Heavy Metals

Radioactive Heavy Metals

The widespread production and use of radioactive heavy metals for nuclear generation of electricity, nuclear weapons, laboratory research, manufacturing, and medical diagnosis have generated unique problems in dealing with accidental poisoning by such metals. Because the toxicity of radioactive metals is almost entirely a consequence of ionizing radiation, the therapeutic objective following exposure is chelation of the metals and their removal from the body as rapidly and completely as possible. Treatment of the acute radiation syndrome is largely symptomatic. Attempts have been made to investigate the effectiveness of organic reducing agents, such as mercaptamine (cysteamine), administered to prevent the formation of free radicals success has been limited. Major products of a nuclear accident or the use of nuclear weapons include 239Pu, 137Cs, 144Ce, and 90Sr. Isotopes of Sr and Ra are extremely difficult to remove from the body with chelating agents. Several factors are involved in...

Heavy Metals

This test is provided to demonstrate that the content of metallic impurities that are colored by sulfide ion, under the specified test conditions, does not exceed the Heavy metals limit specified in the individual monograph in percentage (by weight) of lead in the test substance, as determined by concomitant visual comparison (see Visual Comparison in the section Determine the amount of heavy metals by Method I, unless otherwise specified in the individual monograph. Method I is used for substances that yield clear, colorless preparations under the specified test conditions. Method II is used for substances that do not yield clear, colorless preparations under the test conditions specified for Method I, or for substances that, by virtue of their complex nature, interfere with the precipitation of metals by sulfide ion, or for fixed and volatile oils. Method III, a wet-digestion method, is used only in those cases where neither Method I nor Method II can be used.

[2Halogenophenylmethyloxyalkyl1Himidazoles the econazolemiconazole family

Chemical stability of econazole and miconazole nitrates has been determined in the presence of benzoyl peroxide, 3.471 of miconazole base in vegetable oils, 3.472 in peritoneal fluid, 3.473 and as complexes of heavy metals. 3.474 Autoxidation products of econazole and miconazole have been characteri-zed. 3.475

Environmental Applications

Environmental samples studied by pyrolytic techniques encompass soil, water, and air. Although primarily studied for their possible role in soil fertility and stability, as discussed in the previous section, it is now recognised that humic substances play an important role in environmental problems because of their capacity for binding large amounts of organic and inorganic substances such as pesticide residues and heavy metals, which constitute potential environmental threats (ref. 189). A Curie-point Py-MS study of the organic fraction of river sludge samples from the Rhine delta, containing relatively high heavy metal concentrations, was recently reported by Van de Meent et al. (ref. 190). Although heavy metals appear to be effectively trapped by the strong chelating action of fulvic acids and other organic fractions, drastic changes in sediment pH or other physicochemical parameters might possibly lead to a sudden release of these metals into the environment. As a consequence,...

The Nature of Aquatic Pollution

Demonstration of endocrine dysfunction in fish taken from a polluted habitat, together with high tissue concentration of a chemical such as a PCB, does not demonstrate that the PCB is the cause of endocrine dysfunction. The high PCB level shows only that the fish is inhabiting a polluted habitat and reflects a potential tissue burden of other pollutants released by the same urban or industrial complex as the PCB. Only by exposing fish under controlled laboratory conditions to a single chemical can cause and effect be clearly established, and even then this may be the action of just one chemical in a vastly complex cocktail. The very high concentrations of heavy metals, PCBs, PAHs and pesticides in fish taken from the North Sea, the Baltic and the Great Lakes is simply a reflection of proximity to industrial, agricultural and urban outlets. Such fish have clearly defined endocrine disorders that may or may not be caused by the chemicals measured, but nevertheless they provide evidence...

Hypothalamic and Pituitary Abnormalities

The close neural relationship of the hypothalamus and the pituitary gland with the brain makes them particularly vulnerable to neurotoxins such as the organophosphate pesticides and the heavy metals lead and mercury. Although the numbers of studies on these tissues are few, reflecting their very small size and inaccessibility, there is clear evidence that both these heavy metals, and the organochlorine and carbamate pesticides, can damage the neurones of the hypothalamus which are responsible for GnRH release, leading to failure of ovaries and testes to produce yolky eggs and viable sperm. Organochlorine and organophosphate pesticides, cyanide, PAHs, PCBs, cadmium and mercury can all cause degeneration of the secretory cells of the pituitary gland and decrease its release of hormones.2 Industrial pollutants, such as paper mill effluents, can also affect the responsiveness of the pituitary to GnRH released by the hypothalamus.6 The feedback signal to the pituitary, which regulates...

