A short history of dapsone, or an alternative model of drug development

Journal of the History of Medicine and Allied Sciences

Volumn 66, Issue 4, 2011, Pages 425-467

  Barr, Justin ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AIDS; antimalarials; dapsone; drug development; drug testing; HIV; malaria; military history; off label use; randomized clinical trial; Vietnam

Indexed keywords

4 AMINOAZOBENZENE; ANTIMALARIAL AGENT; DAPSONE; DRUG DERIVATIVE; GLUCOSULFONE; LEPROSTATIC AGENT; SULFAMIDOCHRYSOIDINE;

DRUG INDUSTRY; HISTORY; HUMAN; LEPROSY; MALARIA; MILITARY MEDICINE; PNEUMOCYSTIS PNEUMONIA; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SOLDIER; STATISTICS; WAR;

ANTIMALARIALS; DAPSONE; DRUG INDUSTRY; HISTORY, 20TH CENTURY; HUMANS; LEPROSTATIC AGENTS; LEPROSY; MALARIA; MILITARY MEDICINE; MILITARY PERSONNEL; P-AMINOAZOBENZENE; PNEUMONIA, PNEUMOCYSTIS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; VIETNAM CONFLICT;

EID: 80053521873     PISSN: 00225045     EISSN: 14684373     Source Type: Journal    
DOI: 10.1093/jhmas/jrq068     Document Type: Review

References (294)

1. Other names for the drug include: p, p0-sulfonyldianiline, bis(4-aminophenyl)sulfone, 4,40-diaminodiphenyl sulfone, Dumitone, DADPS, 1358F, Avlosulphone, Sulfono-Mae, Croysulfone, Disulone, Sulphadione, Eporal, Diphone, Novophone, Diphenasone, and Udolac.
2. For standard, laboratory-focused histories of drug development, see, for example, William Bud, Penicillin: Triumph and Tragedy (New York: Oxford University Press, 2007)
3. Michael Bliss, The Discovery of Insulin (Chicago: University of Chicago Press, 1982).
4. Jeremy A. Greene, Prescribing by Numbers: Drugs and the Definition of Disease (Baltimore: The Johns Hopkins University Press, 2007).
5. Elizabeth Watkins has presented a different facet of this reinvention story with regard to estrogen and hormone replacement therapy in her book The Estrogen Elixir: A History of Hormone Replacement Therapy in America (Baltimore: Johns Hopkins University Press, 2007).
6. David Cavalla, "Therapeutic Switching: A New Strategic Approach to Enhance R&D Productivity," IDrugs, 2005, 8, 914-18. The author is grateful to the anonymous reviewer who brought this article to his attention.
7. John E. Lesch, ed., The German Chemical Industry in the Twentieth Century (Dordrecht, Germany: Kluwer Academic Publishers, 2000).
8. V. E. Gottfried Wozel, "The Story of Sulfones in Tropical Medicine and Dermatology," Int. J. Dermatol., 1989, 28, 17-18.
9. James A. Doull, "Sulfone Treatment of Leprosy: Background, Early History and Present Status," Int. J. Lepr., 1963, 31, 43.
10. E. A. Sharp and E. H. Payne, "The Present Status of Sulfones in Therapy," Int. J. Lepr., 1948, 16, 157. This last article includes an extensive medical bibliography on dapsone in the early twentieth century.
11. Walter Sneader, Drug Discovery: A History (West Sussex: John Wiley and Sons, Ltd., 2005), 388-89.
12. John E. Lesch, The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine (Oxford: Oxford University Press, 2007).
13. Thomas Hager, Demon Under the Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor's Search for the World's First Miracle Drug (New York: Harmony Books, 2006).
14. For the chemistry of dapsone, see G. W. Raiziss, "Chemistry and Chemotherapy of 4,40-Diaminodiphenylsulfone, 4-Amino-40-hydroxy-diphenyl Sulfone and Related Compounds," J. Am. Chem. Soc., 1939, 61, 2763-65. Briefly, most of the early sulfa drugs, including Prontosil, were sulfanilamides, which means that the central sulfur atom has an amine group and a variable carbon group bonded to it; sulfones have two variable carbon groups.
15. G. A. H. Buttle et al., "The Treatment of Streptococcal Infections in Mice with 4:40-Diaminodiphenylsulphone," Lancet, 1937, 229, 1331-34. While especially toxic in guinea pigs, the side effects abated considerably when tested in mice and monkeys, although several of the monkeys contracted methaemoglobinaemia. At the same time in France, Ernest Fourneau conducted similar experiments and reached similar conclusions.
16. E. Fourneau et al., "Action antistreptococcique des derives sulfures organiques," Comp. Red. Academie. D. Sc., 1937, 204, 1763. Fourneau was the leading researcher of sulfa drugs in France, recognizing that the German drug Prontosil worked just as effectively without the patented azo bond. This discovery allowed the world to produce sulfanilamides on the cheap, much to the dismay of the German patent holders.
17. Harry W. Feinstone et al., "Observations concerning the Toxicity, Absorption and Therapeutic Effect of Sulphanilamide and Certain Related Organic Sulphur-containing Compounds in Experimental Infections in Mice," Johns Hopkins Bull., 1938, 62, 565-92.
18. Pfizer owns it now. "2000: Pfizer Joins Forces with Warner-Lambert," http://www.pfizer.com/about/history/pfizer-warner-lambert. jsp (accessed 8 February 2010).
19. Wozel, "The Story of Sulfones in Tropical Medicine and Dermatology," 19. Doull, "Sulfone Treatment of Leprosy: Background, Early History and Present Status," 145.
20. Fritz Callomon, "New Derivatives of Diaminodiphenylsulfone," Am. Rev. Tuberc., 1943, 47, 97-106.
21. A. R. Rich and R. H. Follis, Jr., "The Inhibitory Effect of Sulfanilamide on the Development of Experimental Tuberculosis in the Guinea Pig," Bull. Johns Hopkins Hosp., 1938, 62, 77-84.
22. The three scientists credit Rich and Follis in their 1942 publication: William H. Feldman, H. Corwin Hinshaw, and Harold E. Moses, "Promin in Experimental Tuberculosis," Am. Rev. Tuberc., 1942, 45, 303-33.
23. For more on tuberculosis in the United States, see Sheila M. Rothman, Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness in American History (Baltimore: The Johns Hopkins University Press, 1994)
24. Barbara Bates, Bargaining for Life: A Social History of Tuberculosis, 1876-1938 (Philadelphia: University of Pennsylvania Press, 1992)
25. Georgiana Feldberg, Disease and Class: Tuberculosis and the Shaping of Modern North American Society (New Brunswick, NJ: Rutgers University Press, 1995).
26. W. H. Feldman, H. C. Hinshaw, and H. E. Moses, "The Effect of Promin (Sodium Salt of p, p0-Diamino-Diphenyl-Sulfone-N, N0-Dextrose Sulfonate) on Experimental Tuberculosis: A Preliminary Report," Proc. Staff Meet. Mayo Clin., 1940, 15, 695-99.
27. H. Corwin Hinshaw and William H. Feldman, "Treatment of Experimental Tuberculosis," J. Am. Med. Assoc. 1941, 117, 1066-68.
28. William H. Feldman, H. Corwin Hinshaw, and Harold E. Moses, "Promin in Experimental Tuberculosis," Am. Rev. Tuberc., 1942, 45, 303-33.
29. H. Corwin Hinshaw, Karl H. Pfuetze, and William H. Feldman, "Chemotherapy of Clinical Tuberculosis with Promin," Am. Rev. Tuberc., 1944, 50, 52-57.
30. Charles K. Petter and Werner S. Prenzlau, "Treatment of Tuberculosis with Diasone," Am. Rev. Tuberc., 1944, 49, 308-21. Diasone was another chemical derivative of dapsone that closely resembled Promin.
31. Anon., "Mayos See in New Drug a Curb on Tuberculosis," New York Times, 23 November 1940, 19.
32. George D. Kettelkamp and Bernard Friedman, "Diasone Therapy in Pulmonary Tuberculosis," Am. Coll. Chest Phys., 1947, XIII, 23-32.
33. Hinshaw and Feldman both played key roles in the testing and application of streptomycin to tuberculosis; according to Lesch, their previous experience with sulfones instilled in them the faith that drugs could conquer tuberculosis, an attitude that prepared them to recognize the potential of streptomycin. Lesch, The First Miracle Drugs, 282.
