National Academies Press: OpenBook

Pharmaceuticals for Developing Countries: Conference Proceedings (1979)

Chapter: MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS

« Previous: HISTORICAL PERSPECTIVE
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 29
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 30
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 31
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 32
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 33
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 34
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 35
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 36
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 37
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 38
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 39
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 40
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 41
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 42
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 43
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 44
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 45
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 46
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 47
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 48
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 49
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 50
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 51
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 52
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 53
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 54
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 55
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 56
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 57
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 58
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 59
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 60
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 61
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 62
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 63
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 64
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 65
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 66
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 67
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 68
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 69
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 70
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 71
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 72
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 73
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 74
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 75
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 76
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 77
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 78
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 79
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 80
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 81
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 82
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 83
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 84
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 85
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 86
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 87
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 88
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 89
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 90
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 91
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 92
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 93
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 94
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 95
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 96
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 97
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 98
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 99
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 100
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 101
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 102
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 103
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 104
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 105
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 106
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 107
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 108
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 109
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 110
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 111
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 112
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 113
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 114
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 115
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 116
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 117
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 118
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 119
Suggested Citation:"MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
×
Page 120

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES —THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS

MAJOR DISEASE PROBLEMS IN THE DEVELOPING WORLD C. E. Gordon Smith It is customary to address the problem of which are the major disease problems in terms such as that of the WHO estimates in 1971 that in the world then there were 650 million people with ascariasis, 450 million with ancylostomiasis, more than 400 million with trachoma, 350 million with amebiasis, 350 million with trichiuriasis, 250 million with filariasis, 180 million with schistosomiasis, 100 million with malaria (causing 1 million deaths annually), 20 million with tubercu- losis and more than 10 million with leprosy._36/ Impressive figures and designed to be so — probably underestimates by now in view of popula- tion growth. But on what real evidence are these guesstimates based when most of the populations to which they refer have highly defective census data, access only to the most rudimentary of health services and certainly little or none to the diagnostic laboratories which could pro- vide the necessary evidence? There is evidence from surveys but, col- lated, they often give more information about the distribution of para- sitologists or microbiologists than of the diseases. Moreover, health statistics are usually very focal in origin: in Kenya 40 percent of patients attending a health center came from within a five-mile radius and 70 percent from within a ten-mile radius;14/ and one Indian study showed that the proportion of patients attending a dispensary decreased by 50 percent for each additional half-mile they had to travel; another that over 60 percent of patients at a health center came from within a one-mile radius.35/ There is no doubt that these infectious diseases are widespread and that at least some of them cause disease in very large numbers of people. What these figures conceal are the great differences both between and within developing countries. The gaps between rural, peri-urban (squatter) and urban popula- tions are far greater than between similar population groups in indus- trialized countries. The health problems of rural and peri-urban popu- lations are dominated by the diseases characteristic of poverty in wan temperatures, and by parasitic diseases, while the diseases of afflu- ence (alcoholism, coronary heart disease, degenerative and malignant diseases) are of rapidly Increasing relative importance among urban 30

populations in some developing countries. The differences between countries in geography, climate, ecology, population density and distri- bution, stage or direction of economic development, etc., have a pro- found influence on the causes, incidence, and distribution of diseases. Major Diseases Throughout the Tropics Certain diseases are characteristic of poverty and deprivation throughout the tropics — the lethally synergistic combination of gas- troenteritis, malnutrition, and respiratory infections which is the main child killer and probably an important barrier to wider acceptance and implementation of birth control. Moreover, these diseases are often most prevalent at the season most demanding on agricultural labor or at which the roads are impassable and health services particularly inaccessible. They are a dominant health problem of much of southern Asia, the Caribbean, Latin America, and parts of the western Pacific, 37/ widespread among poor rural populations and in the vast peri-urban slums which are a particular problem in Latin America, India, and parts of Africa. This shanty town phenomenon was called "semi-urbanization" by Jacoby 21/ and is now apparently called "peri-urban marginality" by WHO 37/ — neither term doing much to describe the appalling squalor and deprivation combined with lack of social structure, employment, health services or political influence which it represents. The per- centages of the rural populations which migrated to towns and cities between 1950 and 1960 were about 25 in Argentina, 19 in Brazil, and 29 in Chile;2l^/ and WHO 37/ expects this to continue while the population of Latin America doubles before the end of the century. Already it is estimated that more than half of the population of Lima, Peru, lives in shanty towns. In India, migrants make up 64 percent of the populations of Bombay and Delhi and 53 percent of that of Calcutta.j?/ These prob- lems are aggravated by refugees in many parts of the world: between 1961 and 1968 more than 800,000 people in Africa are estimated to have taken refuge in other countries,TJ and the series of wars in recent years can only have aggravated this. Because of the extreme lack of accurate data in most developing countries — particularly on the least healthy sectors of their popula- tions — it is very difficult to assess the relative importance of vari- ous diseases in different parts of the world. In 1970, WHO reported the result of asking 112 tropical and subtropical countries to list their major health problems._10/ These, collated by WHO Region (Table l), show that all Regions listed malaria and diarrheal diseases, and all except the Eastern Mediterranean listed malnutrition. This colla- tion is useful to that extent but because of the great variation within Regions it also conceals a great deal. For example, only the African Region listed schistosomiasis, although this is a major problem in the Philippines and it is estimated that there are as many as six million cases in Brazil.37_/ It is certainly also a major and increasing prob- lem in Egypt (Eastern Mediterranean Region). 31

TABLE 1. MAJOR HEALTH PROBLEMS OF DEVELOPING COUNTRIES NOMINATED BY AT LEAST THREE WHO REGIONS 10/ Problems Regions Afri- Ameri- S. E. W. Paci- E. Medi- can can a/ Asian fic b/ terranean Malaria + + + + + Diarrheal + + + + + diseases Malnutrition + + + + Tuberculosis + + + Leprosy + + + Sexually- + + + transmitted diseases a/Excluding North America. b/Excluding Australia, New Zealand, Japan. The latest report of the Director General,37/ suggests that the present-day picture is not very different. He says that malaria con- tinues to be a major problem in the majority of tropical countries — microscopically diagnosed and reported cases increased from 3.2 million in 1972 to 7.5 million in 1976. Most of Africa south of the Sahara is holo- or hyper-endemic. Reported cases in the South Asian Region increased from 1.9 million in 1972 to 6.5 million in 1976; malaria has re-established itself at its former endemic levels in several areas of Bangladesh, India, and Sri Lanka and has worsened in Thailand. There has been a recent epidemic of over 100,000 cases in south-eastern Turkey. Plasmodium falciparum resistant to chloroquine now occurs in areas with a population of over 45 million and populations of 90 mil- lion are at grave risk. And one-third of all malaria control programs are facing problems of insecticide resistance. The American Region regards infantile gastroenteritis, with respiratory tract diseases and malnutrition, as one of the principal causes of death in Latin America and the Caribbean. The South East 32

Asian Region describes gastroenteritis as the major killer of children, and the Western Pacific Region nominates diarrheal diseases along with sexually transmitted diseases, arbovirus diseases, schistosomiasis, filariasis, malaria, and leprosy, as its major problems. Tuberculosis is estimated still to be causing more than 0.5 million deaths each year — 74 percent of them in Asia. In a study of 88 countries, acute respi- ratory infections were found to account for 6.3 percent of all deaths and for more than 20 percent of deaths in children. Sexually transmit- ted diseases affect 10-20 percent of the population in some countries (which, if correct, must indicate at least twice these figures at sexu- ally active ages) and the proportion of penicillin-resistant gonococci is increasing substantially annually. From all this it is clear that certain diseases — malaria, diarrheal diseases, malnutrition, acute respiratory diseases, and sexu- ally transmitted diseases — are common and important in most tropical countries, particularly in impoverished rural or peri-urban populations. Bryant estimated that 92 percent of the deaths attributed to diarrhea in Colombia occur in children under five years of age.^5/ In some Central American communities half the children will have had at least 10 attacks of diarrhea before their fifth birthday, some five or six attacks in a single year.^36/ Both diarrheal and respiratory infec- tions of children are caused by a multiplicity of organisms, varying in relative importance from place to place but a particularly serious cause of death in overcrowded populations. However, the occurrence or severity of diarrhea may depend as much on nutritional status, particu- lar foods eaten, environmental conditions, behavior or chemical factors as on particular pathogens — viruses (especially rotaviruses), bacteria of several genera, and parasites: giardiasis is probably especially important in young children, at least in some areas; amebiasis is wide- spread, neglected by research, and difficult to assess in relative importance. The mortality and morbidity of diarrheal diseases can at least be sharply reduced by prompt oral rehydration (provided that vomiting is absent or can be controlled) — and this administered local- ly by a health auxiliary is likely to have a larger impact on the mor- tality, especially among rural and peri-urban populations, than belated but sophisticated parenteral rehydration in a distant hospital. But can the parents find time to attend to the child's needs when they have only a few days to plant the maize before the ground hardens? The widespread use of antibiotics, even by quite poor people in poor countries, must be discouraged by controlling their availability, as individual benefits are likely only by chance and disadvantages to the health of the community are a certainty. To take only one example, 76 percent of enterotoxogenic Escherichia coli isolates from the Philip- pines , Korea, Taiwan, and Indonesia were resistant to one or more anti- biotics, 44 percent to four or more antibiotics.12_f Antibiotics are available without prescription in the Philippines and only 80 of l,000 children admitted to hospital with gastroenteritis had not received 33

antibiotics before admission. Antibiotics are also frequently used for pediatric gastroenteritis in Indonesia and Taiwan. General improvements in nutrition, housing conditions, etc., could all substantially reduce mortality and morbidity from at least the majority of acute respiratory infections which include measles, meningo- coccal meningitis, etc. Apart from existing vaccines and the few infec- tions important enough in industrialized countries to make vaccine development economically attractive (e^£«, respiratory syncytial virus infections) there are really no current realistic hopes of controlling these important and widespread diseases by vaccination. There is a very large amount of disease in these same populations which we already know how to prevent, but do not because of the wide- spread deficiencies in financial and trained manpower resources, because of the paucity of reliable data and hence of effective planning, and because of the lack of trained and able management personnel in the middle and lower echelons of health ministries and services. WHO esti- mates that about five million children in developing countries die each year from one or another of diphtheria, measles, pertussis, poliomyeli- tis, tetanus, and tuberculosis; and that 80 million chlidren born each year in thse countries are not immunized against these common diseases. To demonstrate the difficulties, an assessment of the 1972 immunization program in Yaounde, Cameroon, showed that because of poor timing, and poor quality vaccine poorly handled in the field, an estimated 83 per- cent of the measles vaccine used was wasted and no significant benefit to the population achieved.^/ With the advent of a revolving fund from which the cost of vaccines can be obtained, it is hoped to rectify these problems over the next few years. But a much better planned and executed immunization program in Yaounde in 1975-6 showed that one or more doses of DPT, poliomyelitis, BCG, measles, and smallpox vaccines each reached only about a third of the largest population during the first nine months. Inadequate publicity was blamed — only 18 percent of parents attending had heard of the program through radio or posters. 16/ And it is interesting to note that 10 percent of a sample of chil- dren attending had arrived in the city within the previous month. The cost of immunizing one child against the range of infections mentioned was estimated at U.S. $1.90 — greater than the total per capita health services expenditure of perhaps 40 percent of developing countries, of which only 12 of 65 studied were spending more than $5 per head in 1975 35/ — averages which ignore the uneven distribution of health services, with a bias against rural and peri-urban populations. It is probable that the oppressive health problems of such populations (and the associ- ated severe deprivation) cannot, in many countries, be widely improved without a corresponding improvement in the economic status of the affected populations. This is not necessarily measured by the rate of national economic growth, as the failure of most tropical countries to distribute improved wealth (and, more important, health and social ser- vices) at all equitably means that the condition of rural and peri- urban populations can be seen to deteriorate in the face of large 34

