Neutralization of Free Digoxin-like Immunoreactive Components of Oriental Medicines Dan Shen and Lu-Shen-Wan by the Fab Fragment of Antidigoxin Antibody (Digiband)

Amitava Dasgupta, PhD; Kathleen A. Szelei-Stevens, MD


Am J Clin Pathol. 2004;121(2) 

In This Article

Abstract and Introduction

Dan Shen and Lu-Shen-Wan, traditional Chinese medicines used as remedies for heart diseases, demonstrate digoxin-like immunoreactivity. The digoxin-like immunoreactive components of Lu-Shen-Wan show approximately 55% protein binding, while Dan Shen demonstrates concentration-dependent protein binding (68% bound at lower concentrations but only 25% bound at higher concentrations). Because Dan Shen and Lu-Shen-Wan can cause substantial toxic effects in patients, we studied the potential use of Digibind (Fab fragment of polyclonal antidigoxin antibody; Burroughs Wellcome, Research Triangle Park, NC) for neutralizing the pharmacologically active free fractions of Dan Shen and Lu-Shen-Wan. Drug-free serum pools were supplemented with Dan Shen or Lu-Shen-Wan to achieve apparent digoxin concentrations expected in severe overdoses. Aliquots of supplemented serum pools were supplemented further with aqueous Digibind solution to achieve final Digibind concentrations between 5 and 20 µg/mL (expected in vivo range in patients overdosed with digoxin and being treated with Digibind). We observed complete removal of the free apparent digoxin in the presence of Digibind for Dan Shen and Lu-Shen-Wan. Digibind binds free digoxin-like immunoreactive components of Dan Shen and Lu-Shen-Wan in vitro.

Traditional Chinese medicines are readily available in health food stores in the United States. The use of Chinese medicines as a part of complementary and alternative medicines is no longer limited to the Asian population in the United States. They also are used widely by the general population. For example, according to a survey, Asian ginseng is the most popular complementary and alternative medicine used in the United States.[1]

Dan Shen, a traditional Chinese medicine prepared from the root of a Chinese medicinal plant, Salvia miltiorrhiza, has been used in China for many years in the treatment of various cardiovascular diseases, including angina pectoris. Dan Shen is capable of dilating coronary arteries and slowing the heart rate[2] and also is used in the treatment of cerebrovascular diseases and insomnia.[3] Li et al[4] demonstrated dose-dependent hypotensive effects of Dan Shen with positive inotropic and negative chronotropic effects. Dan Shen protects low-density lipoprotein from copper dichloride-induced lipid peroxidation.[5] More than 20 diterpene quinones (tanshinones) have been isolated from Dan Shen root extract. These compounds have a common structural feature, a phenanthrene quinone ring structure.[6] Wahed and Dasgupta[7] and Dasgupta et al[8] reported digoxin-like immunoreactivity of Dan Shen in vitro and also in vivo in a mouse model.

Lu-Shen-Wan, "6 miracle pills" in Chinese, contains 6 medicines: Niu Huang (Calculus bovis), Zhen Zhu (Margarita), Xiong Huang (Realgar), Bing Pian (Borneol), Chan Su (Bufo melanostictus), and She Xiang (Secretio moschus). It is used as a remedy for sore throat, dysphagia, abdominal pain, and agitation. Lu-Shen-Wan also shows cardiotonic effects owing to the presence of bufalin and related bufanodienolides. These active components also are present in the Chinese medicine Chan Su. Panesar,[9] using the fluorescence polarization immunoassay (FPIA) for digoxin, reported an apparent digoxin concentration of 0.88 ng/mL (1.13 nmol/L) in healthy volunteers who ingested Lu-Shen-Wan. Because Dan Shen and Lu-Shen-Wan have cardioactive properties, overdoses from these unregulated Chinese medicines can be troublesome.

The Fab fragment of polyclonal antidigoxin antibody preparation (Digibind, Burroughs Wellcome, Research Triangle Park, NC) is useful in treating severe poisoning with digoxin and digitoxin.[10,11,12] Antidigoxin antibody had been used speculatively and was associated with rapid resolution of toxic effects in a patient who ingested an herbal internal cleansing product (possibly containing Digitalis lantana) and had the clinical features of cardiac glycoside toxic effects.[13] Digibind binds the free fraction of oleandrin in vitro because oleandrin has structural similarity with digoxin.[14] Eddleston et al[15] concluded that antidigoxin Fab fragments are safe and effective for treating patients poisoned with yellow oleander.

Antidigoxin Fab fragment antibodies also have been used to treat poisoning with toad venom.[16] The most toxic components of toad venom are the cardioactive steroids bufalin, cinobufotalin, and cinobufagin. These sterols have structural similarity with digoxin. Because the active components of Dan Shen and Lu-Shen-Wan have structural similarity with digoxin, we studied the possibility of neutralizing the digoxin-like immunoreactive components of these traditional Chinese medicines by using Digibind. To our knowledge, the possibility of binding the active components of Dan Shen or Lu-Shen-Wan using Digibind has not been studied before.


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