Arch Toxicol (2012) 86:831838 DOI 10.

1007/s00204-012-0826-2

REVIEW ARTICLE

Mercury-based traditional herbo-metallic preparations: a toxicological perspective

Sushant U. Kamath Brindha Pemiah Rajan K. Sekar Sridharan Krishnaswamy Swaminathan Sethuraman Uma Maheswari Krishnan

Received: 3 February 2012 / Accepted: 27 February 2012 / Published online: 23 March 2012 Springer-Verlag 2012

Abstract This review aims to explore the toxicological aspects of mercury-based herbo-metallic preparations like cinnabar and Rasasindura that are primarily composed of mercuric sulde (HgS). Cinnabar-containing preparations have been used extensively in Indian and Chinese systems of medicine for treatment of chronic ailments like syphilis, high fever, pneumonia, insomnia, nervous disorders, deafness, and paralysis of the tongue. Contrary to Western medicine, which does not promote the use of mercury due to its toxic effects, Indian and Chinese traditional practitioners believe that mercury-based formulations have potent therapeutic efcacy, while there is no toxicity due to the unique and repeated purication processes employed during preparation. However, lack of
S. U. Kamath R. K. Sekar S. Sethuraman U. M. Krishnan (&) Centre for Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Thanjavur 613 401, Tamil Nadu, India e-mail: umakrishnan@sastra.edu S. U. Kamath e-mail: sushantkamath@scbt.sastra.edu R. K. Sekar e-mail: ksrajan@chem.sastra.edu S. Sethuraman e-mail: swami@sastra.edu B. Pemiah Centre for Advanced Research in Indian System of Medicine, School of Chemical & Biotechnology, SASTRA University, Thanjavur 613 401, Tamil Nadu, India e-mail: brindha@carism.sastra.edu S. Krishnaswamy School of Chemical & Biotechnology, SASTRA University, Thanjavur 613 401, Tamil Nadu, India e-mail: deanks@sastra.edu

proper pharmacovigilance and widespread self-medication has resulted in undesirable effects to certain sections of the consumers of these preparations, which have contributed to the negative publicity for these forms of medicine. Variations in the quality of the preparations coupled with the lack of understanding of the differences in the recommended dosages and treatment strategies adopted by traditional medicine practitioners, further fuels concerns in the Western world on the safety and efcacy of traditional medicine. But in spite of these concerns, concerted efforts to understand the biological interactions and transformations of these preparations are yet to gain momentum. Although scattered reports on the toxicity of these preparations are available in literature, their mechanism of action has not been conclusively established. Long-term pharmacotherapeutic and in-depth toxicity studies are needed to address the apprehensions raised by these herbo-metallic preparations. This review highlights the lacunae in the studies conducted thus far, and assesses the need for further studies to provide signicant data to establish the safety and efcacy of such preparations, as well as develop gold standards for stringent quality control of these preparations. Keywords Mercury Cinnabar Rasasindura Mercuric sulde Herbo-metallic preparations

Introduction Since time immemorial, Indian and Chinese systems of medicine have used herbo-metallic preparations for treatment of chronic ailments (Singh et al. 2009; Wang et al. 2007). Rasa Shastra is one of the disciplines in Indian system of medicine in which herbo-metallic preparations made from incinerated metals were rst described, such as

