J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 Inorganics/bioinorganics: Biological, medicinal and pharmaceutical uses
Bhupinder Singh Sekhon
PCTE Institute of Pharmacy, near Baddowal Cantt, Ludhiana 142 021, India. Email:[email protected] Received May 06, 2011; Accepted May 22, 2011 ABSTRACT
Metal ions function in numerous metalloenzymes, are incorporated into pharmaceuticals and imaging agents.
Several target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer
radiotherapy were developed. Transition metal complexes containing radioactive isotopes have found widespread
use as radiopharmaceuticals in diagnostic nuclear medicine. Metal ions and metal complexes in clinical use
today include diagnostic (radiopharmaceuticals and MRI contrast agents) and therapeutic compounds (cancer,
inflammation, ulcer, arthritis, antibiotics, and chelation therapy). A number of drugs contain metal ions as
essential components such as Pt complexes (anticancer drugs); Fe-bleomycin(anticancer drug); Cu complexes(anti-
inflammatory and anticancer drugs); Zn complexes (topical antibiotics); Au complexes( anti-arthritis, experimental
anticancer drugs); Tc complexes(radioimaging); Gd and Mn complexes (MRI contrast agents); Chelators(treatment
of chronic and acute toxic metal overloads, e.g. Deferoxamine for iron overload); bismuth compounds(antiulcer);
samarium-based compounds (relief of bone pain in intractable cancer), and lanthanum carbonate(treatment of
hyperphosphatemia). Zinc finger proteins offer a potential better route to gene therapy. Ceramics are employed
in a wide range in the medical and dental applications.

Keywords: Metal ions, metal complexes, chelates, therapeutics, inorganics, ceramics, radiopharmaceuticals. metallodrugs,
and Zinc has been reported. Citrate was used for acutelead intoxication in 1941, and since than other chelating The use and significance of inorganic compounds had agents has come into clinical use. Inorganic elements being been invaluable to the medical field. Egyptians used Cu the basic building blocks of our lives are involved in all to sterilize water (3000 BC) and Chinese empire used Au life processes and have been recognized as beneficial in a variety of medicine (2500BC). Hippocrates, and useful in the medical field 4. Scientists believe that considered being the father of medical science (~400 about 26 (both metals and non-metals) of the known 118 BC) described about metal bands wound around teeth in elements in the Periodic Table of Elements are essential effort to straighten them, and mummified remains have to life. [H, C, N , O - 96%]; [ Na, Mg, P, S, Cl, K, Ca - been discovered with metal bands still attached to 3.5%]; [B, Cr, Co, Cu, F, I, Fe, Mn, Mo, Ni, Se, Si, Sn, V, individual teeth, possibly torqued into place using catgut.
Zn - 0.5% ( silicon, nickel, boron, and vanadium may have Hippocrates (~400 BC) used copper to treat leg ulcers some beneficial effects at low levels of exposure).
associated with varicose veins and also used mercury,Paracelsus pioneered the use of minerals in medicine using Biological inorganic chemistry is an interdisciplinary Sb, As, Mg salt (1600s); metals started making an impact subject at the interface of inorganic chemistry and biology/ on modern medicine, K[Au(CN) ] used for tuberculosis, biochemistry. Medicinal inorganic chemistry includes the Salvarsan for the treatment of syphilis (Early 1900s) 1,2.
study of both non-essential and essential elements with Various minerals, metals, clays, and rocks were among applications to diagnosis and therapies. The introduction the natural medicinal substances used by physicians and of metals/metal complexes into biological systems as pharmacists in early times in different cultures, for probes and drugs, and the investigations of inorganic example, the ancient civilizations of Egypt and elements in processes e.g. nutrition, the toxicity of Mesopotamia 3. The evidences of the medicinal uses of inorganic species, including the ways in which such fifteen inorganic substances: Alum, Arsenic, Sulphide, toxicities are overcome both by natural systems and by Asphalt, Jew’s stone, Earth sp., Galena, Haematite, iron, human intervention, and of metal-ion transport and storage Lead, Pyrite, Salt, Sulphur, Thermal water, Green Vitriol, in biology are among major areas of biological inorganic J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 chemistry. The use of metals in medicine involves i) metal- and phosphorus to function properly. Despite extreme based drugs, ii) non-invasive radiopharmaceuticals, iii) toxicity at high concentration, low concentration of carbon Magnetic Resonance Imaging , and iv) mineral monoxide (CO) can confer cytoprotection during ischemia/ reperfusion or inflammation-induced tissue injury.
Likewise, heme oxygenase, an enzyme that produces CO, Medicinal inorganic chemistry can be divided into two biliverdin and iron, as well as a secondary increase in main categories, (i) drugs that target metal ions (free or ferritin synthesis, from the oxidation of heme, can confer protein-bound), and (ii) metal-based drugs where the protection in vivo and in vitro. CO has been shown to central metal ion is usually the key feature of the affect several intracellular signaling pathways, including mechanism of action 6-8. Metal-based and metal-binding guanylate cyclase, which generates guanosine 3':5' cyclic agents are used for design of inorganic drugs. In area of monophosphate and the mitogen-activated protein kinases.
metallotherapeutics, three widely used inorganic Such pathways mediate, in part, the known vasoregulatory, pharmaceuticals include: i) Platinum anticancer drugs anti-inflammatory, anti-apoptotic and anti-proliferative (cisplatin and carboplatin), ii) Gold antiarthritic drugs effects of this gas. Exogenous CO delivered at low (Auranofin), iii) Radiodiagnostic and radiopharmaceutical concentrations is showing therapeutic potential as an anti- drugs (Cardiolyte – a heart imaging agent, a +vly charged inflammatory agent and as such can modulate numerous pathophysiological states 20. CO can provide beneficial Pharmaceutical chemistry is a discipline at the antiapoptotic and anti-inflammatory effects in the context intersection of chemistry, pharmacology, and biology of ischemia-reperfusion injury (IRI) 21. During IRI, involved with designing, synthesizing and developing endogenous CO is generated from heme degradation pharmaceutical drugs. Inorganic compounds and through heme oxygenase-1 activity 22. This pathway has organometallic compounds have many interesting been identified as a natural powerful cytoprotective applications. Many metallodrugs are “prodrugs” they mechanism 23. CO-releasing molecules (CORMs) have undergo ligand substitution and/or redox reactions before been shown to counteract numerous inflammatory they reach the target site. Metallopharmaceuticals used conditions such as sepsis and coronary ischemia 24-27.
as anticancer agents, metal-mediated antibiotics, CORM-2-derived CO protects renal transplants from antibacterials, antivirals, antiparasitics, antiarthritics, and ischemia–reperfusion injury by modulating inflammation radiosensitizing agents have been reported 10-13.
Biological inorganic chemistry is a very hot area and Boric acid is a topical astringent, mild disinfectant the functional roles of selected biological inorganic and eye wash. Sodium borate is used in cold creams, eye elements include: charge balance and electrolytic washes and mouth rinses. Boron compounds are used to conductivity (Na, K, Cl); structure and templating (Ca, enhance the cell selectivity of radiation therapy. The first Zn, Si, S); signaling ( Ca, B, NO); Bronstead acid-base boron-containing approved drug – Velcade(aliphatic buffering (P, Si, CO; Lewis acid-base catalysis (Zn, Fe, boronic acid) for multiple myeloma, inhibits protease Ni, Mn); electron transfer (Fe, Cu); group transfer such enzymes 29. Anacor launched Phase III clinical trials in
as CH , O, S(V, Fe, Co, Ni, Cu, Mo, W); redox catalysis December 2010 for one of its boron-containing (V, Mn, Fe, Co, Ni, Cu, W, S, Se); energy storage (H, P, S, Na, K, Fe) and biomineralization (Ca, Mg, Fe, Si, Sr, Boron-containing two-photon-absorbing fluorophores showed efficient fluorescence in an organic solvent, as Non-metals
well as in water, allowing microscopy on cell cultures 31.
Boron-containing polyether-macrolide antibiotic, Carbon is perhaps the single most important element boromycin was isolated as a potent anti-HIV agent 32.
to life and virtually every part of our bodies is made with Oxaboroles have excellent potential as novel antimalarial large amounts of carbon. Moreover, the carbon atom is agents. AN3661 has been identified as a promising new ideal to build big biological molecules. Our body also need antimalarial drug candidate belonging to a new class of boron in very small amounts to allow calcium, magnesium J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 oxaboroles from Anacor’s boron chemistry platform as a therapeutic gas in the treatment of conditions involving hypoxia. Fluorine is found in teeth and bonesand helps preventing tooth decay. Fluorine has become Hydrogen and oxygen being components of water an essential tool in drug discovery as fluorine atoms in are incredibly important in our bodies. Stomach acid potential medicines can have a variety of dramatic effects (hydrochloric acid) is a compound of hydrogen and on the molecules’ properties. About a fifth of all drugs on chlorine. Also, hydrogen is practically always bound to the market today contain at least one fluorine substituent.
the carbon that our bodies are constructed of. People Blockbuster medicine such as Pfizer’s lipid lowering agent need to breathe oxygen to survive. Nitrogen plays an Lipitor (atorvastatin), TAP Pharmaceuticals proton pump important role in digestion of food and growth. Nitrous inhibitor Prevacid (lansoprazole) and the fluticasone oxide has remained one of the most widely used component of GlaxoSmithKline’s antiasthma combination anesthetics in both dental and medical applications 34.
product Seretide contain fluorine substituents 41.
