George Constantin Cotzias June 16, 1918 — June 13, 1977 By Vincent P. Dole

GEORGE CONSTANTIN COTZIAS was born in the city of Chania on the island of Crete, the eldest child of Constantin and Catherine Stroumboli Cotzias and the grandson of George J. Cotzias, a wealthy merchant in Athens. His father, Constantin George Cotzias, a lawyer and journalist, had recently been banished from Athens because of political activity 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 established 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 expanded role of governmental 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, initiated programs of health and public works, rebuilt the municipal hospital, paved roads, created parks, supported young artists, and established a new municipal symphony orchestra.

This productive period was terminated abruptly by the invasion of Greece in 1940. After an intense but brief resistance, the Greek armies were defeated. The prime minister, Alexandros Koryzis, refusing to acknowledge defeat and collaborate, committed suicide. In this extremity, King George of Greece asked Constantin Cotzias to go to the United States as ambassador-at-large representing the Greek government in exile.

George and his family arrived in New York in August 1941, financially destitute after a desperate four-month journey through warring countries. They remained in New York until the defeat of the Axis powers in 1945 made 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 died shortly afterwards of a heart attack at the age of fifty-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 leading citizen of Athens prior to these events, George Cotzias had a privileged early life, attending the best schools and associating with the most stimulating intellectuals of the city. Reflecting George's mother's interest in literature, the Cotzias home was a meeting place for leading 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 medical 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 immediately volunteered for military service, although as a medical student he was exempt from the draft. At the request of Professor Kondiades, 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 bombing, which killed the entire staff. Military resistance collapsed before the advancing German army. George made 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 medical school to complete his studies. The rejection by Cornell was unequivocal; not only was he found to be deficient in English, he was told that his education in Athens had provided inadequate training in basic biochemistry, pharmacology, and physiology. He would need further premedical training even to be eligible for admission to the first year of medical school. Applications to Columbia, New York University, Johns Hopkins, and Pennsylvania were equally fruitless.

Reminiscing in later years, George recalled critical advice that his father gave him at this low point. "When I ran for the office of councilman, I was defeated. So I ran for mayor and was elected. Choose the leading medical school in the country and apply there." With this advice George applied to Harvard Medical School and had the good fortune to be interviewed by Soma Weiss, a brilliant professor of medicine and himself a refugee a decade earlier from Nazi oppression. After a long conversation in German, which George spoke fluently, Weiss recommended that he be admitted conditionally to the third year of study at the medical school. Two years later he graduated from Harvard cum laude. He then trained as an intern in pathology at Brigham Hospital, as an intern in medicine at Massachusetts General Hospital, and was a resident in neurology at Massachusetts General Hospital.

This brings the story to the point at which I first knew George Cotzias. During the four years of World War II, it was my good fortune to be assigned to a naval medical research unit based at the hospital of Rockefeller Institute (now Rockefeller University) and to work in the department of D. D. Van Slyke. With the end of the war and demobilization, I left Rockefeller and returned to Massachusetts General Hospital, where five years earlier I had trained in medicine. Shortly afterward to my great surprise and delight, the director of the Rockefeller Hospital, Thomas Rivers, invited 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 Dahl to join me; Dahl, a scholarly physician and friend, who was completing a tour as senior medical resident at Massachusetts General Hospital, agreed. Within the hour George burst into my office and announced explosively, "I'm coming, too." This unusual application could have been counterproductive, but fortunately Dahl had worked with Cotzias and gave him an enthusiastic endorsement. Immediately I had two talented associates with whom to start the department, the only difficulty being there was no space for the new laboratory immediately available at Rockefeller. At Rivers's suggestion, my two associates were assigned to Van Slyke's group during his final year (an invaluable experience for them), and I started my new career as department head with a year's sabbatical in Europe.

The five years after my return were busy ones. We studied hypertensive patients, looking for clues to the nature of this disorder in disturbances of salt metabolism and energy balance. George, in addition to loyal work as a team member in the clinical studies, became interested in the metabolism of amines in the tissues. He reasoned that catecholamines, diamines, and histamine have powerful vasomotor effects that might be relevant to hypertensive disorders. In particular, he directed 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 l-DOPA (the amino acid l-dihydroxy phenylalanine) was effective in giving symptomatic relief to patients with disabling Parkinsonism. The most important of these studies were conducted after he left my department in 1954. Dahl left at the same time, both having outgrown the limited opportunities for advancement at Rockefeller. They transferred their work to Brookhaven National Laboratory, where Van Slyke meanwhile had established a strong medical division and was able to provide space and support for each to develop an active, independent laboratory.