34. Luke Demaitre, Leprosy in Premodern Medicine: A Malady of the Whole Body (Baltimore: The Johns Hopkins University Press, 2007).
35. Carole Rawcliffe, Leprosy in Medieval England (Rochester, NY: Boydell and Brewer, 2006).
36. Tony Gould, Don't Fence Me In: Leprosy in Modern Times (London: Bloomsbury, 2005).
37. Michelle T. Moran, Colonizing Leprosy: Imperialism and the Politics of Public Health in the United States (Chapel Hill: University of North Caroline Press, 2007).
38. Heather Varughese, "Translating Leprosy: Public Education as a Means to Fight Stigmatization, 1931-1960" (unpublished paper presented at the Frederick L. Holmes workshop series, New Haven, Conn., 10 September 2007).
39. For more on the germ theory of disease, see K. Codell Carter, The Rise of Causal Concepts of Disease: Case Histories (Burlington, Vermont: Ashgate, 2003)
40. Gerald L. Geison, The Private Science of Louis Pasteur (Princeton: Princeton University Press, 1995)
41. John Parascandola, "Chaulmoogra Oil and the Treatment of Leprosy," Pharm. Hist. 2003, 45, 47-57. Employed for hundreds of years in the East, chaulmoogra oil entered Western medicine with the colonial expansion of the British Army in India during the nineteenth century. British Army physicians noticed the natives applying it to their leprosy patients to some effect and so followed suit. The oil comes from the masticated seeds of the fruit from chaulmoogra trees.
42. For more on the testing of various treatments, see the memoirs of two patients at the Carville leprosarium in Louisiana: Betty Martin and Evelyn Wells, Miracle at Carville (Garden City, New York: Doubleday & Company, 1950), 174-87
43. Stanley Stein and Lawrence G. Blochman, Alone No Longer: The Story of a Man Who Refused to Be One of the Living Dead (New York: Funk & Wagnalls Company, 1963), 217-19.
44. John Parascandola, "The Gillis W. Long Hansen's Disease Center at Carville," Public Health Rep., 1994, 109, 728-30
45. John Parascandola, "'An Exile in My Own Country': The Confinement of Leprosy Patients at the United States National Leprosarium," Medicina nei Secoli, 1998, 10, 111-25
46. Gould, Don't Fence Me In, Chapters 8 and 10. For a description of life in Carville, see Stein, Alone No Longer and Martin, Miracle at Carville.
47. E. V. Cowdry and C. Ruangsiri, "Influence of Promin, Starch and Heptalydehyde on Experimental Leprosy," Arch. Pathol., 1941, 32, 632-40. How Cowdry found out about Promin remains subject to controversy. According to Doull's article "Sulfone Treatment of Leprosy," Cowdry learned of Promin through Walter M. Simpson, an administrator at the Charles F. Kettering Foundation. Doull cites Cowdry's diary to assert that Simpson told Cowdry about the drug on a train ride to Dayton, Ohio, after Simpson had seen it assayed in cancer trials. Cowdry vehemently denied this version of events in a series of angry missives sent to Doull, Hinshaw, Feldman, and other actors in the story. Cowdry avers that Simpson found out about Promin directly from Hinshaw and Feldman even before the duo published their results. Letters from Feldman fail to clarify the situation. Simpson, the man who could best adjudicate this dispute, was unceremoniously fired in 1947, suffered a nervous breakdown, and moved out to California, never to be heard from again.
48. G. H. Faget et al., "The Promin Treatment of Leprosy. A Progress Report," Public Health Rep., 1943, 58, 1729-41.
49. John Parascandola, "Miracle at Carville: The Introduction of Sulfones for the Treatment of Leprosy," Pharm. Hist., 1998, 40, 59-66.
50. Wozel, "The Story of Sulfones in Tropical Medicine and Dermatology," 19-20
51. Lowe, "Studies in Sulphone Therapy," 17-18
52. Stein, Alone No Longer, 205-69
53. Martin "Miracle at Carville" 195-287 .
54. Martin, Miracle at Carville, 195-287
55. Doull, "Sulfone Treatment of Leprosy," 149-55.
56. R. G. Cochrane et al., "Two-and-a-Half Years' Experimental Work on the Sulphone Group of Drugs," Lepr. Rev., 1949, 20, 4-64.
57. John Lowe, "Studies in Sulphone Therapy," Lepr. Rev., 1952, 23, 6, 17-18.
58. D. L. Leiker, "Note on Sulphone Activity in Malaria Infection," Lepr. Rev., 1956, 27, 66-67.
59. L. T. Coggeshall, "The Cure of Plasmodium knowlesi Malaria in Rhesus Monkeys with Sulfanilamide and Their Susceptibility to Reinfection," Am. J. Trop. Med. Hyg., 1938, s1-18, 715-21
60. J. C. Niven, "Sulphanilamide in the Treatment of Malaria," Trans. R. Soc. Trop. Med. Hyg., 1938, 32, 413-18.
61. Lesch, The Miracle Drugs, 58-60, 200, 281.
62. Buttle et al., "The Treatment of Streptococcal Infections in Mice with 4:40- Diaminodiphenylsulphone," 1331-34.
63. L. T. Coggeshall, John Maier, and C. A. Best, "The Effectiveness of Two New Types of Chemotherapeutic Agents in Malaria," J. Am. Med. Assoc., 1941, 117, 1077-81. Promin worked against both the Plasmodium vivax and Plasmodium falciparum strains of malaria. The other drug they tested was sulfadiazone, which also proved somewhat effective against malaria. Coggeshall does not cite any of the TB publications using Promin as an explanation for choosing to study that particular drug, although it seems unlikely that anyone working in the sulfa drug field would be unaware of this research.
64. Leo B. Slater, War and Disease: Biomedical Research on Malaria in the Twentieth Century (New Brunswick, New Jersey: Rutgers University Press, 2009), 102.
65. The connection between dapsone and malaria also appeared in an Italian journal in 1945. The article claims that the Italian army used sulfones as an antimalarial drug during World War II. This usage remained largely unknown in the English-speaking scientific world, at least until Leiker's article drew increased attention to the subject matter. G. Tarabini and E. Secreto, "Il Didestorsion draminodifenilsolfone nella cura della malaria," Boll. Soc. Med-Chirg. Mod., 1945, 1, 19-31.
66. Leiker, "Note on Sulphone Activity," 66. The International Journal of Leprosy thought that this article was important enough to reprint a summarized version of it.
67. See "Note on Sulphone Activity in Malaria Infection," Int. J. Lepr., 1956, 24, 494. This latter citation appears more frequently in future articles, presumably due to the journal's wider circulation.
68. For Leiker's comment about the editorial, see Leiker, "Note on Sulphone Activity," 66. For the editorial.
69. The Action of Sulphones on Various Infections," Lepr. Rev., 1955, 26, 3-4. The editorial comments that since the widespread use of DDS to fight leprosy, physicians have noticed fewer secondary infections in their patients. The editors note that sulphonamides work against a wide array of pathogens and opine that there is no reason sulphones should not act similarly. The editors comment specifically on the protozoan toxoplasmosis and speculate about fungal and filarial infections as well.
70. H. M. Archibald and C. M. Ross, "A Preliminary Report on the Effect of Diamino-Diphenyl Sulphone on Malaria in Northern Nigeria," J. Trop. Med. Hyg., 1960, 63, 25-27. In between Leiker's article and that of Archibald and Ross, Dr. G. Tarabini published his own piece on sulfones and malaria
71. G. Tarabini, "The Anti-protozoal Action of the Sulphones and the Anti-malarial Action in Particular," Lepr. Rev., 1958, 29, 111-13). Here, Tarabini traces a brief history of sulfa drugs and malaria-including his own 1945 study in Italy-and concludes "that the sulphones are very active against human malaria"-a claim he makes with no subsequent experimentation. Most future authors cite both Leiker and Tarabini as identifying the antimalarial properties of DDS in humans; they were certainly the first two publications on the subject (Coggeshall used Promin and Buttle used animals).
72. A voluminous historical literature exists on malaria. For a start, see Gordon Harrison's Mosquitoes, Malaria & Man: A History of Hostilities since 1880 (New York: E. P. Dutton, 1978)
73. Randall M. Packard, The Making of a Tropical Disease: A Short History of Malaria (Baltimore: The Johns Hopkins University Press, 2007)
74. For a general chemotherapy history. see Mary Pudney, "Anti- malarials: From Quinine to Atovaquone," in Fifty Years of Antimicrobials: Past Perspectives and Future Trends, ed. P. A. Hunter, G. K. Darby, and N. J. Russell (Cambridge: Cambridge University Press, 1995), 229-47.
