The Story of Orthoclone, Minipress, Ethrane, Forane

Gideon Goldstein, M.D., Ph.D.
Patrick Kung, Ph.D.

Drs. Goldstein and Kung are honored for their discovery of Ortho Biotech's monoclonal antibody to prevent transplant rejections, ORTHOCLONE OKT®3. In the late 1970s, about half of all kidney transplants failed, even when patients were given standard immunosuppressive therapy to prevent rejection. To find out whether the therapy was actually reaching the white blood cells - called "T" lymphocytes - that were attacking the donated kidney, Drs. Goldstein and Kung of Johnson & Johnson's Ortho Pharmaceuticals Corp. created a series of synthetically created, identical antibodies known as the OKT series that would tag and identify these "T" cells. They suspected that one of their novel antibodies, OKT-3, might even clear these cells from the bloodstream and reverse the rejection. Although many in the scientific community doubted monoclonal antibodies could be used for therapy, in August 1981 the New England Journal of Medicine reported that transplant surgeons at the Massachusetts General Hospital in Boston had successfully treated two patients suffering acute rejection of their donor kidneys with the Ortho's experimental product, later trademarked ORTHOCLONE OKT-3. When FDA received the product licensing application for ORTHOCLONE OKT-3 in June 1986, the agency had approved only one biotechnology product - human insulin - as a therapeutic agent. Now, more than a dozen biotechnology drugs and vaccines are on the market.

Hans-Jurgen Hess, Ph.D.
Dr. Hess is honored for his discovery of Pfizer's prazosin (Minipress®), the first of an important new class of antihypertensives. In 1963, when Dr. Hess of Pfizer Central Research began research on prazosin, high blood pressure was one of the world's most serious undertreated diseases, threatening millions of people. Then-available agents suffered from adverse side effects or they soon stopped working as patients developed tolerance, leading some patients to drop out of treatment because hypertension itself is without symptoms. The major existing antihypertensives interfered nonselectively with blood-pressure control mechanisms of the sympathetic nervous system, which affects many areas of body function, including blood pressure. To avoid these effects, Dr. Hess decided to focus on an agent that would act selectively with these control mechanisms. The result was prazosin, the first agent that works by blocking a subpopulation of receptors called the alpha-1 adrenoreceptor, thus confining its action to the smooth muscle cells of the blood vessels. In addition to lowering blood pressure, prazosin does not adversely affect the blood lipid profile - a major risk in coronary heart disease.

Ross C. Terrell, Ph.D.
Dr. Terrell is honored for his discovery of BOC Healthcare's enflurane (Ethrane®) and isoflurane (Forane®), the most widely used inhalation anesthetics in the world. Along with 20th Century improvements, such as fluoroxene, methoxyflurone and halothane, anesthetics have changed the operating room from a chamber of horrors to a place where - today - some 25 million patients a year in the U.S. undergo even the most invasive surgery without experiencing pain. In 1961, Dr. Terrell's challenge was to find an inhalation agent without any of the serious disadvantages of existing agents - odor, narrow margin of safety, slow recovery, numerous side effects, or flammability. As an organic chemist, Dr. Terrell knew what he was looking for: a fluorinated ether to prevent cardiac arrhythmias, with less than four carbon atoms and not more than one oxygen to prevent vaporation. His group synthesized enflurane in 1963, which had nearly all of the properties they sought, and isoflurane in 1979. Since then, the two agents have been used in several hundred million surgeries, including eight out of ten surgical procedures in the U.S. requiring an inhalation anesthetic. In September 1992, the Food and Drug Administration approved desflurane (Suprane), the third major agent discovered by Dr. Terrell's group before his retirement in 1987.

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