Xi Xin

The most directly useful study on this species. In 15 batches of Asarum heterotropoides root and rhizome, aristolochic acids I, II and IIIa were not detected, while aristolochic acid IVa was present at 66.50-121.03 micrograms per gram and aristolactam I at 19.73-43.75 micrograms per gram. Among 44 Chinese patent medicines, AA I was detected in 70 percent at 0.010-52.450 micrograms per gram and AA IVa in 86.6 percent. In the toxicity arm, AA I was the strongly nephrotoxic member of the class at 40 mg/kg, causing renal tubular necrosis and DNA damage, while AA II, AA IIIa and AA IVa were weakly toxic and aristolactam I was cytotoxic in vitro without renal toxicity at the doses tested. The authors note the Chinese Pharmacopoeia 2020 limit of AA I below 0.001 percent.

The only substantial human study. Prescription records were used to compare Asari Radix users with non-users in a hepatitis B cohort of 49,500 patients and a non-hepatitis B cohort of 133,148 patients. Users did not show excess hepatocellular carcinoma; the hazard ratios were 0.55 in the hepatitis B cohort and 0.61 in the non-hepatitis B cohort, with the protective association concentrated in the 1-30 gram cumulative dose stratum, where about 73 percent of users sat. Two important limits: this addresses liver cancer only, not the renal and urothelial endpoints that define aristolochic acid harm, and cumulative exposures were mostly small, with the maximum aristolochic acid dose evaluated as safe put at 173.8 micrograms. It is reassurance about short low-dose courses of the decocted root, not about the herb in general.

A decoction extract of the roots of this exact variety was not genotoxic in the Ames test, the in vitro chromosome aberration test or the in vivo micronucleus test in rats. Single-dose toxicity in 40 rats at 1000, 2000 and 5000 mg/kg gave an approximate lethal dose above 5000 mg/kg with no clinical pathology changes. In the 13-week study in 140 rats at up to 5000 mg/kg daily, the only treatment-related histopathology was squamous hyperplasia of the forestomach, which resolved during recovery, and the NOAEL was 2000 mg/kg for both sexes. This is the evidence that hot-water extraction of the root is the safer preparation.

The counterpart study, on root POWDER rather than decoction, and of the seoulense variety rather than mandshuricum. The powder was genotoxic: positive in the Ames test against TA100, TA98, TA1537 and E. coli WP2uvrA, positive in the chromosome aberration test, and positive in the stomach in the comet assay, though negative in the micronucleus and pig-a assays. In the 13-week study in 152 rats, irregular and noisy respiration, salivation and reduced body weight appeared at 2000 mg/kg daily, changes in haematology and clinical chemistry from 500 mg/kg, and stomach hyperplasia plus hepatocellular adenoma on microscopy. The NOAEL was 150 mg/kg in males and below 150 mg/kg in females, roughly a thirteenfold lower margin than the decoction extract. The authors conclude the powder is potentially toxic to liver and stomach and that a carcinogenicity study is needed.

A high-resolution LC-MS survey of medicinally used Asarum species found that most samples contained potentially nephrotoxic aristolochic acid analogues, including 9-methoxy aristolactam IV, aristolactam I and aristolactam IV, present in both methanol and water extracts, and detected in all parts of the plant. Aristolactam I was significantly higher in Xixin root samples than in aerial parts (p = 0.03). Aristolochic acid I was found in high amounts in Asarum canadense and Asarum splendens but in only seven samples overall. The two authenticated Asarum heterotropoides var. mandshuricum root and rhizome samples were not cytotoxic to HK-2 human kidney cells, with IC50 above 200 micrograms per millilitre. The authors stress that absence of cytotoxicity does not exclude DNA adduct formation and question whether current recommendations for the medicinal use of Asarum species are justified.

The decisive sensitivity argument. LC-HRMS screening of the underground part of Asarum heterotropoides, described here as the only Aristolochiaceae plant in wide clinical use, revealed 70 trace aristolochic acid analogues, 38 of them newly discovered in this species. Seventeen analogues were detected across 91 batches of the herb and 20 across 166 consumable products. In 141 Asari-containing proprietary products, aristolactam I and aristolactam II-glucoside were present in 98 percent, AA IVa in 91 percent, and aristolochic acid I in 60 percent at 0.03-0.79 ppm. Earlier reports of no detection in this species reflect the limits of HPLC-DAD, not the chemistry of the plant.

An extract of Asarum heterotropoides root and rhizome was evaluated against pain, cartilage integrity and inflammatory responses in in vitro and in vivo osteoarthritis models, guided by network pharmacology predictions, and showed multi-target anti-inflammatory activity. This is preclinical support for the classical use in cold, painful musculoskeletal conditions; it says nothing about the safety of the exposure needed to achieve it.

The source of the safrole and methyleugenol figures for this species. Essential oils were hydrodistilled separately from the roots and the leaves of Asarum heterotropoides var. mandshuricum and analysed by GC-MS. Methyleugenol at 28.67 percent, safrole at 19.61 percent and 3,5-dimethoxytoluene at 12.63 percent were the main components of the root oil, with the leaf oil at 27.05, 15.73 and 6.37 percent respectively. All three compounds were toxic to stored-product insects by fumigation and contact, safrole giving a fumigant LC50 of 18.93 mg per litre of air against Lasioderma serricorne and 0.83 against Liposcelis bostrychophila.