improvements in GNP. It is generally accepted, however, that unless galloping population growth can be brought under control the prospects for general improvement are very poor — and these lethal diseases of babies and young children must make acceptance of birth control more difficult for the worst affected populations. But the incidence of many tropical diseases could, at least theoretically, be greatly reduced by relatively simple measures, and considerable successes are reported from China and Cuba — countries which have the necessary political determination and which have engen- dered a disciplined will among their populations to solve their own health problems. The risk of some mosquito-borne infections could be greatly reduced by the use of mosquito nets, care about exposure to snail-infested waters could reduce the rapidly growing problem of schis- tosomiasis and the wearing of shoes that of ancylostomiasis. "Man-made" malaria can result from excessive reliance on insecticides and the neglect of elementary and often well-tried mosquito control measures._7/ In Karachi, much malaria arose from increased Anopheles stephensi breed- ing in shallow pools, borrow pits, and puddles left by uncontrolled building operations in the rapidly spreading urban periphery.32/ Expensive drugs and vaccines cannot be the only answer and must be supplemented by simple but effective hygienic and behavioral changes. To take an example chosen by the World Bank,^J5/ vaccination against cholera gives about 50 percent protection for four to six months and costs U.S. 15 cents per head. "In admittedly favourable conditions in the Philippines, rudimentary privies were built at a cost of under $1 per privy, excluding self help labor. This is equivalent to a per capita cost of about 15 cents. Such privies, if properly maintained and used, cut cholera rates by about 60 percent .... Even when the cost of privies is three times that of immunization, the privy program will be cheaper after the sixth year .... Where diseases whose inci- dence can be reduced through improved water supply or improved sanita- tion are many, and account for a very large part of the total disease pattern ... privy facilities which are properly used and maintained would be far more economical than personal curative care." Unlikely though it may seem that these behavioral changes can be induced in large impoverished and illiterate populations (and it may be necessary first to achieve some as yet undefined level of basic educa- tion) — it probably is no more likely that they will receive modern vaccines or drug treatment for the multitudinous infections. Few (if any) really serious efforts have been made to assess the requirements or to use the unquestioned powers and skills of the media and the adver- tizing industry to induce desirable behavioral changes for health in developing countries — even less has the problem of how to evaluate such efforts been seriously tackled. These approaches must surely justify a substantial investment at least in experiment and evaluation. 35

Major for Where? The importance of geography and of the contrasts of urban and rural ecologies can be illustrated by consideration of one of the most widely distributed parasites, Wuchereria bancrofti, which is transmitted by a variety of mosquito species in different areas, which has no animal reservoir other than man (perhaps explaining its wide distribution), and which causes disease (elephantiasis, chyluria, lymphadenitis, lym- phangitis) only after prolonged exposure to infection. In rural areas the disease may be very focal with wide differences in prevalence within relatively short distances. The intensity of foci depend on (a) the presence of an efficient mosquito vector in large numbers, (b) close contact between the vectors and the human population, and (c) the proximity of vector breeding sites to human habitations and places of work.20/ Filariasis occurs in high density in many parts of Asia stretching from India to Korea. India alone contains more filarial subjects than all of the rest of the world: in Uttar Pradesh, where an estimated 33 million are at risk, 20 percent of populations studied were infected and disease rates among them ranged from 2 to over 30 percent ._17/ Over recent decades, the infection has become increasingly prevalent and important as an urban disease in India: Hyderabad and Bangalore, for example, were free of filarial transmission until the early 1960s but Culex fatigans now breeds profusely and filariasis is being transmitted in both cities.26/ In the Pacific, the infection is highly focal but some islands have the highest intensities in the world.2Q/ In Africa, information is particularly incomplete but prevalence is higher in East than West Africa. The disease is still almost entirely rural but seems likely to become a major urban disease with the increasing prevalence of C. fatigans in such cities as Lagos, Freetown, Accra, and Luanda; in East Africa, too, C. fatigans is spreading widely with urbanization.33/ In coastal Tanzania, estimates of adult male infection rates range from 6 to as high as 70 percent, and elephantiasis rates are as high as 1.6- 2.4 percent (and hydrocele rates even higher) in some villages ._18/ In the Americas, information is uneven but the disease is mainly urban (except in Guyana) and common only in Brazil, Guyana, and Haiti. Its prevalence in South America appears to be decreasing due to improved mosquito control and special campaigns ._19_/ Thus, Bancroftian filaria- sis is a good example of a rural endemic disease which has become a major problem of squalid tropical cities because of the spread and pro- fuse breeding of C. fatigans in latrines, cesspits, and sewage-polluted waters. During the second half of the 19th century and the first two decades of this, dengue fever was similarly transformed from a rural disease to become an important cause of urban epidemics 27/ transmitted by Aedes aegypti, which breeds readily in any sort of container — 36

particularly the prevalent urban litter of tin cans, automotive tires, and the like. There have been recurrent large epidemics of the classi- cal type of disease in South America and the Caribbean in recent years. In 1958, its haemorrhagic/shock syndrome form appeared in Manila and remains a serious cause of childhood mortality in Bangkok and more recently in cities in Burma, India, and Indonesia. Many other notable geographical differences could be cited. Holo- endemic malaria in Africa is a serious cause of deaths in children; unstable malaria (e^&., in the Punjab) seasonally disables whole popu- lations. Schistosomiasis, except for one tiny focus, is absent from the whole of the Indian subcontinent. Tsetse-transmitted trypanosomia- sis is confined to Africa; triatomid-transmitted Chagas' disease to America. The vast majority of these infections affect rural, not urban populations; and within countries their distributions depend on those of their arthropod or snail hosts. The importance of most major diseases in the tropics thus varies widely both between and within countries, depending on geography, eco- logy, etc. To reach any sort of assessment of which of them are "more" or "most" major one must face the questions: major for whom? ... or what? Major for Whom? At the extreme, the major disease (or, in the tropics, more often diseases) for the individual is the one (or several) affecting him and his family—and if he is influential his needs are likely to be dispro- portionately (in terms of population prevalence) expressed in govern- ment health policy and provisions. His greatest fear may be of one of the "diseases of affluence" (even the South East Asian Region states that cardiovascular diseases are becoming important ,_3_7_/ and he may wish to ensure that, should he have a coronary thrombosis, a sophisticated cardiology team will be available to deal with it. If, on the other hand, he is one of the millions of small farmers in rural areas, or one of the vast numbers of "semi-urbanized" squat- ters who have migrated to the periphery of tropical cities, he is like- ly to regard the lethal combination of malnutrition, gastroenteritis, and respiratory diseases which regularly kills or weakens his children (and thus his prospect of future security) as the major problems. In rural areas, the major parasitic diseases, depending on ecology, are additional crushing burdens. My assessment thus far of what is major has concentrated on mortality, particularly in young children (and its impact on population growth control), and this focuses on the poorest populations. Efforts to assist them must primarily be directed at the provision of the basic health and social services (especially maternal and child health) which 37

they so greatly lack and at sorely needed basic environmental improvements, especially in water supplies and sanitation. These must be planned so that they involve the maximum of self-help and can be afforded and efficiently maintained by the communities they serve. The recent studies of Feachem et al.,13/ of appropriate water supplies for rural populations in Lesotho point the way, but comparable studies are needed against ecologically and culturally different backgrounds. There is far too little evaluation of the effects of "experiments" in the development of health services or of environmental improvements — and indeed little effort even to develop an effective methodology. The British Ministry of Overseas Development has recently created a unit at the London School of Hygiene and Tropical Medicine to begin to tackle this problem. This imaginative move needs to be replicated elsewhere and most particularly in the developing countries themselves which, with better information, better analysis, and better management could undoubtedly get more out of their admittedly sparse health bud- gets, could avoid spending precious funds on ineffective or infeasible programs, and identify cost-effective changes in their activities. Indeed, the magnitude of the problem of getting the best possible value out of health service budgets has only recently been appreciated in the United States and Britain — and scarcely at all in some industrialized countries — but the need is even more pressing in a poor country. The WHO Special Program for Research and Training in Tropical Diseases, although concentrated on six diseases (filariasis, leishmaniasis, leprosy, malaria, schistosomiasis, and trypanosomiasis), is making pro- vision to train and establish epidemiologists, operational research workers, and statisticians to strengthen the ability of the developing countries to measure their own health problems, to plan appropriate con- trol and curative programs and to assess them, and to carry out meaning- ful trials of new vaccines or drugs in the particular circumstances of their own needs. This will help greatly over the whole field of health — if it is not left too late nor the effort developed too slowly. Major for What? This question has a number of possible answers other than mortality in young children: major for morbidity, for the quality of life, for working efficiency or for economic growth? Or major in scien- tific interest or for pharmaceutical companies? If we consider morbidity and the quality of life, such diseases as leprosy and filariasis in most of the tropics, and in certain areas schistosomiasis, hookworm, Chagas• disease, mucocutaneous leishmaniasis, onchocerciasis, and dengue fever come high on the list. WHO conservatively estimates that there are 10 million leprosy cases in the world (6.5 million in Asia, 3.5 million in Africa, and 350,000 in the Americas.J7/ This is not only a disfiguring and 38

disabling disease but still causes such social stigma over most of the world that it is associated with a degree of misery out of propor- tion to the clinical manifestations. Schistosomiasis, which is a serious and increasing problem (associated particularly with irrigation and hydroelectric dam projects) in many areas of Africa, in Brazil, in the Philippines, and part of Indonesia, can also be regarded mainly as a cause of morbidity. The liver damage it can cause and its severe distorting effects on the uri- nary and gastrointestinal tracts greatly affect the quality of life. Molluscicides, chemotherapy, and vaccines are all regarded as essential for its ultimate control, but all are deficient. Chemotherapy is being increasingly used—but the greatest impact could come from improvements in sanitation and water supplies. There are "estimated" to be some seven million cases of Chagas* disease in Latin America and 30 million people are thought to be at risk. It is a disease of poverty and of bad housing which harbors the bugs which transmit it. In its chronic form it is an important cause of cardiomyopathy throughout its distribution, and in some areas the "mega" conditions which it induces in hollow organs (esophagus, bowel, ureters, etc.) cause considerable suffering. The metastatic muco-cutaneous forms of leishmaniasis cause severe mutilation and suffering in tropical Latin America. The incidence of these complications, which depend on the infecting strain of Leishmania, 22/ following a primary skin lesion varies from 2 percent in Panama to 80 percent in Paraguay.^3/ The visceral form of leishmaniasis (Kala azar) appears to be increasing in incidence (and there may be a risk of severe epidemics) in eastern India and in East Africa. An estimated half million people have been blinded by onchocercia- sis in endemic areas of America (mainly in Guatemala and Mexico) and Africa (mainly in the Sudan-savanna and northern Guineasavanna zones in a belt south of the Sahara) — the severity of the ocular disease depending on the biting habits of the particular vector Simulium fly in each area and on the ocular pathogenicity of the strain of worm._l/ A major program of control by insecticide treatment of the rivers where the fly breeds is in progress in seven West African countries and is proving highly successful. If this success is to be maintained in the longer term, however, much more attention must be given to establish- ing the ability of the countries themselves to sustain a control pro- gram after the international effort ends — there is already evidence that re-invasion of the controlled area by flies can readily occur, and there may be need to supplement fly control by mass chemotherapy or vaccination, but neither is available.37/ Over the past few years dengue has caused several major epidemics in the north of South America and in the Caribbean area while in cer- tain cities of South East Asia dengue haemorrhagic fever/shock syndrome 39