75. For a clinical history, see L. J. Bruce-Chwatt, ed., Chemotherapy of Malaria, 2nd ed. (Geneva: World Health Organization, 1986).
76. Quinine proved effective at curing malaria but was less effective when acting as a prophylactic. For the best history of how cinchona bark from Peruvian rain forests spread to the West and emerged as quinine, see Mark Honigsbaum, The Fever Trail: In Search of the Cure for Malaria (London: Pan Books, 2002).
77. L. J. Bruce-Chwatt, "Three Hundred and Fifty Years of the Peruvian Fever Bark," Brit. Med. J., 1988, 296, 1486-87.
78. For an account of how physicians began to understand quinine, see Dale C. Smith, "Quinine and Fever: The Development of the Effective Dosage," J. Hist. Med. Allied Sci., 1976, 31, 343-67.
79. For a brief history of atabrine, see Slater, War and Disease, Chapter 3.
80. L. J. Bruce-Chwatt, "Changing Tides of Chemotherapy of Malaria," Brit. Med. J., 1964, 7, 581.
81. For early American experiences with the drug, see James Steven Simmons et al., Malaria in Panama (Baltimore: The Johns Hopkins University Press, 1939). The Allied fight against malaria in World War II has received considerable attention.
82. For the experience of the British in South and Southeast Asia, see Mark Harrison, Medicine and Victory: British Military Medicine in the Second World War (Oxford: Oxford University Press, 2004), Chapter 5
83. Mark Harrison, "Medicine and the Culture of Command: The Case of Malaria Control in the British Army during the Two World Wars," Med. Hist. 1996, 40, 437-52.
84. For the American experience in the South Pacific, see Mary Ellen Condon-Rall, "U.S. Army Medical Preparation and Outbreak of War: The Philippines, 1941-6 May 1942," J. Mil. Hist., 1992, 56, 35-56
85. Mary Ellen Condon-Rall, "Allied Cooperation in Malaria Prevention and Control: The World War II Southwest Pacific Experience," J. Hist. Med. Allied Sci., 1991, 46, 493-513
86. Mary Ellen Condon-Rall, "The Role of the US Army in the Fight Against Malaria, 1940-1944," War Soc., 1995, 13, 91- 111
87. Neil Cantlie, "Health Discipline," US Armed Forces Med. J., 1950, 1, 232-38
88. Paul F. Russell, "Lessons in Malariology from World War II," Am. J. Trop. Med. Hyg., 1946, 26, 5-13
89. Robert J. T. Joy, "Malaria in American Troops in the South and Southwest Pacific in World War II," Med. Hist., 1999, 43, 192-207
90. Christine Beadle and Stephen L. Hoffman, "History of Malaria in the United States Naval Forces at War: World War I through the Vietnam Conflict," Clin. Infect. Dis., 1993, 16, 320-29.
91. In the early twentieth century, the FDA would approve drugs for safety, while the AMA would attest to their efficacy via their "seal of acceptance" program. The AMA stopped certifying drugs shortly after the Second World War, in part because they became more dependent on pharmaceutical advertising in their journal but also because the deluge of new compounds simply overwhelmed the testing apparatus. The Germans had synthesized chloroquine before World War II but discarded the compound after tests appeared to reveal excessive toxicity. A chemical misidentification delayed American adoption of the drug until after the war. Robert G. Coatney, "Pitfalls in a Discovery: The Chronicle of Chloroquine," Am. J. Trop. Med. Hyg., 1963, 12, 121-28; Slater, War and Disease, Chapters 4-7.
92. Mary Ellen Condon-Rall, "The Army's War against Malaria: Collaboration in Drug Research during World War II," Armed Forces Soc., 1994, 21, 129-43.
93. For an overview of the WHO's campaign, see Harrison, Mosquitoes, Malaria, & Man, especially Chapters 24-27.
94. For more localized approaches, see Marcos Cueto, Cold War, Deadly Fevers: Malaria Eradication in Mexico, 1955-1975 (Baltimore: Johns Hopkins University Press)
95. Frank M. Snowden, The Conquest of Malaria: Italy, 1909-1962 (New Haven, Connecticut: Yale University Press, 2006), Chapter 8.
96. William D. Tigertt, "Present and Potential Malaria Problems," Mil. Med., 1966, 131 (Suppl.1), 853-56.
97. Donald V. Moore and Jack E. Lanier, "Observations on Two Plasmodium falciparum Infections with an Abnormal Response to Chloroquine," Am. J. Trop. Med. Hyg., 1961, 10, 5-9.
98. Martin D. Young and Donald V. Moore, "Chloroquine Resistance in Plasmodium falciparum," Am. J. Trop. Med. Hyg., 1961, 10, 317-19.
99. Martin D. Young, "Amodiaquine and Hyroxychloroquine Resistance in Plasmodium falciparum," Am. J. Trop. Med. Hyg., 1961, 10, 689-93.
100. Martin D. Young, "Failure of Chloroquine and Amodiaquine to Suppress Plasmodium falciparum," Trans. R. Soc. Trop. Med. Hyg., 1962, 56, 252-56.
101. Peter G. Contacos et al., "Drug-resistant falciparum Malaria from Cambodia and Malaya," Trans. R. Soc. Trop. Med. Hyg., 1963, 57, 417-24.
102. Edith D. Box, Quellin T. Box, and Martin Young, "Chloroquine- resistant Plasmodium falciparum from Porto Velho, Brazil," Am. J. Trop. Med. Hyg., 1963, 12, 300-304.
103. W. Peters, "Drug Resistance in Plasmodium berghei Vincke and Lips, 1948. I. Chloroquine Resistance," Exp. Parasitol., 1965, 17, 80-89.
104. Martin D. Young et al., "Drug Resistance in Plasmodium falciparum from Thailand," Am. J. Trop. Med. Hyg., 1963, 12, 305-14.
105. R. D. Powell et al., "Studies on a Strain of Chloroquine-resistant Plasmodium falciparum from Viet-nam," Bull. World Health Organ., 1964, 31, 379-92.
106. William D. Tigertt, "The Malaria Problem: Past, Present, and Future," Arch. Intern. Med., 1972, 129, 605.
107. Tigertt, "Present and Potential Malaria Problems," 853-54.
108. Packard, The Making of a Tropical Disease, 164-67. Packard points out that human factors such as insufficient control over chloroquine and indiscriminate distribution hastened the development of resistance. Chloroquine resistance appeared in 1961
109. In the years immediately following World War II, Europe and the United States had managed to free themselves from endemic malaria. For a detailed study of the eradication of malaria in Italy, see Snowden, The Conquest of Malaria.
110. For the eradication of malaria within the United States, see Erwin H. Ackerknecht, Malaria in the Upper Mississippi Valley, 1760-1900 (Baltimore: The Johns Hopkins University Press, 1945)
111. Margaret Humphreys, Malaria: Poverty, Race, and Public Health in the United States, (Baltimore: The Johns Hopkins University Press, 2001).
112. For a technological explication of colonialism that argues strongly for quinine being an important "tool of empire," see Daniel R. Headrick, The Tools of Empire: Technology and European Imperialism in the Nineteenth Century (New York: Oxford University Press, 1981), especially Part I.
113. The lack of support for diseases largely limited to the underdeveloped world remains a major problem in global health today, as evidenced by the so-called 10/90 gap: only 10 percent of the medical research dollars spent worldwide go to investigate the diseases (like diarrhea and malnutrition) that affect 90 percent of the patients in the world. D. Vidyasagar, "Global Notes: the 10/90 Gap Disparities in Global Health Research," J. Perinatol., 2006, 26, 55-56. For the alarum text.
114. see Commission on Health Research for Development, Health Research: Essential Link to Equity in Development (New York: Oxford University Press, 1990), which reported that 5 percent of research dollars went to investigate medical problems that 93 percent of patients worldwide suffered.
115. By 1965, the U.S. military conducted or funded 90 percent of the malaria research in the United States. "Drug Resistant Malaria Spurs Strong New Drive for Anti-malarial Drugs," Chem. Eng. News, 26 July 1965, 21-22.
