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GEORGE CONSTANTIN COTZIAS June 16, 1918-June 13, 1977 BY VINCENT P. DOLE GEORGE CONSTANTIN COTZ1AS was born in the city of Chania on the island of Crete, the elclest chilcl of Constantin and Catherine Stroumboli Cotzias and the grandson of George ]. Cotzias, a wealthy merchant in Athens. His father, Constantin George Cotzias, a lawyer and journalist, hack re- cently been banished from Athens because of political ac- tivity in support of the king. He was arrested by the fascist government of Eleftherios Venizelos and exiled to Crete to limit his political influence, but he was able to return to Athens eighteen months later. Soon after returning he es- tablishecl an influential newspaper and an advertising agency. Twelve years later, in 1932, he became president of the Greek chamber of commerce and in 1934 was elected mayor of Athens. As mayor and later in the expan(led role of governmen- tal minister for all municipal activities in the region of Greater Athens, Constantin Cotzias shaped the political structure of the modern city of Athens. He reorganized its government, initiates! programs of health anct public works, rebuilt the municipal hospital, paved roads, creates! parks, supported young artists, ant! established a new municipal symphony orchestra. 63

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64 B I O G RA P H I C A L EMOIRS This productive period was terminated abruptly by the Invasion of Greece in 1940. After an intense but brief resis- tance, the Greek armies were defeatecI. The prime minister, ATexanciros Koryzis, refusing to acknowlecige defeat and collaborate, committed suicide. in this extremity, King George of Greece asked Constantin Cotzias to go to the United States as ambassaclor-at-large representing the Greek gov- . — ernment In em e. · . George and his family arriver! in New York in August 1941, financially destitute after a desperate four-month jour- ney through warring countries. They remained in New York until the c3 efeat of the Axis powers in 1945 mac3 e it possible for his parents to return. To complete this account, Constantin Cotzias was reelected mayor of Athens by an overwhelming majority in the first postwar election (1951), but he diec! shortly afterwards of a heart attack at the age of f~fty-nine while resuming his municipal duties. Cotzias Square, next to the town hall of the city of Athens, bears his name. As the eldest son of a leacling citizen of Athens prior to these events, George Cotzias had a privilegecl early life, at- tencling the best schools en c! associating with the most stimu- lating intellectuals of the city. Reflecting George's mother's interest in literature, the Cotzias home was a meeting place for leacling writers of prewar Athens and, of course, as the mayor's residence, it was at the epicenter of public policy. At the age of twenty-two, within one year of graduating from medical school, George apparently was on his way to an uneventful career as a meclical practitioner in Athens, specializing in surgery. He had become an assistant to the professor of surgery, Xenophon Kondiades. However, the invasion of Greece changed all plans. George immecliately volunteerecl for military service, although as a medical stu-

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GEORGE CONSTANTIN COTZIAS 65 clent he was exempt from the ciraft. At the request of Pro- fessor Koncliacles, heading a surgical team at a hospital close to the Albanian front, he was assigned to this unit, but while he was in transit the hospital was obliterated by bomb- ing, which killer! the entire staff. Military resistance col- lapse(1 before the advancing German army. George macle his way back to Athens, rejoined his family, and left Greece with them. After arriving in New York in 1942, George applied for admission to meclical school to complete his studies. The rejection by Cornell was unequivocal; not only was he found to be deficient in English, he was toIcl that his education in Athens hac! proviclec! inadequate training in basic biochem- istry, pharmacology, and physiology. He would need fur- ther premeclical training even to be eligible for admission to the first year of medical school. Applications to Colum- bia, New York University, Johns Hopkins, ant! Pennsylvania were equally fruitless. Reminiscing in later years, George recalled critical advice that his father gave him at this low point. "When ~ ran for the office of councilman, ~ was defeated. So ~ ran for mayor and was elected. Choose the reacting meclical school in the country and apply there." With this advice George applied to Harvarc! Medical School and had the good fortune to be interviewed by Soma Weiss, a brilliant professor of medi- cine anct himself a refugee a decacle earlier from Nazi op- pression. After a Tong conversation in German, which George spoke fluently, Weiss recommenclecl that he be admitted conditionally to the third year of study at the medical school. Two years later he gracluated from Harvard cum laucle. He then trained as an intern in pathology at Brigham Hospital, as an intern in medicine at Massachusetts General Hospi- tal, and was a resident in neurology at Massachusetts Gen- eral Hospital.