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therapeutic formulations using gold, copper, iron, zinc, mercury, etc. These were mixed with organic molecules derived from plant extracts rendering them biocompatible according to Ayurveda, a traditional form of medicine in India (Paul and Chugh 2011). Ayurvedic procedures involve extensive purication and preparation methods and repeated incinerations at specied temperatures to make the minerals ready for human consumption. According to Ayurveda, a puried metal does not react adversely with tissues of the body and, hence, a herbo-metallic drug is considered to be more powerful than almost any other medicinal preparation. Many metals, such as iron, copper, zinc and cobalt, play a vital role in biological systems due to their involvement in the biochemical processes. Elements such as sodium, potassium, magnesium and calcium may aid in improving the bioavailability of drugs in the body (Swamy and Ravikumar 2010). However, the role of heavy metals in biological systems still remains shrouded in controversy. There are many documented reports on the toxic manifestations of heavy metals such as mercury, lead, cadmium and arsenic. Mercury, for instance has been reported to cause dementia and neurological disorders, and it is also wellknown that mercury (II) salts and organic mercury (methyl mercury) are more toxic than elemental mercury (Albers et al. 1988; Chuu et al. 2007). Hence, modern medical practitioners are skeptical about use of mercury for therapya notion not supported by the traditional medicine practitioners. Ayurveda emphasizes the use of specic plant products during the processing of these herbometallic preparationsa trait that is common with other forms of traditional medicine throughout the world (Saper et al. 2008). These herbs are believed to assist the delivery of the drugs to the body and also to contribute to the therapeutic effects. This process of incineration and addition of medicinal herbs is believed to remove impurities and eliminate the harmful effects of the metallic ingredients (Kumar et al. 2006). Unlike proteins, carbohydrates, and lipids, the essential micronutrients for the human body are not biosynthesized in vivo and need to be supplemented through diet (Tontisirin et al. 2002). Traditional medicine believes that the introduction of these ingredients through proper routes and after careful purication can provide ideal therapeutic effects with no toxicity. Interestingly, honey, milk, butter, or ghee are used as the vehicle for most of the Indian herbo-metallic preparations (Sarkar et al. 2010). These may serve as an excellent dispersing medium, and aid delivery and bioavailability of these preparations apart from mitigating any residual toxicity of these medicines (Kumar et al. 2006). Table 1 summarizes the various traditional medicine preparations available in the Indian market containing Rasasinduraa preparation containing mercuric sulde. It

is evident that many preparations contain multiple ingredients, both herbal as well as herbo-metallic, while a few preparations contain only mercury and sulfur.

Toxicology aspects Absence of signicant toxicology data is a major lacuna in herbo-metallic research despite being used since ancient times. Availability of scientic evidence to testify the safety and efcacy of these products is limited since, in most of the reported cases, herbal remedies were self-administered by patients without proper guidance (Chandramouli et al. 2010). Even though the metals are puried and believed to be nontoxic according to Ayurveda, this only refers to the clinical or therapeutic dose, which is minimal. Self-medication may lead to health complications and may prove to be fatal and, hence, Ayurveda does not encourage unsolicited use of its formulations. The permissible limit of heavy metals in dietary contents as per the WHO is lead (10 ppm), cadmium (0.3 ppm), arsenic (10 ppm), and mercury (1 ppm) (Swamy and Ravikumar 2010). Although most of the traditional medicinal preparations have metal contents far greater than the WHO limits, the toxicity of a preparation need not directly correlate with the metal content in the sample. The chemical nature of the metal, route of administration, dosage, residence time within the body, pharmacokinetics and dynamics, bioavailability, metabolic transformations of the preparation, age, gender, physiology, nature and stage of disease, and diet can inuence the toxic manifestations of the herbo-metallic preparations (Hung et al. 1997). Therefore, a careful analysis of all these parameters is required in order to establish the risk involved in a given herbo-metallic preparation.

Cinnabar and Rasasindura Naturally occurring mercuric sulde (HgS) is a component of cinnabar, a Chinese mineral medicine, which has been used as a memory-enhancing drug for more than 2000 years (Young et al. 2002). It has been used as a tranquilizer, and is still used in clinical practice in Asia and the Middle East. In Ayurveda, cinnabar is used as the source to isolate and purify the mercury, which is then amalgamated with sulfur and transformed to Rasasindura (HgS) through mechanochemical processes. Mercury is a well-known toxic element and hence various purication processes exists in Ayurveda, which is believed to render it non-toxic. It is ground with brick dust and garlic and boiled in water after enclosing in a cloth over a gentle re for 3 h. After cooling, it is washed and dried in the sun (Niir Board of Consultants and Engineers 2003). Mercury obtained by sublimation of cinnabar is also considered to be pure.