Entonox (a mix of nitrous oxide 50% and oxygen 50%) isa safe and effective preparation that is well established Phosphorus is essential for proper skeletal and nervous in prehospital care, delivery suites and emergency system formation, function and is critical for proper energy departments, and that incorporates mechanisms that processing in the body. Dietary inorganic phosphate may virtually guarantee its safety 35. Nitric oxide (NO) is be critical for lung cancer prevention as well as treatment primarily responsible for maintaining normal blood as it can activate some signals in living organisms.
pressure, fighting off infections and helping our brain cells Researchers demonstrated that high dietary inorganic communicate with one another. Nitric oxode is an phosphate promoted tumorigenesis and altered Akt intracellular messenger and some biological effects of NO signalling that regulates cell proliferation and survival, cell include: cardiovasculure disease, Parkinson’s disease, growth (size), glucose metabolism, cell motility and impotence (VIAGRA®, sildenafil citrate), angiogenesis 42. Diluted phosphoric acid is employed in neurotransmission, antimicrobial agent, programmed cell scrofula, dropsy, hemoptysis, calculous disease, diabetes death. Nitric oxide restoration may constitute a new and cardialgia. Externally, it has been employed as a local frontier in the fight against the debilitating effects of application in the treatment of caries of the bones and Alzheimers disease 36. Nitric oxide gas, the active osseous tumors. In the past, sulfur use was widespread substance in INOmax®, is a pulmonary vasodilator.
in dermatological disorders such as acne vulgaris, rosacea, INOmax® is a gaseous blend of nitric oxide and nitrogen seborrheic dermatitis, dandruff, pityriasis versicolor, (0.08% and 99.92%, respectively for 800 ppm; 0.01% scabies, and warts. Adverse events associated with and 99.99%, respectively for 100 ppm). Sodium topically applied sulfur are rare and mainly involve mild nitroprusside, an NO donor, have long been used in the application site reactions. Sulfur, used alone or in treatment of angina and hypertensive crises respectively.
combination with agents such as sodium sulfacetamide S-nitrosothiols are another group of NO donors that can or salicylic acid, has demonstrated efficacy in the be structurally modified to release NO at varying rates in treatment of many dermatological conditions. Regarding specific conditions. Scientists designed photoactive “Acne Vulgarisî, in clinical trials, lotions containing sulfur
ruthenium nitrosyls as visible-light-sensitive NO donors 5% with sodium sulfacetamide 10% have been found to be very effective in reducing the number of inflammatorylesions and comedones, as well as reducing seborrhoea.
Inorganic nitrite therapy may hold significant potential Sodium sulfacetamide has demonstrated activity against as an effective and selective NO donor for acute and P. Acnes 43. The combination of sulfur and sodium chronic ischemia secondary to cardiovascular disease 38.
sulfacetamide is available as a lotion, topical suspension, Dietary nitrate intake through NO was found to have a beneficial effect on blood pressure and other vascularfunction in humans because NO can be generated in Iodine is a trace mineral and an essential nutrient mammals from the reduction of nitrite and nitrate 39.
found naturally in the body. Iodine is a topical anti-infective Nitrite has been reported as an antidote for cyanide and agent. Humans require iodine for proper physical and hydrogen sulfide poisoning 40. Oxygen USP is employed mental development. Iodine is a critically important J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 component of thyroid hormones. There are four iodine products (SSKI) are inferior to iodine/iodide products.
atoms per molecule of l-thyroxine, and three per molecule David Marine reported the benefits of treating school- of l-triiodothyronine. Potassium iodide is an antithyroid aged children with iodine/iodide (Lugol’s solution) nearly agent, antisporotrichotic agent, and expectorant. Iodine 70 years ago. Different tissues of the body will keeps our thyroid gland healthy. Sulphur and sulphur preferentially bind different forms of iodine. The illnesses containing compounds are one of the oldest antimicrobial that iodine/iodide has helped are many. These conditions substances in clinical use. One of the most commonly include Fibromyalgia, thyroid disorders, chronic fatigue used sulphur-based antibiotics is cotrimoxazole, a immune deficiency syndrome, autoimmune disorders as combination of sulphamethoxazole (a sulphur compound) well as cancer. Iodine deficiency sets up the immune and trimethoprim (which is not sulphur based). Sulphur system to malfunction which can lead to many of the helps protect the cells in our bodies from environmental above disorders developing 48. Every patient could benefit hazards such as air pollution and radiation, thereby, slows from a thorough evaluation of their iodine levels.Iodine down the aging process and extends our life span. Also, therapeutic action includes: alkanizing agent, antibacterial, sulphur helps our liver function properly, helps us digest anticancer, antiparasitic, antifungal, antiviral, detoxifying the food that we eat and then turn that food into energy.
agent and mycoliting agent 49 (like Guaifenesin). Iodine is Sulfur containing foods such as eggs, garlic and broccoli needed by the thyroid hormone to support metabolism.
contribute to reducing the body burden of susceptible toxic Iodine-131 as sodium iodide is indicated for use in performance of the radioactive iodide uptake test toevaluate thyroid function 50. Inorganic iodine therapy may Halogens
become one of the treatment methods in the patients with Chlorine chemistry carries a host of blockbuster drugs mild Graves’ hyperthyroidism 51. Povidone-iodine and is implicated in the manufacture of 93% of the top- preparation combined with anti-inflammatory agent’s selling drugs46. Chlorine as chloride is important for functions as a potent antidote against skin lesions induced maintaining a normal balance of fluids. Many active by SM at relatively long intervals between exposure and ingredients in over-the-counter or prescription drugs contain bromine. The general anesthetic, halothanecontains a bromine atom in its chemical structure. Many Selenium helps in protecting blood cells from certain others rely on brominated intermediates during their damaging chemicals, and helps keep the pancreas and manufacture. Naproxen (an analgesic), utilizes a heart functioning properly, and together with vitamin E, brominated intermediate in its manufacture. The helps our immune system produce antibodies. Se and the
antihistamine, bromopheniramine maleate, and the cough selenoproteins are essential factors in thyroid metabolism.
medicine dextromethorphan hydrobromide, also utilize Selenium has been used since the 1960s in dandruff bromine in their make-up. Bromhexine improved the shampoos and topical medications for such skin. The performance of amoxicillin in the treatment of pneumonia.
inhibitory effect of methimazole (antithyroid drug) and its Bromocriptine is effective in the treatment of cocaine copper(II) complexes on alkaline phosphastase activity addiction. Many of the commonly used sedatives, antihistamines and antitussives can be made at a lower Semi-metals
cost utilizing bromine chemistry 47. It is well known thatthe the toxicity of modern life (toxic halides, fluoride and Colloidal silicon dioxide is widely used across bromide, having a similar structure as iodine) can pharmaceutical industry. Pharmaceutical grade silicone competitively inhibit iodine absorption and binding in the antifoams (Simethicone) were reported 54. Antimony- body. Potassium bromide is used as an adjunct to containing compounds e.g. Meglumine antimonite, sodium phenobarbital in the treatment of epilepsy.The use of stibogluconate were used to treat leishmaniasis. Hydrated inorganic, non-radioactive iodine has been a wonderful potassium antimonyltartate (tartar-emetic) is used to addition to many physicians practice. In this context, induce sweating and also as an emetic. Antimony and iodized salt is a great success in eliminating goiter in the bismuth compounds are used in the clinic for the treatment world. However, recent results indicated that iodide only of parasitic and bacterial infections 55,56. Bismuth J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 compounds have been used for centuries in medicine.
functional assessment of the lung 61.
Bismuth-containing compounds (e.g., bismuth nitrate,bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, bismuth subsallicylate, colloidal bismuth The iron porphyrin complex of hemoglobin in red blood subcitrate, bismuth tribromphenolate, bismuth citrate) for cells for oxygen transportation and storage, the magnesium medicine from bismuth-contained nitric solutions have been porphyrin complex of chlorophyll in green plants for reported 57. Bismuth subsalicylate and bismuth subcitrate photosynthesis, and cobalt in the coenzyme B for the are used to treat peptic ulcer, against H pylori bacteria transfer of alkyl groups from one molecule to another and as antidiarrhea medicine. There has been no report molecule, are some of the examples naturally occurring of evidence for the toxicity of bismuth when used for coordination compounds and highlighting the role of metal short periods as part of H. pylori eradication therapy.
ions in biological systems 62. Metals are essential for life Bismuth tribromophenate (Xeroform® (Kendall, and scarcity of some metal ions can lead to disease. Well- Convidien)) is used for the treatment of burn wounds, known examples include pernicious anemia resulting from skin grafts, flaps and other indications. Bismuth subnitrate iron deficiency, growth retardation arising from insufficient is used as a hemostatic agent and in animal health for the dietary zinc, and heart disease in infants owing to copper preventation and treatment of mastitis in cows.
deficiency. Overloading of both essential and non-essential metal ions induce toxicity in humans, classic examples (biscarboxyethyl germanium sesquioxide) has been found being mercury, lead, cadmium, iron and copper. Elevated effective for lung cancer, respiratory failure, leukemia and iron levels are associated with many types of lymphatic cancers, brain cancers, arthritis, eye diseases, neurodegenerative disease, such as Alzheimer’s, mercury poisoning, liver disease (including hepatitis), Parkinson’s and Huntington’s diseases. Metals such as osteoporosis, candida albicans, cataracts, heart disease, cadmium, manganese and lead in our environment and in reducing autism. Arsenic containing arsphenamine.( represent a serious health hazard. Producton of oxygen Salvarsan or Compound 606), was the first wonder drug by the water-splitting centre of green plants (photosystem for the cure for syphilis and arsenic drugs were the II), is based on the sophisticated biological use of mainstay of syphilis chemotherapy until the advent of manganese chemistry. Metal ions are electron deficient penicillin rendered them obsolete 58. Arsenic trioxide whereas most biological molecules such as proteins and (As O ), solubilized as the arsenite salt of an alkali metal DNA are electron rich and structural modifications could was used in earlier times as Fowler’s Solution [Arsenic substantially modulate the DNA binding mode and DNA trioxide+ Potassium bicarbonate, 10 mg/mL, non-sterile; damage process, and as a result largely improve the sterile contains alcohol 3% v/v, oral ] and its recent antitumor efficacy of platinum complexes 63. The use of reincarnation, Trisenox® [Arsenic trioxide, sodium many metal-based compounds in the treatment of various hydroxide, 1 mg/mL, intravenous, sterile ] have received diseases highlights the importance of metal compounds FDA approval during 2000 for treatment of relapsed acute in medicine. In terms of anti-tumour activity, a wide range promyelocytic leukemia . As O has also activity against of compounds of both transition metal and main group elements have been investigated for efficacy. Theexistence of a relationship between cancer and metals is Noble gases
widely acknowledged by researcher’s alongwith therecent developments in the field of metal-based anticancer Heavy noble gases are member of the class of nerve- ending drugs. The anesthetic noble gas, xenon, producescardioprotection. Noble gases without anesthetic properties produce cardioprotection by activating Lithium carbonate is a major drug for the treatment prosurvival signaling kinases and inhibiting mPTP opening of manic episodes and for maintenance therapy in bipolar in rabbits 60. Hyperpolarized noble gas MRI has the patients. In multicellular organisms, sodium and calcium potential to provide a comprehensive morphologic and are extracellular, while potassium and magnesium are J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 largely intracellular. Calcium and magnesium are often deficiencies. Pearl calcium’s provide a high quantity of metal activators in proteins to which they bind with assimilable calcium as prescribed in Chinese medical relatively low affinity. Under appropriate circumstances, classics. Calcium-Sandoz contains two forms of calcium, these metal ions induce conformational changes in the calcium glubionate and calcium lactobionate. Calcium protein upon binding and in doing so they may transmit a supplements are also useful in osteoporosis.
signal e.g. the firing of neurons by rapid influx of sodium Mg is needed for the proper growth, formation and ions across a cell membrane or the regulation of function of our bones and muscles. Mg also control insulin intracellular functions by calcium binding proteins such levels in blood and even helps to prevent depression.
as calmodulin. Bone and teeth are made from calcium Barium is used to see inside our bodies. A mixture phosphate in the form of a mineral hydroxyapatite (HAP).
containing barium sulfate is used to coat the inner lining Calcium carbonate biominerals such as calcite and of the intestines to examine a patient’s digestive system.
aragonite are used for structural support.