Male Reproductive Problems in Fish

Abnormal function of the reproductive endocrine system in male and female fish can be caused by disruption of hypothalamic, pituitary or gonadal function, and by changes in the liver that affect the enzymes which deactivate steroid hormones. Both gonads and liver are fatty tissues and rapidly bioaccumulate both non-biodegradable organic pollutants and heavy metals such as mercury and cadmium that can be present at levels several orders of magnitude greater than in either the surrounding water or in muscle tissue. Endocrine dysfunction in the testis may be apparent by changes in its structure, its secretion of hormones, the activity of the enzymes that are necessary for steroid synthesis, the quality and quantity of the sperm produced and in the hormone dependent behaviour patterns of the male fish.

Testicular Structure and Hormones

Endocrine disruption can cause changes in cellular structure or organisation that are specific to the endocrine tissues rather than due to non-specific cytotoxic action. Clear evidence for endocrine disruption of the testis is apparent when its steroid producing cells show increased or decreased activity, the proportions of sperm at different stages of development differ from those of unexposed fish or there is a complete arrest in sperm production. Such changes may be a result of either primary action on the testis or secondary action consequent upon action at the hypothalamic-pituitary complex. Endocrine dysfunction may also result from specific toxic action on the testis owing to selective bioaccumulation so that the endocrine tissues are exposed to higher concentrations than other cells in the organism. There is evidence of such disruption of the male reproductive system following exposure to heavy metals such as arsenic, cadmium, copper, lead and mercury, the organochlorine...

Ovarian Structure and Hormones

The main factor causing the increase in ovarian weight during the reproductive development of fish is the deposition of yolk into the developing eggs. Abnormal development of the ovary, like the testis, can be caused by lack of stimulation by pituitary hormones, failure of steroid synthesis or direct cellular damage. The most commonly observed effect in the ovary is a decrease in the numbers of large yolky eggs together with increased numbers of immature oocytes, suggesting a primary effect on pituitary function. Such changes have been observed with heavy metals (arsenic, cadmium, lead, mercury), organochlorine (DDT, endosulfan, aldrin, chlordecone, y-BHC, methoxychlor), organophosphate (monocrotophos, fenthion, cythion, fenitrothion, phenthoate, malathion, chlorfenvinphos, tetrach-lorvinphos, mevinphos) and carbamate (carbaryl, carbofuran) pesticides. Among industrial chemicals, effects have been shown predominantly for PCBs and PAHs, and contaminated aquatic ecosystems such as those...

Carboxyethylgermanium sesquioxide

2-Carboxyethylgermanium sesquioxide (1) received much attention in the nineties. The biochemical significance of this crystalline structure consisting of Ge6O6 rings23 will become apparent in discussing organic germanium compounds' ability to scavenge free radicals, protect against radiation, enrich the body's oxygen supply and rid the body of heavy metals. The synthesis is carried out by hydrolysis of an organogermanium trichloride10

Potential Applications of Biosurfactant

Biosurfactants are becoming important biotechnology products for industrial and medical applications due to their specific modes of action, low toxicity, relative ease of preparation and widespread applicability.63-65 Biosurfactants also exhibit natural physiological roles in increasing bioavailability ofhydrophobic molecules and can complex with heavy metals, promoting improved degradation of chemical contaminants.66 They can be used as emulsifiers, de-emulsifiers, wetting and foaming agents, functional food ingredients and as detergents in petroleum, petrochemicals, environmental management, agrochemicals, foods and beverages, cosmetics and pharmaceuticals, commercial laundry detergents and in the mining and metallurgical industries.67-71

Gainoffunction Models

In studying the function of genes, where the (over)-expression induces a deleterious phenotype, e.g. early in development, it is necessary to be able to control the activity of that transgene. This can be achieved by using an inducible promoter. Two such promoters have been used extensively the mouse mammary tumour virus (MMTV) long terminal repeat, and the metallothionein promoter (for review see Palmiter and Brinster, 1986). The generally unpredictable tissue specificity and the relatively high basal level of expression have limited their use. In addition, the stimuli used, steroids or heavy metals, exhibit undesired side effects. More recent studies have identified cis-acting elements from several genes that respond to other physiological and environmental stimuli altering the carbohydrate and protein content of the diet can markedly alter the activity of the PEPCK promoter (McGrane et al., 1988) hypoxia induces the erythropoietin gene (Semenza et al., 1991) reduced temperature...

