Chan Chu

A phase 1 dose-escalation study of huachansu, the intravenous preparation of dried toad venom from B. gargarizans or B. melanostictus, in 15 patients (11 hepatocellular, 2 non-small-cell lung, 2 pancreatic). Doses ran from 10 to 90 mL/m2 over 14 days on, 7 days off. No dose-limiting toxicity was seen even at eight times the dose typically used in China, and 11 patients had no drug-related toxicity above grade 1. Six patients had stable disease (median 6.0 months) and one hepatocellular patient had 20% regression lasting 11 months at the lowest dose level. Plasma bufalin peaked at 0.81 to 3.38 ng/mL. This is a small uncontrolled phase 1 trial: it establishes tolerability of a standardised intravenous product, not efficacy, and says nothing about oral or self-administered toad preparations.

Six previously healthy men developed vomiting and bradycardia after ingesting a purported topical aphrodisiac. All had positive apparent digoxin levels; the first four died of cardiac dysrhythmias and the last two survived after digoxin-specific Fab fragments. Analysis showed the product was identical to Chan Su, the Chinese medication made from toad venom. The first reported use of digoxin Fab to treat toad venom poisoning.

Mice given an approximate LD90 dose of ethanolic Chan Su extract were pretreated with digoxin-specific Fab fragments or saline. All 30 control mice had seizures and died, against 11 seizures and 7 deaths among 15 treated mice (p = 0.00003 for mortality). The paper also states plainly that Chan Su and the Love Stone aphrodisiac are both made from dried venom of B. gargarizans and contain bufalin, cinobufotalin, cinobufagin and other bufadienolides, and that deaths have followed ingestion of these products.

Aqueous and organic extracts of Chan Su showed marked digoxin-like immunoreactivity: 20 microL of a 1 mg/mL aqueous extract added to 2 mL of drug-free serum read 2.76 ng/mL digoxin equivalent by FPIA, 0.94 ng/mL by MEIA and nothing by CLIA. In patient serum the extract raised the FPIA digoxin result and falsely lowered the MEIA result. Because Chan Su components are highly protein-bound while digoxin is only about 25% bound, measuring free digoxin removed the interference in both directions in these two assays.

Chan Su and the Chan Su-containing pill Lu-Shen-Wan cross-reacted significantly with the newer Digoxin III assay. A digoxin serum pool at 0.94 ng/mL supplemented with 5.0 micrograms/mL Chan Su extract read 6.60 ng/mL by Digoxin III and 6.99 ng/mL by FPIA, but a falsely low 0.72 ng/mL by Digoxin II. Unlike the older assays, the Digoxin III interference could not be eliminated by measuring free digoxin. Mice fed either medicine showed apparent digoxin in serum, confirming the interference occurs in vivo.

Two new bufadienolide derivatives, bufalactamides A and B, were isolated from the skins of B. gargarizans along with argentinogenin, desacetylcinobufagin, desacetylcinobufaginol, cinobufaginol, bufalin and gamabufalin. Argentinogenin, cinobufaginol, bufalin and gamabufalin were potently cytotoxic (IC50 < 2.5 microM) against A549, HCT-116, SK-Hep-1 and SKOV3; the desacetyl compounds were moderate (IC50 < 50 microM); and the two new lactams were inactive (IC50 > 100 microM).