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1.  Effect of mineral-enriched diet and medicinal herbs on Fe, Mn, Zn, and Cu uptake in chicken 
The goal of our study was to evaluate the effects of different medicinal herbs rich in polyphenol (Lemon balm, Sage, St. John's wort and Small-flowered Willowherb) used as dietary supplements on bioaccumulation of some essential metals (Fe, Mn, Zn and Cu) in different chicken meats (liver, legs and breast).
In different type of chicken meats (liver, legs and breast) from chickens fed with diets enriched in minerals and medicinal herbs, beneficial metals (Fe, Mn, Zn and Cu) were analysed by flame atomic absorption spectrometry. Fe is the predominant metal in liver and Zn is the predominant metal in legs and breast chicken meats. The addition of metal salts in the feed influences the accumulations of all metals in the liver, legs and breast chicken meat with specific difference to the type of metal and meat. The greatest influences were observed in legs meat for Fe and Mn. Under the influence of polyphenol-rich medicinal herbs, accumulation of metals in the liver, legs and breast chicken meat presents specific differences for each medicinal herb, to the control group that received a diet supplemented with metal salts only. Great influence on all metal accumulation factors was observed in diet enriched with sage, which had significantly positive effect for all type of chicken meats.
Under the influence of medicinal herbs rich in different type of polyphenol, accumulation of metals in the liver, legs and breast chicken meat presents significant differences from the group that received a diet supplemented only with metal salts. Each medicinal herb from diet had a specific influence on the accumulation of metals and generally moderate or poor correlations were observed between total phenols and accumulation of metals. This may be due to antagonism between metal ions and presence of other chelating agents (amino acids and protein) from feeding diets which can act as competitor for complexation of metals and influence accumulation of metals in chicken meat.
Graphical abstract
PMCID: PMC3337232  PMID: 22429523
Chicken liver; Chicken legs meat; Chicken breast meat; Medicinal herbs; Beneficial metals; Feeding diets; Polyphenol
2.  Lead, Mercury, and Arsenic in US- and Indian-Manufactured Ayurvedic Medicines Sold via the Internet 
Lead, mercury, and arsenic have been detected in a substantial proportion of Indian-manufactured traditional Ayurvedic medicines. Metals may be present due to the practice of rasa shastra (combining herbs with metals, minerals, and gems). Whether toxic metals are present in both US- and Indian-manufactured Ayurvedic medicines is unknown.
To determine the prevalence of Ayurvedic medicines available via the Internet containing detectable lead, mercury, or arsenic and to compare the prevalence of toxic metals in US- vs Indian-manufactured medicines and between rasa shastra and non–rasa shastra medicines.
A search using 5 Internet search engines and the search terms Ayurveda and Ayurvedic medicine identified 25 Web sites offering traditional Ayurvedic herbs, formulas, or ingredients commonly used in Ayurveda, indicated for oral use, and available for sale. From 673 identified products, 230 Ayurvedic medicines were randomly selected for purchase in August–October 2005. Country of manufacturer/Web site supplier, rasa shastra status, and claims of Good Manufacturing Practices were recorded. Metal concentrations were measured using x-ray fluorescence spectroscopy.
Main Outcome Measures
Prevalence of medicines with detectable toxic metals in the entire sample and stratified by country of manufacture and rasa shastra status.
One hundred ninety-three of the 230 requested medicines were received and analyzed. The prevalence of metal-containing products was 20.7% (95% confidence interval [CI], 15.2%–27.1%). The prevalence of metals in US-manufactured products was 21.7% (95% CI, 14.6%–30.4%) compared with 19.5% (95% CI, 11.3%–30.1%) in Indian products (P=.86). Rasa shastra compared with non–rasa shastra medicines had a greater prevalence of metals (40.6% vs 17.1%; P=.007) and higher median concentrations of lead (11.5 μg/g vs 7.0 μg/g; P=.03) and mercury (20 800 μg/g vs 34.5 μg/g; P=.04). Among the metal-containing products, 95% were sold by US Web sites and 75% claimed Good Manufacturing Practices. All metal-containing products exceeded 1 or more standards for acceptable daily intake of toxic metals.
One-fifth of both US-manufactured and Indian-manufactured Ayurvedic medicines purchased via the Internet contain detectable lead, mercury, or arsenic.
PMCID: PMC2755247  PMID: 18728265
3.  Metal-on-Metal Total Hip Resurfacing Arthroplasty 
Executive Summary
The objective of this review was to assess the safety and effectiveness of metal on metal (MOM) hip resurfacing arthroplasty for young patients compared with that of total hip replacement (THR) in the same population.
Clinical Need
Total hip replacement has proved to be very effective for late middle-aged and elderly patients with severe degenerative diseases of the hips. As indications for THR began to include younger patients and those with a more active life style, the longevity of the implant became a concern. Evidence suggests that these patients experience relatively higher rates of early implant failure and the need for revision. The Swedish hip registry, for example, has demonstrated a survival rate in excess of 80% at 20 years for those aged over 65 years, whereas this figure was 33% by 16 years in those aged under 55 years.
Hip resurfacing arthroplasty is a bone-conserving alternative to THR that restores normal joint biomechanics and load transfer. The technique has been used around the world for more than 10 years, specifically in the United Kingdom and other European countries.
The Technology
Metal-on-metal hip resurfacing arthroplasty is an alternative procedure to conventional THR in younger patients. Hip resurfacing arthroplasty is less invasive than THR and addresses the problem of preserving femoral bone stock at the initial operation. This means that future hip revisions are possible with THR if the initial MOM arthroplasty becomes less effective with time in these younger patients. The procedure involves the removal and replacement of the surface of the femoral head with a hollow metal hemisphere, which fits into a metal acetabular cup.