Vitamin E As An Antioxidant

Vitamin E is liposoluble and as such is mostly present in cell membranes and in low-density lipoproteins (LDL). Free radicals are created both in metabolic processes and as a result of environment pollution (e.g., superoxide, hydroxyl radicals, nitrogen dioxide, ozone, heavy metals, halogenated hydrocarbons, ionizing radiation, and cigarette smoke).

Copper Accumulating in the Body and Its Toxicity

Copper in the liver, kidneys, and other organs and tissues of the normal functioning body is present in nontoxic forms, bound mainly to Cu enzymes and, when in excess, to MT, an inducible low-molecular-weight protein rich in cysteinyl residues having a high capacity to bind heavy metals such as zinc (Zn), Cu, and cadmium (Cd) (13). On the other hand, Cu accumulating in the liver of Wilson's disease patients and its animal model, Long-Evans rats with a cinnamonlike coat color (LEC rats), is bound mainly to MT (Cu-MT and Cu,Zn-MT) because of the mutation of the transporter of Cu for the efflux of Cu, ATP7B (14-16). Monovalent Cu is a potent reducing agent and catalyzes one electron reduction of reactive oxygen species (i.e., reduces hydrogen peroxides to hydroxyl radicals by the Fenton reaction Fig. 2 ) (2325). The supply of monovalent Cu produces the reactive oxygen species in the medium, which is assumed to cause acute hepatitis in LEC rats, the animal model of Wilson's disease. The...

Treatment of patients with terminal kidney failure

Since then, the quality of hemodialysis membranes has improved and the present high flux membranes are superior to the standard dialysis membrane in removing the larger middle molecules. Even then, the clearance is still much less than compared to the better hemoperfusion devices. Hemoperfusion devices are usually manufactured by manufacturers of hemodialysis machines and membranes. In those countries with strong hemodialysis companies, the hemoperfusion devices are extremely expensive. On the other hand, in those countries with no large dialysis industries, hemoperfusion devices are not expensive and therefore continued to be used in renal failure patients. In all the countries, hemoperfusion continues to be commonly used for uremic patients with aluminium or iron overload. This is based on the earlier clinical demonstration of the use of deferoxamine to bind these heavy metals and of hemoperfusion to remove the complex (Chang and Barre, 1983 Chang, 1986d...

Other Suggested Mechanisms For

Epidemiological studies indicate that there is an increasing incidence of ALS, which would imply that environmental agents are important. However, ALS triggering by specific toxic agents such as contamination of drinking water and poisoning by heavy metals has never been satisfactorily proven.

Mammalian Copperiron Link

In mammals at a whole-body level, copper absorption from the small intestine is, to some extent, regulated, with increased uptake when the animal is copper deficient and decreased uptake when the diet is adequate in copper (82). Details of the molecular mechanisms regulating absorption remain to be elucidated. The control of copper excretion, which is also an important part of the protection against excess copper exposure, is regulated by the liver, with excess copper being disposed of through the bile (83). Within the cell, excess copper is detoxified by at least two mechanisms sequestration by metal-binding proteins such as metallothioneins (MT) and enhanced export by the copper ATPases, MNK, and WND (84). Although a definitive biological role for MTs remains elusive despite years of research, MTs are known to be small cysteine-rich proteins that bind heavy metals, including copper, zinc, and cadmium, through cysteine thiolates (85,86). There are l7 genes encoding four isoforms of...