has become an important endemic cause of mortality and morbidity in young children. Apart from their seriousness as a cause of lost work- ing days, the American epidemics pose a threat to the receptive south- ern United States. They probably inhibit tourism (so economically important in many of the islands), and they clearly indicate a wholly unsatisfactory state of control of the vector mosquito, Aedes aegypti, which was so well controlled by Soper many years ago by the disciplined and planned elimination of urban breeding places. As the same mosquito transmits urban yellow fever — an infection still enzootic in the Ama- zon basin with a small outbreak in Colombia only last year — the whole of the countries affected by the dengue outbreaks must be regarded as receptive to this much more lethal disease which in the past has reached as far north as Philadelphia. If we turn to working efficiency or economic growth as criteria for the importance of diseases, the answers can again be different. The economic effects of diseases in industrialized countries are usu- ally measured by estimates of the absence from work which they cause. Although their impact, particularly on scarce, highly skilled personnel cannot be less in developing countries, it cannot be measured because of the absence of adequate records, the high levels of unemployment and the impossibility of using such criteria to measure effects in the rur- al and peri-urban populations most at risk. However, Winslow concluded that industrial absenteeism had been substantially reduced by malaria control programs in the Philippines and southern Africa and by yaws con- trol programs in Haiti.^/ A World Bank study of construction and rub- ber plantation workers in Indonesia showed an 85 percent prevalence of hookworm with iron deficiency anaemia in 45 percent of the victims.35/ Treatment of the anemia at U.S. 13 cents per head was estimated to increase productivity by 19 percent. However, it may be unwise to cor- rect iron deficiency in the face of quiescent infection (£.£., malaria, tuberculosis, brucellosis) in isolated (e^j>. , nomadic) populations in equilibrium with it.^4/ It took very careful work to demonstrate scien- tifically that schistosomiasis has an adverse effect on working capacity which relates to the intensity of infection._ll/ The plantation indus- tries have long known that they needed health services if their labour populations were to be efficient — and there is increasing realization of this need among construction and mining companies. Incidentally, the World Bank estimates that the cost of feeding intestinal parasites, and the loss of food due to malabsorption following intestinal infec- tions, may amount to U.S. $10 per head per year in populations with high rates of intestinal infections._3_5/ Hookworms alone have been esti- mated to cause a loss of blood equivalent to the daily exsanguination of 1.5 million people._3/ Certain diseases, in high prevalence, inhibit the development of valuable agricultural land or other resources: e^j*., onchocerciasis has restricted access to land and other resources in western Africa; and fear of leishmaniasis may have had a similar effect in the tropi- cal forests of America. In parts of Nepal, Sri Lanka, and Mexico, 40

malaria eradiation induced movements of capital and labor into more resource-rich areas with a net increase in output; and a similar effect of trypanosomiasis control was seen in Nigeria._35/ Sleeping sickness is ubiquitous over large areas of tropical Africa and is a highly lethal disease. It requires constant (and expensive) vigilance and control if severe epidemics (the most recent last year in Uganda) are to be prevented. And trypanosomiasis in cattle is probably the main barrier to the development of extensive beef production in Africa. Many developing countries depend heavily on tourism and many more have potential for this valuable source of foreign currency. But cer- tain diseases act as deterrents. The risk of trypanosomiasis in game parks is one example; and the World Bank recently concluded that the common occurrence of diarrheal diseases among tourists was an important inhibiting factor. Large outbreaks of disease (cholera, dengue, menin- gococcal meningitis, etc.) can have a major effect, sometimes even affecting trade and commerce because of vaccination requirements and/or restrictions on movement. On the other hand, land and water developments can expose new disease problems or seriously aggravate existing ones. More and more dams are being built (for hydroelectric power, irrigation or urban water supplies) throughout the developing countries, £.£. , in Angola, Argentina, Congo, Cambodia, Ghana, India, Ivory Coast, Mozambique, Nigeria, Pakistan, Paraguay, Rhodesia, Senegal, Surinam. These man- made lakes can be potent sources of mosquito breeding, especially of malaria vectors. Shallow shorelines are particularly dangerous and can occur seasonally, or where a constant water level is maintained, wave action can produce sandbars and pools which favour mosquito breeding. The latter appears to be happening on a large scale in Lake Nasser and if the area were re-invaded by Anopheles gambiae the resulting malaria problem might be very severe. Man-made lakes are also important sources of schistosomiasis.29/ When the Volta Dam first filled (around 1960) aquatic weeds harbouring snails were widespread, Schistosoma haematobium was probably introduced to the dam by fishermen from the lower Volta, and the disease reached epidemic proportions among both migrants and local people. In Lufira Lake (Zaire) the main sources of snails and of schistosomiasis were the associated swampy areas, the slow-flowing tributaries of the lake, and its canals.^5/ Lake Nasser not only poses a danger of schistosomiasis to those who live around the lake but is also greatly aggravating the prevalence and intensity of the disease in the Nile Valley, where snails are now thriving in constantly irrigated areas where seasonal drying used to kill them. Argentina is believed to be free of schistosomiasis but the large number of hydroelectric dams planned for its northern border areas must pose a threat of introduction and establishment of the disease — well-planned surveillance should be mounted as soon as possible. 41

Irrigated agriculture is also a prolific source of mosquito breeding. The higher relative humidity it creates may increase the lon- gevity of the mosquitoes and hence their probability of transmitting infections. Throughout its distribution, Japanese encephalitis is par- ticularly associated with irrigated ricefields in which its mosquito hosts, in the Culex vishui complex, breed. Malaria vectors also breed in irrigated ricefields: the dramatic change in a mosquito population biting man when a dry area is irrigated was demonstrated by Surtees et al., in Kenya:J1/ a change from 99 percent Mansonia species to 65 per- cent A gambiae. Food crops also encourage the development of dense small mammal populations and of transmission of infections which they maintain — notable examples are leptospirosis and Argentinian haemor- rhagic fever. Kyasanur Forest disease, a previously unknown disease, became epidemic in Mysore, India, when human population pressure on arable land led to the grazing of cattle in forest.47 Even the highly desirable existence of hospitals and clinics with modern drugs and syringes (but not enough of the latter nor enough training in their use) provided the opportunity for the accelerated development of recent epidemics of an exceptionally lethal disease, Ebola fever, in the Sudan 15/ and Zaire._5/ We can expect further epi- sodes of such "new" diseases, perhaps at an accelerating rate, as the pressures on land and intrusion into new territories increase with world population, and we need to develop much improved surveillance and reporting of outbreaks and create adequate capabilities for a rapid and effective response to investigate and control them — sooner or later one of them may have pandemic potential.30/ Conclusions The great lack of accurate data on the incidence, prevalence, mortality, and morbidity of all diseases in most tropical developing countries makes confident assessment of the relative importance of various diseases very difficult even if the criteria for importance are defined. Most estimates have been of the "broad brush" variety and against undefined criteria. Whatever the criteria, however, it is clear that malaria and the childhood poverty diseases of malnutrition, diarrhea, and respiratory infections (including measles) are the most important health problems of the largest number of people in the tropics. They are a particular- ly intractable set of problems because they most affect those popula- tions most deprived of health and social services, adequate water sup- plies or sanitation. Peri-urban growth, in some areas, is outstripping the ability to contain, far less cure, the problems it creates. Only policies and provisions which reverse rural-urban flow may bring peri- urban problems within range. It may be that for many populations only the cure of poverty and illiteracy will provide lasting solutions to all these problems and this means the better distribution of wealth and 42

welfare as well as increases in national wealth. But none of this excuses us from efforts to find ways of alleviating this intolerable widespread deprivation. Much more effort could and should be made to devise, apply, and evaluate ways in which affected communities could help themselves: especially economically feasible means of improving nutrition (now recognized to be mainly general undernutrition rather than the lack of specific components such as protein), water supplies, and sanitation. A really major effort is urgently needed to use all possible resources (and particularly exploiting local cultural and social influences) for the health education of impoverished and largely illiterate tropical populations. Such efforts should however be much better designed, analyzed, and evaluated (and largely by developing indigenous expertise) so that progress can be recognized, improved upon, and extrapolated. There is a pressing need for better operational research methodologies and for more and better trained personnel to oversee and evaluate so-called experiments in the provision of health services and to discover why they represent improvements or deteriorations in outcome. Primarily, this is going to depend on the establishment of viable cen- ters of expertise for research and training. As the health sector is at present weak everywhere in this subject area, no time should be lost. The presently available weapons for malaria control are faltering and new drugs, insecticides, and vaccines are clearly desirable addi- tions for the armoury. But, along with these efforts, there should be a re-examination and as far as possible a return to the labour-inten- sive methods of mosquito control which were effective against many ano- pheline species in the past. An urgent and constructive thought is needed about how optimal packages of integrated control could be devised in various ecological circumstances and about how new (and inevitably expensive) weapons are going to be delivered to their tar- gets in rural areas. A proportion of the respiratory infections are preventable by immunization programs (diphtheria, pertussis, measles), but the WHO Expanded Immunization Program will succeed only if it reaches deprived populations, if the demographic implications for coverage in a rapidly growing population are recognized,^/ and if coverage can be kept up from year to year from national resources. Large scale once-and-for- all vaccination programs funded from aid sources and not subsequently maintained provide only a short-term benefit and may have serious long- term consequences. The success of smallpox vaccination cannot at pre- sent be extrapolated. There are other important and widespread diseases causing high morbidity in certain geographical areas. Of the endemic diseases, the most important are schistosomiasis, intestinal parasites, filariasis, onchocerciasis, Chagas' disease; of epidemic diseases, African trypano- somiasis, and dengue fever. Of these, schistosomiasis, filariasis, and 43

dengue have been increasing in recent years and none of them will be adequately controlled (even by new drugs and vaccines) without much more attention to environmental sanitation, water supplies, health education, and the better use of available manpower. If we consider the quality of life, then leprosy is important in most tropical countries, onchocerciasis, and filariasis in several areas, and the mutilating mucocutaneous forms of leishmaniasis in parts of South America. Economically, the most important losers of vast amounts of working time may well turn out to be the multitudinously caused febrile ill- nesses (which may include leptospirosis, virus diseases, and many others as well as malaria). But the debilitating effect of a variety of sub- clinical (or mainly subclinical) intestinal infections, and of seasonal al infections which may coincide with important phases of agriculture, must be important in reducing rural productivity in many areas. In all large scale developments in tropical countries — especially those involving water — provision must be made for a prior survey of disease risks which may be aggravated, for the health of the construc- tion force, and for active surveillance and appropriate health provi- sions for the population living in and servicing the development (^.£., usually expected to service the interest on the loans with which it was financed). Overall, there is a pressing need for better data on health and particularly for improved surveillance and investigation of outbreaks. 30/ The model of the PAHO Caribbean Epidemiology Center at Port of Spain, Trinidad, is strongly commended — preferably as a resource serving a group of countries and providing training and assistance in surveillance, diagnosis, investigation, and control of outbreaks and disease problems. The opportunities for research, from the most fundamental to the most applied, on all manner of diseases abound and have intense inter- est for those who become involved. In terms of its "six diseases" the WHO Special Program and several foundations (McConnell Clark, Rockefel- ler, Wellcome) are drawing new and high-powered biomedical science into the field. There is probably at least enough money in these diseases to support all the available research workers with good ideas. The Wellcome Trust has just launched a new program to encourage the develop- ment of research in more neglected areas — gastroenterology, respira- tory diseases and others — based on cooperation between strong depart- ments in Britain with counterpart departments in the tropics but with the center of gravity of the work firmly in the tropics. Much less attention has been, and is being, given to trying to ensure that the results of research are applied and evaluated in the field: the great- est need is for more gifted, experienced, and well-trained people to bridge the gap between the laboratory and the field and to help ensure 44

the applicability as well as the application of new discoveries — and old but neglected ones. There is a serious shortage, especially in the tropics, of well-trained epidemiologists and statisticians. The most pressing need in the developing countries is for more trained personnel capable of measuring problems, of devising possible practical solutions, and of evaluating their application. This is not a demand for "folkloric" research (rightly resented by developing country research workers) but for fundamental studies of behaviour, and of the best use of ideas and resources (new and old), in relation to health — an area only just beginning to receive the attention it deserves in industrialized countries — and an opportunity for important innova- tions of world-wide importance. These efforts must be backed by a real effort to devise and test culturally and socially appropriate methods of health education. A major effort is urgently needed to attract, select, train, and develop able personnel for these neglected areas of expertise — but their countries will retain them only if they provide satisfactory career and research facilities for them. 45