Hip resurfacing arthroplasty is a technically more demanding procedure than is conventional THR. In hip resurfacing, the femoral head is retained, which makes it much more difficult to access the acetabular cup. However, hip resurfacing arthroplasty has several advantages over a conventional THR with a small (28 mm) ball. First, the large femoral head reduces the chance of dislocation, so that rates of dislocation are less than those with conventional THR. Second, the range of motion with hip resurfacing arthroplasty is higher than that achieved with conventional THR.
A variety of MOM hip resurfacing implants are used in clinical practice. Six MOM hip resurfacing implants have been issued licences in Canada.
Review Strategy
A search of electronic bibliographies (OVID Medline, Medline In-Process and Other Non-Indexed Citations, Embase, Cochrane CENTRAL and DSR, INAHTA) was undertaken to identify evidence published from Jan 1, 1997 to October 27, 2005. The search was limited to English-language articles and human studies. The literature search yielded 245 citations. Of these, 11 met inclusion criteria (9 for effectiveness, 2 for safety).
The result of the only reported randomized controlled trial on MOM hip resurfacing arthroplasty could not be included in this assessment, because it used a cemented acetabular component, whereas in the new generation of implants, a cementless acetabular component is used. After omitting this publication, only case series remained.
Summary of Findings
Health Outcomes
The Harris hip score and SF-12 are 2 measures commonly used to report health outcomes in MOM hip resurfacing arthroplasty studies. Other scales used are the Oxford hip score and the University of California Los Angeles hip score.
The case series showed that the mean revision rate of MOM hip resurfacing arthroplasty is 1.5% and the incidence of femoral neck fracture is 0.67%. Across all studies, 2 cases of osteonecrosis were reported. Four studies reported improvement in Harris hip scores. However, only 1 study reported a statistically significant improvement. Three studies reported improvement in SF-12 scores, of which 2 reported a significant improvement. One study reported significant improvement in UCLA hip score. Two studies reported postoperative Oxford hip scores, but no preoperative values were reported.
None of the reviewed studies reported procedure-related deaths. Four studies reported implant survival rates ranging from 94.4% to 99.7% for a follow-up period of 2.8 to 3.5 years. Three studies reported on the range of motion. One reported improvement in all motions including flexion, extension, abduction-adduction, and rotation, and another reported improvement in flexion. Yet another reported improvement in range of motion for flexion abduction-adduction and rotation arc. However, the author reported a decrease in the range of motion in the arc of flexion in patients with Brooker class III or IV heterotopic bone (all patients were men).
Safety of Metal-on-Metal Hip Resurfacing Arthroplasty
There is a concern about metal wear debris and its systemic distribution throughout the body. Detectable metal concentrations in the serum and urine of patients with metal hip implants have been described as early as the 1970s, and this issue is still controversial after 35 years.
Several studies have reported high concentration of cobalt and chromium in serum and/or urine of the patients with metal hip implants. Potential toxicological effects of the elevated metal ions have heightened concerns about safety of MOM bearings. This is of particular concern in young and active patients in whom life expectancy after implantation is long.
Since 1997, 15 studies, including 1 randomized clinical trial, have reported high levels of metal ions after THR with metal implants. Some of these studies have reported higher metal levels in patients with loose implants.
Adverse Biological Effects of Cobalt and Chromium
Because patients who receive a MOM hip arthroplasty are shown to be exposed to high concentrations of metallic ions, the Medical Advisory Secretariat searched the literature for reports of adverse biological effects of cobalt and chromium. Cobalt and chromium make up the major part of the metal articulations; therefore, they are a focus of concern.
Risk of Cancer
To date, only one study has examined the incidence of cancer after MOM and polyethylene on metal total hip arthroplasties. The results were compared to that of general population in Finland. The mean duration of follow-up for MOM arthroplasty was 15.7 years; for polyethylene arthroplasty, it was 12.5 years. The standardized incidence ratio for all cancers in the MOM group was 0.95 (95% CI, 0.79–1.13). In the polyethylene on metal group it was 0.76 (95% CI, 0.68–0.86). The combined standardized incidence ratio for lymphoma and leukemia in the patients who had MOM THR was 1.59 (95% CI, 0.82–2.77). It was 0.59 (95% CI, 0.29–1.05) for the patients who had polyethylene on metal THR. Patients with MOM THR had a significantly higher risk of leukemia. All patients who had leukemia were aged over than 60 years.
Cobalt Cardiotoxicity
Epidemiological Studies of Myocardiopathy of Beer Drinkers
An unusual type of myocardiopathy, characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure, occurred as an epidemic affecting 48 habitual beer drinkers in Quebec City between 1965 and 1966. This epidemic was directly related the consumption of a popular beer containing cobalt sulfate. The epidemic appeared 1 month after cobalt sulfate was added to the specific brewery, and no further cases were seen a month after this specific chemical was no longer used in making this beer. A beer of the same name is made in Montreal, and the only difference at that time was that the Quebec brand of beer contained about 10 times more cobalt sulphate. Cobalt has been added to some Canadian beers since 1965 to improve the stability of the foam but it has been added in larger breweries only to draught beer. However, in small breweries, such as those in Quebec City, separate batches were not brewed for bottle and draught beer; therefore, cobalt was added to all of the beer processed in this brewery.
In March 1966, a committee was appointed under the chairmanship of the Deputy Minister of Health for Quebec that included members of the department of forensic medicine of Quebec’s Ministry of Justice, epidemiologists, members of Food and Drug Directorate of Ottawa, toxicologists, biomedical researchers, pathologists, and members of provincial police. Epidemiological studies were carried out by the Provincial Ministry of Health and the Quebec City Health Department.
The association between the development of myocardiopathy and the consumption of the particular brand of beer was proven. The mortality rate of this epidemic was 46.1% and those who survived were desperately ill, and recovered only after a struggle for their lives.