Factors influencing mineral contents in seaweed

Unfortunately, higher amounts of some minerals in seaweed have been the result of pollution of the seawater or natural environment. Thus, many studies were conducted with respect to the contamination of seaweed by heavy metals. Because of their high sorption capacity, they were also probed for their utilization as biosorbents to remove heavy metals from the environment and to elucidate mechanisms of metal biosorption by seaweeds (Davis et al., 2003 Murphy et al., 2008 Suzuki et al., 2005). Further, these conclusions could be utilized for the understanding of the uptake mechanisms by seaweed. Finally, endogenous and exogenous factors have participated on the variability of seaweed mineral composition. Chojnacka, 2010). On the contrary, Baumann et al. (2009) observed higher affinity of a red seaweed Palmaria palmata to accumulate heavy metals Cd and Cr than those of brown seaweeds. Different affinity of metals to various seaweed compounds also results in the variability of mineral...

Lflvkkpdgtipgyephehggataksgesge P Tggaaahe H E H

This protein consists of 310 amino acids. The C-terminal domain is rich in cysteines (23 out of 68 amino acids) and has a similarity to metallothioneins. The amino-terminal domain does not show significant similarity to proteins in the databases. The protein has been described first for S. albogriseolus as a putative repressor of the expression of an extracellular protease (79). Metallothioneins are small proteins (68 amino acids) that bind heavy metals such as Cu, Zn, Cd, and

Definition of the Endocrine Disruption Hypothesis

Anthropogenic chemicals, such as pesticides, surfactants, industrial compounds, and heavy metals are widely distributed throughout the planet 1216 . Given the interaction between the nervous, endocrine, and immune systems 17 , and the ability of many of these compounds effectively to mimic, inhibit, or block the actions of native hormones and other signaling systems, there is concern for wildlife, domestic-animal, and human health 3,10 .

Gonad Hormone Production

Other steroid synthetic pathways in other organs can also be affected, as plasma cortisol concentrations were suppressed in BKME-exposed fish from Jackfish Bay subjected to stress during sampling 54 . Fish exposed to environments contaminated with polycyclic aromatic hydrocarbons (PAHs), polychlo-rinated biphenyls (PCBs), or heavy metals also show a suppressed stress response as measured by plasma cortisol concentrations 54,55 . In contrast, fish exposed to pesticides can exhibit an augmented stress response and elevated plasma cortisol concentrations compared to reference fish (Orlando, Binczik, Kroll, and Guillette, unpublished data). Likewise, alligators living in a pesticide-contaminated lake exhibit similar basal concentrations of corticosterone 47 but show a more rapid response to stressful stimuli when compared to reference animals 56 .

Receptors in Brain Gonad and Liver Hormone Action

Most research in the field of endocrine disruption has focused on xenobi-otics that mimic estrogens, although more recently some research has been carried out on environmental androgens, antiandrogens, and antiestrogens. Environmental xenobiotic compounds such as pesticides, surfactants from detergents, industrial waste, sewage treatment plant effluent, paper mill effluent, heavy metals, and phytosterols have been shown to be estrogenic 71 . Certain fungicides, such as the metabolites of vinclozolin, have been identified as an-tiandrogens in rats. Interestingly, metabolites of other compounds can have very different receptor-binding affinity from the parent compound. For example, o,p'-DDT is a known estrogen agonist, and one of its metabolites p,p'-DDE is antiandrogenic in rodents 72 .

Other Hormone Axes and Possible Levels of Disruption

As an example, the stress axis is known to affect the reproductive and growth axes in fish. Increases in stress hormones are associated with impaired reproductive function and decreases in growth rate 39 . There is still a great deal of research needed to understand the normal endocrine mechanisms involved in these relationships. Recently, glucocorticoid receptors were immunolocalized in the neurons in the part of the brain associated with the control of reproduction and the pituitary of rainbow trout (Oncorhynchus mykiss) 104 . This research suggests a mechanistic connection between stress hormones and the brain-level control of reproductive steroid hormones. A few studies have examined the modulation of the stress axis in fish by xenobiotics such as paper mill effluent and PCBs and heavy metals 54,55,105 . Even fewer studies have been implemented to look at the possible effects of the stress response on reproductive steroid hormones of contaminant-exposed fish 54 . Given the...