The move to Brookhaven also provided 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 and blood can be determined with unprecedented sensitivity and specificity. George seized the opportunity. In a series of basic studies over the following decade, he elucidated the distribution, absorption, elimination kinetics, and 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 (rigidity, retardation of motion, tremors, lack of coordination), and as a pathologist he was attracted by the opportunity to correlate specific structural lesions made by a known toxin to disturbances of brain function. In both disorders the main lesions found in the brain involve the substantia nigra, a region made conspicuous by a deposit of dark melanin pigment. It was known that this region of the brain is rich in the neurotransmitter dopamine and also that both melanin and dopamine are derived 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 dopamine to the neurones in this region. However, dopamine 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 look for precursors of dopamine that are not excluded by the barrier, administer them in large doses, and hope that when the molecules arrive at the critical site enough will be converted into dopamine to have a therapeutic effect. Other investigators had pursued this idea with little success, although the validity of the approach was shown by the transient benefit seen after injection of the precursor, dihydroxy-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 doses of DOPA, given orally every two hours under continued observation, and gradually increasing the dose over a period of several weeks as permitted by the development of tolerance, he was able to stabilize patients on large enough doses to cause a dramatic remission of their symptoms. He further improved the treatment by utilizing the active isomer, l-DOPA, recognizing that the inactive isomer, d-DOPA (which constitutes 50 percent of the dose in a racemic mixture) is 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 standard treatment for Parkinsonian symptoms. To his credit, Cotzias realized that this success was only one step toward a definitive treatment. After having a remission, many patients show a disturbing tendency to relapse, even with continued treatment, or to develop movement disorders. He therefore was engaged during the last decade of his life in testing supplementary treatments, especially those utilizing structural analogs of dopamine (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 development of new medications when his career was terminated by lung cancer. Like his father, he died at age fifty-nine, before his work was finished.

George was a large man physically and intellectually--restless, fiercely loyal, informed, intuitive, quick in conversation with an infectious laugh that began as a furtive chuckle and grew into a roar. Basically he remained the intense young medical resident 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 and awards received 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 Award in Natural Sciences (1954), the Albert Lasker Award in Clinical Medical Research (1969), the Borden Award of the Association of American Medical Colleges (1972), and the annual award of the American College of Physicians (1974). He received honorary degrees from Catholic University, Santiago (1969); Women's Medical College of Pennsylvania (1970); St. John's University, New York (1971); and the National University, Athens (1974).

SELECTED BIBLIOGRAPHY

1947

With W. H. Sweet, J. Seed, and P. Yakovlev. Gastrointestinal hemorrhages, 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 J. H. Baxter. Effects of proteinuria on the kidney. Proteinuria, renal enlargement and renal injury consequent on protracted parenteral administration of protein solution in rats. J. 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 patients on the rice-fruit diet. J. 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 related to the therapeutic effect. J. Clin. Invest. 30:584-95.

With V. P. Dole. A nomogram for the calculation of relative centrifugal 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 localization of monoamine oxidase. Proc. Soc. Exp. Biol. Med. 78:157-60.

1952

With V. P. Dole. The activity of histaminase in tissues. J. Biol. Chem. 196:235-42.

Monoamine oxidase: substrates and inhibitors. In Transactions of the Second Conference on Shock and Circulatory Homeostasis, ed. H. D. Green. New York: Josiah Macy, Jr., Foundation.

1953

With V. P. Dole, L. K. Dahl, I. L. Schwartz, J. H. Thaysen, and C. Harris. Dietary treatment of hypertension. III. The effects of protein on appetite and weight. J. 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. J. Clin. Invest. 33:1397-1406.

With H. A. Eder, H. 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. J. Clin. Invest. 33:636-56.

With I. Serlin and J. J. Greenough. Preparation of soluble monoamine oxidase. Science 120:144-45.

1955

With L. S. Maynard. The partition of manganese among organs and intracellular organelles of the rat. J. Biol. Chem. 214:489-95.

With I. Serlin. Microdiffusion of acetic acid as an assay for acetylcholinesterase. J. 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. Radiat. Res. 6:55-66.

1958

With J. J. Greenough. Concomitant analysis for oxygen uptake and 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. J. 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. J. Clin. Invest. 37:1269-78.

Manganese in health and disease. Physiol. Rev. 38:503-32.

With A. J. 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. J. Bertinchamps and J. J. Greenough. Thirst for bile in rats with bile fistulas. Nature 184:1405.

With J. J. Greenough. Quantitative estimation of amineoxidase. Nature 183:1732-33.

Diagnostic uses of radioisotopes. Symposium and panel discussion on the uses of radioisotopes in clinical practice. NY State J. Med. 59:18.

