Cang Er Zi

An outbreak of vomiting progressing rapidly to unconsciousness and death struck nine villages in Sylhet District after the 2007 monsoon floods. Of 76 identified patients, 19 (25 percent) died. Of 33 cases interviewed in depth, 31 (94 percent) had eaten Xanthium strumarium seedlings, locally called ghagra shak, as a main meal in the hours before onset because other food was unavailable. Presenting features were vomiting, raised liver enzymes and altered mental status, consistent with carboxyatractyloside poisoning. This is the human evidence that the toxin is lethal at food-quantity exposures, and that seedlings as well as fruit carry it.

A 55-year-old man with allergic rhinitis self-treated with roughly 20 g daily (35 to 40 fruits) of unprocessed Xanthii Fructus each night for two months. He presented with anorexia, nausea, abdominal pain, hiccups and falling urine output, and was found to have ALT 8453 U/L, AST 3515 U/L, direct bilirubin 135 micromol/L, ammonia 435.79 micromol/L, creatinine 809 micromol/L, coagulopathy, thrombocytopenia and myoglobin 856 ng/mL. Despite haemodialysis and plasma, multiorgan failure progressed and he died. This is the clearest single human record of the dose, the preparation state and the outcome.

Bioassay-guided fractionation of the water extract of the fruit identified atractyloside, carboxyatractyloside and 4'-desulphate-atractyloside as the three major hepatotoxic constituents, all showing significant cytotoxicity in liver cell lines. The work establishes that the hepatotoxicity of the aqueous decoction, the form patients actually take, is carried by the kaurene diterpene glycosides rather than by the sesquiterpene lactones or phenolics.

Raw and stir-baked fruit were compared in MIHA liver cells and LPS-stimulated RAW 264.7 macrophages. Stir-baking reduced carboxyatractyloside content 27.0-fold and increased atractyloside 13.3-fold, and the processed drug was less cytotoxic in all four solvent fractions (for example n-butanol IC50 271.8 versus 512.9 micrograms/mL). Anti-inflammatory activity was preserved or improved, with the processed form giving stronger inhibition of iNOS mRNA. This is the direct chemical and biological validation of roasting as detoxification rather than a traditional assumption.

Water extracts of raw and processed fruit were tested in HK-2 renal cells, in acute toxicity studies in Kunming mice and in a 12-week chronic study in SD rats. At 400 g/kg, roughly 240 times the human therapeutic dose, mortality was 80 percent for raw and 40 percent for processed fruit. Chronic dosing produced congestion and focal necrosis in liver and renal tubules, with rises in BUN and serum creatinine after week 9 and a sustained rise in serum hyaluronic acid and procollagen III from week 4 to week 8 suggesting fibrosis risk. The kidney is a target organ alongside the liver, and processing reduces but does not remove toxicity.

Fifteen randomised controlled trials with 1361 children were pooled. Cang-Er-Zi-San, the classical formula in which this herb is the chief, gave a higher effective rate than comparator therapies (RR 1.21, 95% CI 1.15 to 1.26), with better symptom relief time, recurrence rate and adverse event profile. The authors caution that the included trials were at risk of bias and that high-quality studies are still needed. Note that this is evidence for the multi-herb formula, not for the single drug, and it does not address the hepatotoxicity seen with prolonged single-herb use.

The caffeoylquinic acid fraction of the fruit relieved allergic and inflammatory nasal responses in rodent models of allergic rhinitis, and toxicity testing found no obvious toxicity for the fraction. This separates the therapeutic phenolic fraction from the hepatotoxic diterpene glycoside fraction, and supports the traditional indication for nasal obstruction without implicating the toxins.

Targeted metabolomics of energy metabolites was used to compare raw and processed fruit. The hepatotoxicity of Xanthii Fructus was reduced after processing, consistent with the fall in atractyloside and carboxyatractyloside content, and the metabolite signature is that of disrupted mitochondrial energy metabolism, which is the expected consequence of adenine nucleotide translocase inhibition.

The kaurene glycoside fraction of the fruit was administered to mice and produced hepatotoxicity, confirming in a whole animal what cell work had suggested: the diterpene glycosides, not the extract as a whole, carry the liver injury.