Similar cases were seen in Omaha (Nebraska). The epidemic started after a cobalt additive was used in 1 of the beers marketed in Nebraska. Sixty-four patients with the clinical diagnosis of alcoholic myocardiopathy were seen during an 18-month period (1964–1965). Thirty of these patients died. The first patient became ill within 1 month after cobalt was added to the beer, and the last patient was seen within 1 month of withdrawal of cobalt.
A similar epidemic occurred in Minneapolis, Minnesota. Between 1964 and 1967, 42 patients with acute heart failure were admitted to a hospital in Minneapolis, Minnesota. Twenty of these patients were drinking 6 to 30 bottles per day of a particular brand of beer exclusively. The other 14 patients also drank the same brand of beer, but not exclusively. The mortality rate from the acute illness was 18%, but late deaths accounted for a total mortality rate of 43%. Examination of the tissue from these patients revealed markedly abnormal changes in myofibrils (heart muscles), mitochondria, and sarcoplasmic reticulum.
In Belgium, a similar epidemic was reported in 1966, in which, cobalt was used in some Belgian beers. There was a difference in mortality between the Canadian or American epidemic and this series. Only 1 of 24 patients died, 1.5 years after the diagnosis. In March 1965, at an international meeting in Brussels, a new heart disease in chronic beer drinkers was described. This disease consists of massive pericardial effusion, low cardiac output, raised venous pressure, and polycythemia in some cases. This syndrome was thought to be different from the 2 other forms of alcoholic heart disease (beriberi and a form characterized by myocardial fibrosis).
The mystery of the above epidemics as stated by investigators is that the amount of cobalt added to the beer was below the therapeutic doses used for anemia. For example, 24 pints of Quebec brand of beer in Quebec would contain 8 mg of cobalt chloride, whereas an intake of 50 to 100 mg of cobalt as an antianemic agent has been well tolerated. Thus, greater cobalt intake alone does not explain the occurrence of myocardiopathy. It seems that there are individual differences in cobalt toxicity. Other features, like subclinical alcoholic heart disease, deficient diet, and electrolyte imbalance could have been precipitating factors that made these patients susceptible to cobalt’s toxic effects.
In the Omaha epidemic, 60% of the patients had weight loss, anorexia, and occasional vomiting and diarrhea 2 to 6 months before the onset of cardiac symptoms. In the Quebec epidemic, patients lost their appetite 3 to 6 months before the diagnosis of myocardiopathy and developed nausea in the weeks before hospital admission. In the Belgium epidemic, anorexia was one of the most predominant symptoms at the time of diagnosis, and the quality and quantity of food intake was poor. Alcohol has been shown to increase the uptake of intracoronary injected cobalt by 47%. When cobalt enters the cells, calcium exits; this shifts the cobalt to calcium ratio. The increased uptake of cobalt in alcoholic patients may explain the high incidence of cardiomyopathies in beer drinkers’ epidemics.
As all of the above suggest, it may be that prior chronic exposure to alcohol and/or a nutritionally deficient diet may have a marked synergistic effect with the cardiotoxicity of cobalt.
MOM hip resurfacing arthroplasty has been shown to be an effective arthroplasty procedure as tested in younger patients.
However, evidence for effectiveness is based only on 7 case series with short duration of follow-up (2.8–3.5 years). There are no RCTs or other well-controlled studies that compare MOM hip resurfacing with THR.
Revision rates reported in the MOM studies using implants currently licensed in Canada (hybrid systems, uncemented acetabular, and cemented femoral) range from 0.3% to 3.6% for a mean follow-up ranging from 2.8 to 3.5 years.
Fracture of femoral neck is not very common; it occurs in 0.4% to 2.2% of cases (as observed in a short follow-up period).
All the studies that measured health outcomes have reported improvement in Harris Hip and SF-12 scores; 1 study reported significant reduction in pain and improvement in function, and 2 studies reported significant improvement in SF-12 scores. One study reported significant improvement in UCLA Hip scores.
Concerns remain on the potential adverse effects of metal ions. Longer-term follow-up data will help to resolve the inconsistency of findings on adverse effects, including toxicity and carcinogenicity.
Ontario-Based Economic Analysis
The device cost for MOM ranges from $4,300 to $6,000 (Cdn). Traditional hip replacement devices cost about $2,000 (Cdn). Using Ontario Case Costing Initiative data, the total estimated costs for hip resurfacing surgery including physician fees, device fees, follow-up consultation, and postsurgery rehabilitation is about $15,000 (Cdn).
Cost of Total Hip Replacement Surgery in Ontario
MOM hip arthroplasty is generally recommended for patients aged under 55 years because its bone-conserving advantage enables patients to “buy time” and hence helps THRs to last over the lifetime of the patient. In 2004/2005, 15.9% of patients who received THRs were aged 55 years and younger. It is estimated that there are from 600 to 1,000 annual MOM hip arthroplasty surgeries in Canada with an estimated 100 to 150 surgeries in Ontario. Given the increased public awareness of this device, it is forecasted that demand for MOM hip arthroplasty will steadily increase with a conservative estimate of demand rising to 1,400 cases by 2010 (Figure 10). The net budget impact over a 5-year period could be $500,000 to $4.7 million, mainly because of the increasing cost of the device.
Projected Number of Metal-on-Metal Hip Arthroplasty Surgeries in Ontario: to 2010
PMCID: PMC3379532  PMID: 23074495
4.  A Computational Framework for Proteome-Wide Pursuit and Prediction of Metalloproteins using ICP-MS and MS/MS Data 
BMC Bioinformatics  2011;12:64.
Metal-containing proteins comprise a diverse and sizable category within the proteomes of organisms, ranging from proteins that use metals to catalyze reactions to proteins in which metals play key structural roles. Unfortunately, reliably predicting that a protein will contain a specific metal from its amino acid sequence is not currently possible. We recently developed a generally-applicable experimental technique for finding metalloproteins on a genome-wide scale. Applying this metal-directed protein purification approach (ICP-MS and MS/MS based) to the prototypical microbe Pyrococcus furiosus conclusively demonstrated the extent and diversity of the uncharacterized portion of microbial metalloproteomes since a majority of the observed metal peaks could not be assigned to known or predicted metalloproteins. However, even using this technique, it is not technically feasible to purify to homogeneity all metalloproteins in an organism. In order to address these limitations and complement the metal-directed protein purification, we developed a computational infrastructure and statistical methodology to aid in the pursuit and identification of novel metalloproteins.
