In the case of Changshan, it is not resistance that has been the problem leading to disuse of the drug, as we have seen, but nausea and vomiting associated with the known emetic effects of febrifugine. Not surprisingly, however, at least three of the other ingredients in the classical formulation studied in China in the mid-20th century would seem to be candidates for offsetting the emetic properties of Changshan. They are Zingiber officinale (ginger), Glycyrrhiza glabra (liquorice), and Areca catechu (betel nut).
Zingiber officinale, ginger, is an ingredient in the classical formula and has been found through a large body of experimental and clinical research to be effective against nausea. A systematic review of the evidence from randomised controlled trials (RCTs) of ginger for nausea and vomiting found that six studies met all inclusion criteria. Of three RCTs on postoperative nausea and vomiting, two suggested that ginger was superior to placebo and as effective as metoclopramide. RCTs examining the effects of ginger on seasickness, morning sickness, and chemotherapy-induced nausea also supported the other data to collectively favor ginger over placebo in the reduction of nausea (Ernst and Pittler, 1998). A cautionary note comes from rodent studies investigating reproductive toxicity from ginger. In rats fed ginger in their drinking water, it was found that while there was no maternal toxicity, there was increased early embryo loss, with increased growth in surviving fetuses (Wilkinson, 2000).
Z. officinale is used as an antimalarial in Zambia (Vongo, 1999); in India, where the rhizome is mixed with goat's milk into a paste, especially to treat malaria during pregnancy (Singh and Anwar Ali, 1994; Sharma, 1999); and in Sierra Leone, where a stem infusion is mixed with pepper to treat malaria (Lebbie and Guries, 1995). The root decoction is used as an antipyretic in Nicaragua (Coe and Anderson, 1996).
Chang and But (1987, p. 1076) note that the emetic effect of Changshan may be reduced "by stir-frying the herb in ginger juice or yellow wine or using it with the tuber of Pinellia ternate, the whole plant of Pogostemon cablin, or Citrus peel."
Glycyrrhiza glabra (Leguminosae), liquorice, has been the basis for an aqueous solution in which D. febrifuga has been soaked, in a classical Chinese method to remove the nausea-inducing effects. A simple reason for using liquorice may have been to overcome the unpalatable taste of the bitter D. febrifuga. It has certainly been used for similar purposes in Western herbal and medical traditions, including offsetting the taste of bitter antimalarials. A classic Victorian textbook of Materia Medica (Hale White, 1897, p. 552) states that:
Liquorice or its preparations are contained in many preparations, generally to cover their nauseous taste. They hide very well that of aloes, cascara sagrada, chloride of ammonium, hyoscyamus, senega, senna, turpentine, and bitter sulphates, as sulphates of quinine It is used to hide the taste of nasty medicines, and as a basis for pills.
Of specific interest is the fact that G. glabra is one of the traditional means of treating malaria in Ayurveda, the classical health care system of India (Sharma, 1999). Liquorice is also known to have gastrointestinal effects and is used in Ayurvedic medicine to treat gastric and duodenal ulcers (www.herbmed.org). It has been found in purified form to stimulate and accelerate gastric mucus formation and secretion (van Marle et al., 1981). These gastrointestinal effects of liquorice would suggest some effect on nausea. In clinical research in Japan, glycyrrhizin, the aqueous extract of liquorice root, has been shown to prevent hepatotoxic responses to chemicals and is used in treating chronic hepatitis (Shibayama, 1989). It also reduces the side effects, including nausea, resulting from chemotherapy in postoperative breast cancer patients (Akimoto et al., 1986). Liquorice is also known to have synergistic effects with other ingredients of plant-based medicines (Williamson, 2001) and may serve such a role in facilitating the mechanism of action of other ingredients in the traditional formula.
Areca catechu, betel nut, another ingredient of the traditional formula, is commonly used in Asian medical traditions. It also has widespread social usage, as it is thought to soothe the digestion and to be a stimulant. It is reportedly chewed regularly by at least 10% of the world's population, is the fourth most widely used addictive substance, and, with regular use, is associated with increased tumor risks (Boucher and Mannan, 2002).
Throughout Asia, betel chewing is believed to produce a sense of well-being, euphoria, warm sensation of the body, sweating, salivation, palpitation, heightened alertness, and increased capacity to work. This collective experience across time would suggest that A. catechu consumption affects the central and autonomic nervous systems.
Specific arecal alkaloids act as competitive inhibitors of gamma aminobutyric acid (GABA) receptors and have widespread effects in the body, including actions on the brain, cardiovascular system, lungs, gut, and pancreas (Boucher and Mannan, 2002). The pro-convulsant properties of GABA antagonists may account for some of the brain stimulation. A dichloromethane fraction from A. catechu has been found to inhibit monoamine oxidase type A isolated from the rat brain (Dar and Khatoon, 2000). There is evidence indicating that A. catechu interacts with central nervous agents and can produce exacerbation of extrapyramidal effects with neuroleptic drugs (Fugh-Berman, 2000). There is also evidence to suggest that A. catechu consumption enhances extrapyramidal functioning in schizophrenic patients (Sullivan et al., 2000).
The combined central and autonomic effects of A. catechu make it an additional candidate, with ginger and liquorice, in offsetting any emetic effects of D. febrifuga in the classical formula.
The remaining three ingredients are used classically in a range of traditional medicines:
Ziziphus jujuba, the red date, has, like D. febrifuga, been found to stimulate nitric oxide generation (Tamaoki et al., 1996) and hence to have possible antimalarial relevance. An extract of its seeds enhances the permeability of cell membranes to assist with cross-membrane transport of drugs and other substances (Eley and Dovlatabadi, 2002), which may be important in the context of synergism in the case of Changshan and the traditional pharmacological use of potentiating agents.
Prunus mume (Sieb.) Sieb. et Zucc., the black plum, is widely used in the Chinese pharmacopoeia as an additive to herbal formulae to prolong, enhance, and harmonise the effect of the other ingredients. One of its specific applications is to moderate the toxicity of potent drugs (http://www.foodsnherbs.com/new_page_47.htm). It has been found to have hepatoprotective effects (Sinclair, 1998), increase blood flow (Chuda et al., 1999), and activate complement via the alternative pathway (Dogasaki et al., 1994). On its own, complement activation could also be associated with such adverse effects as toxic shock, anaphylaxis, and tissue damage.
Amydae carapax, the soft-shelled Chinese tortoise (Trionyx sinensis Wiegmann, family Trionychidae) has been used historically in TCM to correct what is known as yin deficiency. The shell (A. carapax), which contains colloid, keratin, iodine, and several vitamins, may serve to inhibit the hyperplasia of connective tissue and enhance the function of plasma proteins (Ou Ming, 1989; http://botanicum.com/singles/biejia.htm). Its direct relevance to malaria cannot be determined from the very limited amount of pharmacological research available, but is best understood within the classical framework of being applied by TCM practitioners to correct what they assess to be yin deficiencies. Naturally, the use of animal species in contemporary applications of traditional medicine raises both ethical issues on animal welfare and issues of conservation of endangered species and their protection as addressed under the Convention on the International Trade in Endangered Species (CITES).
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