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66 BIOGRAPHICAL MEMOIRS This brings the story to the point at which ~ first knew George Cotzias. During the four years of WorIcI War TI, it was my good fortune to be assigned to a naval meclical research unit based at the hospital of Rockefeller Institute (now Rockefeller University) ant! to work in the clepart- ment of D. D. Van Slyke. With the end of the war and demobilization, T left Rockefeller and returned to Massa- chusetts General Hospital, where five years earlier ~ hac] trained in medicine. Shortly afterward to my great surprise ant! delight, the director of the Rockefeller Hospital, Tho- mas Rivers, invites! me to return to Rockefeller. He asked me to form a new department, replacing that of Van Slyke, who planned to move to Brookhaven National Laboratory the following year. My first act was to invite Lewis Dah! to join me; DahI, a scholarly physician and friend, who was completing a tour as senior medical resident at Massachusetts General Hospi- tal, agreed. Within the hour George burst into my office anct announced explosively, "I'm coming, too." This unusual application conic! have been counterproductive, but fortu- nately Dah! tract worked with Cotzias and gave him an en- thusiastic endorsement. Immecliately ~ had two taTentecI as- sociates with whom to start the department, the only clifficulty being there was no space for the new laboratory immecli- ately available at Rockefeller. At Rivers's suggestion, my two associates were assigned to Van Slyke's group cluring his final year (an invaluable experience for them), and ~ started my new career as department head with a year's sabbatical . . In ~ urope. The five years after my return were busy ones. We stucT- iec! hypertensive patients, looking for clues to the nature of this disorcler in disturbances of salt metabolism and energy balance. George, in acIdition to loyal work as a team mem- ber in the clinical studies, became interested in the me-

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GEORGE CONSTANTIN COTZIAS 67 tabolism of amines in the tissues. He reasoned that cat- echolamines, cliamines, and histamine have powerful vaso- motor effects that might be relevant to hypertensive disor- ders. In particular, he clirected his attention to the enzymes that limit their biological activity by oxidizing them. George thus initiated studies that led him some fifteen years later to the demonstration that T-DOPA (the amino acid I-clihyciroxy phenylalanine) was effective in giving symp- tomatic relief to patients with clisabling Parkinsonism. The most important of these studies were concluctec! after he left my department in 1954. Dab! left at the same time, both having outgrown the limited opportunities for acivance- ment at Rockefeller. They transferred their work to Brookhaven National Laboratory, where Van Slyke mean- while hacl established a strong mectical division an c! was able to provide space and support for each to develop an active, inclependent laboratory. The move to Brookhaven also provident George with a new resource for metabolic studies, namely a cyclotron. When activated by a beam of high-energy neutrons, trace metals in samples of tissue en cl bloocI can be cleterminec] with un- prececlentec! sensitivity and specificity. George seized the opportunity. In a series of basic studies over the following clecacle, he eTuciciatec! the distribution, absorption, elimina- tion kinetics, ant! probable function of manganese. At the same time he became interested in its toxicity, manifest especially in the neurological symptoms of Chilean miners excavating manganese ore. As a neurologist he was impressed by the similarity of the symptoms to those of classical Parkinson's disease frigidity, retardation of motion, trem- ors, lack of coordination, en c! as a pathologist he was at- tractect by the opportunity to correlate specific structural lesions made by a known toxin to disturbances of brain function. In both clisorclers the main lesions found in the

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68 BIOGRAPHICAL MEMOIRS brain involve the substantia nigra, a region made conspicu- ous by a deposit of dark melanin pigment. It was known that this region of the brain is rich in the neurotransmitter clopamine and also that both melanin and clopamine are clerivec! from common precursors. Further, it was known that this region is deficient in both substances in patients with Parkinson's disease. A possible remedy, as was evident to several investigators at the time, is to increase the supply of clopamine to the neurones in this region. However, clopamine administered as a medication (orally or by injection) cannot reach the site in significant concentration because it does not pass the blood-brain barrier. As an alternative, one can Took for precursors of dopamine that are not excluded by the bar- rier, administer them in large closes, and hope that when the molecules arrive at the critical site enough will be con- verted into dopamine to have a therapeutic effect. Other investigators had pursued this idea with little success, al- though the validity of the approach was shown by the tran- sient benefit seen after injection of the precursor, clihydroxy- phenylalanine (DOPA). But this effect was only of theoretical interest. It was not of practical value as a treatment because of the severe toxicity associated with the injection. Cotzias, at this point, made a critical observation that converted the transient response into a successful, large- scale treatment. By starting with very small closes of DOPA, given orally every two hours under continued observation, and graclually increasing the dose over a perioc! of several weeks as permitted by the clevelopment of tolerance, he was able to stabilize patients on large enough closes to cause a dramatic remission of their symptoms. He further im- provecl the treatment by utilizing the active isomer, T-DOPA, recognizing that the inactive isomer, cI-DOPA (which con- stitutes 50 percent of the dose in a racemic mixture) is