Heavymetal Antagonists

The effectiveness of a chelating agent for the treatment of poisoning by a heavy metal depends on numerous factors the relative affinity of the chelator for the heavy metal as compared with essential body metals, the distribution of the chelator in the body as compared with the distribution of the metal, and the capacity of the chelator to remove the metal from the body once chelated. Consider the properties of an ideal chelating agent high solubility in water, resistance to biotransformation, ability to reach sites of metal storage, capacity to form nontoxic complexes with toxic metals, ability to retain chelating activity at the pH of body fluids, and ready excretion of the chelate. A low affinity for Ca2+ also is desirable because Ca2+ in plasma is readily available for chelation, and a drug might produce hypocalcemia despite high affinity for heavy metals. A therapeutic chelating agent must bind the metal more avidly than endogenous ligands bind the metal. The large number of...

Regulatory Disulfides Controlling Transcription Factor Activity in the Bacterial and Yeast Responses to Oxidative Stress

Oxidative stress has been defined as a disturbance in the prooxidant-antioxidant balance in favor of prooxidants.40 Thus oxidative stress can result from increased levels of reactive oxygen species such as superoxide anion (02* ), hydrogen peroxide (H202), hydroxyl radical (HO*) and alkyl hydroperoxides (ROOH). Reactive oxygen species are byproducts of normal metabolic processes but elevated levels of these prooxidants can be generated by environmental factors such as ionizing radiation, heavy metals or other redox-active chemicals such as the 02* generating compound menadione. If allowed to accumulate unchecked these molecules exceed the normal antioxidant buffering capacity of the cell leading to indiscriminate damage to cellular components including DNA, proteins and lipids. Cells also may experience oxidative stress resulting from a drop in the thiol disulfide ratio within the cytosol or within an organelle. This drop in the thiol disulfide ratio can occur under certain growth...

How Can I Use Glyco-a Antiminth

The antidotal properties of BAL are associated with the property of heavy metals to react with sulfhydryl (SH) groups in proteins (e.g., the enzyme pyruvate oxidase) and interfere with their normal function. 1,2-Dithiol compounds such as BAL compete effectively with such proteins for the metal by reversibly forming metal ring compounds of the following type

Coupled Or Auxiliary Enzyme Assays

(a) Heavy metals Although the labels on many so-called reagent-grade chemicals, such as sodium phosphate, boast that they contain only 2-5 parts per million of heavy metals like lead, a 0.1 M sodium phosphate buffer would contain upwards of 1 mM heavy metal ions. Given the fact that many heavy metals for extremely tight complexes with proteins (Kd 10-30 pM), 1 mM heavy metal ion concentrations are very high.

Halogen Containing Compounds In Local Anti Infective Agents

Leuco Compound Crystal Violet

Until the 1920s, most successful anti-infective agents were based on the group-IIB element mercury and the group-VA elements arsenic and antimony. Atoxyl (sodium arsanilate and arsphenamine) was used for sleeping sickness.4 Certain dyes, such as gentian violet and methylene blue, were also found to be somewhat effective, as were a few chemical congeners of the quinine molecule. Some of these agents represented significant achievements in anti-infective therapy, but they also possessed some important limitations. Heavy metal toxicity after treatment with mercury, arsenic, and antimony severely limited the usefulness of agents containing these elements.

Potential Of Seaweeds As A Source To Develop Functional Foods

The free amino-acid fraction of seaweed is a mixture of amino acids and is mainly composed of taurine, alanine, amino butyric acid, omithine, citrulline, and hydroxyproline (Holdt and Kraan, 2011). Taurine is an amino acid present in high concentration in red algae. It also acts as an antioxidant and protects against toxicity of various heavy metals such as lead and cadmium by preventing their absorption in the stomach. Taurine has been shown to be effective in reducing the secretion of serum lipids and apolipoprotein B100, a structural component of low density lipoproteins, thereby reducing the risk of atherosclerosis and coronary heart disease. These finding have been followed and supported by several other research reports that taurine supplementation exerted a hypocho-lesterolemic effect in young overweight adults. Taurine has also shown its capability to relieve complications in people with congestive heart failure by increasing the force and effectiveness of heart-muscle...