Similarly, to enhance examination of the stomach and Nerve cells depend on potassium. In fact, without esophagus, the patient drinks a chalky barium sulfate liquid.
potassium, cells lose control of what can enter and leave When the patient is X-rayed, the barium coating inside them. Without sodium, our cells could not get the nutrients the digestive tract absorbs a large proportion of the they need to survive. Sodium also allows our bodies to radiation. This highlights the black-and-white contrast of maintain the right blood chemistry and the correct amount the X-ray photograph, so that doctors can better diagnose of water in our blood. Salt is really a compound of sodium digestive problems 66. Radioactive radium has medical and chlorine. Potassium chloride is used to prevent or to applications such as cancer treatment and as a tracer for treat low blood levels of potassium (hypokalemia).
medical imaging. However, it is rarely used any more Potassium gluconate is needed for normal functioning of because safer radioactive elements have been discovered.
cells, nerve conduction, muscle contraction, kidneyfunction, and acid-base balance. Losartan (I, 2-n-butyl- Transition metals
4-chloro-1-[p-(o-1H-tetrazol- 5-ylphenyl) benzyl]- Transition metals have an important place within imidazole-5methanol monopotassium salt) is a highly medicinal biochemistry. Research has shown significant selective, orally active, non-peptide angiotensin II receptor progress in utilization of transition metal complexes as antagonist indicated for the treatment of hypertension.
drugs to treat several human diseases like carcinomas, Potassium iodide protects the thyroid gland against internal lymphomas, infection control, anti-inflammatory, diabetes, uptake of radioiodines that may be released in the unlikely and neurological disorders. Transition metals exhibit event of a nuclear reactor accident.
different oxidation states and can interact with a number Ca maintains the cell shape and integrity of of negatively charged molecules. This activity of transition membranes, exo- and endocytisis, mytosis, muscle metals has started the development of metal-based drugs contraction, causing changes in some proteins/enzymes with promising pharmacological application and may offer to modify their function. Ca has the ability to bind unique therapeutic opportunities 67.
carboxylate and phosphate 65. Calcium is needed by the Vanadium compounds at pharmacological doses, body for healthy bones, muscles, nervous system, and display relevant biological actions such as insulin and heart. Women who are estrogen-deprived require an growth factor mimetic or enhancing effects, as well as average oral intake of 1500 mg/d of elemental calcium to osteogenic and cardioprotective activity. On the other remain in calcium equilibrium. The recommendation of hand, depending on the nature of compounds and their the National Institute of Health of 1000 mg elemental concentrations, toxicological actions and adverse side calcium per day for women on estrogen replacement and effects may also be shown. The current knowledge and for men is reasonable. Calcium carbonate also is used as new advances on in vitro and in vivo effects of inorganic an antacid to relieve heartburn, acid indigestion, and upset and organically-chelated vanadium compounds have been stomach. Calcium citrate, calcium chloride and calcium reported 68,69. Vanadium is involved in helping the body gluconate are used to prevent and to treat calcium convert some foods into energy. It has also been suggested J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 that diabetics may benefit from vanadium when trying to stabilize blood sugar levels. Chromium is a mineral that is estrogen. However, more zinc is required by men because essential to humans. Chromium helps regulate sugar levels zinc help in the formation of enzyme which convert by interacting with insulin. Chromium picolinate has been progesterone into testosterone 72. Many people wear used in alternative medicine as an aid to lowering copper bands to help them with inflammatory disease, cholesterol or improving the body’s use of glucose (sugar).
such as arthritis. Much of our “dietary” copper actually However, chromium supplements are not approved by comes from copper pipes, utensils and cookware. Copper is important as an electron donor in various biologicalreactions. Without enough copper, iron won’t work properly Manganese is an essential nutrient involved in many in the body. Cupric sulphate at doses upto 0.1mg/kg daily chemical processes in the body, including processing of have been used to treating copper deficiency. Potential cholesterol, carbohydrates, and protein. It might also be benefits of copper gluconate include: helping reduce high involved in bone formation. A number of iron compounds cholesterol levels in humans, osteoporosis, wound healing, have been found medically useful. For example, ferrous cardiac arrhythmia, hypoglycaemia, peripheral vascular gluconate, Fe(C H O ) 2H O, and ferric pyrophosphate, disease, osteoarthritis, and rheumatoid arthritis. Evolution Fe (P O )xH O, are among the compounds frequently has kept stores of copper and iron in excess during the used to treat anemia. Various ferric salts, which act as reproductive years because they are so vital to life. But coagulants, are applied. Iron compounds include the oxidant damage from these excess stores of metals haemoglobin which keeps our blood red. Other essential builds up as we age, and natural selection ceases to act iron compounds include myoglobin. Iron atoms help join after about age 50 since diseases after that do not organic molecules (derived from quinoxaline), forming contribute to reproductive fitness. Diseases of aging such compounds that act as bactericides (killing bacteria) or as Alzheimer’s disease, other neurodegenerative diseases, bacteriostatic agents (preventing bacteria from arteriosclerosis, diabetes mellitus, and others may all be reproducing) 70. Ferrous sulfate provides the iron needed contributed to by excess copper and iron. Excess copper by the body to produce red blood cells. Ferrous sulfate alongwith high fat diet, lose cognition at over three times comes as regular, coated, and extended-release (long- the normal rate. Inorganic copper in drinking water and acting) tablets; regular and extended-release capsules; in supplements is handled differently than food copper and oral liquid (syrup, drops, and elixir) to take by mouth.
Cobalt is essential in small amount for proper nutrition.
Zinc is considered to be one of the most important Cobalt contained in vitamin B is important in protein elements to a healthy immune system and is also needed formation and DNA regulation. Cobalt- 60, a radioactive for the growth and repair of tissues throughout our bodies.
isotope, is used as commercial source of high energy Zinc oxide topically (applied to the skin) is used to treat radiation in medicine to destroy cancerous tissue. Cobalt- diaper rash, minor burns, severely chapped skin, or other 57 is also used in medicine. It can be used to work out minor skin irritations. Zinc-amino acid chelate provides how much vitamin B is being taken in by the human better absorption (60% - 70%), better bioavailability and body. Cobalt containing drugs are used as cyanide better tolerance than zinc salts 74. Gallium mimics ferric antidote. Cyanide ions will bind to cobalt which can be iron. Gallium, in the form of intravenously administered supplied in the form of either i) hydroxocobalamin/ dicobalt gallium nitrate (Ganite®), was approved by the U.S. FDA edetate. Cyanide will also bind to methaemoglobin formed in 1991 for the treatment of cancer-related hypercalcemia, after administration of sodium ntitrie.
a disorder that occurs in about 10-20% of cancer patients.
Historic uses of copper compounds in medicine are Molybdenum is found in all tissues of the human body, available 71. Thyroid and immune system health are but tends to be the most concentrated in the liver, kidneys, crucially dependent upon copper and copper deficiency skin and bones. Molybdenum is important for transforming is the most important factor in the development of sulfur into a usable form in humans. It is required for the hyperthyroidism. Women need more of copper than men proper function of several chemicals in the human body.
because copper is required for the production of the Metal ions and proteins interaction is important J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 regarding binding, stability and folding. Fe, Cu and Zn are of gold. Gold is nonreactive in the instruments and is highly strongly associated with proteins and form the so-called reliable in the electronic equipment and life-support devices metalloproteins. For example, ferritin stores iron in the body.Metal cofactors can help catalyze unique chemical Metal-based medicine could treat diseases in the
reactions and perform specific physiological functions.
Fe 3+/Fe 2+ and Cu 2+/Cu + redox couples play critical Metals have the option of completely destroying the roles as cofactors for electron transfer reactions in the target while most drugs inhibit through binding to a protein/ catalysis of redox reactions. Some metal ions found deeply DNA molecule and just block its function. Metal buried within proteins interact with the protein and helps complexes work in one of two ways. Many use a process insure the optimal protein structure and contributes to the called redox chemistry to steal electrons from the bonds stability and appropriate acid-base behavior necessary for holding the target molecule together 76. Metal binding the physiological function. For example, the Zn 2+ ions in agents in human body include chloride, phosphate and Zn fingers are necessary for the adoption of the proper carbonate. Other metals use hydrolysis, meaning that shape of the protein, which allows it to interact with DNA.
they break down the target’s chemical waterproofing, so Non-essential metals
that the water that is naturally present in a cell dissolvesthe target. The clinical utility of complexes such as cis- Non-essential metals are also used in medicinal and [PtCl (NH ) )] (cisplatin, cis-DDP) and [Pt(CBDCA) pharmaceutical chemistry. The three platinum-containing (NH ) )] (carboplatin, CBDCA = 1,1-cyclobutane- drugs that have been thus far approved by the FDA - dicarboxylate) are the basis for successful chemotherapy cisplatin, carboplatin and oxaliplatin - have had a significant effect in the treatment of patients with some malignanciessuch as testicular, ovarian and colorectal cancer.
