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III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.1. Pain and Inflammation Management Morphine Used from the early 1800s to decrease the sensation of pain, morphine was extracted from raw opium. The Hungarian pharmacist Janos Kabay revolutionized morphine production in the 1920s by extracting it not only from the immature poppy-head but from the dry poppystraw. It was studied in 1923 to determine its chemical structure in an effort to synthesize a potent analgesic free from undesirable properties such as addiction and respiratory depression. Understanding how the naturallyoccurring extract worked on the human body allowed a synthetic version of morphine to be developed and subsequent safer drugs to be created, such as nalorphine and naloxone in 1961. Acetylsalicylic acid The thomb of Janos Kabay in Budapest, Hungary Aspirin In 1890, salicylic acid was being manufactured as a cheap and effective inflammation reliever for rheumatoid arthritis, despite its unpleasant side effects (nausea, gastric catarrh). Acetylsalicylic acid (or aspirin) was synthesized in 1897 by the German chemist Felix Hoffmann at Bayer and tested pharmacologically by Heinrich Dreser. Production started in 1899 and the first pills were sold in 1900. Aspirin soon became popular because it had far fewer side-effects than salicylic acid. Aspirin, the first medicine to be produced at and industrial level, is still manufactured in large quantities today. Aspirin was consumed mainly as an anti-headache drug until the mid-eighties, when its beneficial effects in preventing heart attacks were discovered. Cortisone In the 1940s, studies of the adrenal gland cortex identified that certain naturally-occurring hormones (also called steroids) as having anti-inflammatory properties. First isolated from its natural source in 1936, cortisone was later synthesized by the American Lewis Hastings Sarett in 1948. It was already being commercially manufactured in the next year due to its miraculous affect on rheumatoid arthritis. Subsequent clinical studies showed that it did not cure arthritis, and triggered serious side effects, but enjoyed additional uses in asthma and allergy treatments. Further studies of steroid synthesis led to the creation of prednisone, prednisolone, and dexamethasone as better antiinflammatory agents with reduced side effects. Lewis Hastings Sarett Deformity induced by joint inflammation III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.2. Psychotherapeutic Agents Chlorpromazine Chlorpromazine (Thorazine, Hibernal) was first used to treat schizophrenia in 1954, after its original creation as an antihistamine anti-allergic. This new therapy proved itself dramatically effective and heralded the modern era of antipsychotic therapy. Controlling mental illness through medication soon supplanted earlier treatment methods, such as electroshock, insulin shock, prefrontal lobotomy (a surgical treatment disconnecting prefrontal hemispheres), and helped to decrease the rate of institutionalization worldwide. Later research shed light on the pharmacological mechanism of chlorpromazine and served as a basis for the development of many other anti-psychotic drugs, such as Haloperidol and Olanzapine. Pictures from the film: One Flew Over the Cuckoo’s Nest (1975), which portrays the disastrous effects of mental illness The onset of depression following labour Tricyclic antidepressants In 1958, a clinical study of Imipramine, a drug which was originally developed as an antipsychotic, revealed its antidepressant properties. It functions therapeutically by affecting the activity of neurotransmitters (stimulus transmitting agents) in the brain. The many subsequent drugs that were developed in this class became collectively known as `tricyclic’ antidepressants. Tricyclic antidepressants soon become the standard of therapy for this dehabilitating disease. Benzodiazepines In 1959, Chlordiazepoxide (Librium) launched a potent new class of anti-anxiety agents, the benzodiazepines. This drug and its subsequent derivatives rapidly replaced barbiturates and Meprobamate, an earlier, moderately successful anxiolytic agent discovered in 1950, and are considered to be some of the most successful drugs of this era. The highly tolerable and safe benzodiazepines also proved successful as hypnotic agents, muscle relaxants, and as a treatment for epilepsy. Neurotransmitters in the brain III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.3. Hormones and Hormone Regulators Insulin Insulin, a protein hormone produced by special cells of the pancreas, controls the level of blood sugar (glucose) in the body. Lack of insulin leads to the development of type 1 diabetes, a disease that was considered fatal until the early 1920s. Two young Canadian doctors, Frederick Banting and Charles H. Best, isolated and purified a new