1960

With J. J. Greenough. Dependence of periodic activation and inhibition 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. J. Bertinchamps. Clinical experience with manganese. In Metal-Binding in Medicine, ed. M. J. 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 vivo? Fed. Proc. pt. II, suppl. 10, 20:98-103.

With P. S. Papavasiliou. Neutron activation analysis: the determination of manganese. J. Biol. Chem. 236:2365-69.

With D. C. Borg and B. Selleck. Specificity of the zinc pathway in the rabbit: zinc-cadmium exchange. Am. J. Physiol. 201:63-66.

With D. C. Borg and B. Selleck. Virtual absence of turnover in cadmium metabolism: Cd¹⁰⁹ studies in the mouse. Am. J. Physiol. 201:927-30.

With D. C. Borg, A. J. Bertinchamps, E. R. Hughes, and P. S. Papavasiliou. Nuclear studies in medicine: manganese metabolism. In Symposium Nuklear under Klinike (with special reference to cancer and cardiovascular diseases) Wissenschaftliche abhandlungen der arbeitsgemeinschaft fur forschung des landes 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. J-M. Bordeleau, vol. 20, pp. 193-98. Montreal: University of Montreal.

With E. R. Hughes. Adrenocorticosteroid hormones and manganese metabolism. Am. J. 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. J. 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. Formation of free radicals. III. Theoretical part. Proc. Natl. Acad. 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: Academic 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: 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. J. Physiol. 206:787-92.

With P. S. Papavasiliou, M. H. Van Woert, and A. Sakamoto. Melanogenesis and extrapyramidal diseases. Fed. Proc. 23:713-18.

Der Manganmetabolismus und seine Storungen. Verhandlungen 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. J. 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 extrapyramidal 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 mitochondria of hepatocytes. Nature 208:810-11.

1966

Manganese, melanins and the extrapyramidal system. J. Neurosurg. 24:170-80.

With M. H. Van Woert. Anion inhibition of monoamine oxidase. Biochem. Pharmacol. 15:275-85.

With S. T. Miller and J. Edwards. Neutron activation analysis: the stability of manganese concentrations in human blood and plasma. J. Lab. Clin. Med. 67:836-49.

With A. A. Britton. Dependence of manganese turnover on intake. Am. J. Physiol. 211:203-6.

With E. R. Hughes and S. T. Miller. Tissue concentrations of manganese and adrenal function. Am. J. Physiol. 211:207-10.

With P. S. Papavasiliou and S. T. Miller. Role of the liver in regulating distribution and excretion of manganese. Am. J. Physiol. 211:211-16.

With A. J. Bertinchamps and S. T. Miller. Interdependence of routes excreting manganese. Am. J. Physiol. 211:217-24.

1967

Manganese in biological system. In Encyclopedia of Biochemistry, ed. R. J. Williams and E. M. Lansford, Jr., p. 506. New York: Reinhold.

With M. H. Van Woert and L. Schiffer. Aromatic amino acids and modification of Parkinsonism. N. Engl. J. 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 J. M. Gulibon. The discrimination between magnesium and manganese by serum proteins. J. Gen. Physiol. 50:2255.

Importance of trace substance in environmental health as exemplified by manganese. Paper presented at the First Annual Conference on Trace Substances in Environmental Health, University of Missouri, Columbia.

Dopa and Parkinsonism (Letter to the Editor) Br. Med. J. 3:497.

With P. S. Papavasiliou. Therapeutic studies of Parkinsonian patients: long-term effects of D-L and L-dopa. In Progress in Neuro-Genetics, ed. A. Barbeau, and J-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 accelerated by prednisone. J. Clin. Invest. 47:992-1001.

With K. Horiuchi, S. Fuenzalida, and I. Mena. Chronic manganese poisoning: clearance of tissue manganese burdens with persistence 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. J. Med. 278-630.

With P. S. Papavasiliou, R. Gellene, and R. B. Aronson. Parkinsonism and dopa. 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. Nature 220:74-75.

Dihydroxyphenylalanine treatment of Parkinsonism. JAMA 205:129.

1969

With P. S. Papavasiliou, R. Gellene, R. B. Aronson, and I. Mena. Long-term effects of dopa 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 dopa. 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 Office.

With P. S. Papavasiliou and R. Gellene. Modification of Parkinsonism: chronic treatment with L-dopa. N. Engl. J. Med. 280:337-45.

With P. S. Papavasiliou. Autoimmunity in patients treated with L-dopa. JAMA 207:1353-54.

L-dopa (_L-DOPA) treatment of Parkinsonism. JAMA 207:1522.

Parkinsonism and dopa: an editorial. J. Chronic Dis. 22:297-301.

With I. Mena, K. Horiuchi, and K. Burke. Chronic manganese poisoning: 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 manganese poisoning. In Proceedings of the Eighth International Congress of Gerontology, vol. I.