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GEORGE CONSTANTIN COTZIAS 69 responsible for 50 percent of the toxicity but contributes nothing to the therapeutic result. The result was soon confirmed by other investigators and has now become the stanciarc! treatment for Parkinsonian symptoms. To his credit, Cotzias realizer! that this success was only one step toward a definitive treatment. After hav- ing a remission, many patients show a disturbing tendency to relapse, even with continued treatment, or to clevelop movement disorders. He therefore was engaged cluring the last clecade of his life in testing supplementary treatments, especially those utilizing structural analogs of (lopamine (like apomorphine) that could penetrate the blood-brain barrier and substitute for dopamine without having to be converted by local enzymes. By a remarkable coincidence, his early interest in the function of bioactive amines in tissues and his subsequent investigations of the toxicity of manganese converged on this problem. Cotzias was at work on the de- velopment of new medications when his career was termi- nated by lung cancer. Like his father, he diec! at age fifty- nine, before his work was finished. George was a large man physically and intellectually- restless, fiercely loyal, informed, intuitive, quick in conver- sation with an infectious laugh that began as a furtive chuckle ant! grew into a roar. Basically he remained! the intense young medical resiclent who burst into my office in 1946 announcing, "I'm coming, too." He is survived by his widow, Betty, and a son, Constantin George Cotzias. Among the honors ant! awards receiver! by George Cotzias were election to the National Academy of Sciences (1973), election to the American Academy of Arts and Sciences (1970), the A. Cressy Morrison Awarc! in Natural Sciences (1954), the Albert Lasker Awarc! in Clinical Meclical Re- search (1969), the Borden Award of the Association of Ameri- can Medical Colleges (1972), and the annual aware! of the

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70 BIOGRAPHICAL MEMOIRS American College of Physicians (19741. He receiver! honor- ary degrees from Catholic University, Santiago ~ ~ 969~; Women's Medical College of Pennsylvania (1970~; St. founds University, New York (1971~; ant! the National University, Athens (1974~.

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GEORGE CONSTANTIN COTZIAS SELECTED BIBLIOGRAPHY 1947 71 With W. H. Sweet, I. Seed, and P. Yakovlev. Gastrointestinal hemor- rhages, hyperglycemia, azotemia, hyperchloremia and hypermatremia following lesions of the frontal lobe in man. In The Frontal Lobes, ed. J. F. Fulton, C. D. Aring, and S. B. Wortis, vol. 27, pp. 795- 822. Baltimore: Williams & Wilkins. With G. I. Lavin and D. D. Van Slyke. Observations on normal and pathologic kidney tissue with ultraviolet photomicrography. Acta Med. Scand. (Suppl.) 196:259. 1949 With I. H. Baxter. Effects of proteinuria on the kidney. Proteinuria, renal enlargement and renal injury consequent on protracted parenteral administration of protein solution in rats. i. Exp. Med. 89:643-67. 1950 With V. P. Dole, L. K. Dahl, H. A. Eder, and M. E. Krebs. Dietary treatment of hypertension. Clinical and metabolic studies of pa- tients on the rice-fruit diet. [. Clin. Invest. 29:1189-1206. 1951 With V. P. Dole, L. K. Dahl, D. D. Dziewiatkowski, and C. Harris. Dietary treatment of hypertension. II. Sodium depletion as re- lated to the therapeutic effect. J. Clin. Invest. 30:584-95. With V. P. Dole. A nomogram for the calculation of relative cen- trifugal force. Science-113:552-53. With V. P. Dole. Metabolism of amines. I. Microdetermination of monoamine oxidase in tissues. J. Biol. Chem. 190:665-72. With V. P. Dole. Metabolism of amines. II. Mitochondrial localiza- tion of monoamine oxidase. Proc. So c. Exp. Biol. Med. 78:157-60. 1952 With V. P. Dole. The activity of histaminase in tissues. /. Biol. Chem. 196:235-42. Monoamine oxidase: substrates and inhibitors. In Transactions of the