injectable extract from bovine pancreas in 1921. Their first patient was a dying 14-year-old boy, who was released from the hospital after a few weeks. Insulin was manufactured from bovine pancreas by Eli Lilly and Company in 1922. The first insulin engineered from human sources using recombinant DNA technology was produced in 1982. Frederick Banting and Charles H. Best in a painting Testosterone Testosterone is responsible for the development of the male sexual organs and secondary sexual characteristics. It is a steroid hormone, structurally similar to cholesterol. Testosterone was first synthesized from cholesterol in 1935 to treat hormone deficiency diseases. Testosterone can be manufactured by chemical and microbiological modification of readily available naturally-occurring materials. Progestins, estrogens and oral contraceptives In the 1930s, two female hormones were isolated and produced from natural sources, the urine of pregnant mares and the Mexican sweet root. Progestins (progesterone, luteal hormone) were discovered to maintain gestation, and estrogens (follicular hormones) were understood to affect menstrual cycles. In the 1950s, synthetic versions of these hormones were produced and their effects on human conception and pregnancy were studied. Their excellent contraceptive qualities led to the development of oral contraceptives (birth control pills) for women. Enovid, marketed in the USA in 1960, was the first birth control pill to contain a mixture of estrogens and progestins for maximum effectiveness. III.4. Gastro-intestinal Agents Evolution of ulcer therapy In 1972, James Black, a Scottish pharmacologist, and his colleagues at Smith, Kline & French shed light on the basis of surplus acid secretion in the stomach. This type of pharmaceutical research is now known as “rational drug design”. By 1976, they developed the drug Cimetidine (Tagamet) which inhibits gastric acid secretion with minimal side-effects, and its widespread use for gastric ulcers dramatically decreased the need for surgery. Tagamet soon became medicine’s most frequently prescribed drug. III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.5. Medical Testing and Disease Diagnostics Medical imaging technologies Devices such as x-ray machines and MRI (magnetic resonance imaging) scanners, revolutionary at the time of their discovery, are now a routine part of medical diagnosis and care. Wilhelm Konrad Roentgen, the German physicist who discovered x-rays in 1895, first produced an image of the bones in his wife’s hand. By 1900, every large hospital had an x-ray machine. Nuclear magnetic resonance (NMR) technology was used to determine chemical structures in the 1970s, and Magnetic Resonance Imaging scanners were approved for human use in 1985. Chemical contrasting agents and special film emulsions improve the diagnostic value of x-rays, CT scans (three-dimensional x-ray imaging, computer tomography), and MRI and ultra sound images. The transilluminated hand of Ms.Roentgen Medical isotopes Medical imaging has been much aided by the use of medical isotopes to determine the function of internal organs, following the pioneering work of Georg Hevesy, the Hungarian Nobel Laureate (1943). In 1935 Hevesy determined the phosphor metabolism mechanism using radioactive nuclides. Compounds are labeled with radioactive isotopes (such as technetium-99m and thallium-201) or radio-opaques (such as barium and iodine compounds). The radio-labeled compounds can then be tracked through the body by gamma-detecting cameras to provide useful images of the organs to which they are transported. The diagnostic applications of medical isotopes include tumor detection, diagnosis of liver disease, and the stress test for cardiac function. Development of chemical assays Today, we determine medical conditions by studying disease markers or drugs residues that can be chemically detected in blood, urine, feces, saliva, and perspiration. Laboratory testing, sophisticated computer-assisted analytical instruments, and at-home testing all measure fundamental chemical reactions. In the early 19th century, diagnoses was based on observing clinical symptoms; if a patient responded positively to a disease-specific treatment, then he or she must have the disease. Diagnostic testing began in 1882 when Paul Ehrlich observed that only the presence of typhoid bacillus (as identified by a certain dye) could prove a diagnosis of typhoid fever. Before, the diagnosis was based on the color of the patient’s skin. Evolution of personal monitoring Simplified at-home test kits facilitate the personal monitoring of human health. For example, diabetic patients once had to visit a laboratory to determine if sugar was present in their urine. In 1941, Miles Laboratories introduced the first convenient sugar-in-urine assay for home use. Although difficult to develop, dip-and-read urine tests were