Metal compounds still offer excellent opportunities Aluminium may be involved in the action of enzymes such to find new ‘leads’ against the major protozoan diseases a succinic dehydrogenase and d-aminolevulinate such as malaria, leishmaniasis and trypanosomiasis. A few dehydrase (involved in porphyrin synthesis). Aluminium metal-based drugs are already available in this therapeutic hydroxide is used as antacid in the treatment of gastric area, and others are currently being developed 77. The ulcers and as a phosphate binder in cases of long-standing crystal structures for metal-oxicam compounds are renal failure. Aluminium compounds are also used in interpreted in order to look for characteristics that might antiperspirants, antiseptics solutions and as adjuvant in be significant for possible biological activities, for vaccines. An arsenic trioxide has been approved by the innovative strategies aimed to administering the metal Food and Drug Administration to treat a rare and deadly based drugs in vivo 78. Reviews on metal-anti- form of leukemia called acute promyelocytic leukemia, inflammatory drugs have been published 79-81. Pd (II) and or APL. Gold is used in dentistry as well as a drug to Pt (II) complexes with antibiotics of tetracycline family treat a small number of medical conditions. Injections of are more potent against E.coli HB101/pBR322, a bacterial weak solutions of sodium aurothiomalate or strain resistant to tetracycline. Cu (Fen) (dmf) and aurothioglucose are sometimes used to treat rheumatoid Cu (Fen) (caf) produce similar effect than Fenoprofen arthritis. Small amounts of gold are used to remedy a calcium salt in central pain, both complexes present a condition known as Lagophthalmos, which is an inability more potent analgesic effect for peripheral pain 82. Recent of a person to close their eyes completely. This condition developments in inorganic medicinal chemistry have is treated by implanting small amounts of gold in the upper identified several alternative novel targets for metal-based eyelid. The implanted gold “weights” the eyelid and the drugs. In this context, biological molecules with essential force of gravity helps the eyelid close fully. Radioactive thiol groups are attractive targets. Cathepsin cysteine gold is used in diagnosis. It is injected in a colloidal solution proteases have numerous physiological functions, and that can be tracked as a beta emitter as it passes through have been implicated in diseases including cancer, the body. Many surgical instruments, electronic equipment autoimmune and inflammatory, and parasitic diseases.
and life-support devices are made using small amounts Several classes of metal complexes including J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 cyclometalated organo gold(III) and Pd(II) complexes, are much more stable in aqueous media than derivatives and a series of rhenium(V) mixed ligand oxorhenium complexes were investigated in the context of possible Metals and metal complexes have played key role in therapeutic applications including cancer and parasitic the development of modern chemotherapy -15. The single disease as inhibitors of cathepsin cysteine proteases 83.
coordination compound administration can have a series Transition metal complexes
of beneficial effects that come from the metal ion alone,and from the metal and the ligand(s) after the coordinate Transition metals exhibit different oxidation states and bond(s) dissociate in the target tissue. The metal ion and can interact with a number of negatively charged the ligand(s) can have a synergic effect, the metal can molecules. Transition metal complexes are used as drugs stabilize the ligand against possible enzymatic degradation to treat several human diseases like carcinomas, before reaching the target, the coordination molecule can lymphomas, infection control, anti-inflammatory, diabetes, have a better hydrophilicity/hydrophobicity ratio than the and neurological disorders 84. Gold(III), platinum(II), free ligand, etc. Metal based drugs have been developed ruthenium(II, III, IV), iron(II) and vanadium(IV) to treat/cure a variety of ailments viz. diabetes, ulcer, complexes for anti-cancer, anti-HIV treatments , and as rheumatoid arthritis, inflammatory and cardiovascular enzyme inhibitors for potential therapeutic applications were reported 85,86. The anticancer activity of cisplatin Metals can play an important role in modifying the and other closely related platinum compounds arises from pharmacological properties of known drugs after their ability to damage DNA in cancer cells, leading to coordinating to a metal. Chelation causes drastic change cell death. Compounds containing platinum with a 4+ in biological properties of ligands as well as metal moiety charge (non- toxic) must be converted to platinum 2+ and in many cases it causes synergistic effect of metal compounds using a directed fine beam of (laser) light ion and ligand both 97,98. For example, complexation of before they kill cells. The bicyclam AMD3100 (a potent nonsteroidal anti-inflammatory drugs to copper overcomes anti-HIV agent) has an unusual mechanism of action being some of the gastric side effects of these drugs 99. Metal active at the fusion/uncoating step.
complexes are supposed to exert their effect by inhibition A number of ionic titanocene compounds exhibit of enzymes, interaction with intracellular biomolecules, excellent cytotoxicity against different human tumour cell enhanced lipophilicity, alteration of cell membrane lines including a defined cisplatin resistant cell line. In functions and arrest of cell cycle etc. Metal compounds addition, a range of biological assays have been carried as anti-diabetic, anti-inflammatory, antimanic , out to determine levels of cytotoxicity and levels of DNA antimicrobial, antiparasitic, antiulcer, antihypertensive interstrand crosslinking 87. Metanium, a type of medicine agents were reported 100. Traces of metals are essential called a barrier ointment, contains titanium dioxide, titanium for the biological processes as about 30 - 40 % of all peroxide, titanium salicylate in a water-repellent, siliconised known proteins including metalloenzymes require metal base, is used to treat nappy rash 88. The compound titanium cofactors (e.g., Fe, Cu, Zn, Ni, Mn) for their proper folding dioxide absorbs UV light and is used in sunscreen. The into an active three dimensional (3-D) structure 101,102.
non-reactive properties of titanium make it ideal for use Silver (I) chlorhexidine [Ag(I)CHX] and Ag(II)CHX in the body as hip replacements and pacemakers, which showed superior antibacterial activity and faster killing won’t be attacked by body fluids. Titanocene dichloride kinetics compared with chlorhexidine and AgNO 103.
(Cp TiCl ) 89 or diketonato-complexes like budotitane Metals in pharmaceuticals have played an increasingly [Ti(bzac) (OEt) ; Hbzac = Phenylbutane-1,3-dione] 90 important role in medicine, particularly in cancer therapy have been used to treat cancer. The main disadvantages and diagnostic imaging methods. Medicinal applications of these titanium complexes are their fast hydrolysis under of coordination chemistry focus on the role that transition physiological conditions: in an aqueous environment, and metals play in clinical applications 104. Active trans moreover, the loss of the labile groups occurs within complexes and potent di- and tri-Pt anticancer complexes seconds 91,92. Titanium salan complexes containing tetradentate ONNO ligands with anti-cancer properties J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 Two promising ‘new-generation’ platinum agents are starving them to death. The total concentration of biogenic Bis-acetato-ammine dichloro-cyclohexylamine magnetite(magnetic iron oxide magnetite, Fe O ) is platinum(IV) (Satraplatin (JM-216) and cis- generally higher in the AD brain 112. The serum Zn and amminedichloro, 2-methylpyridine, platinum(II) (picoplatin, Cu levels were low in most of the beta-thalassaemic formerly ZD0473)picoplatin (JM-/AMD-473) – which patients. Iron is absorbed from food into enterocytes lining have shown promising clinical activity; satraplatin (an the duodenum via the divalent metal transporter (DMT1).
orally available drug) in hormone-refractory prostate Iron must therefore be in the divalent form for uptake.
cancer and picoplatin in small-cell lung cancer 106. The This may be achieved by reduction of Fe 3+ to Fe 2+.
unwanted side-effects of platinum drugs would greatly Fe(II) transport by divalent metal transporter-1 can be reduce if platinum drugs could be made harmless until modulated by cellular redox status and ebselen may act they enter the cancer cells 107. Chemotherapy is a therapeutically to limit iron-catalyzed damage due to treatment for cancer that works by damaging DNA in diseased cells. However, this form of treatment is also damaging to healthy cells, often causing serious side The main properties of ruthenium compounds well effects. The use of metal-containing compounds as new suited to medicinal application include: (i) rate of ligand chemotherapeutic agents has been reported. The organic exchange, (ii) the range of accessible oxidation states and drug AMD3100 (Mozobil) mobilise stem-cells from bone (iii) the ability of ruthenium to mimic iron in binding to marrow. It is a highly potent and selective anti-HIV agent, certain biological molecules. Many Ru(II) and Ru(I1I) but significant side-effects unfortunately led to its complexes have been evaluated for treatment of cancer withdrawal after Phase II trials. Research is in progress due to their low toxicity . This is in part due to the ability on the metal-bound version of the compound 107. A new of ruthenium to mimic the binding of iron to biomolecules, copper(II) containing bis-macrocyclic CXCR4 chemokine exploiting the mechanisms that the body has evolved for receptor antagonist have improved binding properties to nontoxic transport of iron 114-116. Two ruthenium the receptor protein in comparison to the drug AMD3100 compounds, namely [ImH]trans-[RuCl4(Im)(dmso-S)] (Plerixafor, Mozobil). The interaction of the metallodrug (NAMI-A, Im = imidazole) and [IndH] trans- has been optimized by using ultrarigid chelator units that [RuCl4(Ind)2] (KP1019, Ind = indazole) have already offer an equatorial site for coordination to the amino acid completed phase I clinical trials as anticancer agents 117.
side chains of the protein. Binding competition assays withanti-CXCR4 antibodies showed that the new compound Nuclear medicine
stays bound longer and it has improved anti-HIV potency Today radiopharmaceutical therapy and/or imaging are the fastest growing branch of nuclear medicine.
“Co-Aspirin”, a hexacarbonyldicoboalt-aspirin Nuclear medicine involves the injection of a complex, inhibited cyclooxygenase COX activity radiopharmaceutical (radioactive drug) into a patient for differently to aspirin. Experiments with zebra fish embryos either the diagnosis or treatment of disease or both.
showed that in contrast to aspirin, Co-Aspirin inhibits both Metallic radionuclides are the mainstay of both diagnostic cell growth and the formation of small blood vessels and therapeutic radiopharmaceuticals. Great interest exists (angiogenesis) 109. The antimicrobial properties of cobalt for developing target specific radiopharmaceuticals based (3+) coordination complexes were reported 110. Both cobalt on radiometals for non-invasive disease detection and polyglucopyranose and cobalt disodium ethylenediamine cancer radiotherapy 118. The selection of a particular tetra-acetate have higher therapeutic indexes, as radionuclide relates directly with its intended clinical use, determined in the rat, than does cobalt chloride 111. Iron that is, whether a diagnostic or therapeutic result is desired.
is both essential for healthy brain function elevated iron Radioisotopes which emit gamma rays are used diagnostically whilst those that are beta particle emitters neurodegenerative disease, such as Alzheimer’s, are used therapeutically. Iodine-131 radioisotopes emit a Parkinson’s and Huntington’s diseases. Metalloantibiotics combination of gamma and beta particles, which allow might block iron uptake by pathogenic bacteria, in effect their use in both areas. Radionucleotides are used for J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 imaging and therapy, Technetium (99m Tc), a β-emitting Radiopharmaceuticals labeled with 64Cu have been radionucleotide, is used in > 85% of all diagnostic scans developed and the thiosemicarbazones Cu-PTSM is in hospitals because of its ideal properties. i.e. it has a trapped in all tissues and measures blood flow, while Cu- half life long enough to allow accumulation in the target ATSM is being used in patient studies evaluating hypoxia tissue, yet short enough to minimize the radiation dose to in the brain, heart and tumors 124-126.
the patient 119.