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72 BIOGRAPHICAL MEMOIRS Second Conference on Shock and Circulatory Homeostasis, ed. H. D. Green. New York: Josiah Macy, tr., Foundation. 1953 With V. P. Dole, L. K. Dahl, I. L. Schwartz, I. H. Thaysen, and C. Harris. Dietary treatment of hypertension. III. The effects of pro- tein on appetite and weight. i. Clin. Invest. 32:185-91. 1954 With L. K. Dahl and B. G. Stall III. Metabolic effects of marked sodium restriction on hypertensive patients; changes in the total exchangeable sodium and potassium. {. Clin. Invest. 33:1397-1406. With H. A. Eder, FI. D. Lauson, F. P. Chinard, R. Greif, and D. D. Van Slyke. A study of the mechanisms of edema formation in patients with the nephrotic syndrome. [. Clin. Invest. 33:636-56. With I. Serlin and I. I. Greenough. Preparation of soluble monoam- ine oxidase. Science 120:144-45. 1955 With L. S. Maynard. The partition of manganese among organs and intracellular organelles of the rat. [. Biol. Chem. 214:489-95. With I. Serlin. Microdiffusion of acetic acid as an assay for acetyl- cholinesterase. [. Biol. Chem. 215:263-68. With L. S. Maynard. The study of certain phases of cell dynamic states with short lived isotopes as exemplified by Mn56 partition studies in organs and intracellular organelles. In Proceedings of the International Conference on Peaceful Uses of Atomic Energy, vol 12, pp. 444-46. Geneva: United Nations. With L. K. Dahl and B. G. Stall. Metabolic effects of marked sodium restriction in hypertensive patients. Skin electrolyte losses. J. Clin. Invest. 34:462-70. 1957 With I. Serlin. State of tissue acetylcholinesterase as determined by Cobalt60 gamma radiation inactivation. Radial. Res. 6:55-66. 1958 With J. I. Greenough. Concomitant analysis for oxygen uptake and

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GEORGE CONSTANTIN COTZIAS 73 ammonia evolution during the monoamine oxidase reaction. Arch. Biochem. Biophys. 75:15-23. With J. J. Greenough. Specificity of the manganese pathway through the body. [. Clin. Invest. 37:1298-1305. With D. C. Borg. Manganese metabolism in man: rapid exchange of Mn56 with tissue as demonstrated by blood clearance and liver uptake. [. Clin. Invest. 37:1269-78. Manganese in health and disease. Physiol. Rev. 38:503-32. With A. l. Bertinchamps. Dosimetry of radioisotopes. Science 128:988- 90. With D. C. Borg. Incorporation of manganese into erythrocytes as evidence for a manganese porphyrin in man. Nature 182:1677-78. 1959 With A. I. Bertinchamps and l. I. Greenough. Thirst for bile in rats with bile fistulas. Nature 184:1405. With I. l. Greenough. Quantitative estimation of amineoxidase. Na- ture 183:1732-33. Diagnostic uses of radioisotopes. Symposium and panel discussion on the uses of radioisotopes in clinical practice. NY State I. Med. 59:18. 1960 With J. J. Greenough. Dependence of periodic activation and inhi- bition of monoaminoxidase by aliphatic compounds upon chain- length. Nature 185:384-85. Metabolic relations of manganese to other minerals. Symposium on Interactions of Mineral Elements in Nutrition and Metabolism. Fed. Proc. 19:655-58. With D. C. Borg and A. I. Bertinchamps. Clinical experience with manganese. In Metal-Binding in Medicine, ed. M. I. Seven and L. A. Johnson, pp. 50-58. Philadelphia: Lippincott. 1961 Manganese versus magnesium: Why are they so similar in vitro and so different in viva? Fed. Proc. pt. II, suppl. 10, 20:98-103. With P. S. Papavasiliou. Neutron activation analysis: the determina- tion of manganese. [. Biol. Chem. 236:2365-69.

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74 BIOGRAPHICAL MEMOIRS With D. C. Borg and B. Selleck. Specificity of the zinc pathway in the rabbit: zinc-cadmium exchange. Am. f. Physiol. 201:63-66. With D. C. Borg and B. Selleck. Virtual absence of turnover in cadmium metabolism: Cdi09 studies in the mouse. Am. f. Physiol. 201 :927-30. With D. C. Borg, A. i. Bertinchamps, E. R. Hughes, and P. S. Papavasiliou. Nuclear studies in medicine: manganese metabolism. In Sympo- sium Nublear under Klinike (with special reference to cancer and cardiovascular diseases) Wissenschaftliche abhandlungen der arbeitsgemeinschaft fur forschung des lances nordrheinwestfalen, ed. L. E. Farr, et al., vol 18, pp. 49-58. Koln: Westdeuchen Verlag. With D. C. Borg, E. R. Hughes, A. J. Bertinchamps, and P. S. Papavasiliou. Phenothiazine: curative or causative in regard to Parkinsonism? In Symposium on the Extrapyramidal System and Neuroleptics, ed. }-M. Bordeleau, vol. 20, pp. 193-98. Montreal: University of Montreal. With E. R. Hughes. Adrenocorticosteroid hormones and manga- nese metabolism. Am. f. Physiol. 201 :1061-64. 1962 With G. C. Borg and B. Selleck. Specificity of the zinc pathway through the body: the turnover of Zn65 in the mouse. Am. f. Physiol. 202:359-63. With E. R. Hughes and E. P. Cronkite. Total body irradiation and manganese metabolism. Nature 193:792-95. With D. C. Borg. Interaction of trace metals with phenothiazine drug derivatives. I. Structure-reactivity correlations. II. Forma- tion of free radicals. III. Theoretical part. Proc. Natl. A cad. Sci. U.S.A. 48:617-42. With P. S. Papavasiliou. State of binding of natural manganese in human cerebrospinal fluid, blood and plasma. Nature 195:823-24. Manganese. In Mineral Metabolism: An Advanced Treatise, ed. C. L. Comar and F. Bronner, vol. II, pt. B. pp. 403-42. New York: Aca- demic Press. With D. C. Borg. Phenothiazines and manganese. In Ultrastructure and Metabolism of the Nervous System, ed. S. R. Korey, A. Pope, and E. Robins, vol. XL, p. 337. Baltimore: Williams & Wilkins. 1963 With P. S. Papavasiliou and S. T. Miller. Neutron activation analysis:

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GEORGE CONSTANTIN COTZIAS 75 clinical and biological studies of manganese. In Third Colloque International de Biologie de Saclay, pp. 287-306. 1964 Trace metals: essential or detrimental to life? Brookhaven Lecture Series, vol. 26, pp. 1-14. With M. H. Van Woert. Manganese poisoning new insights. Lima, Peru. Oct. 1963. Revista de Neuro-Psiquiatria, pp. 392-404. With P. S. Papavasiliou. Primordial homeostasis in a mammal as shown by the control of manganese. Nature 201:828-29. With B. M. Patten, A. Sakamoto, M. H. Van Woert, and P. S. Papavasiliou. Tremorine induced tremor versus extrapyramidal disease. Nature 201 :929-30. With P. S. Papavasiliou and S. T. Miller. Manganese in melanin. Nature 201:1228-29. With P. S. Papavasiliou. The specificity of the zinc pathway through the body: homeostatic considerations. Am. i. Physiol. 206:787-92. With P. S. Papavasiliou, M. H. Van Woert, and A. Sakamoto. Mel- anogenesis and extrapyramidal diseases. Fed. Proc. 23:713-18. Der Manganmetabolismus und seine Storungen. Nlerhandlungen der Deutschen Gesellschaft fur innere Medizin, 70:327-30. German Society of Internal Medicine, Wiesbaden. Transport, homeostasis and specificity in trace metal metabolism. In Proceedings of the Sixth International Congress of Nutrition, pp. 252-69. Edinburgh: E. & S. Livingstone. 1965 With K. N. Prasad and H. A. Johnson. A cytoplasmic organelle of melanocytes. Nature 205:525-26. With K. N. Prasad. A nomogram for the estimation of microcuries and millimicrograms from cpm. [. Nucl. Med. 6:297-99. With E. Homsher. Antidiuretic hormone and bile flow. Nature 208:687- 88. With M. H. Van Woert. Possible roles of melanin in some extrapyra- midal functions. In Monographs Biology and Medicine, p. 95. New York: Grunne & Stratton. With M. H. Van Woert and A. R. Nicholson. Functional similarities between the cytoplasmic organelles of melanocytes and the mito- chondria of hepatocytes. Nature 208:810-11.

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76 BIOGRAPHICAL MEMOIRS 1966 Manganese, melanins and the extrapyramidal system. [. Neurosurg. 24:170-80. With M. H. Van Woert. Anion inhibition of monoamine oxidase. Biochem. Pharmacol. 15:275-85. With S. T. Miller and I. Edwards. Neutron activation analysis: the stability of manganese concentrations in human blood and plasma. {. Lab. Clin. Med. 67:836-49. With A. A. Britton. Dependence of manganese turnover on intake. Am. jr. Physiol. 211:203-6. With E. R. Hughes and S. T. Miller. Tissue concentrations of man- ganese and adrenal function. Am. {. Physiol. 211:207-10. With P. S. Papavasiliou and S. T. Miller. Role of the liver in regulat- ing distribution and excretion of manganese. Am. [. Physiol. 211:211- 16. With A. l. Bertinchamps and S. T. Miller. Interdependence of routes excreting manganese. Am. [. Physiol. 211:217-24. 1967 Manganese in biological system. In Encyclopedia of Biochemistry, ed. R. I. Williams and E. M. Lansford, fir., p. 506. New York: Reinhold. With M. H. Nlan Woert and L. Schiffer. Aromatic amino acids and modification of Parkinsonism. N. Engl. f. Med. 276:374-79. With I. Mena, O. Marin, and S. Fuenzalida. Chronic manganese poisoning: clinical picture and manganese turnover. Neurology 17:128- 36. With M. H. Van Woert and A. Nicholson. Mitochondrial functions of polymelanosomes. Comp. Biochem. Physiol. 22:477-85. With A. C. Foradori, A. Bertinchamps, and I. M. Gulibon. The dis- crimination between magnesium and manganese by serum pro- teins. J. Gen. Physiol. 50:2255. Importance of trace substance in environmental health as exempli- fied by manganese. Paper presented at the First Annual Confer- ence on Trace Substances in Environmental Health, University of Missouri, Columbia. Dopa and Parkinsonism (Letter to the Editor) Br. Med. f. 3:497. With P. S. Papavasiliou. Therapeutic studies of Parkinsonian pa- tients: long-term effects of D-L and L-dopa. In Progress in Neuro-