116. Honigsbaum, The Fever Trail, 240-45.
117. William Tigertt, "Letter to Commanding General, US Army Medical Research and Development Command," 10 December 1964. Walter Reed Army Institute of Research Gorgas Memorial Library, Smadell Archives (hereafter WRAIR Archives), Drawer F-49, Folder 1304-01 Item Case Files Malaria Research PIF after Completion or Termination of Projects (64). Since the 1960s, WRAIR has led efforts to identify antimalaria therapies. For a history of WRAIR, see Nihil Nemo, History of the Army Medical Department Research and Graduate School 1893-1952, (Washington, DC: Walter Reed Army Medical Center, 1952).
118. William D. Tigertt, Letter to Philip C. Armstrong, 15 September 1982, Personal Papers of Robert J. T. Joy. Mr. Armstrong was the Special Assistant to the Assistant Secretary of Defense for Health Affairs. While this letter dates twenty years after the initial decision, other circumstantial evidence lends credence to its veracity. Indeed, Leiker's groundbreaking 1957 article appears in WRAIR's archives among a stack of documents from the 1960s
119. Folder RD Item Case Files (Malaria Research) Permanent PIF after Completion or Termination of Project (66), Drawer F-58, WRAIR Archives. See also Philip M. Boffery, "GIs Fall Before New Viet Enemy - Malaria," Chicago Daily News, 11 December 1965, Folder 1304-01 RD Item Case Files Malaria Research Folder No. 4, Drawer F-49, WRAIR Archives.
120. Basu, Mondal, and Chakrabarti's 1962 publication featured most prominently. The three Indian physicians tested dapsone against the most virulent malaria strains and determined, "a single dose of 250 or 200 mg of DDS was invariably effective in all the P. falciparum infections." P. C. Basu, M. M. Mondal, and S. C. Chakrabarti, "Treatment of Human Malaria by Diamino-Diphenyl-Sulphone (DDS), Singly and in Combination with Pyrimethamine. A Preliminary Study of Their Effects in P. vivax and P. falciparum Infections in Rajasthan, India," Indian J. Malariol., 1962, 16, 171.
121. S. P. Ramakrishnan et al., "Studies on the Toxicity and Action of Diaminodiphenylsulfone (DDS) in Avian and Simian Malaria," Bull. World Health Organ., 1962, 27, 213-21.
122. Ann Bishop, "Resistance to Diamino-Diphenylsulphone in Plasmodium gallinaceum," Parasitology, 1965, 66, 407-14.
123. Richard Degowin et al., "The Effects of Diaphenylsulfone (DDS) against Chloroquine-resistant Plasmodium falciparum," Bull. World Health Organ. 1966, 34, 671- 81.
124. W. G. H. Richards, "The Anti-malarial Activity of Sulphonamides and a Sulphone, Singly and in Combination with Pyrimethamine against Drug-resistant and Normal Strains of Laboratory Plasmodia," Nature, 1966, 212, 1494-95.
125. William Tigertt, Letter to Philip C. Armstrong. William Tigertt, Letter to L. H. Schmidt, 14 June 1965, Folder 1304-01 RD Item Case Files Malaria Research Folder No. 2 (65), Drawer F-49, WRAIR Archives, and "Proposed Acceleration of the Army Research Program on Drug-resistant Malaria," c. 1964, Folder Vietnam, Drawer F-57, WRAIR Archives.
126. Alf S. Alving, Letter to William Tigertt, 20 May 1963, Folder 1304-01 RD Item Case Files Malaria Research (Permanent) PIF after Completion or Termination of Project, Drawer F-49, WRAIR Archives. Part of Alving's concern may have stemmed from the recent death of an inmate in a California prison who was a research subject for an Army study on hepatitis. See anon., "Medical Experiment Fatal to Convict in California Prison," The Evening Star, 6 May 1952.
127. For an account specifically about research on prisoners, although in a different context, see Allen M. Hornblum, Acres of Skin: Human Experiments at Holmesburg Prison (New York: Routledge University Press, 1998).
128. For more on the general history of governmental experimentation, see Jonathan D. Moreno, Undue Risk: Secret States Experiments on Humans (New York: W. H. Freeman and Company, 2000)
129. Andrew Goliszek, In the Name of Science: A History of Secret Programs, Medical Research, and Human Experimentation (New York: St. Martin's Press, 2003).
130. Alf S. Alving, Letter to William D. Tigertt, 20 January 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Projects (64), Drawer F-49, WRAIR Archives. See also Paul E. Carson and Robin D. Powell, Letter to David Jacobus, 15 February 1965, 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Project, Folder No. 1 (65), Drawer F-49, WRAIR Archives.
131. Richard Taylor, "Memorandum for General Blount," 23 January 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Projects (64), Drawer F-49, WRAIR Archives. Taylor, Chief of the Research Division at the Army's Medical Research and Development Command, officially approved Alving's protocol to study dapsone. For a copy of the protocol, see enclosure, Alf S. Alving, Letter to Richard Taylor, 27 January 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Projects (64), Drawer F-49, WRAIR Archives. The author is aware that the dates of these two letters seem reversed.
132. Alf S. Alving, Letter to Leo Rane, 5 February 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion of Termination of Projects (64), Drawer F-49, WRAIR Archives. Alving noted that sulfadiazine, pyrimethamine, and diasone still had a limited effect on P. falicparum malaria, but that none of these drugs-or dapsone for that matter-worked quickly enough to serve as independent therapeutic agents. At this time, the laboratory was not studying prophylactic efficacy.
133. Robin D. Powell, Letter to William Tigertt, 6 November 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Projects (64), Drawer F-49, WRAIR Archives.
134. For a general history of the United States' involvement in Vietnam, see Stanley Karnow, Vietnam: A History, 2nd ed. (New York: Penguin, 1997) or George C. Herring, America's Longest War, 4th ed. (New York: McGraw-Hill, 2002).
135. Robin D. Powell, Letter to William Tigertt, 8 March 1965, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Project, Folder No. 1 (65), Drawer F-49, WRAIR Archives. The researchers had suspected the impotency of injectable dapsone as early as March of 1964. Robin D. Powell, Letter to K. O. Courtney, 13 March 1964, Folder 1304-01 RD Item Case Files Malaria Research PIF after Completion or Termination of Projects (64), Drawer F-49, WRAIR Archives.
136. William Tigertt, Letter to R. J. G. Morrison, 15 July 1965
137. Robin D. Powell, Letter to William Tigertt, 16 August 1965. Both letters can be found in Folder 1304-01 RD Item Case Files Malaria Research Folder No. 3, Drawer F-49, WRAIR Archives.
138. Robert M. Hardaway, Care of the Wounded in Vietnam (Manhattan, Kansas: Sunflower University Press, 1988)
139. Dennis Shanks and Jerome J. Karwacki, "Malaria as a Military Factor in South East Asia," Mil. Med. 1991, 156, 684.
140. Spurgeon Neel, Medical Support of the US Army in Vietnam: 1965-1970 (Washington, DC: Department of the Army, 1973), 36
141. M. R. Smallman-Raynor and A. D. Cliff, War Epidemics (Oxford: Oxford University Press, 2004), 511-29.
142. Frank W. Kiel, "Malaria in Vietnam," Pathol. Annu., 1968, 3, 5-7.
143. Shanks and Karwacki, "Malaria as a Military Factor in Southeast Asia," 156, 684.
144. For the French colonial experience, see William B. Cohen, "Malaria and French Imperialism," J. Afr. Hist., 1983, 24, 23-36.
145. Kiel, "Malaria in Vietnam," 6-7
146. Andre J. Ognibene and O'Neill Barret, Jr., Internal Medicine in Vietnam: General Medicine and Infectious Diseases (Washington, DC: Office of the Surgeon General, 1982), 279-80.
147. see J. Robert Bridges, "A Study of Malaria in the Que Son Mountains of Vietnam," Mil. Med., 1973, 138, 413-17.
148. Andrew J. Cottingham, Stephen Boone, and Llewellyn Legters, "A Prospective Study of Malaria Incidence among Indigenous and US Forces during Combat Operations," in U.S. Army Medical Research Team (WRAIR) Vietnam and Institute Pasteur of Vietnam Annual Progress Report, Sept. 1966-Aug. 1967 (Saigon, 1967), 2-26.
