tubular atrophy. Superimposing a calcineurin inhibitor, itself a cause of chronic interstitial fibrosis, on an aristolochic acid-injured kidney is expected to be additive. In the Belgian cohort that defined the disease, a large proportion of patients reached end-stage renal failure and required transplantation, and prophylactic nephroureterectomy specimens showed urothelial carcinoma in 18 of 39 patients. Direct interaction studies have not been performed, so the mechanism is inferred from the shared target organ rather than measured.

Xun Gu Feng is used for joint pain, which is the same indication for which patients take NSAIDs, so concurrent exposure is the default rather than the exception. NSAIDs reduce renal prostaglandin-dependent perfusion and cause analgesic nephropathy in their own right; adding a Group 1 nephrotoxic carcinogen to that is additive on the same organ. No pharmacokinetic interaction study exists for this species.

This is a substitution hazard in both directions. Aristolochia fangchi was dispensed in place of Stephania tetrandra in the Belgian slimming-clinic outbreak of the early 1990s and produced the index cluster of interstitial nephropathy and urothelial carcinoma; Aristolochia manshuriensis was likewise sold as Mu Tong. Because the UK prohibition order of 2001 names Akebia quinata, Akebia trifoliata, Clematis armandii, Clematis montana, Cocculus laurifolius, Cocculus orbiculatus, Cocculus trilobus and Stephania tetrandra alongside the whole genus Aristolochia, and captures anything labelled Mu Tong or Fangji whatever it actually contains, the regulator treats the naming confusion itself as the hazard. A supply chain that confuses these drugs can deliver Aristolochia to a patient who was prescribed something else.

Recorded as a safety-relevant fact because the regulatory position, not the traditional indication, governs whether this drug may lawfully be supplied.

United Kingdom: The Medicines (Aristolochia and Mu Tong etc.) (Prohibition) Order 2001, SI 2001 No. 1841, in force 1 July 2001, prohibits the sale, supply and importation of any medicinal product for human use consisting of or containing a plant of any species of the genus Aristolochia, or an extract of one. It therefore covers Aristolochia mollissima by genus, without needing to name it. The Order additionally names Akebia quinata, Akebia trifoliata, Clematis armandii, Clematis montana, Cocculus laurifolius, Cocculus orbiculatus, Cocculus trilobus and Stephania tetrandra, and catches products labelled as containing Mu Tong or Fangji whatever they in fact contain. It followed a Medicines Control Agency prohibition in unlicensed medicines in July 1999 and a temporary prohibition order in 2000.

European Union: the European Agency for the Evaluation of Medicinal Products issued a position paper in 2000 urging member states to protect citizens from exposure to aristolochic acid, and the European Commission prohibited aristolochic acid and its salts, and Aristolochia species, in cosmetic products.

United States: the Food and Drug Administration issued a consumer advisory in 2001 on dietary supplements that may contain aristolochic acid and published listings of botanical ingredients of concern.

Australia: the Therapeutic Goods Administration prohibited all Aristolochia species from therapeutic supply and sale in 2001.

China: the higher aristolochic acid herbs were removed first. Guan Mu Tong (Aristolochia manshuriensis) was withdrawn in 2003, and the 2005 Chinese Pharmacopoeia no longer carried Guan Mu Tong, Guang Fang Ji or Qing Mu Xiang. In 2004 the State Food and Drug Administration directed manufacturers to replace Aristolochia fangchi with Stephania tetrandra and Aristolochia debilis with Inula helenium by 30 September 2004. Xun Gu Feng was treated differently: rather than being banned it was placed under special restriction, with the requirement that any Chinese medicinal preparation containing Ma Dou Ling, Xun Gu Feng, Tian Xian Teng or Zhu Sha Lian be strictly managed as a prescription drug. This distinction matters and is easy to misread. That Xun Gu Feng escaped an outright ban in China is a regulatory fact about 2004, not a toxicological finding about the plant, and it sits alongside a 2022 measurement showing this species carries roughly 18 to 35 times the aristolochic acid I content of Aristolochia debilis, which was banned.