Radioactive 188Re and 186Re isotopes are used for The examples of radiopharmaceuticals 120, which are in practice worldwide for various diagnostic purposes Particles of a radioactive gold isotope are implanted include products such as 201Tl , thallous chloride in tissues to serve as a radiation source in the treatment (myocardial imaging), 133Xe xenon gas (pulmonary of certain cancers. Availability of PET tracers like 68Ga ventilation studies), 131I sodium iodide (thyroid uptake, for use in hospital radiopharmacy facilities has also imaging and therapy), Radioiodinated Albumin (Blood enhanced the scope and practice of radionuclide therapy volume studies0, 123I sodium iodide (thyroid uptake, imaging), 89Sr or 153Sm (metastatic bone palative therapy),67Ga gallium citrate (tumor imaging, Abscess and Molecules that selectively accumulate in the organ infection), 32P (therapy), 99mTc pyrophosphate (cerebral or tissue of interest by a specific mechanism such as perfusion imaging, leukocyte labelling), 99mTc receptor binding or interaction with biomolecules are exametazime, 99mTc bicisate (cerebral perfusion imaging, labeled with 99mTc, 68Ga, 153Sm, 186/188Re, 177Lu, among hepatic and bone marrow imaging, gastric emptying others and used as radiopharmaceuticals. However, studies, 99mTc sulfur colloid , 99mTc medronate (bone considerable effort is necessary to combine these imaging), 99mTc sestamibi (myocardial imaging), 99mTc radionuclides with biomolecules relevant to different (mertiatied renal perfusion, anatomical imaging), 99mTc pathological conditions. Intensive research on the mebrofenin (hepatobilliary imaging), 99mTc pentetate (renal coordination chemistry of these metals has led to novel perfusion imaging), and 99mTc (macroaggregated labeling methods that yield stable compounds which retained the original biological activity of the ligand.
Chemical aspects and clinical applications have been described 131. BNCT is still in the early stages of its pharmaceuticals and their uses include: 18F-Fluoride is practical development. One of the main challenges to the used in bone scanning studies as Fluorodeoxyglucose BNCT modality continues to be the discovery of uniquely (FDG) is similar in structure to glucose and is the tumor-selective agents, capable of delivering therapeutic compound most widely used in PET due to the ubiquitous concentrations of 10B to target tumors, with low toxicity use of glucose by the human body. It is used to detect and high specificity. The use of polyhedral boron hydrides and evaluate tumors, to assess myocardial viability, and for cancer treatment is traditionally connected with boron in diagnosing of a number of different neurological neutron capture therapy. More recently, polyhedral borate conditions. Fluoromisonidazole (FMISO) is a hypoxic agent anions were proposed as carriers of radionuclide label which is metabollicaly trapped by viable cells according for targeted radionuclide therapy and diagnostics of to their degree of hypoxia. 82Rb is a cardiac blood flow cancer. Some metal derivatives of carboranes were found tracer with a very short half-life (75 seconds) that allows to demonstrate significant antitumor activity themselves.
The recent work concerning various fields of potential The use of radiopharmaceuticals for therapeutic application of polyhedral boron compounds in anticancer applications ( á - or â “ -emitters) include sodium [ 131 I] diagnostics and therapy was reported 132.
iodide, sodium 32 P-phosphate, 89 Sr-chloride, and 153 Sm-EDTMP (where EDTMP stands for Organometallic compounds
ethylenediaminetetramethylphosphate), Yttrium-90- Arsphenamine and antimony potassium tartrate were labeled anti-CD20 monoclonal antibody is used to treat introduced early in the second decade of the twenty patients with non-Hodgkin’s lymphoma 122,123.
J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 century. Recent years have witnessed a surge of interest induced by bradykinin are not satisfactorily inhibited by in the application of organometallic compounds to treat the usual anti-inflammatory agents. Anticoagulant rare cancer and other diseases. Indeed, the unique properties earth metal compounds inhibited these types of of organometallic compounds, intermediate between those inflammation. In rats, neurogenic inflammation induced of classical inorganic and organic materials provide new either by antidromic electrical stimulation of the saphenous opportunities in medicinal chemistry. A class of nerve, or by orthodromic stimulation of sensory nerve ruthenium(II)-arene complexes that are weakly cytotoxic endings with capsaicin could almost totally be prevented in vitro, but show selective antimetastatic activity in vivo by a neodymium complex of pyrocatechol sodium disulphonate. In rats and rabbits a dose-dependentinhibition of the permeability increase was observed at Some ferrocenium salts exhibit anticancer activity, the site of the injection of bradykinin, kallikrein or bothrops and an experimental drug has been reported which is a venom 141. Fe chelators including silybin and curcumin, ferrocenyl version of an anticancer drug tamoxifen. The both of which are derived from plants, also have a high idea is that the tamoxifen will bind to the estrogen binding potential in the treatment of cancer 142-144.
sites, resulting in a cytotoxicity effect 134,135.
Arene-Cr(CO)ƒ complex for the development of Inorganic nanoparticles
antiphlogistica and pharmacologically relevant NOD2 Various inorganic nanoparticles have been used for inhibitors and potential inhibitors of the Platelet Activating drug delivery, magnetic resonance and fluorescence imaging, and cell targeting owing to their unique properties, such as large surface area and efficient contrasting effect.
Lanthanum and the fourteen elements following it The recent advances in the development of contrast agents (together, called the lanthanide series) are used in medical based on inorganic nanoparticles including semiconductor image visualisation. At a certain concentration, the cerium
quantum dots (QDs), iron oxide NPs and gold NPs for compounds could be possibly involved in the control of molecular imaging, and also touch on contrast cell proliferation and inhibiting the growth of cancer cells enhancement, surface modification; tissue targeting, 138. The lanthanum compound [tris(1,10-phenanthroline) clearance and toxicity have been reported 145,146.
lanthanum(III)]trithiocyanate (KP772; FFC24) exerts in Chelation and chelation therapy
vitro anticancer activity via potent induction of cell cyclearrest and/or apoptosis and has promising in vivo Chelating agent are organic chemicals that form anticancer activity against a human colon cancer coordination bonds with a central metal ion. Chelation therapy is the use of chelating agents, such as edetate Gadolinium plays a major role in MRI (magnetic calcium disodium (EDTA), dimercaprol, deferoxamine, resonance imaging) scans as a contrast agent. Medical D-penicillamine, and succimer, to rid the body of toxic professionals administer solution of gadolinium compounds levels of iron, lead, or other heavy metals. Different intravenously through injections into the patient’s body chelators have been used to selectively remove toxic which then flows into the bloodstream and enhances metals. Depending on the drug used, chelating agents internal structures of the body. As a result, identification specific to the heavy metal involved are given orally, of abnormal cell growths and tumors become a lot easier.
intramuscularly, or intravenously. Once the bound metal This element is also used in other imaging devices such leaves the tissue, it enters the bloodstream, is filtered from as X-ray machines. Gadolinium is used to locate the the blood in the kidneys, and then is eliminated in the urine.
presence of tumors in the inner ear. After injecting Dimercaptol Injection B.P. BAL in oil is used for Arsenic, Gadolinium into the blood stream, it then goes to any tumor Lead , Mercury (inorganic), Dimercaptosiccinic acid that happens to be present in the ear and the tumor appears (DMSA) (Succimer) Chemet is used for Arsenic, Lead, Mercury, Dimercaptopropanesulfonate (DMPS) forarsenic , D-pencillamine for Arsenic Mercury Lead, and Both neurogenically evoked inflammation and that Ethylenediamintetra-acetic acid for Lead. However, there J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 are no FDA-approved over-the-counter chelation metallic and nonmetallic elements such as aluminum & oxygen (alumina - Al O ), calcium & oxygen (calcia - CaO), silicon & nitrogen (nitride- Si N ). The two most Magnesium ascorbate (vitamin C) is a chelate found common chemical bonds for ceramic materials are in orange juice and in nutritional supplements. Chelation involves reversible binding of metals. Thus, ascorbate mayrelease the essential metal magnesium in the body and Living bone is a 70 wt % inorganic component complex with the toxic metal lead to form lead chelate. (apatite) and 30 wt % organic component (collagen).
The lead exits the body complexed as lead chelate, reducing Ceramics are employed in a wide range in the medical the body burden of lead. Chelates generally exit the body specialty. Surgeons use bioceramic materials for repair through the kidneys via urine or through the bile via the and replacement of human hips, knees, and other body stool. However, chelates may not necessarily eliminate parts. A wide range of ceramic materials are being used toxic metals but rather redistribute them in the body. Since in biomedical applications; ranging from bone implants to many orange juice drinkers and one daily vitamin and biomedical pumps. Dentistry has also advanced with mineral tablet users have excess mineral toxicity and ceramic teeth that can be matched to a patient’s natural related diseases, the medical field of clinical metal ones and other applications for improving a patient’s smile.
toxicology has much to offer. Clinical metal toxicology, Hydroxyapatite-zirconia ceramic material with good which includes chelation therapy, deals with various issues biological histocompatibility nature as bone tissue in regard to preventing and reducing metal toxicity. engineering scaffold materials have broad clinicalapplication.
Intravenous Chelation Therapy involves cleansing the Ceramics are also employed to replace diseased heart body of harmful chemicals which are implicated in many valves. The applications are based on the fact that when diseases. With chelation therapy, circulatory conditions used as implants or even as coatings to metal associated with hardening of the arteries leading to stroke, replacements, ceramic materials can stimulate bone hypertension, angina, heart attack, poor memory, poor growth, promote tissue formation and provide protection vision and impotence may be improved. Bypass surgery from the immune system. Moreover, modern ceramic and limb amputation due to poor circulation may be materials play an important role in gadgets used for medical diagnosis including both ultrasonic and X-ray Chelation therapy removes chemicals that form the computed tomography (CT) systems. Transducers utilizing material that makes arteries hard and clogged and interfere lead zirconate titanate (PZT) based piezoelectric ceramicsare the heart of ultrasonic systems. These transducers with normal cellular process. In the United States,hardening of the arteries has been found to be an generate the ultrasonic acoustic waves and detect the underlying condition in most deaths caused by disease.
reflected signals to form the image. Zirconia implants withmodified surfaces result in an osseointegration which is Osteoporosis and arthritic degenerative joint disease canalso be controlled or reversed.
comparable with that of titanium implants 148. Zirconia-ceramic consisting of at least 90% of zirconium dioxide Chelation therapy stimulates the body to restore applications include femoral heads for total hip strength to the bones and removes chemicals that cause replacements, knee joints, shoulders, phalangeal joints, joint stiffening and pain. Chelation has been shown to be spinal implants, endoscopic components and pace maker effective in the prevention of malignancy 147.