REFERENCES 1. Anderson J, Fuglsang H: Trop Dis Bull 74:257, 1977 2. Atangana S, Guyer B: Chron Wld Hlth Org 31:499, 1977 3. Banwell JG, Schad GA: Hookworm: Clinics in Gastroenterology: Intestinal parasites. Edited by PD Marsden. London, Saunders, 1978, 7:l, p 129 4. Boshell MJ: Am J Trop Med Hyg 18:67, 1969 5. Breman JG, Piott P, Johnson KM, White MK, Mbuyi M, Sureau P, Heymann DL, van Nieuwenhove S, McCormick JB; Ruppol JP, Kintoki V, Isaacson M, van der Goren G, Webb BA, Ngvete K: The epidemiology of Ebola haemorrhagic fever in Zaire, 1976. Ebola Virus Haemor- rhagic Fever. Edited by SR Pattyn. Proc Internal Colloq on Ebola Virus Infection and Other Haemorrhagic Fevers, Antwerp, Belgium, December 1977. Amsterdam, New York, Elsevier/North-Holland, 1978, p 103 6. Bruce-Chwatt LJ: E Afr Med J 45:266, 1968 7. Bruce-Chwatt LJ: Misc Publ Ent Soc Amer 7:7, 1970 8. Bryant J: Health and the Developing World. Ithaca, NY, Cornell University Press, 1969 9. Chandra Sekhar A: The International Population Conference, London 1969. Liege, International Union for Scientific Study of Popula- tion, 197l, p 2883 10. Cockburn WC: Proc. Int. Conf. on the Application of Vaccines against Viral, Rickettsial, and Bacterial Diseases of Man (December 1970). Washington, DC, PAHO (WHO), (Scientific Publication No. 226), 197l, p 3 11. Collins KJ, Brotherhood JR, Davies CTM, Dore C, Hackett AJ, Imms FJ, Musgrove J, Weiner JS, Amin MA, El Karim MAA, Ismail HM, Omer AHS, Sukkar MY: Amer J Trop Med Hyg 25:410, 1976 12. Echeverria P, Verhaert L, Ulyangco CV, Komalarini S, Ho MT, Orskov F, Orskov I: Lancet, II, No. 8090, 589, 1978 13. Feachem RGA: Water, Wastes, and Health in Hot Climates. Edited by R Feachem, M McGarry, D Mara. New York, Wiley, 1977, p 75 46

14. Fendall NRE: J Trop Med Hyg 68:12, 1965 15. Francis DP, Smith DH, Highton RB, Simpson DIH, Lolik P, Deng IM, Gillo AL, Idris AA, El Tahir B: Ebola fever in the Sudan, 1976: Epidemiological aspects of the disease, Ebola Virus Haemorrhagic Fever. Edited by R Pattyn. Proc Internat Colloq on Ebola Virus Infection and Other Haemorrhagic Fevers, Antwerp, Belgium, December 1977. Amsterdam, New York, Elsevier/North-Holland, 1978, p 129 16. Guyer B, Atangana S: Bull Wld Hlth Org 55:633, 1977 17. Hawking F: Trop Dis Bull 73:967, 1976 18. Hawking F: Trop Dis Bull 74:649, 1977 19. Hawking F: Trop Dis Bull 76: in press, 1979 20. Hawking F, Denham DA: Trop Dis Bull 73:347, 1976 21. Jacoby EH: Ceres. Rome, 3:48, 1970 22. Lamson R, Shaw JJ: Nature 273: Parasitol Suppl, 1978, p 595 23. Marsden PD, Nonata RR: Revista da Soiciedade Brasiliera de Medicina Tropical. 9:309, 1975 24. Murray MJ, Murray AB, Murray MB, Murray CJ: The adverse effect of iron repletion on certain infections. Brit Med J 2:1113, 1978 25. Ripert C, Cartaret P, Gayte MJ: Bull Soc Path exot 62:57l, 1979 26. Singh D: Bull Wld Hlth Org 37:239, 1967 27. Smith CEG: J Trop Med (Hyg) 59:243, 1956 28. Smith CEG: Proc R Soc Med 63:1l, 118l, 1970 29. Smith CEG: Man-made Lakes and Human Health. Edited by NF Stanley, MP Alpers. London, Academic Press, 1975, p 345 30. Smith CEG: "New" viral zoonoses: past, present, and future. International Microecology Symposium, New Zealand. Proc in Life Sciences: Microbial Ecology. Edited by MW Loutit, JAR Miles. Berlin, Heidelberg, New York, Springer-Verlag, 1978, p 170 31. Surtees G, Simpson DIH, Bowen ETW, Grainger WE: Trans R Soc Trop Med Hyg 64:51l, 1970 47

32. United States Public Health Service: Study of Urban Malaria in Karachi, West Pakistan. Atlanta, Ga, Communicable Disease Center, 1968 33. White GB: E Afr Med J 48:122, 1971 34. Winslow CEA: The cost of sickness and the price of health. WHO Monograph Series No. 7, Geneva, WHO, 1973, pp 22, 25, 30 35. World Bank: Health: Sector policy paper. (Health budgets), Washington, DC, 1975, Annex 3, p 74 36. World Health Organization: Wld Hlth Org Off Rec, No. 192, 1971 37. World Health Organization: Wld Hlth Org Off Rec, No. 243, 1978 48

THE PHARMACEUTICAL INDUSTRY'S PERSPECTIVE ON AVAILABLE AGENTS Paul A. J. Janssen and Denis Thienpont The major diseases of the developing countries are caused by a multitude of worms, fungi, protozoa, bacteria, viruses, rickettsiae, and by a variety of ill-defined pathogens. For the prevention, treatment, and eventual eradication of the well-known infectious diseases, three fundamentally different but mutually complementary strategies are to be considered (Figure l): 1. A first strategy designed to strengthen the ability of the human host to defend himself against the invading pathogens, and based on effective, safe, and inexpensive methods of immunization of the popula- tions at risk, on socio-economic efforts to correct the common nutri- tional deficiencies in many developing countries and, in some instances, on modern drugs like levamisole, designed to correct certain immuno- deficiencies. 2. A second strategy designed to modify the environment so as to lower the probability of contact between the human population at risk and the pathogens living in the environment, and based on a wide variety of methods (hygiene, sterilization, vector and reservoir host control, education, ecology, etc.). 3. A third strategy designed to selectively destroy the pathogens after invasion by chemotherapeutic agents or by specific immunotherapy. Here we need drugs that are not only highly effective, but also safe, easily available, and inexpensive. As we shall see in the following Tables, both the theoretical and practical importance of these three different strategies depend on the nature of the health problem to be solved: a. Worm diseases (Table l). It is unfortunate that the human host cannot yet be immunized against worm infections and that, to the best of our knowledge, scientific progress in this field is so slow that no major practical breakthrough is to be expected until the end of 49

this century. In theory, the incidence of most worm diseases can be easily lowered by simple hygienic measures, or by more complicated pro- grams designed to control the specific vectors or reservoir hosts. The FIGURE 1. STRATEGIES FOR ERADICATION OF INFECTIOUS DISEASES VECTOR PATHOGEN RESERVOIR HOST 50

TABLE 1. WORM INFECTIONS IM a/ VE b/ RH c/ HY d/ CT e/ l(f f/ Onchocerca + + ] Wuchereria + + ] . . .8 Brugia + + ] Schistosoma Mansoni + ++ ] Haematobium + + ] ...7 Japonicum + + + ] Fasciolopsis + + +6 Clonorchis + + +6 Paragonimus + + 6 Dracunculus + ~H- 6 Taenia + r T-t— t- O Echinococcus c J Hymenolepis ~*~ J c Trichinella t- T-r D _L _L_ t £ Larva Migrans + +3 Capillaria Phil. + -H-f 4 Ascaris T- ^ M- *| Trichuris ~*~ ~* ~* y Hookworms + +++ 9 Enterobius ^_l i_ Q S Strongyloides + -H-f- 7 a/A cross (+) in this column signifies that an effective vaccine is available and being used. Jj/A cross (+) in this column indicates that this is a vector- transmitted disease. £/A cross (+) in this column indicates that a reservoir host is known to play an important role in transmission. d/A cross (+) in this column indicates that hygienic measures have been shown to be effective in reducing the incidence of of disease. je/Three crosses (+++) in this column indicate that effective drugs are available. Two crosses (++) indicate that available drugs are much better than placebos, but are not good enough. One cross (+) indicates that available drugs are better than placebos, but are unsatisfactory. f/Estimated incidence in the world today (log to the base 10). 51

low feasibility of these methods of prevention is a frustrating fact of life in most developing countries, and explains the deplorable fact that today more than 50 percent of the world's population is infected with worms. Fortunately, however, a few modern broad-spectrum anthel- mintics, like mebendazole and levamisole, which are highly effective, safe, and inexpensive, are capable of helping to decrease the incidence of the most prevalent of all worm diseases, the soil-transmitted nema- todal infections caused by the classical triad: Ascaris, hookworms, and Trichuris. These same broad-spectrum anthelmintics are the drugs of choice for the treatment of several other nematodal infections which are either less serious (Enterobius), or severe but less common (Trichinella, Capillaria philippinensis). The most serious endemic parasitological problems of the develop- ing countries are caused by the three major schistosome species, and by the filariae of the Onchocerca, Wuchereria, and Brugia species: vector and intermediate host control strategies are notoriously difficult to implement and frustrating; moreover, fully adequate chemotherapy is not yet available. The chemotherapy for trematodal infections is generally inadequate. b. Fungal infections (Table 2). Prevention of fungal diseases is notoriously difficult and often impossible. The human host cannot be immunized against any of the many pathogenic fungi, and environmental manipulations designed to reduce the probability of contact between the population at risk and the fungus cannot be expected to be particularly effective. Antifungal chemotherapy is therefore the only conceivable strategy in most circumstances. A few modern broad-spectrum antifungal drugs, e^£-, miconazole, are highly effective against most superficial fungal infections of the skin, mucous membranes, nails, eyes, and gut. The various dermatophy- toses, tinea versicolor, and superficial Candida infections respond very well to these very safe and widely available drugs. In the tropical and subtropical areas, however, the numerous endemic systemic fungal diseases such as maduromycosis, cryptococcosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis, sporotricho- sis, chromomycosis, and histoplasmosis represent major therapeutic prob- lems which cannot be adequately solved with commonly available antifun- gal agents because only a few parenteral drugs such as miconazole and amphotericin B are known to be effective in these cases. What is urgently needed here are highly effective, safe, and orally active broad-spectrum antifungals to be used as early as possi- ble in the course of these generally progressive, debilitating, and often fatal diseases. Early diagnosis and easy availability of these drugs will also be a conditio sine qua non for therapeutic success. Our current clinical experience with the orally active broad-spectrum 52

antifungal agent ketoconazole leads us to believe that rapid progress in the treatment of most systemic mycoses is being made. TABLE 2. FUNGAL INFECTIONS IM a/ VE b/ RH c/ HY d/ CT e/ Derma tophytoses + -H-+ 8 Tinea Versicolor +++ 7 Superfic. Candidiasis +++ 9 Systemic Candidiasis ++ 6 Cryptococcosis + ++ 6 Coccidioidomycosis + -H- 5 Para Coccidioido- -H- 5 mycosis Blastomycosis -H- 5 Sporotrichosis -H- 5 Chromomycosis -H- 5 Aspergillosis + 5 Maduromycoses + 4 Histoplasmosis + -H- 3 a/-f/See key to Table 1, c. Protozoa (Table 3). The incidence of malaria is on the increase again, largely because of ineffective vector control and the emergence of drug-resistant strains. Most traditional antimalarials are still highly effective, both prophylactically and therapeutically, in many endemic areas. They are safe and inexpensive, but new drugs, effective vaccines, and adequate vector control programmes are essen- tial ingredients in any workable program designed to significantly decrease the incidence of malaria in the world. Modern chemotherapy considerably improved the prognosis of invasive amebiasis, but the incidence of the disease remains extremely high in many tropical countries. Its eradication does not yet appear feasible. There are at least four serious protozoal diseases against which satisfactory chemotherapeutic agents have not yet been found or devel- oped; namely, the various leishmaniases, African and South American try- panosomiasis, and toxoplasmosis. Here again, it is easy in theory but almost impossible in practice in most countries to decrease the inci- dence of these endemic diseases by manipulations of the environment. 53

TABLE 3. PROTOZOAL INFECTIONS IM a/ VE b/ RH c/ HY d/ CT e/ Malaria + i, . g r~r o S. Amer. + + +6 Trypanosom. African + (+) + 4 Trypanosom. Leishmaniosis + +5 Toxoplasmosis -1- +5 Amebiasis + ++ 8 Trichomoniasis +++ 7 Lambl iasis +-H- 6 a/-f/See key to Table 1 d. Bacteria (Table 4). Humans can be effectively immunized against pertussis, diphtheria, tetanus, meningoccal infection, and a limited number of other bacterial infections and toxins. Environmental control is only effective against a few bacterial infections, e^j»., plague and cholera. The present emphasis on chemo- therapy is therefore appropriate. Modern chemotherapy for bacterial infections, which started with the discovery of the first sulfonamides less than half a century ago, and made impressive progress since the Second World War with the dis- covery of many broad-spectrum antibiotics, is still in a period of revolution and adaptation to the continuous emergence of resistant strains. Better methods of immunization and other chemotherapeutic means to increase the defense mechanisms of the human host are being developed and are likely to play an important role in the prevention of bacterial infections. 54

