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96 Akira Endo was not yet a teenager when Alexander Fleming won the Nobel Prize in Physiology or Medicine in 1945 for his discovery of antibiotics from the mold Penicillium notatum in 1928. Endo was fascinated by Fleming’s work and got a job with the Sankyo Chemical Company isolating enzymes from fungi and molds for processing fruit juices while he was pursuing his Ph.D. in the early 1960s. In 1966 he went to Albert Einstein College of Medicine in New York to work for two years on cholesterol, which was becoming a major topic of research interest at that time (Landers 2006). After Endo returned to Sankyo, he convinced his supervisor to allow him to search for fungal substances that would inhibit cholesterol synthesis. He and his colleague Masao Kuroda tested thousands of fungal broths in the early 1970s before finding one that worked on the key enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). They found that Penicillium citrinum produced inhibitor(s) of the enzyme and eventually isolated 23 mg of a crystalline material from about 600 liters of culture (Endo 1992). By the end of 1973 they had determined the structure of the active substance, and it became known as mevastatin, since it suppressed the formation of mevalonate, the product of the reaction catalyzed by HMG-CoA reductase. The same substance was isolated from Penicillium brevicompactum in England in 1976 and named compactin (Brown et al. 1976). The drug is variously known as ML-236B, mevastatin, and compactin. When Endo’s group tested their mevastatin on rats, they found it could decrease plasma cholesterol at high doses (20 mg/kg), but the effects were not reproducible. They tried feeding rats a diet supplemented with 0.1 percent mevastatin for a week, but it resulted in no changes in plasma cholesterol. A chance meeting with a colleague provided an opportunity to study the effects of their new inhibitor in a different animal—female chickens. Feeding the hens a diet containing 0.1 percent mevastatin resulted in about a 50 percent reduction 8 Lipid-Lowering Drugs 96 LIPID-LOWERING DRUGS 97 in plasma cholesterol, without affecting diet consumption, body weight, or egg production. Experiments with dogs and monkeys showed it worked in those species as well. They eventually found that rats and mice had an unusual ability to produce several-fold higher levels of HMG-CoA reductase when receiving multiple exposures to the inhibitor, although inhibition was effective with a single acute dose (Endo 1992). In 1977 Endo approached Akira Yamamoto, a physician who was treating patients with familial hypercholesterolemia at Osaka University Hospital in Japan. Endo provided some mevastatin to try on one patient with extremely high levels of plasma cholesterol, beginning with a dose of 500 mg per day. After two weeks the plasma cholesterol level decreased by about 20 percent, but levels of creatine phosphate and transaminase were elevated, and the patient developed muscular weakness (Endo 1992). The adverse effects disappeared when the drug was withdrawn. The drug was then given at 200 mg per day without adverse effects on muscle. There was little detectable change in plasma cholesterol, but after five months the xanthomas (lipid-filled nodules under the skin) and other noticeable traits of the disease were markedly reduced. Preliminary tests in other patients with familial hypercholesterolemia and hyperlipidemia also showed reductions in plasma cholesterol levels over several months at various doses. These early studies were done before internal review boards and other strict regulations became commonplace in clinical trials. When managers at Sankyo saw the results Yamamoto had with hypercholesterolemic patients, they decided to test mevastatin in formal clinical trials. Endo was offered an academic position at Tokyo Noko University. Sankyo management was not pleased with Endo’s departure, and the company rarely mentioned him in its publicity about the discovery of the first statin drug. Endo received recognition for his discovery by winning several awards and prizes, including the 2008 Albert Lasker Medical Research Award. In 1976 the Sankyo Chemical Company entered into an agreement with the pharmaceutical giant Merck and Company, providing Merck with samples and unpublished data regarding mevastatin. Merck scientists repeated the work with laboratory animals and achieved similar results. They soon isolated a mevastatin analog from another fungus, Aspergillus terreus, which they named lovastatin (Endo 1992). Lovastatin was slightly more active than mevastatin at inhibiting HMG-CoA reductase. Endo also had independently isolated lovastatin in his first year at Tokyo Noko...

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