Ceramics in medical and dental applications
Porous ceramic biomaterials (artificial bone) are now According to Gilman in 1967, a ceramic is an earthy in demand in the field of regenerative medicine on hard material usually of silicate nature and may be defined as tissues. Four different porous calcium phosphate ceramic a combination of one or more metals with a non-metallic materials were studied to induce osteogenic differentiation element usually oxygen. The Ceramics are typically of multipotent cells in vitro and in vivo 149,150.
crystalline in nature, and are compounds formed between Hydroxyapatite (HAp) is one of the ceramic materials J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 that is commonly used to substitute bone tissue in to act as attracting signals for bone cells to promote bone orthopedic and dental implants. A composite of regeneration process. Finally, recent research examples hydroxyapatite and biocompatible oxides (for example, of organic–inorganic hybrid bioceramics, such as stimuli- TiO , Al O , ZrO or Y O ) is preferred as a harder responsive drug delivery systems and nanosystems for composite with greater strength under compression and targeting of cancer cells and gene transfection were resistance to breakage than pure hydroxyapatite 151.
Various recently introduced diagnostic and working toolsof which ceramics play an integral part include: Radio Zinc fingers
Visio Graphy (RVG) Pulp tester Apex locators 1st Zinc finger reactions with inorganic ions such as Co2+ generation - resistance based. 2nd generation - impedance and Cd2+ and coordination compounds has given structural, based 3rd generation -frequency based 152.
thermodynamic and kinetic information on zinc fingers Natural bones are composed mainly of hydroxyapatite and zinc-finger-DNA/RNA interactions.Some inorganic supported by collagen fibers. In this regard, many compounds such as those of As(III) and Au(I) may exert hydroxyapatite /carbon nanotubes hybrid composite their biological effects through inactivation of zinc fingers materials were successfully synthesized via a and novel approaches to specifically attack the zinc-bound biomineralization process that employs poly(dopamine) ligands using Co(III)-Schiff bases and Platinum(II)- (PDA), a synthetic mimic of mussel adhesive proteins. It Nucleobase compounds have been proposed 155. Zinc- has been reported that the formation of a poly(dopamine) finger nucleases are synthetic “designer” proteins ad-layer on the surface of carbon nanotubes changed the combining a zinc-finger domain, engineered to bind a hydrophobic carbon nanotubes to become bioactive. This particular DNA sequence, with an enzyme that breaks enabled interaction between the carbon nanotubes and both DNA strands at the targeted site. Zinc finger proteins mineral ions (e.g., Ca2+) facilitated the mineralization of could offer a better route to gene therapy. Zinc finger hydroxyapatite . Carbon nanotubes functionalized with nucleases that disrupt the CCR5 gene in CD4+ human T- poly(dopamine) accelerated the formation of HAp upon cells as a potential treatment for HIV/AIDS were incubation in a simulated body fluid and exhibited a minimal cytotoxic effect on bone osteoblast cells compared to Sangamo collaborates with pharmaceutical partners pristine or carboxylated carbon nanotubes,thereby, in developing ZFP Therapeutics and is conducting clinical showing the potential of carbon nanotubes-poly(dopamine) trials to treat numerous diseases such as diabetic as a scaffold material for bone tissue regeneration and neuropathy, peripheral artery disease, HIV based on ZFP Sangamo is pursuing numerous other disease Hybrid bioceramics have remarkable features resulting treatments using ZFPs: diabetes, sickle cell disease, from the synergistic combination of both inorganic and ischemic heart disease (caused by the narrowing of the organic components that make them suitable for a wide coronary artery), congestive heart failure, cancer, range of medical applications. Certain bioceramics, such neuropathic pain, hepatitis B, Wiscott-Aldrich Syndrome as ordered mesoporous silicas, can exhibit different kind and X-linked severe combined immunodeficiency “bubble of interaction with organic molecules to develop different boy” disease. 157. A new way of turning genes on and off functions. The weak interaction of these host matrixes is promising to transform treatment of conditions such as with drug molecules confined in the mesoporous channels HIV/AIDS, heart disease and diabetes. This technique allows these hybrid systems to be used as controlled allows scientists to act with unprecedented precision delivery devices. Moreover, mesoporous silicas can be against genes that affect a wide range of diseases, used to fabricate three (3D)-dimensional scaffolds for switching them on or off permanently 158. The most bone tissue engineering. In this last case, different advanced of Sangamo’s drugs uses a zinc-finger nuclease osteoinductive agents (peptides, hormones and growth to treat diabetic neuropathy, a common complication of factors) can be strongly grafted to the bioceramic matrix diabetes that causes nerve damage and pain. The drug J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 binds to a gene called VEGF-A, which is known to protect References
the nervous system, and switches it on to prevent nerve 1. Jaouen G (Ed.). Bioorganometallics, 1st Ed. Wiley-VCH 2006,
damage. The same gene is also being targeted to treat peripheral arterial disease which causes blocked arteriesin the limbs. A zinc-finger drug that has started safety 2. Orvig C, Abrams MJ. Medicinal inorganic chemistry: introduction. Chem Rev 1999; 99:2201-2204.
trials aims to stimulate VEGF-A activity, which canpromote the growth of new arteries 159.
3. Lev E. Medicinal exploitation of inorganic substances in the Levant in the Medieval and early Ottoman periods.
Conclusions and perspectives
Adler Mus Bull 2002;28:11-16.
Inorganic compounds/drugs account for only small 4. Sekhon BS, Gandhi L. Medicinal uses of inorganic compounds – 1. Resonance 2006;11:75-89.
proportions of all those in modern therapeuticarmamentamium. Metal ions and metal complexes in 5. Gielen M, Tiekink ERT, Eds., Metallotherapeutic drugs and clinical use today include diagnostic and therapeutic metal-based diagnostic agents. The Use of Metals in compounds. The development of metalbased drugs with Medicine, Wiley, Chichester, 2005.
promising pharmacological application has the potential 6. Thompson KH. Medicinal Inorganic Chemistry: An to treat neurodegenerative diseases. Carbon nanotubes Introduction. Encyclopedia of Inorganic Chemistry,
functionalized with poly(dopamine) highly accelerated the formation of HAp when incubated in a simulated body 7. Kozarich JW. Medicinal Inorganic Chemistry: Promises and fluid and exhibited a minimal cytotoxic effect on bone Challenges 2005, Chapter 2, pp 4-14.
osteoblastcells compared to pristine or carboxylated 8. Norman JF, Hambley TW. Targeting strategies for metal-based carbon nanotubes. The potential of ceramic materials for therapeutics, in Bioinorganic Medicinal Chemistry (ed their use as biomaterial have been demonstrated and in E. Alessio), Wiley-VCH Verlag GmbH & Co. KGaA, this context, a composite of hydroxyapatite and biocompatible oxides such as TiO , Al O , ZrO or Y O 9. Ikotun OF, Higbee EM, Ouellette W, Doyle RP.
helps to obtain a harder composite with greater strength Pyrophosphate-bridged complexes with picomolar under compression and resistance to breakage than pure toxicity J Inorg Biochem 2009;103:1254–1264.
hydroxyapatite. Porous ceramic biomaterials, namely, 10. Tripathi KA. Review – Can metal ions be incorporated into “artificial bone” are achieving some mainstream drugs? Asian J Res Chem 2009;2:14-18.
acceptance in the field of regenerative medicine on hard 11. Thompson, K. H. Medicinal Inorganic Chemistry: tissues and further research is required in this direction.
Metallotherapeutics for Chronic Diseases.
Research on Hydroxyapatite - zirconia ceramic material Encyclopedia of Inorganic Chemistry. 2011.
with good biological histocompatibility nature, as bone 12. Enzo Alessio (Ed.). Bioinorganic Medicinal Chemistry, tissue engineering scaffold materials should be Wiley-VCH Verlag GmbH & Co. KGaA 2011.
strenghenedfor broad clinical application. Metal ionsfunction in numerous metalloenzymes, are incorporated 13. van Rijt SH, Sadler PJ. Current applications and future into pharmaceuticals and imaging agents. The greatest potential for bioinorganic chemistry in thedevelopment of anticancer drugs. Drug Discov Today benefit of medicinal bioinorganic chemistry has been the discovery of the utility of injecting gadolinium agents intopeople before MRI. Metallic radionuclides are the 14. mainstay of both diagnostic and therapeutic 15. Bertini I, Gray HB, Stiefel EI, Valentine JS. Biological radiopharmaceuticals. Several target specific Inorganic Chemistry: Structure and Reactivity.
radiopharmaceuticals based on radiometals for non- University Science Books, Sausalito, California, 2007.
invasive disease detection and cancer radiotherapy were 16. McGowan PC. 29 Metal complexes as pharmaceuticals.
developed. Transition metal complexes containing Annu Rep Prog Chem Sect A: Inorg Chem 2005;101:631- radioactive isotopes have found widespread use as radiopharmaceuticals in diagnostic nuclear medicine J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 17. Moody L, Holder AA. Inorganic pharmaceuticals. Annu 31. Nicoud JF, Bolze F, Sun XH, Hayek A, Baldeck P. Boron- Rep Prog Chem Sect A: Inorg Chem 2008;104:477-497.
containing two-photon-absorbing chromophores. 3.(1)One- and two-photon photophysical properties of p- 18. Moody L, Holder AA. Inorganic pharmaceuticals. Annu.Rep carborane-containing fluorescent bioprobes. Inorg Prog Chem Sect A: Inorg Chem 2009;105:505-524.
19. Holder AA. Inorganic pharmaceuticals. Annu Rep Prog Chem 32. Kohno J, Kawahata T, Otake T, et al. “Boromycin, an anti- Sect A: Inorg Chem 2010;106:504-525.
HIV antibiotic”. Biosci Biotechnol Biochem1996;60:1036–1037; 20. Ryter SW, Otterbein LE. Carbon monoxide in biology and medicine. Bioessays 2004;26:270-280.