Role Of Free Radicals In Brain Disease A Schizophrenia

The intake of excessive levels of heavy metals including iron is a risk factor for Parkinson's disease (31). In India the vegetarian Hindus have a much lower prevalence of Parkinson's disease than the meat-eating Parsees (56). One source of iron in the diet is the heme from myoglobin. Iron adsorption is inhibited by the polyphenols present in spices of which the Hindus eat a large amount. In Parkinson's disease the glia have raised levels of heme oxygenase-1. This enzyme catalyzes heme breakdown to biliverdin and produces CO and free iron as byproducts. Lewy bodies, which consist of cross-linked neurofilaments, also have greatly raised levels of this enzyme (76). There is also evidence of excess dopamine quinone formation (15,49), which correlates with the fact that the cells that are destroyed in the disease are those that contain neuromelanin, which is the end-product of dopamine quinone metabolism. Neuromelanin is normally neuroprotective as it chelates large amounts of toxic heavy...

Classification and Distribution of Plastids

Occur also in cells engaged in the secretion of different substances, in senescent leaves, in the leaves during their regreening, in early phases of plastid development in tissue cultures, in the actinorhizal root nodules, and in degenerated leaves after the effect of herbicides, antibiotics, and heavy metals 11,19, 21-25 . These findings indicate that formation of pleomorphic plastids is a metabolic response induced by environmental factors. The presence of ameboid plastids contributes to the structural heterogeneity in plastid population.

Exceptions To The Rules

Normally, one would not consider a silver compound such as silver sulfadiazine (Fig. 2.8) as a drug candidate, owing to the potential for heavy metal poisoning. Indeed, the toxicity of silver sulfadiazine is the key to its usefulness as an antimicrobial. However, this compound is administered only topically as Silvadene Cream 1 . Because of the topical application, very little of the compound enters the body. This makes it useful for the treatment of wound sepsis in patients with second- and third-degree burns. This illustrates that researchers should keep the application in mind when determining what molecular properties can be considered drug-like.

Abnormal Thyroid Activity

Many pollutants increase the activity of the adrenal gland of fish as a result of their action as irritants or of their inhibition of the respiratory function of the gills. It is important to recognise that these changes are simply a normal stress response and differ little from that which occurs in a fish subject to capture or attack by a predator. Similarly, xenobiotic induced changes in the gills may lead to an imbalance in mineral or water balance and the observed hormonal changes are simply a natural effort to restore equilibrium, while failure to do so may cause a stress response. These effects cannot be considered as endocrine disruption since the primary site of action is not disruption of the endocrine system. Measurement of basal levels of stress hormones are in fact very difficult since capture of the fish almost inevitably involves stress. This, however, provides a good method for determining whether there is endocrine disruption of the adrenal gland since impairment of...

Cys 434 S

However, these are unusual, specialized structures. Artificially, though, a whole series of metals have been incorporated into man-made or naturally occurring 3Fe clusters.37,41 These turned out to be useful materials for exploring the electronic structure of Fe-S clusters, because it was possible to incorporate non-magnetic metals. Why are such clusters not found in nature An answer was proposed by Armstrong and Williams 5 They argued that heavy metals are known not to float around freely in tissue they are carefully guided and chaperoned by special proteins. Thus, metals like Zn, for instance, or Cd, which are known to have, in vitro, a higher affinity for the 3Fe cluster than Fe,22 are bound so tightly to their chaperones that is, in this example, metallothionein for Zn and Cd that they cannot compete with Fe for the 3Fe cluster. For instance, it was determined that the 3Fe cluster of aconitase competes for Fe2+ with some success even with EDTA the formation constant for the iron...

Alginate

The alginates are binding agents that absorb toxic heavy metals and radioactive isotopes from the body by binding with them in the gastrointestinal tract when they are present in the bile. It operates as a pump, pumping out heavy metals and other toxins. It is suggested that if L. jap nica is consumed on a regular basis for at least 4 months, levels of dangerous metals like mercury, lead, and aluminum can be significantly reduced. Alginate also prevents a person from harmful impact of

Conclusion

Both inorganic and chelated vanadium compounds have been demonstrated by a great many in vitro and in vivo observations to have insulin-mimetic activity. Vanadium compounds have been used to improve STZ-induced IDDM in experimental animals, and vanadyl sulphate has been shown to improve human NIDDM.59,60 This encourages researchers in the field of vanadium chemistry, biochemistry and physiology to investigate this important issue. Despite the potential of vanadium compounds in the oral treatment of both types of diabetes, only one compound, the VO(IV) maltolato complex, has been introduced in clinical tests on humans.7 There are several reasons why pharmaceutical companies have so far shown only marginal interest in vanadium compounds for the treatment of diabetes. Among the obvious reasons is the toxicity of vanadium compounds. There is a general feeling that drugs containing heavy metals will not be accepted by the market (cf. gold and platinum complexes in practical use in...

