There is a fine yet blurred line between what we consider a medicine and what we consider a poison. Philippus Aureolus Paracelsus (1493-1541) stated several centuries ago that “all drugs are poisons, the benefit depends on the dosage. ” The numerous substances we call medicinal drugs, are in all aspects, poisons; poisons which we carefully select and control the intake of in a hope to combat the numerous diseases and ailments we face. We take drugs for the darkest of diseases; the chemotherapy drugs that cure leukemia are the same substances that destroy our kidneys and livers.
We even take drugs for the faintest of ailments; we take aspirin to cure a persistent headache, but an overdose (or drinking a beer while taking it) can cause damage to the intestinal track. We know these risks exist, but we choose to try to cure these ailments with these drugs because, sometimes, they work. In a recent visit to my doctor he stated that “the therapeutic levels of most drugs fall well below their physiological toxic levels… and anyway therapeutic benefits of a drug on the market far outweighs their risks.
” The level of toxicity of these select poisons of course varies from one to the other. Some have low levels of toxicity such as aspirin (a potentially lethal dosage of aspirin is about 500mg/kg weight, meaning a 55kg person would need to take about 80 regular sized aspirin tablets at once to kill themselves). While others have extremely high levels of toxicity such as Melarsoprol (a drug used to combat African sleeping sickness, which has a lethal dose of only 22mg/kg weight).
A certain group of drugs are almost all found within this later category of highly toxic drugs: the heavy metal drugs. In a recent episode of one my favorite shows, House M. D. , I was caught off guard and bewildered by the conversation between House and his staff on giving a patient with an unknown disease, arsenic in an attempt to cure her. Until then I only knew of arsenic as a very potent poison, something you would use if you wanted to kill something or, dare I say someone, in a discrete manner.
My curiosity was sparked, although not entirely as I thought to myself, “Meh… using a very poisonous metal to cure some disease only happens in TV shows and rarely in real life. ” That was the case until I heard about a seminar titled ‘Heavy Metal Medicine’ presented by the University of British Columbia’s Dr. Chris Orvig. I attended the seminar at first thinking ‘Heavy Metal Medicine’ was just a small field of research fueled by the self interest of a few people. This was quickly changed as Dr. Orvig discussed the relatively new but large and ever growing field of medicinal inorganic chemistry.
My interest quickly grew and I knew I had to learn about this new and revolutionary field focused in using heavy metals in the etiology, diagnosis, and therapy of disease. Metal Based Drugs through the Ages Throughout human history, the practice of medicine has always relied on drugs in some way, shape, or form. Prehistoric medicine incorporated plants (herbalism), animal parts, and physical modifications to alter one’s inner energy (known as Qi in Chinese culture and vitalism in western culture).
However, when thinking about the history of drug use in medical practices, one type of substance is often overlooked: the heavy metals. Indeed, modern pharmacology developed from herbalism (a traditional medicinal practice based on the use of plants and plant extracts) and many drugs today are derived from plants and other biological organisms. Examples include: penicillin (secreted by the fungus Penicillium notatum), aspirin (found in willow barks), and morphine (produced in opium poppies). Yet minerals and metals have been used as medicines for centuries prior to our modern medical system.
Past civilizations have all used metals in their medical practices. Copper was used in Ancient Egypt some 5000 years ago where it was used to sterilize water. Gold was used in a variety of medicines in Arabia and China 3500 years ago and in medieval Europe (although much of its healing power came from the belief that something that rare and beautiful could not be anything but healthy). Heavy metals have also been used in more recent history such as Mercury (II) chloride which was once used to treat syphilis in the 16th to 18th centuries.
An interesting phrase came from the treatment of syphilis, a sexually transmitted disease, with mercury – “A night in the arms of Venus, leads to a lifetime of Mercury” emphasizing the prominent use of the drug at the time. Even arsenic, the notoriously poisonous metal has had its role in medicine. Several arsenic compounds were used as medicines from the 18th to the 20th centuries such as Arsphenamine, which was used to treat syphilis and was also the first modern chemotherapeutic (anti cancer) agent.
However for many of these metallic drugs, detrimental side effects were clearly visible such as with mercury where sometimes the symptoms of its toxicity were confused with those of the syphilis it was believed to treat. It was also known that one could easily become poisoned from the intake of heavy metals; thus the symptoms of ‘heavy metal poisoning’ was described, a disease that still exists today. Metals, the Forgotten Drug Although the use of metals in or as drugs was extensive in many medical practices throughout human history, the focus on metals quickly shrank during the development of the modern medical system in the west.
The system developed in the 19th century in Europe where the gradual shift away from the ‘traditional authority’ approach to medicine (that had been occurring for centuries since the black plague of the 14th century) finally manifested itself (The ‘traditional authority’ approach, in its simplest form, stated that because some prominent person in the past said something must be so, then it was so, and anything observed to the contrary was an anomaly).
Scientific biomedical research was now demanded in medicine and so drugs became of greater importance to the treatment of diseases. It also came under greater scrutiny. Thus due to their high toxicity and clear health detriments, metals were quickly pushed aside in favor of organic compounds, and until recently only a few metallic based drugs were developed. The effect of this shunning away from metals in medicine is still existent to this day where when one thinks of drugs, one thinks of organic compounds.