33. 21. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med 34. Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. Spring2007;54(1):9-18.
22. Wu L, Wang R. Carbon monoxide: endogenous production, physiological functions, and pharmacological 35. Sullivan IO, Benger J . Nitrous oxide in emergency medicine.
applications. Pharmacol Rev 2005;57:585–630.
Emerg Med J 2003;20:214–217.
23. Courtney AE, Maxwell AP. Heme oxygenase 1: does it have 36. Butler AR, Rhodes PS. Nitric oxide in physiology and a role in renal cytoprotection? Am J Kidney Dis medicine. In: Uses of Inorganic Chemistry in Medicine, 24. Sun B, Sun Z, Jin Q et al. CO-releasing molecules (CORM-
37. Fry NL, Mascharak PK. Photoactive ruthenium nitrosyls as 2)-liberated CO attenuates leukocytes infiltration in the NO donors: How To sensitize them toward visible light.
renal tissue of thermally injured mice. Int J Biol Sci Acc Chem Res 2011;44:289-298.
38. Kevil CGPatel RP. Preserving vessel function during ischemic 25. Liu DM, Sun BW, Sun ZW et al. Suppression of inflammatory
disease: New possibilities of inorganic nitrite therapy.
cytokine production and oxidative stress by CO- Expert Rev Cardiovasc Ther 2008;6:1175–1179.
releasing molecules-liberated CO in the small intestineof thermally-injured mice. Acta Pharmacol Sin 39. Gilchrist M, Shore AC, Benjamin N. Inorganic nitrate and nitrite and control of blood pressure Cardiovasc Res2011;89:492-498 26. Sun BW, Chen X, Chen ZY et al. Molecular mechanism of
inhibition of early pulmonary injury and inflammatory 40. Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite response by exogenous carbon monoxide: experiment and nitrate. Circulation. 2008;117:2151-2159.
with mice. Zhonghua Yi Xue Za Zhi 2007;87:3148–3151. 4 1 . h t t p : / / w w w. h a l o c a r b o n . c o m / h a l o c a r b o n _ m e d i a / 27. Sun BW, Jin Q, Sun Y et al. Carbon liberated from CO- releasing molecules attenuates leukocyte infiltration inthe small intestine of thermally injured mice. World J 42. Jin H, Xu CX, Lim HT, et al. High dietary inorganic phosphate Gastroenterol 2007;13:6183–6190. increases lung tumorigenesis and alters akt signaling.
Amer J Respirat Critical Care Med 2009;179:59-68.
28. Caumartin Y, Stephen J, Deng JP, Lian D, Lan Z, Liu W, Garcia B, Jevnikar AM, Wang H, Cepinskas G, Luke PPW.
43. Tarimci N, Sener S, Kilinc T. Topical sodium sulfacetamide/ Carbon monoxide-releasing molecules protect against sulfur lotion. J Clin Pharm Ther 1997;22:301.
ischemia-reperfusion injury during kidney 44. Gupta AK, Nicol K .The use of sulfur in dermatology. J
transplantation. Kidney Int 2011;79: 1080-1089.
Drugs Dermatol ; Find 19 May, 2011. http:/ 29. Acne-Fighting Boron Compounds, Anacor, and Medicis / compounds-anacor-and-medicis/992444/, Dated Feb 45. Gupta AK. The use of sulfur in dermatology. J Drugs Dermatol Find,2011.http://f i n d a r t i c l e s . c o m / p / a r t i c l e s / m i _ m 0 P D G / i s _ 4 _ 3 / 30. McCoy M. Betting on boron. J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 46. The benefits of chlorine chemistry in pharmaceuticals. Global 58. Sneader W. Drug discovery: The evolution of modern medicines. John Wiley & Sons, Chichester, England, w w w . a m e r i c a n c h e m i s t r y . c o m / s _ c h l o r i n e / doc.asp?CID=1132&DID=8850&CTYPEID=107.
59. Kyle RA, Rajkumar SV. Multiple myeloma. N Eng J Med 47. 60. Pagel PS, Krolikowski JG, Shim YH. Noble gases without 48. Brownstein D. Clinical experience with inorganic non- anesthetic properties protect myocardium against radioactive iodine/iodide; infarction by activating prosurvival signaling kinases spl2/clinical-experience-iodine.html, November 4, 2010.
and inhibiting mitochondrial permeability transition invivo. Anesth Analg. 2007;105:562-569.
49. iodine-for-health-some-resources.html.
61. Salerno M, Altes TA, Mugler JP, Nakatsu M, Hatabu H, de Lange EE. Hyperpolarized noble gas MR imaging of the 50. Risher JF, Keith LS. Iodine and inorganic iodides: human lung: Potential clinical applications. Eur J Radiol health aspects. Volume 72 of Concise international chemical assessment document, World HealthOrganization, World Health Organization, 2009.
62. Solomon EI. Spectroscopic methods in bioinorganic chemistry: Blue to green to red copper sites. Inorg Chem 51. Noh JY, Chino T, Ito K. Treatment with inorganic iodine for Graves’ hyperthyroidism. Nippon Rinsho 2006;64:2269-2273.
63. Editorial [Hot topic: Metal-containing drugs and novel coordination complexes in therapeutic anticancer 52. Wormser U, Sintov A, Brodsky B, Casillas RP, Nyska A.
applications - Part II (Guest Editor: Kostova I)] Anti- Protective effect of topical iodine containing anti- Cancer Agents in Medicinal Chemistry 2010;10:352- inflammatory drugs against sulfur mustard-induced skin lesions. Arch Toxicol 2004;78:156-166.
64. X. Wang. Fresh platinum complexes with promising antitumor 53. Urquiza NM, Manca SG, Moyano MA, et al. Copper(II) activity. Anti-Cancer Agents in Medicinal Chemistry complexes of methimazole, an anti Grave’s disease drug.
Synthesis, characterization and its potential biologicalbehavior as alkaline phosphatase inhibitor. BioMetals 65. Ochiai E. Bioinorganic chemistry: a survey, medical applications of inorganic compounds, Chapter 12,Academic Press, 2008, pp 311-326.
54. Lukevics E, Ignatovich L. Si biological activity of organo- silicon compounds. Gielen M, Tiekink ERT.
66. Barium - used, first, body, produced, uses, Barium and Metallotherapeutic drugs and metal-based diagnostic agents: the use of metals in medicine, John Wiley and w w w. d i s c o v e r i e s i n m e d i c i n e . c o m / B a r - C o d / 55. Research and markets: Biological chemistry of arsenic, 67. Rafique S, Idrees M, Nasim A, Akbar H, Athar A. Transition antimony and bismuth - An essential overview of the metal complexes as potential therapeutic Agents. biological chemistry of these three elements Biotechnol Mol Biol Rev 2010;538-545. 68. Srivastava AK, Mehdi MZ. Insulino-mimetic and anti- diabetic effects of vanadium compounds. Diabetic Med2005;22:2–13.
56.Yan S, Jin L, Sun H. Sb Antimony in Medicine, in Metallotherapeutic Drugs and Metal-Based Diagnostic 69. Barrio DA, Etcheverry SB. Potential use of vanadium Agents: The Use of Metals in Medicine (eds M. Gielen compounds in therapeutics. Curr Med Chem and E. R. Tiekink), John Wiley & Sons, Ltd, Chichester, 70. Tarallo MB, Urquiola C, Monge A, et al. Design of novel 57. Udalova TA, Logutenko OA, Timakova EV. Afonina LI, iron compounds as potential therapeutic agents against Naydenko ES, Yukhin Yu M. Bismuth compounds in tuberculosis. J Inorg Biochem 2010;104:1164-1170.
medicine. Strategic Technologies, 2008. IFOST 2008.
Third International Forum on Issue Date: 23-29 June 71. Dollwet HHA, Sorenson JRJ. Historic uses of copper compounds in medicine, Trace Elements in Medicine1985;2:80-87.
J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 89. Strohfeldt K, Tacke M. Bioorganometallic fulvene-derived titanocene anti-cancer drugs. Chem Soc Rev 73. Brewer GJ. Risks of copper and iron toxicity during aging in humans. Chem Res Toxicol 2010;23:319–326.
90. Melendez E. Titanium complexes in cancer treatment. Crit 74.
Rev Oncol Hematol 2002;42:309–315.
91. Toney JH, Marks TJ. Hydrolysis chemistry of the metallocene dichlorides M(ç5-C H ) Cl , M = Ti, V, Zr.
76. Dabrowiak JC. Metals in Medicine. John Wiley and Sons, Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents. J Am 77. Navarro M, Gabbiani C, Messori L, Gambino D. Review: Metal-based drugs for malaria, trypanosomiasis and 92. Köpf H, Grabowski S, Voigtlander R. Spectrometric and leishmaniasis: recent achievements and perspectives.
preparative studies on the hydrolysis of titanocene Drug Discov Today 2010;15:1070-1078.
dichloride. J Organomet Chem 1981;216:185–190.
78. Tamasi G. Metal-oxicam coordination compounds: Structure, 93. Immel TA, Groth U, Huhn T, Öhlschläger P. Titanium Salan
biological activity and strategies for administration. The complexes displays strong antitumor properties in vitro Open Crystallography Journal 2010;3:41-53.
and in vivo in mice. PLoS ONE 2011;6: e17869.
79. Weder JE, Dillon CT, Hambley TW, et al. Copper complexes 94. Nakai M, Sekiguchi F, Obata M, et al. Synthesis and insulin- of non-steroidal anti-inflammatory drugs: an mimetic activities of metal complexes with 3- opportunity yet to be realized. Coord Chem Rev hydroxypyridine-2-carboxylic acid. J. Inorg. Biochem 80. Kovala-Demertzi D. Recent advanced on non-steroidal 95.Chaviara T, Christidis PC, Papageorgiou A, Chrysogelou E, antiinflamatory drugs, NSAIDs: Organotin complexes Hadjipavlou-Litina DJ, Bolos CA. J. Inorg. Biochem NSAIDs. J Organomet Chem 2006;691:1767-1774.
81. Cini R. Anti-inflammatory compounds as ligands in metal 96. Sadler PJ, Guo Z. Metal complexes in medicine: Design and complexes as revealed in X-ray structural studies.
mechanism of action. Pure and Appl Chem 1998;70;863- Comments Inorg Chem 2000;22:151-186.