We demonstrate that our methodology enables predictions of metal-protein interactions using an experimental data set derived from a chromatography fractionation experiment in which 870 proteins and 10 metals were measured over 2,589 fractions. For each of the 10 metals, cobalt, iron, manganese, molybdenum, nickel, lead, tungsten, uranium, vanadium, and zinc, clusters of proteins frequently occurring in metal peaks (of a specific metal) within the fractionation space were defined. This resulted in predictions that there are from 5 undiscovered vanadium- to 13 undiscovered cobalt-containing proteins in Pyrococcus furiosus. Molybdenum and nickel were chosen for additional assessment producing lists of genes predicted to encode metalloproteins or metalloprotein subunits, 22 for nickel including seven from known nickel-proteins, and 20 for molybdenum including two from known molybdo-proteins. The uncharacterized proteins are prime candidates for metal-based purification or recombinant approaches to validate these predictions.
We conclude that the largely uncharacterized extent of native metalloproteomes can be revealed through analysis of the co-occurrence of metals and proteins across a fractionation space. This can significantly impact our understanding of metallobiochemistry, disease mechanisms, and metal toxicity, with implications for bioremediation, medicine and other fields.
PMCID: PMC3058030  PMID: 21356119
5.  Predicted metal binding sites for phytoremediation 
Bioinformation  2009;4(2):66-70.
Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP's). Earlier work on MAP's have shown that heavy metals accumulated by aromatic and medicinal plants do not appear in the essential oil and that some of these species are able to grow in metal contaminated sites. A pattern search against the UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high specificity of the motifs designed for the ions of nickel, lead, molybdenum, manganese, cadmium, zinc, iron, cobalt and xenobiotic compounds. Motifs were also studied against PDB structures. Results of the study suggested the presence of binding sites on the surface of protein molecules involved. PDB structures of proteins were finally predicted for the binding sites functionality in their respective phytoremediation usage. This was further validated through CASTp server to study its physico-chemical properties. Bioinformatics implications would help in designing strategy for developing transgenic plants with increased metal binding capacity. These metal binding factors can be used to restrict metal update by plants. This helps in reducing the possibility of metal movement into the food chain.
PMCID: PMC2823383  PMID: 20198171
Phytoremediation; medicinal and aromatic plants (MAPs); putative metal binding sites
6.  Adverse Events Associated with Metal Contamination of Traditional Chinese Medicines in Korea: A Clinical Review 
Yonsei Medical Journal  2014;55(5):1177-1186.
This study was performed to review studies carried out in Korea reporting toxic reactions to traditional Chinese medicines (TCMs) as a result of heavy metal contamination. PubMed (1966-August 2013) and International Pharmaceutical Abstracts (1965-August 2013) were searched using the medical subject heading terms of "Medicine, Chinese Traditional," "Medicine, Korean Traditional," "Medicine, Traditional," "Metals, Heavy," and "Drug Contamination". For Korean literature, Korea Med (, the Korean Medical Database (, National Discovery for Science Leaders (, Research Information Sharing Service (, and Google Scholar were searched using the terms "Chinese medicine," "Korean medicine," "herbal medicine," and "metallic contamination" in Korean. Bibliographies of case reports and case series, identified using secondary resources, were also utilized. Only literature describing cases or studies performed in Korea were included. Case reports identified clear issues with heavy metal, particularly lead, contamination of TCMs utilized in Korea. No international standardization guidelines for processing, manufacturing and marketing of herbal products exist. Unacceptably high levels of toxic metals can be present in TCM preparations. Health care providers and patients should be educated on the potential risks associated with TCMs. International advocacy for stricter standardization procedures for production of TCMs is warranted.
PMCID: PMC4108800  PMID: 25048473
Medicine; Korean traditional; medicine; chinese traditional; metals; heavy
7.  Profile of heavy metals in some medicinal plants from Ghana commonly used as components of herbal formulations 
Pharmacognosy Research  2010;2(1):41-44.
The levels of some heavy metals in 27 medicinal plant species from Ghana were studied in order to evaluate their health implications. These plant species, especially those used in the treatment of diseases such as hypertension, diabetes and asthma may require long term usage. The metals were copper, zinc, iron, manganese, nickel and cadmium. Atomic Absorption Spectrophotometry (wet digestion) was used for the analyses, and content of metals per sample was expressed as percent µg/g. Daily total intake of these metals is discussed based on the recommended daily intake of the medicinal plants or their corresponding formulations. From the results of the study zinc, copper and cadmium were present in all the plant species examined. Manganese was present in all species except V. amygdalina. Iron was found in all except five species (82%), whilst nickel was (rather rare) detected in only eight (30%) of the plant species. Significant variations in metal content existed (P<0.05) among the medicinal plant species with respect to the heavy metals evaluated. The concentrations of copper, zinc, cadmium and manganese were within their respective maximum permissible daily levels. However, some species, especially Ocimum canum (8), Clausena anisata and Rauwolfia vomitoria had levels of iron higher than the maximum permissible level of 1000 µg/day and may require care to avoid iron toxicity. The results also highlighted the differences in contents of minerals in Lippia multiflora obtained from different locations in Ghana. The findings generally suggest that the use of these plant species for the management of diseases will not cause heavy metal toxicity and may be beneficial to the users in cases of micronutrient deficiency, as these metals were found to be present in readily bioavailable form.
PMCID: PMC3140128  PMID: 21808538
Health implications; heavy metals; herbal formulations; medicinal plant
8.  Phytosynthesis of nanoparticles: concept, controversy and application 
Nanoscale Research Letters  2014;9(1):229.