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Arch Toxicol (2012) 86:831838 Table 1 Commercially available formulations of Rasasindura (containing HgS) in India Drug name Rasasindur Rasaraj ras Formulation Powder Liquid Components Puried mercury, puried sulfur, ammonium chloride Ras sindur, Motipishti, Suvarna bhasma, Abhrak bhasma, Loh bhasma, Suvarnamakshika bhasma, Praval Pishti, Vanga bhasma, Withania somnifera, Syzygium aromaticum, Myristica fragrans Aloe vera juice, Solanum nigrum juice Rasraj ras Tablet Rasa sindur, Abhrak bhasma, Swarna bhasma, Lauha bhasma, Rajata bhasma, Vanga bhasma, Ashvagandha, Lavanga, Jatiphala, Kshir kakoli Rasasindur, Muthanga, Gandhaka, Punarva Rasa sindur, Shuddha, Gandhaka, Kanta Lauha bhasma, Vanga bhasma, Naga bhasma, Tamra bhasma, Abhraka bhasma, Tikshna Lauha bhasma, Shunthi, Pippali, Maricha Extracts of spreading hoog weed, Indian drum stick tree, mustard leaves, Buch-ham, Clove, Tecoma undulata, Sarveshvar parpati, Liquorice extract, Rasasindur, Tinospora extract, puried mercury chloride, extracts of malabar nut and winter cherry root, Calcs of Mica (1,000 times calcined), Calcs of copper, gold, diamond, emerald, turmeric and white pepper Purnachandrodaya ras, Suvarnavang, Muktashukti bhasma, Suvarnamakshik bhasma, Shilajit shuddha, Abhrak bhasma Makardhwaj rasa, Rasa sindur Paralysis, hemiplegia, lockjaw Indications Bronchial asthma, pleurisy with effusion

833

Stroke, hypertension, diabetes, erectile dysfunction, oligospermia, kidney disorders, vata disorders

Destone Ekangavir ras

Capsules Tablets

Urinary tract infections, kidney stones, prostate gland inammation and leucorrhoea Paralysis, Bells palsy, hemiplegia, brachial palsy and sciatica

Carwin

Capsule

Deep seated wounds, tumors, loss of appetite, diminished growth, strength and vital elements along with haematopoiesis, physical and general ill health due to radiation and chemotherapy of various cancer patients

Addyzoa

Capsules

Increases sperm count Enhances sperm motility Improves sperm morphology (prevents DNA damage to sperms) Enhances the chances of pregnancy Increases sexual desire

Rasa sindur Brento

Powder Tablets

Puried mercury, puried sulfur Ashwagandha, Brahmi, Shankpushpi, Yashtimadhu, Pushkarmool, Sarpagandha, Vacha, Jatiphala, Rasa sindur Sunthi, Pippali, Cavya, Pippalimool, Citraka, Hingu, Ajmoda, Sarsapa, Sveta Jiraka, Krsanjiraka, Renuka, Indrayava, Patha, Vidanga, Gajapippli, Katuka, Ativisa, Bharagngi, Vaca, Murva, Haritki, Bibhitaka, Amalaki, Vangabhasma, Abraka bhasma, Mandura bhasma, Parad (Rasa sindur), Guggulu suddha Abhrak bhasma, Bang bhasma, Loha bhasma, Makshik bhasma, Mandur bhasma, Nag bhasma, Rasa sindur, Yograj guggul, Maha rasnadi quath (solid extract) Swarna bhasma, Rajat bhasma, Abhraka bhasma, Lauha bhasma, Pravala bhasma, Mukta bhasma, Rasasindur Rasa sindur, Abharaka Bhasma, Lauha bhasma, Shudda shilajatu, Vidanga, Makeshika bhasma Swarna bhasma, Rajat bhasma, Vanga bhasma, Naga bhasma, Lauha bhasma, Abhraka bhasma, Pravala bhasma, Mukta bhasma, Rasa sindur Swarna bhasma, Rajata bhasma, Abraka bhasma, Lauha bhasma, Pravala bhasma, Mukta bhasma