TABLE 4. BACTERIAL INFECTIONS IM a/ VE b/ RH c/ HY d./ CT e/ Tetanus + H h + 5 Diphtheria + + 4 Pertussis + 5 Meningococcus + +++ 5 Plague + H i- -H- 2 Tuberculosis 1- ++ 7 Salmonellosis H h -H- 6 Brucellosis h + 5 Clostridia ^ H + 5 Anthrax 1- +++ 4 Actinomycosis ^ h + 4 Nocardiosis H + 4 Leptospirosis ^ 1- + 4 Staphylococci +-H- 8 Streptococci +++ 8 Gonorrhoea ++ 7 Syphilis ++ 7 Shigella -H- 7 N. Ven. -H- 6 Treponematosis Leprosy -H- 4 Cholera + + 4 a/-f/See key to Table 1. e. Viruses (Table 5). The available chemotherapeutic agents are practically ineffective in the treatment of most if not all systemic viral infections. The widely available antiviral vaccines are designed to prevent yellow fever, poliomyelitis, smallpox, mumps, rubeola, and rubella, and are effective, safe, and inexpensive. Mankind is in need (1) of safe and effective vaccines capable of preventing the many other viral infections such as the various types of influenza, parainfluenza, hepatitis, herpes, etc.; (2) of effective and safe chemotherapeutic agents for the treatment of virtualy all types of viral diseases; and (3) of other methods to strengthen the ability of the host to defend himself against chronic viral infections. Levamisole is a first step in this direction. 55

TABLE 5. VIRAL INFECTIONS IM a/ VE b/ RH c/ HY d/ CT e/ 10nf/ Yellow Fever + + + 3 Mumps + 7 Rubeola + 7 Rubella + 7 Poliomyelitis + 5 Variola + 1 Dengue + 5 Rabies + 3 Influenza 9 Rhinovir uses 9 Parainf luenza 8 Herpes Simplex + 8 Varicella 7 Inf. Hepatitis A 7 Inf. Hepatitis B 6 Cytomegalovirus 6 Mononucleosis 6 a/-f/See key to Table 1. f. Rickettsias (Table 6). In comparison with the other problems, the treatment of rickettsial infections with available chemotherapeutic agents is minor, several available drugs being quite effective and safe against most known strains. In conclusion, our perspective of the available methods of immunization and chemotherapy for the prevention and treatment of the 87 diseases listed in the Tables can be summarized as follows: (l) excellent methods of mass immunization exist against ten of these diseases; 56

(2) excellent, highly effective and safe chemotherapy exists against 23 other diseases, for a total of 33 out of 87; (3) satisfactory chemotherapy exists against 22; (4) unsatisfactory chemotherapy exists against another 22; and (5) no chemotherapy at all exists against ten of these 87 diseases. TABLE 6. RICKETTSIAL INFECTIONS IM a/ VE b/ RH c/ HY d/ CT e/ 10nf/ Fever + i i J i f l Fitf a D Murine Typhus + + +-H- 5 Epidemic Typhus + + +-H- 4 Scrub Typhus + 1 • I • £ S. Am. Spotted + 1 i i i O Fever Fievre + + +++ 3 Boutonneuse a/-f/See key to Table 1. 57

ASSESSMENT OF EFFECTIVENESS, SAFETY, AND ACCESSIBILITY OF AVAILABLE AGENTS A. DRUGS AGAINST PARASITIC DISEASES Wallace Peters Introduction From the content of other papers in this Conference it will be evident that diseases afflicting countries of the "Developing World" include those that affect also the countries of what may be termed the "Developed World," modified by genetic, climatic, and socio-economic factors. In addition to these, however, there are other diseases, the geographical distribution of which on the whole is restricted by the same local factors, especially where these control the presence or prevalence of intermediate hosts and vectors. The less specific but universal conditions, ^.£., bacterial, viral, immunological, and degen- erative diseases account for a considerable level of morbidity and mor- tality (^.£. , mundane intestinal infections in infancy, pneumonia in the older age groups). As drugs used in their treatment, particularly antibiotics, are not specific to developing countries they will not be considered at length in this paper. The main point to be stressed is not lack of effectiveness per se of sulfonamides or antibiotics, for example, but lack of control over their distribution and usage. In certain countries they are grossly misused through being openly adver- tised in media such as newspapers and the cinema screen, and unrestrict- ed sales are permitted in shops and the open market place. This all too common trend has, not surprisingly, led to rapid development and spread of bacterial resistance to such medicaments. One should also mention here, in passing, the unrestricted use of antibiotic feed addi- tives in agricultural practice in some areas, and abuse and indiscrimi- nate application of potent insecticides, as for protection of cotton crops in many countries, for example, which have resulted in the inci- dental development of resistance to a wide spectrum of insecticides by important disease vectors, notably malaria-carrying Anopheles mosquitoes. More specific to developing countries are those diseases caused by parasites, and it is drugs used specifically for prevention or treat- ment of these conditions on which this paper will focus. Parasitic dis- eases will be considered in two main groups, those caused by protozoa, and those caused by helminths. 59

The Parasite Burden Protozoal Infections Without a doubt malaria remains, in spite of two decades of efforts at eradicating it, the most serious protozoal disease afflict- ing man, and a major cause of mortality. In 1976, it was estimated that 848 million people still lived in areas where transmission con- tinued although active control measures of one sort or another were being undertaken, while 343 million, mainly on the African continent, were receiving virtually no protection at all._17/ In the last few years, the situation has deteriorated with a massive resurgence of transmission on the Indian subcontinent (Figure l) and elsewhere. FIGURE 1. NUMBERS OF POSITIVE BLOOD SLIDES REPORTED IN INDIA FROM 1962 - 1977 (in millions) 60- 5.0- _o o E 2.0 H i4* o 1.0- 1960 1965 1970 1975 60

Epidemic waves of malaria have been recorded in Turkey, for example, a few years ago almost freed of the disease, but in 1977 the site of over 120,000 cases.22/ TABLE 1. NUMBER OF AUTOCHTHONOUS MALARIA CASES (in thousands) FROM 1972 to 1976, BY REGION 22/ Region 1972 1973 1974 1975 1976 Total 3251 4073 5181 7004 7517 The Americas 284 280 269 356 379 South-East Asia 1920 2694 4210 5992 6539 Europe 21 13 8 12 39 Eastern Mediterranean 855 883 524 447 350 Western Pacific 171 203 170 197 a/ 210 a/ Ratio of Change 100 125 159 215 231 (1972=100) ^/Excluding China, Democratic Kampuchea, and Viet Nam. Next to malaria, trypanosomal infections of Africa and the New World vie with the complex of diseases known as the leishmaniases for second place as serious public health problems, not so much in terms of absolute numbers of cases, as for the morbidity they cause. The numbers of cases reported by World Health Organization are certainly a gross underestimate. While perhaps some 35 million Africans are exposed to sleeping sickness and other forms of African tsetse-borne trypanosomia- sis, the actual numbers of cases are unknown. Epidemics arise from time to time, £.£. , in Zaire in the 1960s when up to 18 percent preva- lence of infection was reported in some foci.^8/ An epidemic of unknown but serious proportions is currently raging in the Sudan. African try- panosomiases moreover are a major obstacle to pastoral development and meat production in the tsetse belt of tropical Africa. Several species of this parasite are highly pathogenic for most exotic strains of cat- tle and other domestic animals that have been introduced to improve the stock, the trypanosome-tolerant local cattle being poor meat-yielding 61

animals. In South America, Chagas' disease caused by another type of trypanosome carried by large biting bugs affects perhaps another 10 million people. Heart failure in early adulthood and, in some areas, severe functional changes in the intestine result from chronic infec- tion in those who survive the acute stages of this, so far, almost untreatable disease. The different parasites in the genus Leishmania, a genus widely distributed from China through much of the Old World, and extending through the greater part of Central and South America, produce a varie- ty of diseases of the tegument and of the deep organs of the body such as liver and spleen. Cutaneous leishmaniasis, while frequently self- limiting if untreated, may nevertheless cause disfigurement and disabil- ity. The variety that involves mucous membranes of the nose and face can lead to extreme tissue destruction with wholesale loss of facial tissue of a degree rarely encountered today with any other disease. The visceral type of leishmaniasis may occur in epidemic fashion. India is currently in the throes of just such an epidemic. In excess of 100,000 cases of kala azar were estimated to have occurred in Bihar and West Bengal in 1976, leading to more than 4,000 deaths. The roots of this epidemic (as of the malaria epidemic) lie in cessation of DDT spraying against malaria-carrying mosquitoes, a procedure that inciden- tally killed off house-haunting leishmaniasis-carrying Phlebotomus sandflies. As will be seen in the following pages, drug treatment is available for prevention and treatment of certain kinds and stages of malaria in individuals, but not in communities. Drugs currently in our hands are grossly inadequate to cope with the other protozoal diseases mentioned here. Helminth Infections To estimate prevalence of helminth infections is an extremely difficult task because of the inadequacy of most of the available sta- tistical data. The writer estimated recently 12/ that in the 1975 world population of just under 4,000 million, there were nearly 4,500 million worm infestations Multiple infections are the rule rather than the exception, especially in developing countries. Thus, in the tropics and subtropics 136 percent of the 3,000 million population, and in the temperate zones of the world only 44 percent of 965 million peo- ple may be infested. While some of these data no doubt represent con- siderable overestimates (£•£. , in the USSR and China where large strides have been made in controlling parasitic infections), data for some other areas are probably underestimates. The two groups of helminthiases on which this paper will focus are the schistosomiases and the filariases. Three forms of schistosomiasis are common in man, leading to disorders of the bowel, the urogenital 62

tract, and the liver and hepatosplenic circulation. The World Health Organization estimate of 180 to 200 million cases is less than that of the writer, whose estimate is around 270 million. As Weller pointed out, prevalence data, such as there are, frequently are fragmentary, inadequate for technical reasons, outdated, or invalidated by a rapidly changing ecology._16/ Schistosomiasis extends in parallel with the increasing opening up of land for agriculture through development of irrigation systems, as is currently being observed, for example, in the Gezira region of the Sudan and Northern Nigeria.13_/ In the absence of adequate control of the molluscan intermediate hosts of these worms and satisfactory application of mass chemotherapy, reliance on health educa- tion is worthless except where the level of social discipline is excep- tionally high. Thus, Friedheim stated that China and Japan have attained a large measure of schistosomiasis control through social measures based on the proper disposal of excreta._5/ This they have achieved through "a persuading national and semi-religious ideology culminating in a sense of responsibility of the individual towards his personal health and its repercussions on the health of the community." Currently, available schistosomicidal drugs, some of which show great promise, have yet to prove their worth in really large scale control programs. The important filariases are of several types, the most serious being those that cause damage to the lymphatic system and which are transmitted by mosquitoes, and one that is carried by Simulium (black- flies) which affects primarily the skin and eyes. The former lead to swollen limbs, the condition called "elephantiasis" in many areas of the tropics, while the latter, caused by Onchocerca volvulus, produces "river blindness" in parts of Africa and Central America. Mosquito- borne Wuchereria bancrofti and Brugia malayi may afflict more than 250 million people (although only a small proportion actually develop elephantiasis) ._19/ Some 20-40 million are exposed to river blindness. Not one safe drug is known that is guaranteed to destroy adult worms in man. Other filarial infections of importance are Loa loa (causing "Calabar swelling") and Dracunculus medinensis or "Guinea worm." Malaria and Antimalarial Drugs In order to explain the outstanding problems relating to antimalarial drugs, it is necessary to recall some features of the para- sites that cause this disease. Three common species and one uncommon one infect man. 1. Plasmodium falciparum Man is infected by the bite of an Anopheles mosquito. The para- sites that the mosquito injects pass into the liver where they undergo one cycle of development before entering red blood cells. There the asexual parasites grow repeatedly through a 48-hour cycle which leads 63