Nanotechnology is an exciting and powerful discipline of science; the altered properties of which have offered many new and profitable products and applications. Agriculture, food and medicine sector industries have been investing more in nanotechnology research. Plants or their extracts provide a biological synthesis route of several metallic nanoparticles which is more eco-friendly and allows a controlled synthesis with well-defined size and shape. The rapid drug delivery in the presence of a carrier is a recent development to treat patients with nanoparticles of certain metals. The engineered nanoparticles are more useful in increasing the crop production, although this issue is still in infancy. This is simply due to the unprecedented and unforeseen health hazard and environmental concern. The well-known metal ions such as zinc, iron and copper are essential constituents of several enzymes found in the human system even though the indiscriminate use of similar other metal nanoparticle in food and medicine without clinical trial is not advisable. This review is intended to describe the novel phytosynthesis of metal and metal oxide nanoparticles with regard to their shape, size, structure and diverse application in almost all fields of medicine, agriculture and technology. We have also emphasized the concept and controversial mechanism of green synthesis of nanoparticles.
PMCID: PMC4031915  PMID: 24910577
Metal; Metal oxide; Carbon nanomaterials; Green synthesis; Agriculture; Medicine
9.  Lead Encephalopathy Due to Traditional Medicines 
Current drug safety  2008;3(1):54-59.
Traditional medicine use is common in developing countries and increasingly popular in the western world. Despite the popularity of traditional medicines, scientific research on safety and efficacy is limited. However documented fatalities and severe illness due to lead poisoning are increasingly recognized to be associated with traditional medicine use. As society becomes more globalized, it is imperative for pharmacists and health care providers to learn about the safety of traditional medical practices. The information presented educates and alerts pharmacists and health care providers about the potential of traditional medicines to cause lead encephalopathy. Case reports were located through systematic literature searches using MEDLINE, CINAHL, AMED, CISCOM, EMBASE and The Cochrane library from 1966 to the February 2007. Reference lists of identified articles and the authors' own files were also searched. Inclusion criteria were cases of human lead encephalopathy associated with traditional medical practices. There were no restrictions regarding the language of publication. Data were subsequently extracted and summarized in narrative and tabular form. We found 76 cases of lead encephalopathy potentially associated with traditional medicine. Ayurvedic medicines were associated with 5 cases (7%), Middle eastern traditional medicines with 66 cases (87%) and 5 cases (7%) with other traditional medicines. Of the 76 cases, 5% were in adults and 95% were in infants and young children. Of the 4 adult cases, at least one was left with residual neurological impairment. In infants and young children, among 72 cases 8 (11%) were fatal, and at least 15 (21%) had residual neurological deficits. Traditional medicine users should be screened for lead exposure and strongly encouraged to discontinue metal–containing remedies. Therefore, the United States Food and Drug Administration and corresponding agencies in other countries should require and enforce heavy metal testing for all imported traditional medicines and “dietary supplements”.
PMCID: PMC2538609  PMID: 18690981
Lead encephalopathy; traditional medicines; CAM; herbal medicines; folk medicine; herbal medicines
10.  Heavy Metal and Pesticide Content in Commonly Prescribed Individual Raw Chinese Herbal Medicines 
The Science of the total environment  2011;409(20):4297-4305.
Heavy metal and pesticide contamination has previously been reported in Chinese Herbal Medicines (CHMs), in some cases at potentially toxic levels. This study was conducted to determine general patterns and toxicological significance of heavy metal and pesticide contamination in a broad sample of raw CHMs. Three-hundred-thirty-four samples representing 126 species of CHMs were collected throughout China and examined for arsenic, cadmium, chromium, lead, and mercury. Of the total, 294 samples representing 112 species were also tested for 162 pesticides. At least 1 metal was detected in all 334 samples (100%) and 115 samples (34%) had detectable levels of all metals. Forty-two different pesticides were detected in 108 samples (36.7%), with 1 to 9 pesticides per sample. Contaminant levels were compared to toxicological reference values in the context of different exposure scenarios. According to a likely scenario of CHM consumption, only 3 samples (1%) with heavy metals and 14 samples (5%) with pesticides were found with concentrations that could contribute to elevated background levels of contaminant exposure. According to the most conservative scenario of CHM consumption, 231 samples (69%) with heavy metals and 81 samples (28%) with pesticides had contaminants that could contribute to elevated levels of exposure. Wild collected plants had higher contaminant levels than cultivated samples. Cadmium, chromium, lead, and chlorpyrifos contamination showed weak correlations with geographic location. Based on our assumptions of the likely mode of consumption of raw CHMs, the vast majority (95%) of the 334 samples in this study contained levels of heavy metals or pesticides that would be of negligible concern. However, given the number of samples with detectable contaminants and the range between the more likely and more conservative scenarios of contaminant exposure, more research and monitoring of heavy metals (especially cadmium and chromium) and pesticide residues (especially chlorpyrifos) in raw CHMs are advised.
PMCID: PMC3163780  PMID: 21824641
Traditional Chinese Medicine (TCM); heavy metals; pesticide residues; herbal products; exposure assessment
11.  Novel Metals and Metal Complexes as Platforms for Cancer Therapy 
Current pharmaceutical design  2010;16(16):1813-1825.
Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[PtII(NH3)2Cl2], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.
PMCID: PMC3759287  PMID: 20337575
Cancer; metal; zinc; copper; platinum; metal complex; DNA; proteasome
12.  Clawing Back: Broadening the Notion of Metal Chelators in Medicine 
The traditional notion of chelation therapy is the administration of a chemical agent to remove metals from the body. But formation of a metal-chelate can have biological ramifications that are much broader than metal elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. This review highlights recent examples that showcase four general strategies of using principles of metal chelation in medicinal contexts beyond the traditional notion of chelation therapy. These strategies include altering metal biodistribution, inhibiting specific metalloenzymes associated with disease, enhancing the reactivity of a metal complex to promote cytotoxicity, and conversely, passivating the reactivity of metals by site-activated chelation to prevent cytotoxicity.