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GEORGE CONSTANTIN COTZIAS 77 Genetics, ed. A. Barbeau, and }-R. Brunette, pp. 357-65. Amsterdam: Excerpta Medica Foundation. 1968 With P. S. Papavasiliou, E. R. Hughes, L. Tang, and D. C. Borg. Slow turnover of manganese in active rheumatoid arthritis accel- erated by prednisone. i. Clin. Invest. 47:992-1001. With K. Horiuchi, S. Fuenzalida, and I. Mena. Chronic manganese poisoning: clearance of tissue manganese burdens with persis- tence of the neurological picture. Neurology 18:376-82. With A. C. Foradori. Trace metal metabolism. In The Biological Basis of Medicine, ed. E. E. and N. Bittar, vol. 1, chap. 3, pp. 105-21. New York: Academic Press. L-dopa for Parkinsonism. N. Engl. [. Med. 278-630. With P. S. Papavasiliou, R. Gellene, and R. B. Aronson. Parkinsonism and dope. Trans. Assoc. Am. Physicians 81:171-83. With P. S. Papavasiliou and S. T. Miller. Functional interactions between biogenic amines, 3', 5'-cyclic AMP and manganese. Na- ture 220:74-75. Dihydroxyphenylalanine treatment of Parkinsonism. {AMA 205:129. 1969 With P. S. Papavasiliou, R. Gellene, R. B. Aronson, and I. Mena. Long-term effects of dope on Parkinsonism: a proposal. In Third Symposium on Parkinson's Disease, ed. F. G. Gillingham and I. M. L. Donaldson, pp. 178-81. Edinburgh: E. & S. Livingstone. With P. S. Papavasiliou and R. Gellene. Modification of Parkinsonism: dyskinesias accompanying treatment with dope. In Psychotropic Drugs and Dysfunctions of Basal Ganglia: A Multidisciplinary Workshop, Public Health Series Publication 1938, ed. G. E. Crane and R. Gardner, Jr., pp. 140-47. Washington, D.C.: U.S. Government Printing Of- fice. With P. S. Papavasiliou and R. Gellene. Modification of Parkinsonism: chronic treatment with L-dopa. N. Engl. I. Med. 280:337-45. With P. S. Papavasiliou. Autoimmunity in patients treated with L- dopa. fAMA 207:1353-54. L-dopa (~ -DOPA) treatment of Parkinsonism. jrAMA 207: 1522. Parkinsonism and dope: an editorial. [. Chronic Dis. 22:297-301. With I. Mena, K. Horiuchi, and K. Burke. Chronic manganese poi-

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78 BIOGRAPHICAL MEMOIRS sorting: individual susceptibility and absorption of iron. Neurology 19:1000-6 With P. S. Papavasiliou, R. Gellene, C. Fehling, and I. Mena. L-dopa in the treatment of Parkinson's syndrome and of chronic manga- nese poisoning. In Proceedings of the Eighth International Congress of Gerontology, vol. I. With P. S. Papavasiliou and R. Gellene. L-dopa in Parkinson's syn- drome. N. Engl. f. Med. 281:272. Metabolic modification of some neurologic disorders. [AMA 210:1255- 62. 2-aminoNhydroxy-~7-dimethyletrahydropteridine in Parkinson's disease. {AMA 210:1594. 1970 Limiting factors in the treatment with dope. In L-dopa and Parkinsonism, ed. A. Barbeau and F. H. McDowell, pp. 3-5. Philadelphia; F. A. Davis. With I. Mena, I. Court, S. Fuenzalida, and P. S. Papavasiliou. Modi- f~cation of chronic manganese poisoning: treatment with L-dopa or 5-OH tryptophan. N. Engl. J. Med. 282:5-10. With P. S. Papavasiliou, C. Fehling, B. Kaufman, and I. Mena. Simi- larities between neurological effects of L-dopa and of apomorphine. N. Engl. I. Med. 282:31-33. Catecholamines in the brain. N. Engl. I. Med. 282:513. With S. Duby, I. Z. Ginos, A. Steck, and P. S. Papavasiliou. Dopam- ine analogues for studies of Parkinsonism. N. Engl. I. Med. 283:1289. 1971 Levodopa in the treatment of Parkinsonism. The George R. Minot Memorial Lecture, Chicago, Ill., June 22, 1970, fAMA 218:1903-8. With P. S. Papavasiliou, A. Steck, and S. Duby. Parkinsonism and levodopa. Clin. Pharmacol. Ther. 12:319-22. With P. S. Papavasiliou, l. Z. Ginos, A. Steck, and S. Duby. Meta- bolic modification of Parkinson's disease and of chronic manga- nese poisoning. Ann. Rev. Med. 22:305-26. With L. Tang, J. Z. Ginos, A. R. Nicholson, and P. S. Papavasiliou. Block of cerebral actions of L-dopa with methyl-receptor sub- stances. Nature 231 :533-34.