With P. S. Papavasiliou and R. Gellene. L-dopa in Parkinson's syndrome. N. Engl. J. Med. 281:272.

Metabolic modification of some neurologic disorders. JAMA 210:1255-62.

2-amino-4-hydroxy-6-7-dimethyletrahydropteridine in Parkinson's disease. JAMA 210:1594.

1970

Limiting factors in the treatment with dopa. In L-dopa and Parkinsonism, ed. A. Barbeau and F. H. McDowell, pp. 3-5. Philadelphia; F. A. Davis.

With I. Mena, J. Court, S. Fuenzalida, and P. S. Papavasiliou. Modification 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. Similarities between neurological effects of L-dopa and of apomorphine. N. Engl. J. Med. 282:31-33.

Catecholamines in the brain. N. Engl. J. Med. 282:513.

With S. Duby, J. Z. Ginos, A. Steck, and P. S. Papavasiliou. Dopamine analogues for studies of Parkinsonism. N. Engl. J. Med. 283:1289.

1971

Levodopa in the treatment of Parkinsonism. The George R. Minot Memorial Lecture, Chicago, Ill., June 22, 1970, JAMA 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, J. Z. Ginos, A. Steck, and S. Duby. Metabolic modification of Parkinson's disease and of chronic manganese 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 substances. Nature 231:533-34.

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 J. Z. Ginos. Melatonin and abnormal movements induced by L-dopa in mice. Science 173:450-52.

With I. Mena and J. Court. Levodopa, involuntary movements and fusaric acid. JAMA 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 effects with a peripheral inhibitor. N. Engl. J. Med. 286:8-14.

Levodopa-orally or intravenously; negative pyridoxine effect. JAMA 219:226.

With W. H. Lawrence, P. S. Papavasiliou, S. E. Duby, J. Z. Ginos, and I. Mena. Apomorphine and Parkinsonism. Trans. Am. Neurol. Assoc. 97:156-59.

With J. Z. Ginos, A. LoMonte, and S. Wolf. Apomorphine: its dopaminergic 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. J. Steck, and J. 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. JAMA 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.

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. Nicotinamide ineffective in Parkinsonism. N. Engl. J. Med. 287:147.

Limitations of controlled double-blind studies of drugs. N. Engl. J. Med. 287:937.

Metabolic responses to levodopa. N. Engl. J. 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 treatment of Parkinsonism with levodopa. J. Am. Diet. Assoc. 62:525-28.

Levodopa and related drugs. Medical Letter 15:21-24.

With P. S. Papavasiliou and W. H. Lawrence. Levodopa and dopamine in cerebrospinal fluid. Neurology 23:756-59.

With J. Z. Ginos, A. LoMonte, A. K. Bose, and R. J. Brambilla. Synthesis of tritium- and deuterium-labeled apomorphine. J. 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. J. Med. 288:320-21.

With P. S. Papavasiliou, I. Mena, and M. Bell. Oxybate sodium for Parkinsonism. JAMA 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. Manganese and catecholamines. Adv. Neurol. 5:235-43.

With I. Mena, P. S. Papavasiliou, and J. Mendez. Unexpected findings with apomorphine and their possible consequences. Adv. Neurol. 5:295-99.

With I. Mena, P. S. Papavasiliou, J. Mendez, and F. C. Brown. Chronic treatment with Levodopa and growth hormone release. Adv. Neurol. 5:471-76.

With J. S. Mendez, P. S. Papavasiliou, and I. Mena. "On-off" phenomenon during treatment of Parkinsonism with L-dopa. In Current 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 J. C. Page. The acute toxicity of l-dopa. Toxicol. Appl. Pharmacol. 28:1-7.

With S. T. Miller, A. R. Nicholson, Jr., 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 J. Z. Ginos. Monoamine oxidase and cerebral uptake of dopaminergic drugs. Proc. Natl. Acad. 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. J. 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 neonatal mouse. Am. J. Physiol. 4:1080-84.

With P. S. Papavasiliou, S. T. Miller, H. W. Kraner, R. Hsieh. Sequential analysis: manganese, catecholamines and L-dopa induced dyskinesia. J. Neurochem. 25:215.

With J. 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, J. 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 J. Z. Ginos, E. Tolosa, L. C. Tang, and A. LoMonte. Cholinergic effects of molecular segments of apomorphine and dopa-minergic effects of N, N-dialkylated dopamines. J. Med. Chem. 18:1194-1200.

With P. S. Papavasiliou, E. S. Tolosa, J. S. Mendez, and M. Bell-Midura. The treatment of Parkinson's disease with aporphines: possible role of growth hormone. N. Engl. J. 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.