PMCID: PMC3634900  PMID: 23332666
13.  Investigation of heavy metals in frequently utilized medicinal plants collected from environmentally diverse locations of north western India 
SpringerPlus  2013;2:676.
The increasing prevalence of environmental pollution, especially soil contamination with heavy metals has led to their uptake in the human food chains through plant parts. Accumulation and magnification of heavy metals in human tissues through consumption of herbal remedies can cause hazardous impacts on health. Therefore, chemical profiling of nine heavy metals (Mn, Cr, Pb, Fe, Cd, Co, Zn, Ni and Hg) was undertaken in stem and leaf samples of ten medicinal plants (Acacia nilotica, Bacopa monnieri, Commiphora wightii, Ficus religiosa, Glycyrrhiza glabra, Hemidesmus indicus, Salvadora oleoides, Terminalia bellirica, Terminalia chebula and Withania somnifera) collected from environmentally diverse regions of Haryana and Rajasthan states in North-Western India. Concentration of all heavy metals, except Cr, was within permissible limits in the tested stem and leaf samples. Leaf samples had consistently more Cr compared to respective stem samples with highest concentration in leaf samples of Bacopa monnieri (13.19 ± 0.0480 ppm) and stem samples of Withania somnifera (4.93 ± 0.0185 ppm) both collected from Bahadurgarh (heavy industrial area), Haryana. This amount was beyond the permissible limit of 2.0 ppm defined by WHO for raw herbal material. Other two most perilous metals Pb (2.64 ± 0.0260) and Cd (0.04 ± 0.0274) were also recorded in Bahadurgarh region, although below permissible limits. Concentration of Hg remained below detectable levels in all the leaf and stem samples tested. These results suggested that cultivation of medicinal plants and other dietary herbs should be curtailed near environmentally polluted especially industrial areas for avoidance of health hazards.
PMCID: PMC3877414  PMID: 24386622
AAS; Heavy metals; Herbal plants; Soil pollution; Toxicity
14.  The Contents of Heavy Metals (Cd, Cr, As, Pb, Ni, and Sn) in the Selected Commercial Yam Powder Products in South Korea 
Yam (Dioscorea) has long been used as foods and folk medicine with the approved positive effects for health promotion. Although consumption of yam products is increasing for health promotion, reports for the metal contamination in commercial yam powder products to protect the consumers are lacking. In this study, we aimed to assess whether the commercial yam powder products were heavy metal contaminated or not using the yam products from six commercial products from various places in South Korea. The contents of heavy metals (Cd, Cr, As, Pb, Ni, and Sn) in yam powder products were measured and compared to national and international food standard levels. Also, the metal contamination was monitored during the food manufacturing steps. The study results showed that the contents of heavy metals (Cd, Cr, As, and Pb) in yam powder products are similar to those in national ‘roots and tubers’ as well as in various crops. In comparison to three international standard levels (EU, Codex and Korea), Cd content in yam powder products was lower but Pb content was 5 times higher. Also, Pb, Ni, and Sn may have the potential to be contaminated during food manufacturing steps. In conclusion, the level of heavy metals (Cd, Cr, As, Ni, and Sn) except Pb is considered relatively safe on comparison to national and international food standard levels.
PMCID: PMC3925214  PMID: 24551826
Dioscorea; yam; heavy metals (Cd, Cr, As, Pb, Ni, and Sn); food safety
15.  Detecting metabolites of different transition metallithospermate B complexes after intravenous injection in rats 
Acta Pharmacologica Sinica  2014;35(7):937-944.
Lithospermate B (LSB) isolated from the traditional Chinese medicine danshen (Salvia miltiorrhiza) is an effective Na+/K+-ATPase inhibitor and used to treat congestive heart failure. The inhibition of LSB on Na+/K+-ATPase is potentiated by forming complexes with transition metal ions. Here we investigated the safety and metabolites of different transition metal-LSB complexes in rats.
LSB complexed with six different transition metal ions (Mg2+, Zn2+, Cr3+, Co2+, Ni2+ and Mn2+) were prepared. Adult male SD rats were injected with the different metal-LSB complexes (50 mg/kg, iv), and their bile and blood samples were collected. The metabolites of the metal-LSB complexes in the samples were analyzed using mass spectroscopy.
In rats injected with LSB complexed with Mg2+, Zn2+, Cr3+, Ni2+ or Mn2+, LSB and its four putative metabolites were equivalently detected in their bile samples. Mn2+-LSB exhibited distinct metabolite profiles compared with the other four metal-LSB complexes. The four putative metabolites were identified as 3-monomethyl-LSB, 3,3′′-dimethyl-LSB, 3,3′′′-dimethyl-LSB and 3,3′′,3′′′-trimethyl-LSB. The tracking of successive bile samples of rats injected with Mg2+-LSB, Zn2+-LSB and Mn2+-LSB concurrently demonstrated that LSB was firstly methylated at position 3, then at position 3′′, and, finally, the 3′′′ hydroxyl group. All rats injected with Co2+-LSB died.
Zn2+-LSB, Cr3+-LSB, Ni2+-LSB or Mn2+-LSB produces identical four methylated metabolites of LSB in rats, and seemed to be as safe as LSB or Mg2+-LSB.
PMCID: PMC4088287  PMID: 24989253
lithospermate B; transition metal complex; drug metabolism; metabolite; methylation; Na+/K+-ATPase inhibitor; danshen; traditional Chinese medicine
16.  ‘New Trends for Metal Complexes with Anticancer Activity’ 
Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selected delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in ‘metals in medicine’.
PMCID: PMC2923029  PMID: 18155674
17.  Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation 
Nucleic Acids Research  2011;39(18):8200-8212.
Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transition metal–and in particular platinum compound–DNA site selectivity in the nucleosome core, we establish that steric accessibility, which is controlled by specific structural parameters of the double helix, modulates initial guanine–metal bond formation. Moreover, DNA conformational features can be linked to both similarities and distinctions in platinum drug adduct formation between the naked and nucleosomal DNA states. Notably, structures that facilitate initial platinum–guanine bond formation can oppose cross-link generation, rationalizing the occurrence of long-lived therapeutically ineffective monofunctional adducts. These findings illuminate DNA structure-dependent reactivity and provide a novel framework for understanding metal–double helix interactions, which should facilitate the development of improved chromatin-targeting medicinal agents.
PMCID: PMC3185412  PMID: 21724603
18.  Antioxidant and anti-inflammatory activities of selected Chinese medicinal plants and their relation with antioxidant content 
The main aim of this study is to evaluate the antioxidant and anti-inflammatory properties of forty four traditional Chinese medicinal herbal extracts and to examine these activities in relation to their antioxidant content.
The antioxidant activities were investigated using DPPH radical scavenging method and yeast model. The anti-inflammatory properties of the herbal extracts were evaluated by measuring their ability to inhibit the production of nitric oxide and TNF-α in RAW 264.7 macrophages activated by LPS and IFN- γ, respectively. The cytotoxic effects of the herbal extracts were determined by Alomar Blue assay by measuring cell viability. In order to understand the variation of antioxidant activities of herbal extracts with their antioxidant contents, the total phenolics, total flavonoids and trace metal (Mg, Mn, Cu, Zn, Se and Mo) quantities were estimated and a correlation analysis was carried out.
Results of this study show that significant levels of phenolics, flavonoids and trace metal contents were found in Ligustrum lucidum, Paeonia suffuticosa, Salvia miltiorrhiza, Sanguisorba officinalis, Spatholobus suberectus, Tussilago farfara and Uncaria rhyncophylla, which correlated well with their antioxidant and anti-inflammatory activities. Some of the plants displayed high antioxidant and anti-inflammatory activities but contained low levels of phenolics and flavonoids. Interestingly, these plants contained significant levels of trace metals (such as Zn, Mg and Se) which are likely to be responsible for their activities.
The results indicate that the phenolics, flavonoids and trace metals play an important role in the antioxidant activities of medicinal plants. Many of the plants studied here have been identified as potential sources of new antioxidant compounds.
PMCID: PMC3534023  PMID: 23038995
Antioxidant activities; Anti-inflammatory properties; Phenolics; Flavonoids; Trace metals
19.  pH-Dependent Metal Ion Toxicity Influences the Antibacterial Activity of Two Natural Mineral Mixtures 
PLoS ONE  2010;5(3):e9456.
Recent studies have demonstrated that several mineral products sold for medicinal purposes demonstrate antimicrobial activity, but little is known about the physicochemical properties involved in antibacterial activity.
Methodology/Principal Findings
Using in vitro mineral suspension testing, we have identified two natural mineral mixtures, arbitrarily designated BY07 and CB07, with antibacterial activity against a broad-spectrum of bacterial pathogens. Mineral-derived aqueous leachates also exhibited antibacterial activity, revealing that chemical, not physical, mineral characteristics were responsible for the observed activity. The chemical properties essential for bactericidal activity against Escherichia coli were probed by testing antibacterial activity in the presence of metal chelators, the hydroxyl radical scavenger, thiourea, and varying pH levels. Chelation of the BY07 minerals with EDTA or desferrioxamine eliminated or reduced BY07 toxicity, respectively, suggesting a role of an acid-soluble metal species, particularly Fe3+ or other sequestered metal cations, in mineral toxicity. This conclusion was supported by NMR relaxation data, which indicated that BY07 and CB07 leachates contained higher concentrations of chemically accessible metal ions than leachates from non-bactericidal mineral samples.
We conclude that the acidic environment of the hydrated minerals significantly contributes to antibacterial activity by increasing the availability and toxicity of metal ions. These findings provide impetus for further investigation of the physiological effects of mineral products and their applications in complementary antibacterial therapies.
PMCID: PMC2830476  PMID: 20209160
20.  Therapeutic potentials of metals in ancient India: A review through Charaka Samhita 
The Ayurvedic system of medicine has stood the test of time for four millennia or more. The ancient seers found that drugs of different origin (herbal, metal or animal) in addition to codes of conduct and dietary regulations are suitable tools to maintain health in healthy and eradicating diseases in diseased. Use of metallic preparations in healthcare is a unique feature in this system. Processed metals including Mercury, Gold, Silver, Lead, Zinc, Copper etc. were used very frequently by seers of the Indian tradition in different disease conditions with great authority. It is generally claimed, that these metals are detoxified during the highly complex manufacturing processes described in Ayurvedic, especially Rasashastra texts. Charaka Samhita, one of the scheduled books of Ayurveda also holds ample of references regarding the use of metals for different purposes, which are summarized in the current paper.
PMCID: PMC3131772  PMID: 21760689
Ayurveda; Charaka Samhita; lead; mercury; metals
21.  Photoactivatable metal complexes: from theory to applications in biotechnology and medicine 
This short review highlights some of the exciting new experimental and theoretical developments in the field of photoactivatable metal complexes and their applications in biotechnology and medicine. The examples chosen are based on some of the presentations at the Royal Society Discussion Meeting in June 2012, many of which are featured in more detail in other articles in this issue. This is a young field. Even the photochemistry of well-known systems such as metal–carbonyl complexes is still being elucidated. Striking are the recent developments in theory and computation (e.g. time-dependent density functional theory) and in ultrafast-pulsed radiation techniques which allow photochemical reactions to be followed and their mechanisms to be revealed on picosecond/nanosecond time scales. Not only do some metal complexes (e.g. those of Ru and Ir) possess favourable emission properties which allow functional imaging of cells and tissues (e.g. DNA interactions), but metal complexes can also provide spatially controlled photorelease of bioactive small molecules (e.g. CO and NO)—a novel strategy for site-directed therapy. This extends to cancer therapy, where metal-based precursors offer the prospect of generating excited-state drugs with new mechanisms of action that complement and augment those of current organic photosensitizers.