HIV-AIDS Impaired cognitive function, improves overall mental performance, memory, concentration and learning abilities Used in muscular-skeletal disorders; Maha yogaraj guggul is not only anti-inammatory and safe in the long run but has medicinal herbs which strengthen the system and extend remission, through its healthenhancing herbs

Mahayograj guggul

Tablets

Rhumayog

Tablets

Coronary insufciency and ischemic heart disease; the oleoresin of guggul has a cholestrol lowering effect. It has hypolipidaemic and anti-inammatory effects Improves sensory and motor performance in chronic neurological conditions such as hysteria, insomnia and paralysis Rejuvenator. Improves strength, stamina and energy Diabetes, diabetic carbuncle, diabetic neuropathy, diabetic and retinopathy Chronic and recurrent respiratory tract infection such as inuenza, pneumonia, cachexia, emaceration associated with fever

Vrihat Vatchintamani ras Purnachandra ras Vasant Kusumakar Ras Trailokya Chintamani Ras

Tablets

Tablets Tablets

Tablets

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Cinnabar is rubbed with lemon juice for 3 h and then sublimed. The black powder obtained is further triturated with lemon juice and boiled in water (Dutt 1877). Ayurvedic herbo-metallic preparations are expected to be eliminated from the body very quickly and have been envisaged as carriers. The role of Rasasindura may be analogous to this concept. Another important aspect that needs to be probed in-depth is the role of ingredients that are added at various steps during the preparation. The preparation of Rasasindura involves the purication of mercury and sulfur followed by the reaction between puried mercury and sulfur to produce Rasasindura. There are various purication processes for mercury in Ayurveda. One of them involves grinding mercury with calcium carbonate for 18 h (Fig. 1), and then with rock salt and garlic for 12 h (Shastri 1962). Washing with water separates mercury and the mercury thus obtained is deemed to be pure according to Ayurveda. The role of calcium carbonate in purifying mercury and in the removal of impurities or toxins is not well understood. It is more likely that metallic salts like lead or tin commonly associated with mercury can be removed as slags on reaction with limestone (Meriam and Kraige 1986). Garlic has been used as an antidote for mercury poisoning for a great many years (Graeme and Pollack 1998). Although the antioxidant glutathione can remove mercury toxins from the body, high levels of mercury have been reported to deplete the levels of glutathione. Therefore, we hypothesize that the role of garlic might be to supplement the action of glutathione. It is well established in modern science that mercury binds to sulphydrl groups present in garlic and thereby is excreted from the body (Belle et al. 2009). Another fascinating aspect that needs to be considered while assessing the toxicity of such preparations is the

inclusion of phytochemicals during the preparation processes that may contribute to the therapeutic effect of the preparation, unlike the case with pure mercuric sulde. For example, garlic contains allicin, ajoene, S-allyl cysteine, bioactive selenium, etc., which can aid in mitigating not just heavy metal toxicity but also oxidative stress induced by arsenic and metals (Flora et al. 2009). These components also possess medicinal properties that can serve to treat various disorders. It is likely that such herbo-metallic formulations can serve to potentiate the therapeutic effects of individual phytoconstituents and may contribute to the successful use of such formulations in treating various chronic ailments for many centuries. The purication of sulfur involves melting orthorhombic sulfur with butter, which is then poured into fresh milk. This will result in cooling of sulfur and its subsequent solidication along with an allotropic transformation to its amorphous form (Fig. 2). The components of milk are believed to aid in the irreversible allotropic modication and also get incorporated into sulfur to alter the pharmacokinetic and therapeutic index of the nal product. Finally, puried mercury and puried sulfur is ground together to obtain a ne lusterless powder called Kajjali in Ayurveda, which is a-HgS (Fig. 3). The extract from the aerial root of Ficus bengalensis Linn is then added to this powder and ground until it becomes dry. Ficus bengalensis has been proved to have several medicinal properties and contains sterols like Lupeol, b-sitosterol, and b-amyrin acetate. Although it may impart medicinal properties to HgS and make it more potent, studying its coordination chemistry to probe formation of metal ion complexes may provide interesting insights into the biological interactions of these preparations. This is because it has now been recognized that