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GEORGE CONSTANTIN COTZIAS 79 With P. S. Papavasiliou. Blocking the negative effects of vitamin B6 on patients receiving L-dopa. jAMA 215:1504-5. With L. C. Tank, S. T. Miller, and I. Z. Ginos. Melatonin and abnor- mal movements induced by L-dopa in mice. Science 173:450-52. With I. Mena and I. Court. Levodopa, involuntary movements and fusaric acid. fAMA 218: 1829-30. L-dopa and prognosis. In Developments in Treatment for Parkinson's Disease, ed. G. C. Cotzias and F. H. McDowell, pp. 78-84. New York: Medcom Press. With S. E. Duby, A. J. Steck, and P. S. Papavasiliou. Apomorphine versus L-dopa in Parkinsonism. Fed. Proc. 30:126. With S. E. Duby and L. K. Dahl. Coupling of hypotensive and anti- Parkinson effects with two dopaminergic drugs. Trans. Assoc. Am. Physicians 84:289-96. 1972 With P. S. Papavasiliou, S. E. Duby, A. J. Steck, C. Fehling, and M. A. Bell. Levodopa in Parkinsonism potentiation of central ef- fects with a peripheral inhibitor. N. Engl. f. Med. 286:8-14. Levodopa-orally or intravenously; negative pyridoxine effect. MAMA 219:226. With W. H. Lawrence, P. S. Papavasiliou, S. E. Duby, i. Z. Ginos, and I. Mena. Apomorphine and Parkinsonism. Trans. Am. Neurol. Assoc. 97:156-59. With I. Z. Ginos, A. LoMonte, and S. Wolf. Apomorphine: its dopam- inergic action and its spectrofluorimetric determination. Fed. Proc. 31:269, 312. With L. C. Tang, S. T. Miller, D. Sladic-Simic, and L. S. Hurley. A mutation influencing the transportation of manganese, levodopa and tryptophan. Science 176:410-12. With P. S. Papavasiliou, S. E. Duby, A. l. Steck, and I. Z. Ginos. Some newer metabolic concepts in the treatment of Parkinsonism. Neurology 22 (Suppl. ) :82-85. With P. S. Papavasiliou, S. E. Duby, A. J. Steck, M. Bell, and W. H. Lawrence. Melatonin and Parkinsonism. [AMA 221 :88-89. With L. C. Tank and I. Mena. Effects of inhibitors and stimulators of protein synthesis on the cerebral actions of levodopa. In Chemical Approaches to Brain Function, Neurosciences Research, ed. S. Ehrenpreis and I. J. Kopin, vol. 5, pp. 97-108. New York: Academic Press.