finally introduced in 1956. In the 1960s, the first portable, battery-operated blood glucose meter was introduced to work with chemical sticks to detect the glucose, considerably improving the quality of life for diabetic patients. In the 1970s and 1980s, home-use diagnostic kits for fecal occult blood, ovulation, pregnancy, and strep were introduced. III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.6. Anti-infective Drugs Salvarsan and Prontosil Paul Ehrlich, the German bacteriologist, studied arsenic compounds for their anti-bacterial properties and invented Salvarsan in 1909 as a successful treatment for the fatal, sexually transmitted disease, syphilis. This strategy was followed by other researchers to find active compounds for combating infectious diseases. The first sulfa drug, Prontosil, which was formerly used as a textile dye, was discovered in 1932 as chemists searched for an antibacterial drug that could cure the deadly streptococcal infection, a common cause of chronic pneumonia. This discovery was so important that the German biochemist Gerhard Domagk received the 1939 Nobel Prize in medicine for his work in this area. The active antibacterial agent of Prontosil was later discovered to be sulphanilamide. Many other antibiotics were then created from this agent, including Sulphapyridine in 1938. The sulfa drugs were dramatically successful in reducing the mortality rate of lobar pneumonia in the 1940s, and saved the lives of millions. Their importance declined only with the advent of the Penicillin era. Alexander Fleming Penicillium notatum Gerhard Domagk Streptococcus bacteria Prontosil Penicillin In 1928, the Scottish bacteriologist, Alexander Fleming, discovered a potent substance that could kill bacteria, which he isolated from a naturally occurring mold (Penicillium notatum). Penicillin, a drug based on this natural substance, was created during a massive wartime project in 1943; it dramatically reduced infection and amputation among injured soldiers in the American and British armies throughout World War II. This natural Penicillin was so expensive and rare that it had to be recycled from the urine of the treated patients. Chemists attempted a new method of synthesis: to artificially manufacture the natural substance on which the drug was based. The chemical structure of penicillin was determined by the British researcher, Dorothy Crowfoot Hodgkin in the 1940s, enabling its synthesis. By 1957, several pharmaceutical companies synthesized and commercially produced this drug. Their success heralded the beginning of the modern era of antibiotic therapy. Zidovudine (AZT) Zidovudine (AZT) was approved in the United States for the treatment of Human Immunodeficiency Virus (HIV) infection in 1987. This drug was first synthesized in 1964, but proved ineffective as a cancer chemotherapeutic. It was abandoned until 1986, when its activity against retroviruses was discovered by an American research group. AZT and related nucleoside drugs inhibit viral replication by targeting specific viral enzymes. Because of the rapid development of HIV’s drug resistance, first demonstrated with AZT, mono-drug therapy can no longer be used to treat HIV infection. Zidovudine crystals Zidovudine III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.7. Cardiovascular Management Regulating heart beat The ability of the local anesthetic Procaine to regulate the heart beat (also called anti-arrhythmic activity) was discovered in the 1930s. This type of pharmaceutical treatment is complex and can be quite difficult because the drugs that block arrhythmia can also cause arrhythmia under certain conditions. Procaine was the first of many drugs that were eventually approved for this use. Procaine inhibits the cell membrane proteins known as sodium channels. Procaine was followed by numerous drugs, including beta-blockers and potassium or calcium channel antagonists. Treating heart failure Digitalis glycosides, a group of compounds that occur naturally in a number of plants, have been used to treat heart failure for centuries. After research identified how they increase the force with which the heart contracts, Digoxin was extracted from the leaves of grecian foxglove (Digitalis lanata) and approved in 1954 to treat atrial fibrillation and congestive heart failure. It was eventually discovered that anti-hypertensive drugs can also be used to treat heart failure. Busting blood clots Heparin, a natural product isolated from animal livers, was first used to precent thrombosis (blood clotting) during a blood transfusion in 1935, and soon became the most commonly-used anticoagulant (also called a blood thinner). It also prevents clot formation during cardiac and arterial surgery. Wafarin (Coumadin) an orally-active anticoagulant that prevents strokes and treats heart attacks and thrombosis, was approved in 1955. During the 1970s, it was