Fig. 1 a Calcium carbonate and elemental mercury prior to the process of grinding, b calcium carbonate after the process of grinding with mercury

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Fig. 2 Stages of sulfur purication: a sulfur with butter in a pan; b molten sulfur and butter; c quenching of sulfur in milk

Fig. 3 Kajjali preparation

coordination complexes of metals have signicant physiological activities (Zang and Lippard 2003; Selvaraj et al. 2011, 2012). The transformation of beta to alpha HgS is carried out by heating under controlled conditions with mild, moderate, and intermittent heat, and the red-colored product Rasasindura is obtained. However, investigations on the interaction of these preparations on the biological system have not been systematically carried out at the molecular, cellular, and systemic levels, nor have any efforts been directed to understand the chemical composition and constituents in these preparations. Though not many in vivo studies with Rasasindura have been reported in the literature, a few experiments to ascertain the toxicity of mercuric sulde-based preparations have been carried out. Excretion of Makaradhwaja, an Ayurvedic formulation composed of mercuric sulde, showed no traces of mercury in urine samples of healthy men (Niir Board of consultants and Engineers 2003). Cinnabar is reported to be the most inert form of mercury compounds and has been found to exhibit 5,000-fold less toxicity when compared with methyl mercury, based on the results obtained after exposure of brain and liver cells for 48 h to cinnabar-containing traditional Chinese

medicine, An-Gong-Niu-Huang (AGNH) (Wu et al. 2011). This makes clear that the chemical form of the metal is a critical determinant in toxicity evaluation. Experiments have been undertaken to study whether cinnabar was converted to methyl mercury by human intestinal bacteria (Zhou et al. 2010). Cinnabar was incubated with human intestinal bacteria, and analyzed by gas chromatography mass spectrometry (GC-MS) for the formation of methyl mercury. Cold vapor atomic absorption spectrometry was used to analyze the content of mercury in the bacterial media. The results revealed that no methyl mercury was formed in the bacterial media, although a small amount of Hg was released in the ora medium. The results showed that cinnabar might be transformed into mercuric polysuldes rather than methyl mercury under gut ora conditions (Zhou et al. 2010). The molecular mechanism by which HgS may exert its pharmacological action is not yet clear. Mercuric sulde is insoluble and less toxic in vivo, but has been proved to be toxic to the central nervous system. According to previous studies, both cinnabar and mercuric sulde at a high dose of 1 g/kg induced dysfunction of the vestibular ocular reex system and disturbed motor performance in guinea pigs, and caused abnormal auditory brain stem response in mice (Young et al. 2002). It has also been postulated that cinnabar and mercuric sulde may increase nitric oxide generation in the cerebral regulatory system and decrease Na?/K? ATPase activity. Thus, dose is a critical parameter in toxic manifestations of any preparation. This highlights the harmful effects of unsolicited medications. The neurobehavioral toxicities of cinnabar (naturally occurring HgS), mercuric sulde (HgS), and methyl mercury (MeHg) on rats have been studied (Chuu et al. 2001). The results indicated that MeHg and cinnabar irreversibly inhibited Na?/K? ATPase activity in the cerebral cortex whereas HgS reversibly inhibited Na?/K? ATPase activity. This suggests that insoluble HgS and cinnabar can be absorbed from the gastrointestinal (GI) tract and distributed to the brain (Chuu et al. 2001). Studies on neurotoxic effects of MeHg and HgS have revealed that HgS