149. Robert J. T. Joy, Letter to William Tigertt, 8 October, 27 October, and 30 October 1965.
150. Medical Turbine Staff Report, "Logistics Are Improved since the War in Korea," Med. Trib., 1966, 7.
151. For an account of the battle of Ia Drang, see Harold G. Moore and Joseph L. Galloway, We Were Soldiers Once⋯ and Young (New York: Random House, 1992)
152. John A. Cash, "Fight at the Ia Drang, 14-16 November 1965," in Seven Firefights in Vietnam, eds. John A. Cash, John Albright, and Allan W. Sandstrum (Washington, DC: Office of the Chief of Military History, 2005), 3-40. The 1st Cavalry Division (Airmobile), called the 1st Air Cav for short, represented a new type of unit that used helicopters for transportation into and out of a battlefield. Military leaders hoped it would allow for vertical envelopment without the complications of parachutes. The battle of the Ia Drang in Vietnam was the first test of the concept; it became standard military practice for the rest of the Vietnam War.
153. Shanks and Karwacki, "Malaria as a Military Factor in Southeast Asia," 500. Neel, Medical Support of the US Army in Vietnam, 37-39. In November of 1965, the Army began to classify its malaria rates to prevent the enemy from achieving any advantage from that piece of military intelligence. This secrecy resulted in a series of classified letters between Joy and Tigertt that have been lost to history. Subsequent publications have laid out the malaria rates in detail.
154. Leonard Heaton, Letter to William Tigertt, 27 December 1965, Folder 1304-01 RD Item Case Files Malaria Research Folder No. 4, Drawer F-49, WRAIR Archives. Major General Robert E. Blount assured the Surgeon General that the Army had the autumn epidemic under control and were implementing new measures (i.e., dapsone) to prevent a recurrence. Robert E. Blount, "Malaria in Vietnam," Report to the Surgeon General, 29 January 1965, Folder 1304-01 RD Item Case Files, Drawer F-49, WRAIR Archives.
155. U.S. Congressman Robert H. Michel (R-Illinois) suffered from malaria while serving in the army in World War II. On hearing of the outbreak in Vietnam, he offered his own, home-grown remedy that included raw eggs and bourbon. The Army elected not to adopt this particular tonic but thanked Congressman Michel for his concern and suggestions. Robert H. Michel, Letter to LTG Leonard Heaton, 19 November 1965, Folder 1304-01 RD Item Case Files Malaria Research Folder No. 4, Drawer F-57, WRAIR Archives.
156. Robert J. T. Joy, Letter to William Tigertt, 1 December 1965, Folder 1304-01 RD Item Case Files Research Team Vietnam Folder No. 5, Drawer F-59, WRAIR Archives.
157. Major General Robert E. Blount, who had studied malaria during World War II, was sent over to Vietnam to participate in this conference and help sort out realistic solutions
158. For a brief biography of Blount, see Herbert L. DuPont, "Memorial: Major General Robert E. Blount, 1908-2000," Trans. Am. Clin. Climatol. Assoc., 2002, 113, xlviii-l.
159. Robert J. T. Joy, Letter to William Tigertt, 6 December 1965. Personal Files of Robert J. T. Joy.
160. Robert J. T. Joy, ed., "Publications USAMRT WRAIR Vietnam, 1965-1966" (Washington, DC: 1971), Personal Papers of Robert J. T. Joy, 2. In addition to malaria, the team also focused on gastrointestinal diseases, plague, fevers of unknown origin, neuroendocrine studies of combat stress, and environmental physiology. Before 1965, USAMRTV focused on addressing the health concerns of the local population by assisting the Institute Pasteur in Saigon. With the influx of U.S. forces in Saigon, its mission switched to investigating diseases that might affect American troops. "Publications USAMRT WRAIRVietnam, 1965-1966" (Saigon: 1966), Personal Files of Robert J. T. Joy, 1-2.
161. Robin D. Powell, Letter to William Tigertt, 24 February 1966, Folder RD Item Case Files (Malaria Research) Permanent PIF after Completion or Termination of Project (66), Drawer F-58, WRAIR Archives.
162. Robin D. Powell, Letter to David Jacobus, 28 December 1966, Folder 201-48 Organization and Operation Planning Reference Paper Files, COFF 31 Dec. 67 Destroy Jan. 69 or when no longer needed, Drawer F-58, WRAIR Archives. David Jacobus was the chief of the Department of Medicine Chemistry at WRAIR. Boffrey, "GIs Fall before New Viet Enemy - Malaria." 84. Previously, new pharmaceuticals only needed to demonstrate their safety before receiving approval.
163. For a history of the Kefauver-Harris Amendment, see Richard Harris, The Real Voice (New York: Macmillan, 1964)
164. Philip J. Hilts, Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation (New York: Knopf, 2003), Chapters 9 and 10. The thalidomide scandal of 1962 helped the Kefauver-Harris Act pass through Congress. There are some very limited circumstances when the military can dispense drugs not yet approved by the FDA, but these exceptional events must follow strict protocols.
165. William D. Tigertt, "Malaria Chemoprophylaxis in the 1st Brigade, 1st Cavalry Division (Air Mobile), 1 January-15 February 1966," Memorandum to the Surgeon General, Attention Chairmen, Army Investigational Drug Review Board, 12 April 1966, Folder 1304-01 RD Item Case Files (Malaria Research) (66) Folder No. 2, Drawer F-58, WRAIR Archives.
166. Spurgeon Neel, "Drug Suppression of Malaria," Disposition Form to Commander, USMACV, 4 June 1966, Folder RD Item Case Files (Malaria Research) Permanent PIF after Completion or Termination of Project (66), Drawer F-58, WRAIR Archives.
167. Anon., "New Drug against Vietnam Malaria?," Saigon Daily News, 2 January 1966, 5.
168. A.T.C. Bourke and Robert J. T. Joy, "Malaria as Understood by Soldiers," Mil. Med., 1967, 132, 370. The recrudescence of malaria episodes, especially P. vivax infections, in soldiers returning from Vietnam further indicates their failure to complete the prescribed drug regimen.
169. For more on malaria in men rotating home, see George Fisher et al., "Malaria in Soldiers Returning from Vietnam," Am. J. Trop. Med. Hyg., 1970, 19, 27-39.
170. O'Neill Barrett, Jr., et al., "Malaria Imported to the United States from Vietnam: Chemoprophylaxis Evaluated in Returning Soldiers," Am. J. Trop. Med. Hyg., 1969, 18, 495-99.
171. Marion H. Brooks, "Pathophysiology of Acute falciparum Malaria," Am. J. Med., 1967, 43, 735-44.
172. Jerome H. Greenberg, "Public Health Problems relating to the Vietnam Returnee," J. Am. Med. Assoc., 1969, 207, 697-702.
173. Richard P. Wenzel and Victor L. Stoka, "Imported Malaria in Marine Corps Personnel," N. Eng. J. Med., 1972, 297, 1153.
174. William S. Gochenour, Letter to William Tigertt, 8 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team-Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives. For a study in contrast, the Australian Army in Vietnam had especially good malaria discipline and vigorously enforced daily dosing of their antimalaria pills (paludrine and, for a few years, dapsone).
175. R. H. Black, "Malaria in the Australian Army in South Vietnam," Med. J. Aust., 1973, 1, 1265-70.
176. Bourke and Joy, "Malaria as Understood by Soldiers.
177. See for example, Bud, Penicillin, Chapters 5, 6, and 7. One can see similar argument with regard to antipsychotic drugs (Tanya M. Luhrmann, Of Two Minds: An Anthropologist Looks at American Psychiatry (New York: Vintage Books, 2001)
178. and especially with amphetamines like Ritalin and their use in managing behavioral problems (Nicholas Rasmussen, On Speed: The Many Lives of Amphetamines (New York: New York University Press, 2008), 231-37
179. and Peter Conrad, The Medicalization of Society: On the Transformation of Human Conditions into Treatable Disorders (Baltimore: The Johns Hopkins University Press, 2007)), Chapter 3.
180. Quoted in Joy, Preventive Medicine in Vietnam, 86-87.
181. Reuben Kyma and Donald G. McNeil, Jr., "Distribution of Nets Splits Malaria Fighters," New York Times, 9 October 2007, F1.
182. Celia W. Dugger, "Push for New Tactics as War on Malaria Falters," New York Times, 28 June 2006, A1.
183. For vaccines, see Elizabeth Pennisi, "Searching for a Parasite's Weak Spot," Science, 20 October 2000, 290, 434-39. Historically, such "easy fixes" like quinine, DDT, and chloroquine have failed to eradicate the disease.