PMCID: PMC3685452  PMID: 23776303
metal complexes; excited states; photochemistry; phototherapy; imaging; theory and computation
22.  OA01.02. Literary Study on Heavy Metal Poisoning and Ayurveda with Special Reference to Naga Bhasma (Calcined Lead) 
Ancient Science of Life  2012;32(Suppl 1):S2.
Bhasmas are unique Ayurvedic metallic preparations with herbal juices/fruits widely used for treatment of a variety of chronic ailments. The bhasmas are products of classical alchemy, organo-metallic compounds of certain metals and gems in a very fine powdered form, mostly oxides, made in elaborate calcination processes perfected several centuries ago. Recent articles pertaining the alarming level of heavy metals, especially Pb, Hg, and As in Ayurvedic formulations have created a lot of controversy regarding the safety and efficacy of Ayurvedic formulations. It has been reported that lead, mercury, and arsenic have been detected in a substantial proportion of Indian-manufactured traditional Ayurvedic medicines. An attempt was made to study heavy metal poisoning with special reference to current research on toxicity of Naga bhasma. This study clearly shows that Naga bhasma is not just lead, it's a compound form predominantly crystalline i.e. mixture of PbO Pb3O4. XRD data revealed OH and (CO3) 2 group which contain some other essential elements in minute quantity and didn’t have any toxic effect at LD50 which was 160 times higher to that of Therapeutic Equivalent Dose (TED) (12.5 mg/kg) in acute toxicity study.
PMCID: PMC3800896
23.  Canga biodiversity, a matter of mining 
Brazilian name canga refers to the ecosystems associated with superficial iron crusts typical for the Brazilian state of Minas Gerais (MG) and some parts of Amazon (Flona de Carajas). Iron stone is associated with mountain plateaux and so, in addition to high metal concentrations (particularly iron and manganese), canga ecosystems, as other rock outcrops, are characterized by isolation and environmental harshness. Canga inselbergs, all together, occupy no more than 200 km2 of area spread over thousands of km2 of the Iron Quadrangle (MG) and the Flona de Carajas, resulting in considerable beta biodiversity. Moreover, the presence of different microhabitats within the iron crust is associated with high alpha biodiversity. Hundreds of angiosperm species have been reported so far across remote canga inselbergs and different micro-habitats. Among these are endemics such as the cactus Arthrocereus glaziovii and the medicinal plant Pilocarpus microphyllus. Canga is also home to iron and manganese metallophytes; species that evolved to tolerate high metal concentrations. These are particularly interesting to study metal homeostasis as both iron and manganese are essential plant micro-elements. Besides being models for metal metabolism, metallophytes can be used for bio-remediation of metal contaminated sites, and as such are considered among priority species for canga restoration. “Biodiversity mining” is not the only mining business attracted to canga. Open cast iron mining generates as much as 5–6% of Brazilian gross domestic product and dialog between mining companies, government, society, and ecologists, enforced by legal regulation, is ongoing to find compromise for canga protection, and where mining is unavoidable for ecosystem restoration. Environmental factors that shaped canga vegetation, canga biodiversity, physiological mechanisms to play a role, and ways to protect and restore canga will be reviewed.
PMCID: PMC4241825  PMID: 25505476
canga; iron; ecosystem; endemism; restoration
24.  Proteomic Approaches in Understanding Action Mechanisms of Metal-Based Anticancer Drugs 
Metal-Based Drugs  2008;2008:716329.
Medicinal inorganic chemistry has been stimulating largely by the success of the anticancer drug, cisplatin. Various metal complexes are currently used as therapeutic agents (e.g., Pt, Au, and Ru) in the treatment of malignant diseases, including several types of cancers. Understanding the mechanism of action of these metal-based drugs is for the design of more effective drugs. Proteomic approaches combined with other biochemical methods can provide comprehensive understanding of responses that are involved in metal-based anticancer drugs-induced cell death, including insights into cytotoxic effects of metal-based anticancer drugs, correlation of protein alterations to drug targets, and prediction of drug resistance and toxicity. This information, when coupled with clinical data, can provide rational basses for the future design and modification of present used metal-based anticancer drugs.
PMCID: PMC2486358  PMID: 18670610
25.  Buyers Beware: Lead Poisoning due to Ayurvedic Medicine 
Journal of General Internal Medicine  2012;27(10):1384-1386.
A 29-year-old man, who recently emigrated from India, presented with a 2-week history of abdominal pain, as well as nausea, constipation, and fatigue. He underwent removal of a parathyroid adenoma 6 weeks prior to admission and received a locally made Indian traditional medicine (Ayurveda) for pain control; however, this information was not initially available. He was instructed to take approximately 15 g/day. Initial evaluation revealed a normocytic anemia, but other workup including imaging and endoscopy was unrevealing. Given his recent use of Ayurvedic medicines, we tested for lead poisoning and found a blood lead level of 72 mcg/dl. We sent his medicine for analysis and found it had a high lead concentration of 36,000 mcg/g, which is over 25,000 times the maximum daily dose. He improved with cessation of the medicine and treatment with succimer. Lead poisoning can present with a variety of nonspecific signs and symptoms, including abdominal pain and anemia. Ayurvedic medicines, as well as traditional medicines from other cultures, may be a source of lead or other heavy metals. It is essential for physicians to be aware of adverse effects of Ayurvedic medicines as they are easily available and increasing in popularity.
PMCID: PMC3445671  PMID: 22476953
dietary supplements; lead; India; medicine; Ayurvedic; Phytotherapy; plant extracts/chemistry

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