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reversibly delayed the recovery of suppressed compound muscle action potentials and inhibited sciatic nerve Na?/ K? ATPase activity, whereas, MeHg had an irreversible effect (Chuu et al. 2007). The ototoxic effect of cinnabar in rats was studied in the auditory brain stem response (ABR) during 210 weeks administration at 10 mg/kg/day. The results showed that the mercury content of brain stem signicantly increased, accompanied by gradual progressive abnormality of ABR during 410 weeks of cinnabar administration. The incidence of hearing impairment occurred more in male mice. An altered Na?/K? ATPase activity, increase of lipid peroxidation, and decrease of nitric oxide levels were observed. Moreover, accumulation of mercury in brain stem was found to be greater in male mice. An amount of 10 mg/kg/day is equivalent to a clinical dose, which produced ototoxicity after long-term exposure. The study has also opened up the possibility of gender difference in neurotoxic effects, which needs to be investigated for all mercury-based preparations (Huang et al. 2008). The neuropharmacological mechanism of cinnabar was studied wherein an elevated plus maze test was used to evaluate the anxiolytic effect of cinnabar on anxiety-like behaviors in mice (Wang et al. 2007). The results indicated that cinnabar possessed anxiolytic effects after chronic administration through a per oral route at effective doses in association with the declined brain serotonin or 5-hydroxy tryptamine (5-HT) level. Cinnabar showed no effect on the 5-HT metabolism pathway (Wang et al. 2007). Cinnabar at oral doses of 50 and 100 mg/kg/day for 10 days signicantly improved the performance, but at 1,000 mg/kg, a dose 100-fold higher than the human daily dose, it was ineffective. This pharmacological action may be attributed with the decrease in serotonin levels in mouse brain, but the dose-dependent relationship is not clear. In mice, a low dose of cinnabar (10 mg/kg/d) for 11 weeks of continuous administration reduced the locomotor activity and increased the pentobarbital sleeping time, suggesting sedative or hypnotic effects (Liu et al. 2008). The effect of an herbal formulation containing HgS on Swiss albino mice was studied, and the results showed that the drug, even at doses 510 times higher than the normal dose (2040 mg/100 g of mice), did not show any adverse effects (Upadhyay et al. 2008). Histopathological studies did not reveal any toxic effects of the drug. Genotoxic evaluation of HgS-containing Ayurvedic formulations using micronucleus and comet assay on rats have been carried out (Sathya et al. 2009). The investigation revealed no incidences of genotoxicity, in terms of micronuclei induction or DNA damage in animals treated with Kajjali bhasma (predominantly meta-cinnabar), which re-emphasized its safety despite its trace mercury content (Sathya et al. 2009). Mahayograj guggulu, an Ayurvedic medicine

containing 48 g mercuric sulde, was administered to Charles Foster strain albino rats at the doses of 54, 270, and 540 mg/kg, with 54 mg/kg being equivalent to a human therapeutic dose. Mahayograj guggulu was found to be safe at all dose levels, although heavy metal estimation was 0.07 lg/g for mercury (Lavekar et al. 2010). Toxicity in humans after consumption of traditional medicines containing mercuric sulde has been reported (Kew et al. 1993). After consumption of red-brown-colored pills, which primarily consisted of mercuric sulde, a 32-year-old Asian man suffered from diarrhea, sweating, tremor of the hands, and hypertension. Neurological examination revealed reduced sensation in both feet. Mercury concentration in the urine was found to be 105 lg/L 12 weeks after his last exposure to the medicine. Such cases of mercury poisoning from ethnic medicines indicate inappropriate preparation methods resulting in exposure to inorganic mercury. In another report, an 87-year-old man developed a dry cough, fever, and dyspnea after inhaling mercury vapors from heated cinnabar, which was prescribed for treating foot ulcers. Penicillamine and 2,3-dimercapto-1-propanesulfonic acid (DMPS) was administered as chelation therapy. Despite the therapy, the patient died 39 days after being exposed to mercury vapors (Ho et al. 2003). This is a classic case proving that mercury vapors are more toxic than elemental mercury. The discrepancies between the toxic manifestations in animal models and human subjects cannot be attributed to a single factor. The differences in absorption, distribution, metabolism, and excretion (ADME) characteristics, immune response, diet, physical activity, and tolerance limits that exist between animals and humans complicate any possible extrapolation of the safety and toxicity data between the two. Another hurdle in the evaluation of toxicity of these preparations in humans is the lack of documented reports and absence of long-term follow-ups in patients consuming these preparations.