Conclusions

Despite many reported toxic effects and drug interactions resulting from the use of alternative medicines, they remain popular and most users consider them safe. Labeling of herbal products may not accurately reflect their content, and adverse events or interactions attributed to a specific herb may be due to misidentification of the plant or contamination of the plant with pharmaceuticals or heavy metals. The addition of pharmaceuticals to Chinese herbal products is a serious problem. Of 2069 samples of traditional Chinese medicines collected from eight hospitals in Taiwan, 23.7 contained pharmaceuticals, including caffeine, acetaminophen, indomethecin, hydrochlorothiazide and prednisolone.108,109 A fatal case of hepatic failure due to contamination of a herbal supplement with nitrosofen-fluramine has been reported. Analysis of the herbal supplement also revealed the presence of fenfluramine.110 Cole and Fetrow reported the presence of colchicine in gingko biloba and echinacea...

Chloride And Sulfate

Where the individual monograph calls for applying the test to a specific volume of a solution of the substance, and the limit for chloride or sulfate corresponds to 0.20 mL or less of 0.020 N hydrochloric acid or sulfuric acid, respectively, apply the test to the solution without further dilution. In such cases maintain the same volume relationships for the control solution as specified for the solution under test. In applying the test to the salts of heavy metals, which normally show an acid reaction, omit the acidification and do not neutralize the solution. Dissolve bismuth salts in a few mL of water and 2 mL of nitric acid before treating with the precipitant.

Purity

A key component of analytical development is purity determination, which is the actual percentage of the sample, usually by weight, that can be attributed to the drug. This is a simple calculation of weight of drug divided by total weight of drug plus other impurities (x100). Impurities however can range through organic impurities (synthetic intermediates, by-products, related impurities, and degradation products detected by separative quantification techniques), inorganic impurities (heavy metals, salts, and catalysts detected by pharmacopoeial or other methods), and residual solvents (quantified through gas chromatographic methods). The difficulty is that each necessitates the development of specific validated analytical techniques. Also of importance is enantiomeric purity, if the drug is chiral, and polymorphic purity, as discussed below.

Fro2 Fro2

Chlamydomonas does not seem to have genetic information for metallothioneins and probably uses only phytochelatins for detoxification of copper, cadmium, mercury, and other heavy metals (159-161), although it is possible that the metallothioneins of Chlamydomonas have not yet been discovered. Perhaps genomics will provide the answer to this question.

Copper Ion Transport

Several studies have demonstrated a high conservation among copper homeostasis mechanisms in insects and mammals. First, copper appears to be concentrated in specific neurons in the insect CNS (including OAergic neurons) as revealed by a sulphide silver stain for heavy metals 139 . Second, three distinct Drosophila Ctr genes have been identified (CtrA, B, and C) and all three gene products have several structural features in common with other Ctr proteins, including three membrane-spanning domains, a hydrophilic methionine-rich amino terminus, and a Met-Z3-Met motif found in the second transmembrane domain 140 . Recently, another putative symport divalent metal ion transporter has been identified in Drosophila that shares several functional features with Ctr1 proteins 141 . Interestingly,

Selenium

Selenium is an element of fundamental importance to human health. Depending on its chemical form and total concentration, it may exhibit essential or toxic effects with a very narrow tolerance band.112 Thus, the recommended selenium reference nutrient intake (RNI) is 75 and 60 mg day-1 for adult males and females, respectively.113 According to the UK Department of Health, an intake of 750-900 mg is toxic and the maximum safe intake is 450 mg day-1 for adult males.114 The specific biological role of selenium is not fully understood. However, selenocysteine has been characterized as the 21st proteinogenic amino acid, which forms an active center of a number of proteins (selenoenzymes include glutathione peroxidase, iodothyronine deiodinase and thioredoxine reductase and seleno-protein P, among others).112,115,116 Experimental evidence exists on selenium bioactivity in cancer prevention.117,118 The ability of the element to reduce toxic effects of heavy metals