184. The actual dates of the trial were 3 January-19 January 1966. "New Drug against Vietnam Malaria." Robert J. T. Joy, "Publications of USAMRTV WRAIR Vietnam, 1965- 1966," (Washington DC, 1971), 3.
185. Tigertt, "Malaria in Vietnam." Joy, "Publications USAMRT WRAIR Vietnam 1965-1966," 4.
186. Robert J. T. Joy, Letter to William Tigertt, 1 March, 7 March, 12 March, and 18 March 1966, Personal Files of Robert J. T. Joy.
187. Marks, The Progress of Experiment.
188. For example, Joy's studies were not double-blind-the investigators knew who had received dapsone and who had taken a placebo. Additionally, despite Joy's metric of company combat days, the units differed enough in composition, location, and intensity of enemy action to raise questions about their comparability. Recently, clinical investigators working in the field, especially in underdeveloped countries, have begun to push back against this insistence for textbook-perfect RCTs, clamoring for what they call "humanitarian space." They point out that conditions in the Third World will never replicate those in American academic medical centers and that insisting research in both places ascribe to the same standards is unrealistic and unnecessarily delays the development of medical treatment.
189. For the history of military experimentation in the early twentieth century, see Susan E. Lederer, Subjected to Science: Human Experimentation in America before the Second World War (Baltimore: The Johns Hopkins University Press, 1995), 113-14.
190. For a more recent history of human experimentation in the military, see Moreno, Undue Risk. Other institutionalized populations like prisoners and children in orphanages faced similar conditions of enforced compliance, although not with legal penalties. All these populations have come under strict federal protection after the National Research Act passed in the wake of the Tuskegee Syphilis experiments exposé.
191. Robert J. T. Joy, James E. McCarty, and William Tigertt, "Malaria Chemoprophylaxis with 4,40-Diaminodiphenylsulfone (DDS), I. Field Trial with Comparison among Companies of One Division," Mil. Med., 1969, 134, 493-96.
192. Robert J. T. Joy, Letter to William Tigertt, 5 April, 30 April 1966, Folder 1304-01 RD Item Case Files US Army Research Team (Vietnam) Folder No. 2, Drawer F-60, WRAIR Archives.
193. Robert J. T. Joy, "Final Report on Use of DDS for Malaria Chemoprophylaxis in the 1st Brigade, 1st Cavalry Division (AM) (25 March-28 April 1966," 28 May 1966 Folder 1304-01 R&D Case Files Malaria Research Unit-WRGH (66), Drawer F-58, WRAIR Archives.
194. Robert J. T. Joy, "Program for Routine Use of DDS One Tablet Daily, as a Supplement to Weekly Chloroquine-Primaquine Malaria Chemoprophylaxis," Memorandum for the Record. Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
195. Robert J. T. Joy, "Use of DDS as Routine Malaria Chemoprophylactic," Memorandum for the Record, 6 May 1966 Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
196. Robert J. T. Joy, Letter to James McCarty, 25 April 1966 Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
197. The vastly improved malaria rate resulted partly from dapsone but also from improved malaria discipline. This study did not look specifically for markers of patients complying with malaria discipline, but the concentration of cases in the lower ranks (E-3 and E-4) indicates that at least the officers and noncommissioned officers practiced malaria discipline. Not accounting for the variable of malaria discipline and the absence of an internal control undermined the confidence of this study.
198. Robert J. T. Joy and William H. Gardner, "Field Trial of DDS as a Malaria Chemoprophylactic in the 3rd Brigade, 25th Division," Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
199. See also Robert J. T. Joy, William R. Gardner, and William Tigertt, "Malaria Chemoprophylaxis with 4,40-Diaminodiphenylsulfone (DDS), II. Field Trial with Comparison between Two Divisions," Mil. Med., 1969, 134, 497-501.
200. Robert J. T. Joy, "Protocol: Use of Di-amino, Di-phenyl Sulfone (DDS) in the 3rd Brigade 25th Infantry Division as a 'Routine' Malaria Chemo-prophylactic," 9 May 1966, Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
201. Robert J. T. Joy, Letter to William Tigertt, 30 April 1966, Folder 1304-01 RD Item Case Files US Army Research Team (Vietnam) Folder No. 2, Drawer F-60, WRAIR Archives.
202. Robert J. T. Joy, "Use of DDS as a Routine Malaria Chemo-prophylactic," Memorandum for the Record, 6 May 1966, Enclosure B to Robert J. T. Joy, Letter to William Tigertt, 9 May 1966, Folder United States Army Medical Research Team VN May 1966, Drawer F-60, WRAIR Archives.
203. William Tigertt, Letter to Robert J. T. Joy, 6 May 1966, Personal Papers of Robert J. T. Joy.
204. Robert J. T. Joy, "Final Report on Use of DDS for Malaria Chemoprophylaxis in the 1st Brigade, 1st Cavalry Division (AM) (25 March-28 April, 1966)," 28 May 1966, Folder 1304-01 R&D Case Files Malaria Research Unit - WRGH (66), Drawer F-58, WRAIR Archives.
205. Spurgeon Neel, "Drug Suppression of Malaria," Disposition Form to Commander, USMACV, 4 June 1966, Folder RD Item Case Files (Malaria Research) Permanent PIF after Completion or Termination of Project (66), Drawer F-58, WRAIR Archives. "Administration of DDS," 4 June 1966, Enclosure B to Robert J. T. Joy, Letter to William Tigertt, 8 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-58, WRAIR Archives.
206. In addition to then-Lieutenant Colonel Joy, Brigadier General James A. Weir, MC, Colonel Sam Gallup, MC (surgeon for the U.S. Army in Vietnam), and Colonel William S. Gochenour, MC (Deputy Director of WRAIR) convinced Westmoreland to wait for official approval.
207. Robert J. T. Joy, Letter to William Tigertt, 8 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives.
208. William Tigertt, Letter to Robert J. T. Joy, 9 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives. Tigertt predicted to Joy that the drug would be approved; by the time Joy received the letter, he had already heard the news.
209. Leprosy Drug to Fight Malaria," Stars and Stripes (Pacific edition), 10 June 1965, Folder United States Army Medical Research Team VN May 1966, Drawer F-60, WRAIR Archives.
210. Robert J. T. Joy, Letter to William Tigertt, 28 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives.
211. Robert J. T. Joy, Letter to William Tigertt, 14 July 1966, Folder Correspondence US Army Research Team Vietnam, Jan. 1966-Jul. 1966, Drawer F-60, WRAIR Archives.
212. Until this order, surgeons decided to use DDS on a case-by-case basis. John Norton, "Malaria," 24 July 1966, Folder 1304-01 RD Item Case Files USAMRT - VN Folder No. 6 (66), Drawer 60, WRAIR Archives.
213. Craig H. Llewellyn, Letter to Robert J. T. Joy, 19 August 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives.
214. Cottingham, Boone, and Legters, "A Prospective Study of Malaria Incidence among Indigenous and US Forces During Combat Operations," 2-26.
215. Craig H. Llewellyn, Interview with Author (Learning Resource Center Archives, Uniformed Services University of the Health Sciences, Bethesda, Md.), 28-30.
216. See Tara Nowosiwsky, "Malaria Discipline," USARV Medical Bulletin, July-August 1967, 30-31.
217. "Program for Routine Use of DDS One Tablet Daily, as a Supplement to Weekly Chloroquine-Primaquine Malaria Chemoprophylaxis," 6 June 1966, Enclosure A to Robert J. T. Joy, Letter to William Tigertt, 8 June 1966, Folder 1304-01 RD Item Case Files US Army Research Team - Vietnam Folder No. 4 (66), Drawer F-60, WRAIR Archives.
218. Harry G. Dangerfield, Letter to William Tigertt, 6 October 1966, Folder 1304-01 RD Item Case Files US Army Research Team Vietnam, Folder 6 (66), Drawer F-59, WRAIR Archives.
219. Phillip Winter et al., "Field Trial of DDS Plus Chloroquine- Primaquine as Malaria Prophylaxis," South-East Asia Treaty Organization Annual Progress Report, the SEATO Research Laboratory and the SEATO Clinical Research Center, 1 April 1966-31 March 1967" (Bangkok: WRAIR, 15 April 1967).
220. For the development of primaquine in the Korean War, see J. H. Edgcomb et al., "Primaquine, SN 13272, a New Curative Agent in vivax Malaria: A Preliminary Report," J. Nat. Malaria Soc., 1950, 9, 285-92.