Pharmacokinetics and postulated mechanisms Cinnabar contains more than 96% a-HgS and methylation of cinnabar by microbes in the gut is impossible because the poorly soluble HgS can hardly release mercury ions in water. Herbo-metallic preparations involve conversion of the metal into its mixed oxides. It is believed that the zerovalent metal state is converted to a higher oxidation state. This, in turn, completely destroys its toxic nature through transformations into forms that can imbibe medicinal properties into it (Sathya et al. 2009). However, free metal ions have well-established toxicity proles, and hence it is probably the complexed forms that are not toxic. Though some reports have indicated the possibility of existence of

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metal ion complexes in the herbo-mineral preparations, no conclusive evidence has so far been presented, which is the major stumbling block in the global acceptance of these preparations. The distribution pattern of mercury in humans is similar to that of inorganic mercurials (Liu et al. 2008). Kidney is the major organ where the concentration of mercury is found to be high. Mercury salts undergo renal uptake by two routes: initially, from luminal membranes in proximal tubules to form cysteine Sconjugates (CysSHgSCys), and later through organic anion transporters from the basolateral membrane (Bridges and Zalups 2005). The bloodbrain barrier and placenta do not allow the passage of inorganic mercury, but a small portion of absorbed inorganic mercury can be exhaled as mercury vapor due to reduction in tissues. A signicant portion of mercury vapor has also been found to cross the bloodbrain barrier (Klaassen 2001). However, it has been reported that oral administration of cinnabar results in its distribution in brain, especially to the cerebral cortex and cerebellum (Yen et al. 2002). Therefore, it is evident that the controversy surrounding the toxicity of traditional medicine preparation stems from the lack of systemic investigations on their interactions with biological systems. The choice and design of the experiments, the duration, route of administration, concentration, and knowledge about the composition of the preparation, are all critical parameters in pharmacokinetic evaluation.

modern era. The need for patient follow-up after counseling and drug therapy was rare in earlier times, and even now it is not followed stringently. Hence, scientic evidence is lacking to conrm the safety and efcacy of these drugs. Another unexplored facet, which could affect the efcacy and toxicity of such preparations, are drug-drug interaction that occurs when they are given in combination with other herbal preparations. The fact that mercury sulde is insoluble and does not get absorbed through blood circulation eliminates its chances of providing therapeutic benets, since it may not react at all with the cell receptors. However, incorporation of herbal ingredients in these preparations may alter the cell uptake, distribution, and elimination prole as well as the therapeutic properties. No pharmacotherapeutic studies exist to analyze the benets of these drugs. Shortcomings in choice of animal models and proper design of experiments to assess toxicity have hampered the risk assessment of these traditional preparations, and hence there is a requirement for more comprehensive studies to understand the ramications of these therapeutic processes.
Acknowledgments We would like to thank Drugs and Pharmaceuticals Research Programme (VI-D&P/267/08-09/TDT), Department of Science and Technology, New Delhi. We gratefully acknowledge the Nano Mission Council (SR/S5/NM-07/2006 & SR/ NM/PG-16-2007) and to SASTRA University for the infrastructure and support. Conict of interest ict of interest. All the authors declare that they have no con-

Conclusion References Most of the studies conducted thus far on mercury-based traditional medicine preparations in experimental animals have been short-term toxicity studies with use of high doses of HgS, which cannot be correlated with humans. Variations in therapeutic doses are recommended by practitioners for different ailments. Practioners in traditional medicines adopt a holistic approach to treatment and consider the physiological aspects of an individual along with the type of disease and stage of presentation. Diet restrictions also contribute to alterations in the pharmacokinetics, and thus labeling a traditional medicine preparation as toxic based only on the metal content seems inappropriate. However, in-depth and systematic investigations are not available for these preparations. Pre-clinical studies are needed after conversion of the human therapeutic dose to an animal dose, and both short-term and long-term toxicity have to be evaluated. Signicant and substantial amount of data through these studies can provide a platform for designing human clinical trials. Even though cinnabar and Rasasindura have been used for centuries in traditional medicine, pharmaco-vigilance never existed then and does not even prevail in the
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