Oxidation

The expression of both gshl and gsh2 is enhanced in the presence of heavy metals such as cadmium and copper,50 and by the application of jasmonic acid. By contrast expression is not modified by either GSH or GSSG,50 or by the oxidative stress imposed by the application of H202. However, oxidative stress appears to be essential for the translation of the gshl and gsh2 transcripts in stress conditions. This has led to the concept that post-transcriptional regulation gshi and gshl transcripts provides an additional level of control of GSH synthesis49 In this scenario H202 (or low GSH GSSG ratios) enhances translation of the existing gshl and gsh2 transcripts.47 Studies in other systems such as cancer cells have shown that transcription of the y-ECS gene is regulated by protein factors when the cells are challenged with chemotherapeutic agents. This involves conserved antioxidant response elements upstream of the coding y-ECS sequence. In untransformed plants the dipeptide produced by the...

Trityl1Himidazoles

Clotrimazole displays activity against Gram-negative microorganisms such as Legio-nella. 2.316 The detection of trypanocidal activity in the complex RuCl2(clotrima-zole)2 has given hope for a new remedy for Chagas disease, endemic in South Ame-rica. 2.420 This observation stresses the importance of the stability constants of complexes of clotrimazole and other standard antimycotics with heavy metals. 2.421

Dimercaprol

Arsenicals and other heavy metals form a very stable and relatively nontoxic chelate ring with the dimercaprol. It is an oily fluid with a pungent, disagreeable odor typical of mercaptans. Because of its instability in aqueous solutions, peanut oil is the solvent employed in pharmaceutical preparations. Dimercaprol and related thiols are readily oxidized.

Genitourinary Tract

Telenzepine is an analog of pirenzepine that has higher potency and similar selectivity for Mj muscarinic receptors. Both drugs are used in the treatment of acid-peptic disease in Europe, Japan, and Canada, but not currently in the U.S. At therapeutic doses of pirenzepine, the incidence of dry mouth, blurred vision, and central muscarinic disturbances are relatively low. Central effects are not seen because of the drug's limited penetration into the CNS. Pirenzepine's relative selectivity for Mj receptors is a marked improvement over atropine. Pirenzepine (100-150 mg day) produces about the same rate of healing of duodenal and gastric ulcers as the H2 antagonists cimetidine or ran-itidine. Side effects necessitate drug withdrawal in

Gsf Lichtmannegger

Menkes disease is a recessive, X-linked neurodegenerative disease that occurs in approx 1 in 200,000 live births. The affected males manifest a systemic Cu deficiency due to malabsorption caused by a defect in the Menkes (ATP7A) gene, designated MNK, which encodes a transmembrane Cu-transporting P-type ATPase that functions to export dietary Cu from the gastrointestinal tract. Based on homology to known P-type ATPases, the MNK gene product is highly evolutionarily conserved. Copper export from the gastrointestinal tract is activated upon the binding of Cu(I) to the six metal-binding repeats in the amino-terminal domain of the Menkes protein. Each of the Menkes protein amino-terminal repeats contains a conserved -X-Met-X-Cys-X-X-Cys- motif (where X is any amino acid). Such metal-binding repeats are conserved in other cation-exporting ATPases involved in metal metabolism and in proteins, such as metallothionein, involved in cellular defense against heavy metals intoxication. Owing to...

Cisca Wijmenga

Copper is one of the essential heavy metals in the life of all organisms, including man it plays an essential role in cellular respiration, free-radical defense, neurotransmitter function, connective tissue biosynthesis, and cellular iron metabolism (1). Because copper is a necessary metal, it is important that the daily intake of copper in the diet is sufficiently high to maintain these essential functions. The normal human body contains between 70 and 100 mg of copper. Some 15 of the copper taken

Future Directions

And this leads directly to a third need better models. Giving 6-OHDA to young rats, no matter what the protocol, will only get us so far. The approach has been extremely fruitful, as I hope this brief review has shown, but much more is needed. We need older animals (24 month old rodents, 20 year old non-human primates), even more progressive models (many months for rodents several years for primates), toxins that are more relevant to what might be causing PD (pesticides, heavy metals, industrial pollutants), and genetic models, including conditional models, that more completely emulate the pathophysiology of the disease see reviews 44,169,170,171 .