221. A. S. Alving, J. Arnold, D. H. Robinson, "Status of Primaquine. I. Mass Therapy of Subclinical vivax Malaria with Primaquine," J. Am. Med. Assoc., 1952, 149, 1558-62.
222. A. S. Alving et al., "Korean vivax Malaria. II. Curative Treatment with Pamaquine and Primaquine," Am. J. Trop. Med. Hyg., 1953, 2, 970-76.
223. For more general information on malaria in the Korea War, see Albert E. Cowdrey, The Medic's War (Washington, DC: Center of Military History, 1987).
224. Paul E. Carson et al., "Enzymatic Deficiency in Primaquine-sensitive Erythrocytes," Science, 14 September 1956, 124, 484-85.
225. For an article that summed up available scientific knowledge on G6PD during the Vietnam era, see Paul E. Carson and Henri Frischer, "Glucose-6-Phosphate Dehydrogenase Deficiency and Related Disorders of the Pentose Phosphate Pathway," Am. J. Med., 1966, 41, 744-61.
226. In the Korean War, physicians had noticed that primaquine caused this disease to appear much more frequently in black soldiers than white ones but were unable to explain why: Robert S. Hockwald et al., "Toxicity of Primaquine in Negroes," J. Am. Med. Assoc., 1952, 149, 1568-70. Later research showed that those of Middle Eastern descent also disproportionately suffer from G6PD deficiency. Like sickle-cell anemia, G6PD deficiency-in a heterozygous state-can confer some protection against malaria.
227. Hinshaw and Feldman, "Treatment of Experimental Tuberculosis," 1067.
228. Faget, "The Promin Treatment of Leprosy," 1730.
229. Cochrane et al., "Two-and-a-Half Years Work on the Sulphone Group of Drugs," 1949, 42, 56-57.
230. See, for example, Jack Cooksey, "On Glucose-6-Phosphate Dehydrogenase Deficiency," USARV Med. Bull., 1967, 2, 4-8.
231. William H. Fisherman, "Malaria-Chemoprophylaxis and Side Effects," USARV Med. Bull., 1969, 6-8.
232. Fisherman was an epidemiologist attached to the 20th Preventive Medical Unit at Bien Hoa. A later study noted that dapsone led to hemolysis more frequently than primaquine in "healthy" patients, but less frequently than primaquine in those suffering from G6PD deficiency. Walter R. Graham, "Adverse Effects of Dapsone," Int. J. Dermatol., 1975, 14, 494- 500.
233. Fisherman, "Malaria-Chemoprophylaxis and Side Effects," 7.
234. Harry Dangerfield, "Interim Report: Clinical and Epidemiological Studies of Malaria and Related Hematologic Disorders in the Republic of Vietnam, November 1966-May 1967," 23 June 1967, Folder VN-USA Medical Research Team 1967-1968, Drawer F-57, WRAIR Archives. In this study, Dangerfield and others specifically subjected patients with G6PD deficiency to daily doses of DDS, under controlled conditions; few hemolytic incidents occurred.
235. See also "Joint Preventive Medicine and Communicable Disease Control Sub-Committee: Minutes of the Meeting 16 April 1967," 3 May 1967, Folder 1304-01 Vietnam Folder No. 3, Drawer F-57, WRAIR Archives. Marcel E. Conrad, Memorandum for the Record to William Tigertt, 22 April 1966, Folder RD Item Case Files (Malaria Research) Permanent PIF after Completion or Termination of Project (66), Drawer F-58, WRAIR Archives. Conrad worked with inmates in the Illinois prison system and wrote to Tigertt to confirm that none of the prisoners suffered any hemolytic incidents.
236. Ognibene and Barret, General Medicine and Infectious Disease, 298.
237. Different ethnicity groups suffered from different rates of G6PD deficiency. The Sedang people, for example, had zero G6PD deficiency among their population; the Viet Kinh (ethnic, low-land Vietnamese) also had a low rate. The Khmer and Cham people had the highest rates. See James E. Bowman et al., "Hemoglobin and Red Cell Enzyme Variation in Some Populations of the Republic of Vietnam with Comments on the Malaria Hypothesis," Am. J. Phys. Anthropol., 1971, 34, 313-24.
238. See also "Joint Preventive Medicine and Communicable Disease Sub-Committee." Cottingham, Boone, and Legters, "A Prospective Study of Malaria Incidence Among Indigenous and US Forces during Combat Operations.
239. Graham, "Adverse Effects of Dapsone," 494-500.
240. Ognibene and Barrett, General Medicine and Infectious Diseases, 300, 332.
241. Andre J. Ognibene, "Agranulocytosis Due to Dapsone," Ann. Inter. Med., 1970, 72, 521-24
242. Graham, "Adverse Effects of Dapsone," 498.
243. Edward L. Buescher, Letter to Robert Cutting, 11 February 1970, Folder VN Reading File, Jan.-May 1970, Drawer F-57, WRAIR Archives. William Meroney, "Storage, Shipment, and Transport of Dapsone (DDS)," Memorandum to the Surgeon General, 10 February 1970, Folder VN Reading File, Jan.-May 1970, Drawer F-57, WRAIR Archives. Ognibene and Barrett, General Medicine and Infectious Diseases, 332.
244. Ognibene, "Agranulocytosis Due to Dapsone," 524. Some of the old, adulterated pills were shipped back to WRAIR for testing; their chemical composition had not, in fact, changed, making the agranulocytosis outbreak all the more mysterious.
245. Robert Cutting, Letter to Edward L. Buescher, 23 February 1970, Folder VN Reading File, Jan.-May 1970, Drawer F-57, WRAIR Archives.
246. Stuart Auerbach, "U.S. Curtails Anti-malaria Drug After 7 Soldiers Die in Vietnam," Washington Post, 18 July 1970, A11.
247. It did reappear later that decade when the General Accounting Office released a report criticizing the manner in which the Food and Drug Administration approved new drugs. Richard Halloran, "U.S. Agency Finds Drug Testing Lax," New York Times, 21 July 1976, NJ69.
248. Robert J. T. Joy, ed., Preventive Medicine in Vietnam, 1965-1966: Proceedings of a Symposium of the Office of the Surgeon, United States Army, Vietnam, 27-28 June 1966, Drawer F-61,WRAIR Archives, p. 83.
249. See Chart 21, Ognibene and Barrett, General Medicine and Infectious Disease, 337.
250. Harold G. Moore, Letter to Robert J. T. Joy, 29 April 1986, Personal Papers of Robert J. T. Joy.
251. Bruce-Chwatt, Chemotherapy of Malaria, 18-19. William Tigertt, "Malaria and the Army Medical Service," addendum to a letter to Philip C. Armstrong, 15 September 1982, Personal Papers of Robert J. T. Joy.
252. Bioassay of Dapsone for Possible Carcinogenicity, DHEW Publication No. (NIG) 77-820 (Bethesda, Maryland: National Cancer Institute, 1977), viii.
253. Two scientists had already discovered the basic mechanism (inhibiting oxidation of pyruvate) behind dapsone's carcinogenicity: D. L. Wu and K. P. DuBois, "Studies on the Mechanism of the Toxic Action of Diaminodiphenylsulfone (DDS) to Mammals," Arch. Int. Pharmacodyn. Ther. 1970, 183, 36-45.
254. Ironically, at roughly the same time, other physicians were publishing articles claiming that dapsone had the potential to inhibit tumor growth in certain gynecological cancers. While DDS did not have a huge impact-it benefited only two of thirty-three research subjects-it did appear to potentiate the effects of radiation therapy. John Graham and Ruth Graham, "Cancer Treatment with Sulfones," Surgery, Gynecology, and Obstetrics, 1969, 129, 103-7.
255. Anon., "Drug Tested on Troops in Vietnam Is Found to Cause Cancer in Rats," New York Times, 6 December 1977, 22.
256. Drug Tested on GIs in Vietnam Found to Cause Cancer in Rats," Los Angeles Times, 6 December 1977, B6.
257. Battlefield Drug Tied to Cancer, Washington Post, 6 December 1977, A4.
258. Anon., "Veterans Reassured on Drug Tests," New York Times, 9 December 1977, A13.
259. Ognibene and Barret, General Medicine and Infectious Disease, 298. In addition to being used as a prophylactic, dapsone was also employed to treat recalcitrant cases of malaria, further obfuscating the precise number of men who received the drug. Estimates range from 200,000 to 1.3 million.