discovered that even once clots have formed, they can be treated with thrombolytics. Utilizing enzyme activity to dissolve blood clots led to Urokinase (1977), streptokinase (1978), and the genetically engineered recombinant tissue plasminogen activator, tPA (1987). Arterioschlerosis Controlling blood cholesterol levels The buildup of cholesterol deposits inside arteries (arteriosclerosis) is a major cause of coronary heart disease and strokes. Lovastatin (Mevacor) which controls blood cholesterol levels (hypolipemic activity) by inhibiting a critical enzyme from being converted into mevalonate, an early and rate-limiting step in cholesterol biosynthesis, was approved in 1987. Subsequent and more potent drugs, such as Simvastatin and Atorvastatin, have revolutionized the treatment of high level of lipids in the blood (hyperlipidemia) by being highly effective and well tolerated. III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.8. Cancer Chemotherapy Evolution of cancer chemotherapy The use of chemicals to treat cancer (cancer chemotherapy) began in 1942 with the clinical use of nitrogen mustards by Louis S. Goodman and Alfred Gilman. Drugs which block folic acid (also called antimetabolites) were also developed. Aminopterin (1947) was effective against leukemia, but its adverse effects on white blood cells quickly led to its replacement by methotrexate. In the 1950s, George Hitchings and Charles Heidelberger developed the antimetabolitic mercaptopurine for leukemia and Fluorouracil for gastrointestinal and breast tumors. Cytotoxic drugs Cytotoxic drugs (or drugs which are poisonous to cells) were isolated from plants and first introduced into cancer chemotherapy in 1963. These anti-cancer drugs work on the principle that rapidly proliferating cells, such as neoplastic (or cancerous) ones, are more susceptible to damage by cytotoxic drugs. Several variations include vinca alkaloids (vincristine and vinblastine) isolated from periwinkle plants and podaphylotoxin isolated from mayapple in 1970. Taxol was isolated from the pacific yew in 1971 and developed to treat advanced breast cancer and lung cancer in the early 1990s. Tamoxifen Tamoxifen, a synthetic molecule developed in 1971, was introduced in 1977 to treat breast cancer by slowing the growth of estrogen-dependent tumors. High estrogen levels promote the cell proliferation in breast tissue, so this type of chemotherapy blocks the natural hormones that can stimulate growth of cancer cells. Megestrol is a synthetic derivative of the naturally occurring steroid hormone, progesterone, which functions in a similar manner and is used in the treatment of recurrent breast tumours. Mammographic image of a breast tumour Personal monitoring of breasts promotes early diagnosis III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE III.9. Novel Healthcare Materials Artificial limbs and medical devices Modern artificial limbs and organs, replacement joints, contact lenses and hearing aids, and biomaterials which are crafted from specialized plastics and other high-tech materials have all been produced through chemistry. By manipulating the structures of molecules and creating new ones, chemists and engineers have developed new medical materials that are strong, flexible, and durable. A few such medical devices include the 1945 artificial kidney, the 1950s prosthetic heart valves, and the 1982 surgical implantation of a permanent artificial heart. Plastic contact lenses were introduced in 1956, and soft bifocal contacts were refined in 1985. Artificial heart valves Artificial heart Medical equipment Chemistry is used to manufacture nearly all of the plastic and vinyl medical devices used in today’s hospitals and health care clinics. Today’s medical equipment must be durable enough for daily use while helping to create a clean, sterile, and germ-free environment. Many routine medical processes utilize state-of-the-art diagnostic equipment, stethoscopes, bandages and other novel fabrics, syringes, surgical instruments, blood bags, and plastic supplies that are produced through chemistry. Even diapers contain hygroscopic polymers that prevent inflammation of the sensitive skin of babies. Disinfectants and bleach Chemistry makes it possible to sanitize your home, breakdown mold and mildew, and remove stains. In the early 1900s, chemists focused on controlling bacteria and cleaning clothes and home surfaces effectively. In 1913, researchers developed a formula for bleach that was affordable and easy to use. Today, bleach is a household commodity and an effective disinfectant which eliminates billions of germs and bacteria. Chlorine is also a powerful weapon against diseases caused by viruses and bacteria in homes, hospitals, and other buildings. Ignatius Semmelweis, the Hungarian gynecologist, was the first to introduce hand washing with chlorine water to his department in 1847.