III. TECHNOLOGY MILESTONES IN HEALTH AND MEDICINE

1. 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. Streptococcus bacteria Gerhard Domagk Prontosil Alexander Fleming 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. Penicillium notatum 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

2. 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). 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. Arterioschlerosis