260. A balanced historical treatment of the Agent Orange controversy remains to be written. For a polemical account expressing the anger and frustration at the time, see Fred A. Wilcox, Waiting for An Army to Die: The Tragedy of Agent Orange (New York: Random House, 1983).
261. Adrian Peracchio, "Agent Orange Maybe Just One Garnish in a Toxic Cocktail," Washington Post, 20 July 1980, A4.
262. Adrian Peracchio, "'Toxicological Cocktail' Suspected as Cause of Vietnam Veterans' Illnesses," Los Angeles Times, 29 June 1980, I4.
263. Both of these articles cited a retired Navy physician John Stover as stridently opposing the introduction of dapsone in 1966 because of possible side effects. Stover cited contentious debate within the military over the introduction of DDS. In fact, documents in the WRAIR archives do not reveal the said debate and do not even mention Stover. Stover also argued the chloroquine-resistance did not really exist in Vietnam in 1966, which was incorrect. See also, Anon., "Probe Vietnam Drug Experiment in G.I.s' Deaths," New York Magazine, 20 October 1980, 13.
264. Phillip M. Boffery, "Cancer Deaths High for Some Veterans," New York Times, 4 September 1987, A10.
265. David Christie, "Did Vietnam Veterans Get Cancer from Dapsone?," Med. J. Aust., 1993, 159, 500.
266. For the classic, although subjective, account of the early AIDS epidemic, see Randy Shilts, And the Band Played On: Politics, People, and the AIDS Epidemic (New York: St. Martin's Press, 1987).
267. H. Masur et al., "An Outbreak of Community-acquired Pneumocystis carinii Pneumonia," N. Eng. J. Med., 1981, 305, 1431-38.
268. S. Fannin et al., "A Cluster of Kaposi's Sarcoma and Pneumocystis carinii Pneumonia among Homosexual Male Residents of Los Angeles and Range Counties, California," MMWR CSC Surverill Summ., 1982, 31, 305- 7. The author is grateful to Sachin Desai for pointing him to these and other relevant references on PCP.
269. J. R. Catterall, I. Potasman, and J. S. Remington, "Pneumocystis carinii Pneumonia in the Patient with AIDS," Chest, 1985, 88, 758.
270. Catterall, Potasman, and Remington, "Pneumocystis carinii Pneumonia in the Patient with AIDS," 758-762.
271. Larry Josephs, "The Harrowing Plunge," New York Times, 11 November 1990, O38.
272. A Danish researcher had previously reported some success in treating Kaposi's Sarcaoma-another tell-tale infection associated with AIDS-with DDS. This Danish physician, Asmus Poulsen, indicated that the initial idea to use DDS came from Dr. H. B. Svindland in Norway. While Poulsen presented what appeared to be promising results, DDS did not become a standard treatment for Kaposi's Sarcoma. Asmus Poulsen et al., "Regression of Kaposi's Sarcoma in AIDS after Treatment with Dapsone," Lancet, 1984, 8376, 560.
273. Asmus Poulsen et al., "Dapsone in the Treatment of Kaposi's Sarcoma," Acta Derm. Venereol., 1984, 64, 561-63.
274. PCP has since been proven to be caused by a fungus. The species that infects humans is now called Pneumocystis jirovecii pneumonia, although both PCP and PJP are commonly accepted names. For the microbiology and a brief history of the disease, see Peter D. Walzer and A. George Smulian, "Chapter 270: Pneumocystis Species," in Mandell, Douglass, and Bennett's Principles and Practices of Infectious Disease, eds. Gerald Mandell, John Douglass, and Raphael Dolin, 7th ed., (Philadelphia, Pennsylvania: Elsevier Press, 2010).
275. Walter T. Hughes and Bessie L. Smith, "Efficacy of Diaminodiphenylsulfone and Other Drugs in Murine Pneumocystis carinii Pneumonitis," Antimicrob. Agents Chemother., 1984, 26, 436-40; quotation from p. 437.
276. Primaquine has since proven effective against PCP when combined with the antibiotic clindamycin. E. Toma et al., "Clindamycin/primaquine versus Trimethoprim-Sulfamethoxazole as Primary Therapy for Pneumocystis carinii Pneumonia in AIDS: A Randomized, Double-blind Pilot Trial," Clin. Infect. Dis., 1993, 17, 178-84.
277. S. Safrin et al., "Comparison of Three Regimens for Treatment of Mild to Moderate Pneumocystis carinii Pneumonia in Patients with AIDS. A Double-blind, Randomized, Trial of Oral Trimethoprim-Sulfamethoxazole, Dapsone-Trimethoprim, and Clindamycin-Primaquine," Ann. Intern. Med., 1996, 124, 792-802. The latter article indicated that the dapsone-trimethoprim combination and the clindamycin-primaquine combination proved equally effective.
278. Hughes and Smith, "Efficacy of Diaminodiphenylsulfone and Other Drugs in Murine Pneumocystis carinii Pneumonitis," 436-40.
279. Gifford S. Leoung et al., "Dapsone-trimethoprim for Pneumocyctis carinii Pneumonia in the Acquired Immunodeficiency Syndrome," Ann. Intern. Med., 1986, 105, 45-48.
280. Harold M. Schmeck, Jr., "AIDS Drugs Offer Hope but Cure Remains Distant," New York Times, 17 March 1987, A1.
281. See also Gina Kolata, "New Treatment May Help in AIDS Fight," New York Times, 15 October 1987, B12.
282. S. T. Green et al., "AIDS-related Pneumocystis carinii Pneumonia Successfully Treated with Dapsone-Trimethoprim," Brit. J. Clin. Pharmacol., 1988, 26, 487.
283. Belle L. Lee et al., "Dapsone, Trimethoprim, and Sulfamethoxazole Plasma Levels during Treatment of Pneumocystis Pneumonia in Patients with Acquired Immunodeficiency Syndrome," Ann. Intern. Med., 1989, 110, 606-11.
284. For an updated study, see Robert T. Koda et al., "Pharmacokinetics of Trimetrexate and Dapsone in AIDS Patients with Pneumocystis carinii Pneumonia," J. Clin. Pharmocol., 1999, 39, 268-74.
285. U.S. Public Health Service Task Force on Antipneumocysti Prophylaxis in Patients with Human Immunodeficiency Virus Infection, "Recommendations for Prophylaxis against Pneumocystis carinii Pneumonia for Persona Infected with Human Immunodeficiency Virus," J. Acquir. Immune Defic. Syndr., 1993, 6, 46-55.
286. Joseph, "The Harrowing Plunge.
287. Jennifer R. Fishman complicates the standard spontaneity story on the creation of Viagra by arguing that even if Pfizer was not expecting erections, it was only the decadeslong effort to medicalize male impotence that allowed them to create a pharmaceutical out of an unanticipated side effect.
288. See "Making Viagra: From Impotence to Erectile Dysfunction," in Medicating Modern America: Prescription Drugs in History, eds. Andrea Tone and Elizabeth Watkins (New York: New York University Press, 2007) 229-52.
289. See also: Meika Loe, The Rise of Viagra: How the Little Blue Pill Changed Sex in America (New York: New York University Press, 2004).
290. D. C. Radley, S. N. Finkelstein, and R. S. Stafford, "Off-label Prescribing among Office-based Physicians," Arch. Intern. Med., 2006, 166, 1021-26.
291. See Cavalla, "Therapeutic Switching," and Kate Murphy, "With Aid of Drug Laboratory, New Remedies from Old," New York Times, 27 April 2009, D5. Academic researchers usually must limit their studies to drugs that are no longer patented. The author is grateful to Wen Shen for pointing him towards this article.
292. There have been reports of the leprosy bacillus developing resistance to dapsone; physicians have since turned to a three-drug cocktail that includes rifampin and clofazimine. Gould, Don't Fence Me In, 16.
293. Lawrence K. Altman, "Leprosy Patients Show Resistance to Sulfone Drug," New York Times, 28 January 1972, 20.
294. Dapsone is also used to treat a number of dermatological conditions, specifically those related to inflammatory diseases, autoimmune dermatoses, and illnesses that involve neutrophil infiltration of the skin like dermatitis herpetiformis and sweet syndrome. V. E. Gottfried Wozel, "Innovative Use of Dapsone," Dermatol. Clin. 2010, 28, 599-610.