to destruction of the host cells. P. falciparum is the most dangerous parasite since it can rapidly kill by destroying red cells in large num- bers and by blocking capillaries in the brain. If the patient survives the initial onslaught he builds up an active defence which helps him to overcome later stages of the infection, and gives him a partial immunity against subsequent challenge by this parasite. P. falciparum, known as the "malignant tertian" parasite, is widely distributed in the tropics and is the dominant species in tropical Africa where it may represent 95 percent of all infections. In large parts of its distribution strains have emerged that are resistant to a wide variety of antimalari- al drugs. 2. P. malariae This parasite follows a similar life cycle to P. falciparum but rarely causes a life-endangering infection. It is liable to become very chronic, and hence is the parasite usually responsible for malaria that results from transfusion with blood donated by people who may have been infected many years before. P. malariae is widely distributed throughout the tropics. Unlike the other species its cycle in red blood cells lasts 72 hours. 3. P. vivax The "benign tertian" parasite has the same general cycle as the others, but secondary forms developing in the liver are responsible for late relapses of parasitaemia and fever. Vivax malaria rarely affects people of Negro stock who are genetically less susceptible than whites. The infection produced by the blood stages (in a 48-hour cycle) is rare- ly dangerous, but produces anaemia and chronic loss of condition for up to three years if untreated. P. vivax is widely distributed except in Africa, and can survive in a somewhat cooler climate than the other species. 4. P. ovale This uncommon parasite with a patchy distribution has a 48-hour cycle similar to P. vivax. Antimalarial drugs in current use have a limited spectrum of activity against the different stages of the life cycle. Some act against the first generation of liver stages (causal prophylactics), others against asexual stages in the red cells (blood schizontocides), some against the sexual blood stages that infect the mosquito (gameto- cytocides) or the stages in the mosquito (sporontocides), while one drug affects the secondary liver stages of P. vivax (anti-relapse or tissue schizontocidal action). No single drug possesses all these pro- perties. Moreover, the range of action of these drugs differs accord- ing to the species of Plasmodium. A summary appears in Figure 2. 64

FIGURE 2. SIMPLIFIED LIFE CYCLE OF MALARIA PARASITE TO SHOW POINTS OF ACTION OF DIFFERENT TYPES OF ANTIMALARIAL DRUGS MOSQUITO SPORONTOCIDES P. foiciporum P. molarioe P. vivax P ovale GAMETOCYTOCIOES P falciparum P. malariae P. vivax P ovale ANTI- RELAPSE DRUGS BLOOD SCHIZONTOCIDES P vivax ? P. ovale 65

Provided that there is no question of the parasites being actually resistant to a drug, there is a choice of compound that can be used either for prevention or cure of malaria in the individual. However, each drug has its own limitations as regards tolerability even for the individual. Of more significance for the present Conference are the limitations of these compounds when used on a large scale for the con- trol of malaria in human communities. The available compounds are shown in Table 2. Table 3 shows that the only compounds regarded as completely safe are the "antifols," proguanil, and pyrimethamine. These, however, are too slow in their action to be used for treatment of an acute malaria attack. Moreover, malaria parasites readily become resistant to anti- fols when used alone, and many resistant strains are encountered over a wide geographical area. This problem is overcome when such compounds are used in association with a sulfonamide or sulfone with which they produce a potentiating action. Several such mixtures are available, and pyrimethamine-sulfadoxine is one example (Fansidar®). Other com- binations are pyrimethamine-sulfalene, trimethoprim-sulfalene, and pyri- methamine-dapsone (Maloprim(1^ ). The safety of long-term prophylactic use of these compounds, and their safety in pregnancy have not yet been established completely. Chloroquine and amodiaquine are known to accumulate in retinal tissue and pigmented cells of the skin when given for long periods of time. These compounds are poorly tolerated by some Nigerian people. They may also cause gastrointestinal disturbances in some individuals. Strains of P. falciparum resistant to chloroquine and also resistant to antifols are common in South and Central America, South East Asia, and the Western Pacific. Such strains may also be appearing on the African continent. These problems apart, however, chloroquine and amodiaquine remain the best available compounds for treatment of acute malaria in most cases, and are valuable prophylactics in many areas. Quinine may have to be used for therapy in a few especially severe cases of falci- parum malaria. Primaquine is essential to prevent relapses of P. vivax. Courses of treatment range from 5 to 14 days, the shorter courses invit- ing a 10 percent or greater risk of failure. This drug cannot be given in normal dosage to people with genetically determined blood enzyme deficiencies such as that of glucose 6-phosphate dehydrogenase (G6PD) as it causes severe haemolysis. For treatment of chloroquine-resistant falciparum malaria only quinine, antifol-sulfa mixtures (e^- , Fansidar (R) ), and mefloquine are effective. Quinine is toxic in the high doses needed and does not always produce radical cure of the infection. Fansidar (Jy is usually curative but is probably best given following a course of quinine thera- py which can be administered intravenously in an emergency. Mefloquine is the product of ten years' intensive research and development by the Walter Reed Army Institute of Research (WRAIR) that has cost the United States taxpayer some U.S. $10 million per year. It shows great promise 66

TABLE 2. SPECTRUM OF ACTIVITY AGAINST DIFFERENT SPECIES OF PARASITES SENSITIVE (S) OR RESISTANT (R) TO CHLOROQUINE a/ OR ANTIFQLS (F) P.falci- parum P.malariae P.vivax S R S F S F Causal prophylactics proguanil (chlorguanide) pyrimethamine Blood schizontocides _b/ chloroquine + amodiaquine + quinine cj + mef loquine d/ + pyrimethamine-sulfa— + doxine (=Fansidar (§)) pyrimethamine-dapsone + (=Maloprim(fp ) Anti-relapse drug not applicable primaquine Gametocytocide e/ primaquine Sporontocides e/ proguanil + - + - + - pyrimethamine + - + - + - a/P. falciparum strains resistant to chloroquine are usually also resistant to antifols. _b/Blood schizontocides may be used either for suppression of blood infections (^..je., prophylaxis) or treatment of an acute attack of malaria. They produce a radical cure of P. falci- parum and probably P. malariae, but not of P. vivax. For this, the anti-relapse drug primaquine is also needed. ^/Quinine is no longer used for routine prophylaxis or therapy. d/Mefloquine is still in clinical trial and not yet generally available. e/Gametocytocidal or sporontocidal drugs are of value for interruption of transmission in a community, but are not necessary for treatment of the individual. 67

TABLE 3. SAFETY OF STANDARD ANTIMALARIALS Safe for Compound Prophylactic indefinite Treatment Safe in dose well long-term dose pregnancy tolerated prophylaxis tolerated chloroquine amodiaquine quinine proguanil pyrimethamine pyrimetha- mine-sulfa- doxine d/ primaquine mefloquine not used + a/ + a/ not used not used not used not used not used + b/ ? + ? £/ ? a_/WHO advises giving chloroquine only up to a cumulative dose of lOOg.jZO/ Larger doses may lead to retinal defects. b/Causes acute haemolysis in certain genetic enzyme-deficient individuals. _c/Usually not administered during first trimester of pregnancy. d/Contra-indicated in sulfonamide hypersensitive individuals. for prevention and treatment of all malarias, including chloroquine- resistant P. falciparum, but is still reserved for carefully controlled clinical trials run jointly by the World Health Organization, the United States Army and a Swiss pharmaceutical company. The latter has donated material and resources for this purpose as a contribution to the UNDP/ World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (TDR Program). All these drugs need to be given repeatedly at fairly frequent intervals if they are to be employed for prophylaxis. They therefore do not lend themselves to mass drug administration in large communities. Long and bitter experi- ence has shown that malaria control using repeated drug administration is almost always doomed to failure. To succeed as a mass control mea- sure, a preparation would need to be administrable with complete safety 68

to entire communities, at infrequent intervals (perhaps from three to six months), and preferably by injection. No such compound or prepa- ration exists at the present time, and its development is a priority objective of the Scientific Working Group (SWG) on the Chemotherapy of Malaria of the TDR Program.17/ The recent malaria epidemic in India, more than 90 percent of which was due to P. vivax infections, well illustrates the logistic limitations imposed by the current world production of antimalarials. The Indian Government estimated that its annual antimalarial require- ments in metric tons would be: chloroquine 300, primaquine 4, quinine 8, pyrimethamine 3.5, sulfadoxine 4, and tetracycline 5 (the value of the last as an antimalarial is highly debatable.j>/ Annual production of chloroquine in India runs at 30 tons. Sixteen tons of quinine are produced but almost all is exported. In India, the problem is not one of drug resistance but of the need to treat acute vivax malaria with chloroquine, and to prevent relapse with primaquine. Physicians in India, however, regard primaquine with great suspicion in the light of its reputation for causing serious side effects in G6PD-deficient sub- jects of whom there are many in that country. In Assam and the neigh- boring states of northeastern India, chloroquine-resistant falciparum malaria does pose a threat, and stocks of quinine and Fansidar R are being sought in case they are needed there. The market price of these two preparations, however, is a serious deterrent in India and elsewhere. In summary, it is seen that, although excellent antimalarial drugs are available, their deployment and procurement still pose many prob- lems that are far from being resolved while. For mass drug administra- tion, however, suitable drugs are not available. Other Antiprotozoal Drugs The situation is considerably worse with regard to drugs for prevention and treatment of trypanosomiasis in Africa or South America, or for use against the leishmaniases. It may be summarized: African Trypanosomiasis 1. Prophylactic drugs — pentamidine (for human use) This was used extensively, especially in Francophone Africa, to protect communities living in highly endemic areas. While some success was claimed in reducing the infection rate, pentamidine-resistant strains of trypanosomes are by no means uncommon. This drug is also toxic and side effects are fairly frequent.j?/ More- over, early infections may actually be concealed by pentamidine.4,18/ 69

quinpyramine (for animal use) Resistance rapidly developed against this and related drugs when they were used for protection of domestic cattle. The same fate has met drugs belonging to other chemi- cal groupings when used prophylactically in animals, ^.£. , homidium, isometamidium, and diminazene. 2. Drugs for treatment — organic arsenicals These are essential for destruction of parasites that have entered the central nervous system. Tryparsamide has been replaced by melarsoprol, which is toxic, although much less so than tryparsamide. Arsenic-resistant strains of trypanosomes affecting man are fairly common, £•£., in Zaire. suramin A complex organic non-metallic compound, suramin is nephrotoxic. It is also effective only against trypanosomes before they enter the brain where they produce the changes leading to "sleep- ing sickness". pentamidine The use of pentamidine is no longer favored in human therapy since it is likely not to produce complete cures and thus may permit insidious development of cerebral infection. It, too, is inef- fective against trypanosomes in the brain. diminazene aceturate This is diamidine has been used with some success in limited clinical trials against arsenic-resistant instances of West and East African trypanosomiasis._14/ Recent studies suggest, however, that it possesses potential neurotoxicity, and the manufactur- ers do not encourage further human studies with this drug. It is still used fairly widely in cattle. nitrofuranes Several nitrofuranes have been used in the past. All may cause neurotoxity and changes in carbohydrate metabolism in man, and haemolytic anaemia in G6PD-deficient subjects. Recent clinical studies with levofuraltadone are not very promising.14/ In short, completely safe drugs exist for treatment of established infection either with the West African parasite, Trypanosoma gambiense, or against the East African T. rhodesiense. Chemoprophylaxis in man is no longer considered of significant practical value with the only avail- able compound, pentamidine, and attempts to protect cattle have been marred by drug resistance. South American Trypanosomiasis (Chagas' Disease) No drug is suitable for prophylaxis of Chagas• disease caused by T. cruzi. Improvement of housing and residual insecticide spraying of homes and animal shelters are probably the best prophylactic methods 70

that can be used. Experience in Venezuela and elsewhere has proven the efficacy of these measures. No safe and well-tolerated drugs are available for treatment of chronic Chagas• disease, although all the following may be effective if the disease is diagnosed in the acute stage. nifurtimox This compound must be given in very prolonged courses. It is often poorly tolerated and patients therefore frequently fail to complete the treatment. In some areas, cure rates do not excced 80 percent. benznidazole The evidence so far on this relatively new drug suggests that it may be superior to nifurtimox. It is also toxic, and must be given in rather long courses. A safe drug that can be administered in a short, intensive course of therapy and produces complete cure of Chagas' disease has not yet been identified. Nitrofurazone has proved too toxic and is no longer used.4/ The Leishmaniases Claims have been made for the therapeutic value of many drugs for treatment of cutaneous leishmaniasis, but most are based on uncontrolled studies in cases which would probably have healed spontaneously. Only three groups of specific antileishmanials are available. In addition, the two drugs mentioned above in relation to Chagas' disease are under- going clinical trials against leishmaniasis. Drugs for prophylaxis are not available. pentavalent antimonials Sodium stibogluconate and meglumine antimoniate are the only safe and highly specific antileishmanial agents. However, even these must be given in prolonged courses, and there is some tendency for accumulation of antimony in some patients, with subsequent risk of cardiac and other toxicity. Both drugs are very expensive and in short supply. pentamidine Pentamidine is used as a second-1ine drug in some cases of leishmaniasis which fail to respond satisfactorily to antimoni- als. The response in such cases to pentamidine is variable, and prob- lems of drug toxicity must also be faced. amphotericin B This antibiotic is used as a last resort in a few patients, especially those with mucocutaneous diseases who fail to respond to antimonials. It is highly nephrotoxic and can only be administered under carefully controlled hospital conditions. 71