Compounds produced in organisms which we isolate and purify since they, at certain concentrations, have therapeutic effects on us. However, the role of metals in biological systems during this time was also better understood, as it was discovered that several minerals are necessary for living organisms in many processes. Thus the essential minerals (or dietary minerals) were described. In humans sixteen minerals are known to be required to support human biochemical processes (such as roles in cell structure and function as well as electrolytes).
These include the well known iron (which is necessary component of hemoglobin, the oxygen carrying enzyme of red blood cells), copper (which is needed by several enzymes, especially those involved in redox reactions) and zinc (required for several enzymes including the ever important liver alcohol dehydrogenase, the enzyme responsible for the break down of alcohol into a non toxic form). This understanding has lead to the field of nutritional sciences and since then large numbers of supplements have come into the market.
However despite the gain in knowledge in the importance of essential metals in biological systems, the use of non essential metals and compounds remained largely stagnant in medicine. It was limited to the substances used in the past to which no alternative has been found (such as Arsenic tetroxide which is still used today against leukemia), and in more traditional medicines such as traditional Chinese herbology and Ayurvedic medicine (traditional medicine native to India).
The perception of metals as toxic, though rightly placed, made it quickly lose favor in the medical community, and thus until recently metals fell out of the medical limelight. The Rebirth of Heavy Metal Medicine The idea that metals can be a source of potential medicines was only rediscovered about 30 years ago with the discovery of cisplatin [Pt(NH3)2Cl2] as a anti-tumor drug. (It should be noted that cisplatin was discovered almost accidentally when scientists found that cell division in E.
coli was inhibited when exposed to the products of the electrolysis of a platinum electrode, in their studies on the effects of electric fields on bacterial growth). Since then a whole field known as ‘Medicinal Inorganic Chemistry’ came to be as the search for novel metal-containing drugs began at many universities, research institutes and companies. Since the discovery of cisplatin, research in Medicinal Inorganic Chemistry has substantially diversified.
Elements such as ruthenium, gold, rhenium, titanium, iron and others have entered the field, and some novel metal-based drugs are already in clinical trials or close to being introduced into the market such as a series of platinum and zinc based compounds used against cancer. Dr. James Cowan of Ohio State university stated that “most drugs are designed to inhibit – that is, they will bind to a protein molecule and just block its function… But with metals you have the option of completely destroying the target. ” Such is the case with metallic based drugs today.
Once the reason for their disfavor in medicine, their high levels of toxicity are now taken advantage of, as metal based drugs can efficiently stop cancer cells from spreading and kill them quickly eliminating the diseased tissue from the body. Metal based drugs can also play important roles in the diagnosis of diseases. Lanthanide has recently been described as a potential MRI (Magnetic resonance imaging, a non invasive, non radiative method of looking into the human body) agent which produces higher resolution images.
Due to their molecular weight, magnetic properties and limited abundance in biological systems, metal based substances can be used as probes for better imaging of diseased tissues. This will aid in the diagnosis of several difficult to detect diseases. The applications of heavy metal medicine seem almost limitless. Heavy Metal Medicine, the Future? Still today, pharmaceutical companies tend to make drugs from the same limited set of ingredients, drawing upon only about a half-dozen of the more than 100 known chemical elements (specifically the organic compounds such as carbon, oxygen, hydrogen, etc).
At the same time, drug-resistant bacteria and viruses are emerging, and the chemotherapy drugs used to combat cancers sometimes causes more damage then the cancer itself. By looking into the other 95% of the periodic table we are able to broaden the landscape of drug design. New forms of chemotherapeutics, such as the anticancer agents, metal-mediated antibiotics, antibacterials, antivirals, antiparasitics, and radiosensitizing agents can be created using metal containing complexes.
It is hoped that some of these complexes could destroy a target, and then move on to another, eventually destroying many targets, so a smaller dose of a metal complex could do the work of a larger dose of a traditional drug. Metal based drugs could also be the building block for multi-functional drugs (drugs that work on more than one target). With multi-functional drugs, fewer drugs would need to be taken to cure the same difficult to treat disease which today often require a cocktail of different drugs to be treated. A prime example is HIV which requires as many as ten different pills a day to combat.
The role of cisplatin as the pioneer heavy metal drug can be compared to penicillin as the pioneer antibiotic drug (and we all know how much better our lives have become thanks to antibiotics). Both unsurprisingly were discovered by accident (it’s funny to think what would have happened if the scientists who discovered each one simply just threw away these accidents, seeing them as mistakes instead of something interesting. ) This rediscovery of metal based drugs has opened up a totally new and exciting field in biomedical and pharmacological research.
Although there are still many hurdles to conquer such as: the lack of a procedure in many government drug regulatory agencies for approving the compounds, and the still persistent perception of metals as toxic substances. Both of which still make large drug companies reluctant to invest into heavy metal drugs, thus forcing most of the research into this field to come from smaller companies such as AnorMED and Kinetek Pharmaceutical in British Columbia and in Universities such as those done by Dr. Orvig at UBC.
Still the formation of the field of heavy metal medicine is a revolution back to the days before the modern medical system while still maintaining the ideals of trial and error research. With so many potential usable elements to which the metals represent, new and better medicines are surely just around the corner. Further Readings Sessler, J. L. ed. Medicinal Inorganic Chemistry. London: Oxford University Press, 2005. Alberto, R. ed. Metals in Medicine. London: CHIMA International Journal for Chemistry Vol. 61, 2007