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80 BIOGRAPHICAL MEMOIRS With S. E. Duby, P. S. Papavasiliou, and W. H. Lawrence. Injected apomorphine and orally administered levodopa in Parkinsonism. Arch. Neurol. 27:474-80. With W. H. Lawrence, P. S. Papavasiliou, and S. E. Duby. Nicotina- mide ineffective in Parkinsonism. N. Engl. f. Med. 287:147. Limitations of controlled double-blind studies of drugs. N. Engl..~. Med. 287:937. Metabolic responses to levodopa. N. Engl. f. Med. 287:1302-3. 1973 With P. S. Papavasiliou and I. Mena. L-meta-tyrosine and Parkinsonism. JAMA 223:83. With N. G. Gillespie, I. Mena, and M. A. Bell. Diets affecting treat- ment of Parkinsonism with levodopa. [. Am. Diet. Assoc. 62:525-28. Levodopa and related drugs. Medical Letter 15:21-24. With P. S. Papavasiliou and W. FI. Lawrence. Levodopa and dopam- ine in cerebrospinal fluid. Neurology 23: 756-59. With I. Z. Ginos, A. LoMonte, A. K. Bose, and R. I. Brambilla. Synthesis of tritium- and deuterium-labeled apomorphine. {. Am. Chem. Soc. 95:2991-94. With I. Mena and P. S. Papavasiliou. Overview of present treatment of Parkinsonism with Levodopa. Adv. Neurol. 2:265-77. With I. Mena, F. C. Brown, P. S. Papavasiliou, and S. T. Miller. Defective release of growth hormone in Parkinsonism improved by levodopa. N. Engl. f. Med. 288:320-21. With P. S. Papavasiliou, I. Mena, and M. Bell. Oxybate sodium for Parkinsonism. COMA 224:130. 1974 Levodopa, manganese and degenerations of the brain. In The Harvey Lectures, series 68, pp. 115-47. New York: Academic Press. With P. S. Papavasiliou and I. Mena. Short and long-term approaches to the "on and off,' phenomenon. Adv. Neurol. 5:379-86. With P. S. Papavasiliou, I. Mena, L. C. Tang, and S. T. Miller. Man- ganese and catecholamines. Adv. Neurol. 5:235-43. With I. Mena, P. S. Papavasiliou, and I. Mendez. Unexpected find- ings with apomorphine and their possible consequences. Adv. Neurol. 5:295-99. With I. Mena, P. S. Papavasiliou, J. Mendez, and F. C. Brown. Chronic

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GEORGE CONSTANTIN COTZIAS 81 treatment with Levodopa and growth hormone release. Adv. Neurol. 5:471-76. With I. S. Mendez, P. S. Papavasiliou, and I. Mena. "On-off" phe- nomenon during treatment of Parkinsonism with L-dopa. In Cur- rent Concepts in the Treatment of Parkinsonism, ed. M. D. Yahr, pp. 151-60. New York: Raven Press. With W. G. Clark, M. K. Menon, L. R. Hines, R. M. Hoar, S. M. Kurtz, P. A. Mattis, I. Iwai, H. Watanabe, and I. C. Page. The acute toxicity of l-dope. Toxicol. Appl. Pharmacol. 28: 1-7. With S. T. Miller, A. R. Nicholson, fir., W. H. Maston, and L. C. Tang. Prolongation of the life-span in mice adapted to large amounts of L-dopa. Proc. Natl. Acad. Sci. U.S.A. 71:2466-69. With L. C. Tang and I. Z. Ginos. Monoamine oxidase and cerebral uptake of dopaminergic drugs. Proc. Natl. A cad. Sci. U.S.A. 71:2715- 19. With L. C. Tang and M. Dunn. Changing the actions of neuroactive drugs by changing brain protein synthesis. Proc. Natl. Acad. Sci. U.S.A. 71:3350-54. 1975 With J. S. Mendez, I. Mena, and P. S. Papavasiliou. Diphenylhydantoin: blocking of levodopa effects. Arch. Neurol. 32:44-46. With I. Mena. Protein intake and treatment of Parkinson's disease with levodopa. N. Engl. f. Med. 292:181-84. With S. T. Miller and H. A. Evert. Control of tissue manganese: initial absence and sudden emergence of excretion in the neona- tal mouse. Am. J. Physiol. 4:1080-84. With P. S. Papavasiliou, S. T. Miller, H. W. Kraner, R. Hsieh. Se- quential analysis: manganese, catecholamines and L-dopa induced dyskinesia. i. Neurochem. 25:215. With l. S. Mendez, E. W. Finn, and K. Dahl. Rotatory behavior induced in nigra-lesioned rats by N-propylnoraporphine, apomorphine and levodopa. Life Sci. 16:1737-42. With P. S. Papavasiliou, I. Z. Ginos, and E. Tolosa. Treatment of Parkinson's disease and allied conditions. In The Nervous System, ed. D. B. Tower and T. N. Chase, vol. 2., pp.323-29. New York: Raven Press. With I. Z. Ginos, E. Tolosa, L. C. Tang, and A. LoMonte. Cholin- ergic effects of molecular segments of apomorphine and dopa-

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82 BIOGRAPHICAL MEMOIRS minergic effects of N. N-dialkylated dopamines. {. Med. Chem. 18:1194-1200. With P. S. Papavasiliou, E. S. Tolosa, I. S. Mendez, and M. Bell- Midura. The treatment of Parkinson's disease with aporphines: possible role of growth hormone. N. Engl. f. Med. 294:567-72. 1976 With L. C. Tang. Modification of the actions of some neuroactive drugs by growth hormone. Arch. Neurol. 33:131-34. 1978 With P. S. Papavasiliou, V. F. L. Rosal, and S. T. Miller. Treatment of Parkinsonism with N-n-propyl norapomorphine and levodopa (with or without carbidopa) . Arch. Neurol. 35:787-91.

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