The majority of sufferers from these conditions, with the exception of some residents of the economically more favored countries of the Arab world, are poor peasants or labourers who can ill afford the time or money to pay for treatment. Moreover, health services of the countries in which these diseases are endemic are often unable either to mount an effective service for detection and treatment of patients or, in extreme cases, unable even to afford the few drugs that are available. In India, recently faced with an epidemic situation in which possibly 100,000 people developed kala azar, adequate stocks of pentavalent antimonials were impossible to come by even with the assis- tance of the World Health Organization and bilateral funding agencies. An acute shortage of pentamidine eventuated. This drug is used for treatment of what were believed to be a high proportion of antimony- resistant cases. (Most of these were later found to have been treated inadequately for a variety of reasons, including the high price charged for injections by some unscrupulous private practitioners). The response of the Indian government was to set up a "crash program" for synthesis of sodium stibogluconate within the country. As a result, the drug is now produced by three Indian pharmaceutical manufacturers, and at a very modest price. As regards the search for and development of new drugs for treatment of African or South American trypanosomiasis, very little effort is being put forth by the private sector, mainly because of the enormous effort involved with absolutely no hope that research and development costs can be recovered, to say nothing of a profit being realized. It has been estimated, for instance, that only 1 in 50,000 compounds screened would have any chance of success.]JJ/ Almost the only work in this field, and with antileishmanials (an even more neglected field),_1O/ is being carried out either in academic labora- tories or by scientists associated with WRAIR. Because of the poten- tial importance of some protozoal diseases to the military, the huge inventory of drugs accumulated during the United States antimalarial program is now being examined for candidate compounds against these other protozoal diseases. Research is now also proceeding at WRAIR, in London, and in Liverpool on new approaches to development of exist- ing antiprotozoal agents through the use of such measures as liposome incorporation. Other laboratories are investigating different ways of making better use of available drugs by making them lysosomotrophic._7/ Much fundamental work in biochemistry is also being undertaken under the auspices of the Ministry of Overseas Development of the United Kingdom, and of the Special Working Groups on the Chemotherapy of Trypanosomiasis and of Leishmaniasis of the World Health Organiza- tion TDR Program in the hope of developing a rational approach to dis- covery of new antiprotozoal agents, as an alternative to empirical screening. It must be noted, however, that the latter approach has in practice proven to be the most fruitful for discovering radically new drugs,_15/ whereas the rational approach is necessary to show how new drugs work and to develop superior analogues. 72

Anthelmintic Drugs As mentioned earlier in this paper, the intestinal helminths impose a vast burden on mankind. It is not surprising, therefore, to find that many drugs have been introduced over the years to serve as vermifuges. These range from natural products such as oil of chenopodi- um and extract of male fern, long used to remove the common roundworm, Ascaris lumbricoides, and the large tapeworms, respectively, to modern synthetic compounds such as dichlorvos (an organophosphate) and mebenda- zole (a benzimadazole), both of which are active against a broad spec- trum of helminths._15/ Davis summarized the activity of then currently employed synthetic anthelmintic agents (Table 4) showing that none of the existing drugs were effective against all species of intestinal nematodes.^/ Advances have been made since that time, especially in the direction of benzimadazoles, some of which exhibit a remarkably broad spectrum but also some inherent toxicity to the host that has yet to be fully evaluated. Another new compound, praziquantel, is also actove against schistosomes, and will be discussed below. Many of these newer agents are relatively expensive, and few of them approach 100 percent effectiveness in a single dose, both very practical considerations for drugs to be employed extensively in poorer communities of the develop- ing world. It is interesting to realise that several newer agents were discovered in the course of screening for anthelmintics to be used in the veterinary field, since the market prospects for veterinary pharma- ceutical products of this nature are far more rewarding than anthelmin- tics to be used to treat poor people. Praziquantel is one such drug. Dichlorvos was not developed as an anthelmintic, but as an insecticide, and it took considerable effort before the company producing it could be persuaded to examine it seriously as an anthelmintic. Metrifonate is another compound of this nature to be discussed below. Schistosomiasis Until the advent of the newer schistosomicidal agents mentioned here, tartar emetic was essentially the only compound used for mass treatment of schistosomiasis. This is a remarkably effective but very toxic organic antimonial which undoubtedly accounted for many deaths due to treatment, and not to the disease. One of the first non-antimonial synthetic agents was lucanthone which proved fairly effective, especial- ly against S. haematobium, but which also proved toxic to the liver, especially in people whose livers were already damaged by the disease. One of the features of schistosomiasis is that any particular drug tends to be more active against one species of parasite than against another. The general trend was for S. haematobium to be more suscepti- ble than S. mansoni, and S. japonicum to be the least responsive of all. This situation has changed with some of the newer drugs. Table 5 shows the compounds currently In use or undergoing clinical trials. 73

H CO co 3 O 1 >; ••H -8 -' 1 O 60 cn O CU f. C 1 4J 1 4-1 C 0 0 • CS CO CO a i-H iH O •H I-l CX •H cd S i-1 V-i 4J a £j I-l O CO H <n CO o O 4-1 cn co 1 1 -H a •Hi-lB CO CO CO CO 1 CO 0 0 d O 1 •H (n CU CU CO t-l -H (4 >d- ^f 4-1 CO CO I-i CU CO e CO 1 1 1 4J 3 i- H en cn cn cn *^- C -H 0 3 U & > u i-l I-l • 0 1 1 Ij 60 CO o 0 a 0 O co <t CN o h w 0 •H CO 1 1 1 •H cn CN •-4. 4J o 4-J i- H >> CO CO •-l CO (4 1 J_| 0 ^^ C co < u CM 0 .- H C Jtal 4J •H O o 1 ^^ CO CO CO i-l 4J •H CO cn cn 0 CO CO 3 4-1 cd 3 1 1 jf* 4-1 •H O Cd u 0 c CN CM CN CN CM CN w CO C B oi M S 0 e cd u •H CO C 4J S5 S u § e co a1 o H •- H CO 4-1 C i (4 z CU M 3 CU M *M M ff. H u a o £ o « 0 >-J t3 33 S 0 • i~H < u 1 O i- H en en cn ^ J3 pr* 4-1 >J4J 1 cd 1 1 1 4J CO g— 4 4J a co o e CN CM CM CM CN CN •H I-l 2 •H C 0 3 0 > cd <£| B <:|H •o •0 •H a CO • 4-1 0 Qd C • >» o a ^ CO <d >~, 4J cd C I-i CO 4-1 i-l fH W 4-1 •H •H > T3 S 1 ^t I-l 3 > -H 0 C iH o 3 •H •H 4-1 0 Oi fa iH c JS 4J O 00 4-1 o O c o O O i-l .- H rH •- H cn cn O CO I4-l • C/3 O iH •H •H CO X O 1C ^4 iH 4J I-l •U .H 3 ^J co cn H 4J cu o oo co i-i CO 0 4-1 O C -H T3 iH 60 CO 60 -H M B C 1-j T3 CU QJ fa CO -H CO 1 CU >~> C 4J J3 PK c •H •H co T3 I-l CO CO 4J U CO 60 ^ M 0 ^ O CU 4-1 Id t-l 60 cd J3 •o 1 B > co .- U H 0 O e •H cn CN CN -d- ~* -* 4-1 r O l-l CO g o 1 1 3 0 H <: iH u i 1 o M e i-l 3 O CO . = : l u -H i! 0 - oi oi 1 s 4J CU 4-1 4-1 CO oi i-i i-i id I-i 3 3 r B~S 3 (X CO C 3 O O CU O H M C 0 u = : h CN cd H O J3 : 3 1 > ^2 aI aI -o B 5~S 6~S O O CU 4j , — i B oi cu s~! o o r CU 1 CO O CU CU CO i- H O v£> CTi CU QJ C B>~>ONrH BOO cs 1 1 8-s ,c J= 0 iH 3 X .^ cd O i- H 3 ^ N 1 O 0 0 H 4J <r NCO-HO4JT3COCUi-lI-lCO o CN vo o> fi cd 4-1 c3 M f•- C i~l 4J C O *O s al'rt.ci'S.m'^ ^ rt'^!c £ II I1 lI 11 4J PQ D.co'a.jS c*cd > 2 M O.JO i- H CM cn ~* 3 < •H CU -H 0 >> >»i -H 0 ^~^ H CX J3 4-1rHCXCXT3S cd| 74

TABLE 5. SCHISTOSOMICIDES IN CURRENT USE Susceptibility of Chemical S.haema- S.man- S.japoni- Type tobium son! cum Toxicity niridazole metrifonate nitro- thiazole organo- phosphate especially on central nervous system inhibits cholinest- erase lucanthone hycanthone oxamniquine praziquantel thiaxan- digestive thone tract and liver thiaxan- digestive thenone tract, ?mutagenic tetrahydro- very few quinoline side effects pyrozinoi- (in clini- soquinol- cal trial) inone C9333-GO/ (+ ++) (+++) (+++) isothio- (in clini- GGP4540 cyanate cal trial) Ro 1l-0761 (+ +) (++) (?) thiophene (in clini- cal trial) ( ) * laboratory data. All the above compounds are administered orally, except hycanthone (a synthetic metabolite of lucanthone). Hycanthone was the first sin- gle-dose, injectable preparation produced, and it gave very promising results in early clinical trials. It proved less effective against S. mansoni than against S. haematobium, but was active enough to arouse considerable interest, particularly in view of the obvious logistic advantage presented by any compound that could be administered in this 75

way for mass drug therapy programs. It lost favour for two reasons: First, there is a suspicion that it is mutagenic; and second, several patients died from acute liver failure. It is still uncertain whether these are real or exaggerated hazards, but even the suspicion suffices today to damn the most promising compounds, especially if considered for large scale use. After lucanthone, which rapidly fell out of favour because of its serious side effects, niridazole was the first highly active, non-metal- lic synthetic schistosomicide. It proved very active against S. haema- tobium, and was extremely well tolerated in children in whom it is still widely used. It is less well tolerated by some adults, side effects being seen especially in the central nervous system. Niridazole is given by mouth over seven to ten days. One of the most effective drugs against S. mansoni is oxamniquine, usually given orally for one or two days. It is well tolerated, but is unfortunately only poorly active against other schistosome species. In South America, oxamniquine is considered to be the drug of choice against S. mansoni despite its high price (about U.S. $6.00 per adult treatment course). The organophosphate metrifonate is one of the cheapest and most active compounds in current use against S. haematobium. It depresses parasite cholinesterase and will, in excessive dosage, also depress this enzyme in the host. This is most likely to occur in individuals with genetic enzyme variants or hepatic damage from any cause in whom side effects can, fortunately, be overcome with various antidotes. On the whole, metrifonate is safe for mass treatment of S. haematobium for which it is currently widely used. It is of little use against the other species. The newest star on the schistosomicide horizon is praziquantel which appears effective against all three schistosome species when administered in a single oral dose. It is likely to remain expensive because of the complicated synthetic procedure required for its manu- facture, even despite its coming into wide use in veterinary practice. The remaining two compounds are in the early stages of clinical trial, and it is too early to pass judgment. Both show high levels of activity in laboratory models. C9333-Go, at least, exhibits a broad spectrum of action against intestinal helminths and all three schisto- some species. In summary, therefore, several effective compounds are currently available for treatment of one or another form of schistosomiasis. All manifest defects, be it a question of limited spectrum of activity, side effects, or price, and the ideal drug for mass use has yet to be found. If a compound can be developed which, like praziquantel or C9333-Go, is of practical value against human or veterinary helminths 76