82. Agotegaray MA, Gumilar FA, Minetti SA Quinzani OV.
97. Bharti SK, Singh SK. Recent developments in the field of Analgesic properties of new copper(ii) coordination anticancer metallopharmaceuticals. Inter J PharmTech Res 2009;1:1406-1420.
w w w . f b i o y f . u n r . e d u . a r / r i c i f a /R e s u m e n e s 2 0 1 0 % 5 C F a r m a c o l o g i a / 98. Sanchez-Delgado RA, Lazardi K, Rincon L, Urbina JA.
Towards a novel metal-based chemotherapy againsttropical diseases. 1. Enhancement of the efficacy of 83. Fricker SP. Cysteine proteases as targets for metal-based clotrimazole against trypanosoma cruzi by complexation drugs. Metallomics 2010;2: 366-377.
84. Garbutcheon-Singh KB, Grant MP, Harper BW, et al. Transition metal based anticancer drugs. Curr Topics 99. Weder JE, Dillon CT, Hambley TW, et al. Copper complexes of non-steroidal anti-inflammatory drugs: an 85. Che CM, Siu FM. Metal complexes in medicine with a focus opportunity yet to be realized . Coord Chem Rev
on enzyme inhibition. Curr Opin Chem Biol 2010; 100. Bharti SK, Singh SK. Metal based drugs: Current use and 86. Sun RW, Ma DL, Wong EL, Che CM. Some uses of transition future potential. Der Pharmacia Lett 2009;1;39-51.
metal complexes as anti-cancer and anti-HIV agents.
101. Kastenholz B. Comparison of the electrochemical behavior of the high molecular mass cadmium proteins in 87. Allen OR, Gott AL, Hartley JA, et al. Functionalised Arabidopsis thaliana and in vegetable plants on using cyclopentadienyl titanium compounds as potential preparative native continuous polyacrylamide gel.
anticancer drugs. Dalton Trans 2007;5082-5090.
Electroanalysis 2006;18:103-106.
102. Kastenholz B. New hope for the diagnosis and therapy of J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 alzheimer ’s disease. Protein & Peptide Letters 116. Casini A, Karotki A, Gabbiani C, et al. Reactivity of an antimetastatic organometallic ruthenium compound withmetallothionein-2: relevance to the mechanism of action.
103. Pal S, Yoon EJ, Park SH, Choi EC, Song JM.
Metallopharmaceuticals based on silver(I) and silver(II)polydiguanide complexes: activity against burn wound 117. Ioannis Bratsosa, Stephanie Jednera, Teresa Gianferrarab, pathogens. J Antimicrob Chemother 2010;65:2134-2140.
and Enzo Alessio. Ruthenium Anticancer Compounds:
Challenges and Expectations. Chimia 2007;61:692–697.
104. Jones CJ, Thornback JR. Medicinal Applications of 118. Bhattacharyya S, Dixit M. Metallic radionuclides in the development of diagnostic and therapeutic 105. van Rijt SH, Sadler PJ. Current applications and future radiopharmaceuticals. Dalton Trans 2011; Advance potential for bioinorganic chemistry in the development Article DOI: 10.1039/C1DT10379B, Perspective.
of anticancer drugs. Drug Discov Today 2009;14:1089–1097.
119. 106. Kelland L. Broadening the clinical use of platinum drug- based chemotherapy with new analogues. Satraplatin 120. and picoplatin. Expert Opin Invest Drugs 2007;16:1009- 121. Chapter 13.Radiations in medicine. http:// 107.
108. Khan A, Nicholson G, Greenman J, et al. Binding optimization through coordination chemistry: CXCR4 chemokine 122. Nuclear Medicine - Chemistry Encyclopedia - metal, gas receptor antagonists from ultrarigid metal complexes. J Amer Chem Soc 2009;131:3416-3417.
109. Ott I, Modulation of the biological properties of aspirin by 123. Sadler PJ, Muncle C, Shipman MA. Metals in medicine , formation of bioorganometallic derivative, Chapter VII, pp 95-136, In: Ivano Bertini. Biological Organometallic compounds as new drugs? Cobalt- inorganic chemistry: structure and reactivity. University containing aspirin complex with potential anti-tumor properties. Angew Chem Inter Ed 2009;48;1160-1163.
124. 110. Chang EL, Simmers C, Knight DA. Cobalt complexes as antiviral and antibacterial agents. Pharmaceuticals 125. Nuclear Medicine - Chemistry Encyclopedia - metal, gas 111. Murdock HR, Klotz LJ. A pharmacologic evaluation of certain cobalt-containing hemopoietic agents. J Amer 126. Nuclear Medicine - Chemistry Encyclopedia - metal, gas Pharm Assoc 1959;48:143–148. 112. Pankhurst Q, Hautot D, Khan N, Dobson J. Increased levels of magnetic iron compounds in Alzheimer’s disease. J 127. Dilworth JR, Parrott SJ. The biomedical chemistry of Alzheimers Dis 2008;13:49-52.
technetium and rhenium. Chem Soc Rev 1998;27:43–55.
113. Wetli HA, Buckett PD, Wessling-Resnick M. Small- 128. The Tungsten-188 and Rhenium-188 Generator Information.
molecule screening identifies the selanazal drug ebselen Oak Ridge National Laboratory. 2005. Dated 2008-01- as a potent inhibitor of DMT1-mediated iron uptake.
09; Retrieved 2008-02-03.
114. Allardyce CS, Dyson PJ. Ruthenium in medicine: Current clinical uses and future prospects. Platinum Metal 129. Zolle I. Technetium-99m pharmaceuticals: preparation and review 2001;45:62-69.
quality control in nuclear medicine, Springer, 2007.
115. Yan YK. Melchart M, Habtemariam A, Sadler PJ.
130. Scheffler J, Derejko M, Bandurski T, Romanowicz G.
Organometallic chemistry, biology and medicine: Application of rhenium-188 HEDP in bone metastases ruthenium-arene anticancer complexes. Chem Commun therapy. Nucl Med Rev Cent East Eur 2003;6:55-57.
J Pharm Educ Res Vol. 2, Issue No. 1, June 2011 131 Rey AM. Radiometal complexes in molecular imaging and 144. Demicheli C, Frezard F, Mangrum JB, Farrell NP., Interaction
therapy. Curr Med Chem 2010;17:3673-3683.
of trivalent antimony with a CCHC zinc finger domain:potential relevance to the mechanism of action of 132. Bregadze VI, Sivaev IB, Glazun SA. Polyhedral boron antimonial drugs. Chem Commun 2008;4828-4830.
compounds as potential diagnostic and therapeuticantitumor agents. Anti-Cancer Agents in Medicinal 145. Cho EC, Chen J, Glaus C, Welch MJ, Xia Y. Inorganic nanoparticle-based contrast agents for molecularimaging. Trends Mol Med, 2010;16:561-573.
133. Ang WH, Casini A, Sava G, Dyson PJ. Organometallic ruthenium-based antitumor compounds with novel 146. Xing ZC, Chang Y, Kang IK. Immobilization of biomolecules modes of action. J Organomet Chem 2011;696:989-998.
on the surface of inorganic nanoparticles for biomedical
applications. Sci Technol Adv Mater 2010:11 014101
134. Top S, Vessières A, Leclercq G, et al. Synthesis, biochemical properties and molecular modelling studies oforganometallic specific estrogen receptor modulators 147. (SERMs), the ferrocifens and hydroxyferrocifens: 148. Depprich R, Zipprich H, Ommerborn M, et al.
evidence for an antiproliferative effect of Osseointegration of zirconia implants compared with hydroxyferrocifens on both hormone-dependent and titanium: an in vivo study. Head & Face Medicine hormone-independent breast cancer cell lines.
Chemistry, A Eur J 2003;9:5223–36.
149. Boyan BD, Schwartz Z. Regenerative medicine: Are calcium 135. Dagani R.The Bio Side of Organometallics. Chem Eng News phosphate ceramics ‘smart’ biomaterials?. Nat Rev 136. Bielig H, Velder J, Saiai A, et al. Anti-inflammatory arene— 150. Caruta BM. Ceramics and composite materials: new chromium complexes acting as specific inhibitors of NOD2 signalling. ChemMedChem 2010;5:2065-2071.
151. The potential of ceramic materials for their use as 137. Tsoupras AB, Roulia M, Ferentinos E, Stamatopoulos I, biomaterial. Posted: May 9th, 2011; http:// Demopoulos CA, Kyritsis P. Structurally diverse metal coordination compounds, bearing imidodiphosphinateand diphosphinoamine ligands, as potential inhibitors 152. Sukumaran VG, Bharadwa N. Ceramics in dental of the platelet activating factor. Bioinorg Chem Appl applications. Trends Biomater Artif Organs 2010;20:7- 2010 (2010), Article ID 731202, 8 pages doi:10.1155/2010/ 11;] 153. Lee M, Ku SH, Ryu J, Park CB. Mussel-inspired 138. Palizban AA, Sadeghi-Aliabadi H, Abdollahpour F. Effect functionalization of carbon nanotubes for of cerium lanthanide on Hela and MCF-7 cancer cell hydroxyapatite mineralization. Mater Chem growth in the presence of transferring. Res Pharm Sci 154. Vallet-Regí M, Colilla M, González B. Medical applications 139. Heffeter P, Jakupec MA, Körner W, et al. Anticancer activity of organic–inorganic hybrid materials within the field of the lanthanum compound [tris(1,10-phenanthroline) of silica-based bioceramics. Chem Soc Rev 2011;40: lanthanum(III)]trithiocyanate (KP772; FFC24). Biochem 155. Quintal SM, dePaula QA, Farrell NP. Zinc finger proteins 140. as templates for metal ion exchange and ligand reactivity.
Chemical and biological consequences. Metallomics2011;3:21-139.
141. Jancsó-gábor A, Szolcsányi J. Action of rare earth metal complexes on neurogenic as well as on bradykinin- 156. Pablo T et al. Autologous T-Cells genetically modified at induced inflammation. J Pharm Pharmacol 1970;22:366– the CCR5 gene by zinc finger nucleases SB-728 for HIV 142. Kovacevic Z, Kalinowski DS, Lovejoy DB, et al.The 157. Fighting Disease with Zinc-Finger Proteins. http:// Medicinal chemistry of novel iron chelators for the treatment of cancer. Curr Topics Med Chem 2011;11:483-
158. 143. Anzellotti AI, Farrell NP. Zinc metalloproteins as medicinal 159. Zinc-finger proteins promise new treatment for HIV/AIDS targets. Chem Soc Rev 2008;37:1629-1651., dated March 18, 2008.


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