other than schistosomes, then it should be possible in time to reduce the price as larger quantities are manufactured and development costs recovered by the manufacturers. The Filariases One drug, and only one drug is known to reliably and safely kill the blood-dwelling larvae (microfilaria) of the pathogenic mosquito- borne filarias, Wuchereria bancrofti and Brugia malayi, that infect man (Table 6). Diethylcarbamazine (DEC) was discovered some 30 years ago and has never been superceded. It kills the skin-dwelling microfilaria of Onchocerca volvulus that also invade the eye, causing "river blind- ness", but the reaction to dead larvae is so severe that DEC can rarely be used in patients with this condition. DEC can be used against W. ban- crofti to interrupt transmission since the larvae are infective to blood-sucking mosquitoes and these, therefore, are the forms responsible for continuation of the parasite's life cycle. The reaction to dead larvae of B. malayi is also often severe, and thus restricting use of DEC for mass treatment campaigns in areas where B. malayi is common. TABLE 6. USES OF DIETHYLCARBAMAZINE IN THE TREATMENT AND CHEMOPROPHYLAXIS OF FILARIAL INFECTIONS l/ Side Type of Chemo- Micro- Macro- Mass reactions infection prophy- filari- filari- treat- fre- severi- laxis cide cide ment quency ty W. bancrofti B. malayi (+) -H- + + + -H- -H- (+) 0 -H- 0 ( + ) ? -H- + ? -H- + + + to -H- -H- + to ++ L. loa 0. volvulus D. strepto cerca M. ozzardi 0000 0 (+) ? 0 D. perstans 77

DEC kills some but not all W. bancrofti and B. malayi adults, these being responsible both for continuing production of infective microfilaria, and for mechanical damage to the lymphatic system which may result in elephantiasis. DEC also kills adults of Loa loa, but side effects may be serious. Another drug, suramin, does kill adult 0. volvulus. Suramin was originally developed for treatment of sleep- ing sickness due to African trypanosomes. As stated earlier, it is toxic and cannot be used safely in mass campaigns. In fact, no safe "macrofilaricide" exists that will kill adults of any of these filarial worms. Hence, there is no way to ensure interruption both of disease in affected individuals, and further transmission through vectors. Of the other filarial worms pathogenic to man, Loa loa is limited to West and Central Africa where it produces ephemeral swellings in the limbs, and may cross the front of the eye causing optic damage. The adult of this worm is very small. This stage migrates through the body and may be removed physically when it appears in a suitable and accessi- ble site such as under the conjunctiva. Guinea worm is another filarial disease that causes severe damage to subcutaneous tissues and joints where adults may lodge. Several drugs, including niridazole, help to kill adults which may then be care- fully withdrawn from tissues. Guinea worm infection (Dracunculus medinensis) is acquired by swallowing infective larvae which live in "water fleas" (Daphnia, Cyclops, etc.) that occur commonly in poorly maintained wells or other open sources of drinking water. These are contaminated by larvae emerging from open wounds in the feet or legs of infected water carriers. New macro- and microfilaricides are urgently needed, and limited studies are currently being undertaken to identify such agents. Broad spectrum anthelmintic agents such as levamisole and metrifonate are being examined in man, while new compounds are being screened in vari- ous animal models. Unfortunately, all existing and widely used animal models are open to criticism concerning the validity of data so derived to the various infections in man. The use of Brugia species for second- ary screening has been advocated,J5/ and B. pahangi in cats is used extensively.^/ An animal model suitable for laboratory studies on the chemotherapy of 0. volvulus is not yet available. General Remarks This paper has focused attention both on existence and lack of specific drugs for prevention or treatment of several important proto- zoal and helminth infections of man. What cannot be over-emphasised is that chemotherapy is but one means of controlling parasitic infections. Limitation of breeding sites for insect vectors and destruction of larvae, £•£. , Anopheles mosquito carriers of malaria, or of the Simulium

vector of "river blindness" breeding in waterfalls in the Volta River, and their control by insecticides, killing of snails that spread schis- tosomiasis by molluscicides, are all of vital importance, as is destruc- tion of adult insect vectors by such means as residual spraying of houses with DDT or newer compounds. Neither are the latter measures adequate without use of drugs to kill the parasites. The collaboration of the human sufferers, themselves, and of their governments is an essential part of any control program. One of the main reasons why malaria eradication failed was because sufficient weight was not given to the human factors in the epidemiological equations. Reliance on any one single measure is doomed to failure, a point that those concerned with the current campaign to eliminate onchocerciasis in the Volta basin would do well to remember. Destruction of Simulium larvae with insecticides alone will not stop this disease. Simple improvements in personal hygiene, in water supplies, in disposal of excreta, and in housing do more to reduce or even eliminate many parasitic diseases than the use of specific antiparasitic drugs. Wearing shoes will reduce hookworm infection. A piped water supply will eliminate many hazards due to parasites and to bacterial infection. Putting a plaster finish on mud walls will remove breeding sites for the triatomid bugs that carry Chagas* disease. Constructing a simple ceiling in the bedroom of thatch huts in East Africa has been shown to reduce greatly exposure to W. bancrofti-carrying pest mosquitoes. Nevertheless, and for the foreseeable future, we will continue to need new and better drugs to help prevent and control many parasitic condi- tions of which a few examples are given here. Full collaboration of the pharmaceutical industry with its impressive physical and intellectu- al potential for drug development is essential if new antiparasitic agents are to be discovered. In this effort, much help can be given through an agency such as the Council for International Organizations of Medical Science (CIOMS) to smooth the way between industry and national drug regulatory agencies.2\J Support must also be given to academic research laboratories where many fundamental questions can be answered._lp_/ As Van den Bossche indicated, "Most of the available para- sitic agents and, so far as I know, all the lead chemicals had their origin in a rational exploitation of massive empirical screening".15/ This has certainly been the experience of industrial laboratories and of government agencies, such as WRAIR. It is also essential to strengthen the facilities for clinical trials of new drugs as they emerge. This is a feature to which the World Health Organization TDR Program is giving particular attention with the establishment of cli- nical research centers in endemic areas, and the training of clinical pharmacologists to work in them. These specialists in turn must be pro- vided with career posts that give them security in their professions, a point that is all too often ignored. 79

REFERENCES 1. Buck AA: Clinical and epidemiological factors in the chemotherapy of filarial infections, Development of Chemotherapeutic Agents for Parasitic Diseases. Proceedings of the International Conference, Versailles, 1l-13 June 1974. Amsterdam, Oxford, North-Holland Publishing Co, 1975, pp 49-65 2. Davis A: Drug treatment in intestinal helminthiases. Geneva, WHO, 1973, pp l-125 3. Denham DA, McGreevy PA: Brugian filariasis: epidemiological and experimental studies, Advances in Parasitology, Vol 15. Edited by B Dawes. London, Academic Press, 1977, pp 244-309 4. de Raadt P: African and American trypanosomiasis and their treatment, Development of Chemotherapeutic Agents for Parasitic Diseases. Proceedings of the International Conference, Versailles, 1l-13 June 1974. Amsterdam, Oxford, North-Holland Publishing Co., 1975, pp 105-111 5. Friedheim EAR: Discussion, Development of Cheynotherapeutic Agents for Parasitic Diseases. Proceedings of the International Confer- ence, Versailles, 1l-13 June 1974. Amsterdam, Oxford, North-Hol- land Publishing Co, 1975, p 45 6. Indian Council of Medical Research: Research in malaria (an out- line). New Delhi, ICMR, 1977, pp l-35 7. Jadin JM, Trouet A, Van Hoof F, Bioul-Marchand M, Maldaque, P, Jadin-Nyssens M: Etude comparative d'une chimiotherapie lysosomo- trope dans la maladie de Chagas et dans le Nagana. Ann Soc belge Med trop 57:525-530, 1977 8. Lammler G, Herzog H, Gruner D: Experimental chemotherapy of filariasis, Development of Chemotherapeutic Agents for Parasitic Diseases. Proceedings of the International Conference, Versailles, 1l-13 June 1974. North-Holland Publishing Co, Amsterdam, Oxford, 1975, pp 157-175 9. Limbos P, Thomas H, Beelaerts W, van Caesbroeck D: Insuffisance renale au cours du traitement de la trypanosomiase a T. rhodesiense par la pentamidine. Ann Soc belge Med trop 57:495-499, 1977 80

10. Peters W: The search for antileishmanial agents, Biochemistry of Parasites and Host-parasite Relationships. Edited by H van den Bossche. Amsterdam, Elsevier/North-Holland Biomedical Press Association, 1976, pp 523-535 11. Peters W: The role of university research departments in the development of antiparasitic chemotherapy, Chemotherapy, Vol 6. Edited by JD. Williams, AM Gedden. New York, Plenum Publishing Corporation, 1976, pp 29-34 12. Peters W: Medical aspects — comments and discussion II, The Relevance of Parasitology to Human Welfare Today. Edited by AER Taylor, R Muller. Oxford, Blackwell Scientific Publications, 1977, pp 25-40 13. Pugh RNH, Gilles HM: Malumfashi endemic diseases research project III. Urinary schistosomiasis: a longitudinal study. Ann trop Med Pararsit 72:47l-482, 1978 14. Ruppol JR, Burke J: Follow-up des traitements centre la trypano- somiase experimentes a Kimpangu (Republique de Zaire). Ann Soc belg Med trop 57:48l-49l, 1977 15. Van den Bossch,e H: Chemotherapy of parasitic infections. London, Nature 273:626-630, 1978 16. Weller TH: The increasing impact of schistosomiasis in a changing global ecology, Development of Chemotherapeutic Agents for Parasi- tic Diseases. Proceedings of the International Conference, Versailles, 1l-13 June 1974. Amsterdam, Oxford, North-Holland Pub- lishing Co, 1975, pp 2l-29 17. WHO: Malaria (WHO cyclostyled report for Special Progamme for Research and Training in Tropical Diseases). TDR/WP/76.6, 1976 18. WHO: Trypanosomiasis (WHO cyclostyled report for Special Program- me for Research and Training in Tropical Diseases). TDR/WP/76.12, 1976 19. WHO: Filariasis (WHO cyclostyled report for Special Programme for Research and Training in Tropical Diseases). TDR/WP/76.10, 1976 20. WHO: Information on the world malaria situation. Wkly Epidem Rec 51:18l-200, 1976 81

21. WHO: The need for new drug development. WHO Chronicle 32:154-155, 1978 22. WHO: Receptivity to Malaria and other Parasitic Diseases. Report on a working group convened by the WHO Regional Office for Europe of the WHO Izmir. September 1978. Copenhagen, WHO, 1979 82

B. ACCESSIBILITY OF VACCINES William H. Foege It has frequently been said that vaccines are among the oldest, most dependable, and most trusted tools of public health. Yet we are reminded, as we begin The International Year of the Child, that more than 2.5 million children will die this year from four diseases which can be prevented by currently available vaccines. Why the great gap in application? Experience of the last decade indicates that technolo- gy could greatly improve the situation, but a lack of social will has been a major constraint to successful application. In the United States, we have recently taken stock of our social will and set new targets to immunize 90 percent of our children against seven childhood diseases by October l, 1979. We are well on the way to achieving this goal. So well, in fact, that we have set an additional goal — the elimination of measles as an indigenous disease in the United States by 1982. Our efforts are being coordinated with those of the World Health Organization which we will assist with the "Expanded Program of Immunization." We still have a distance to go before everyone in this country is freed from fear of crippling or death from vaccine-preventable diseases. But the developing nations have much greater distances to travel — a fact shown clearly in Table 1. The Table shows that there are 15 infant deaths per l,000 live births in the United States, and the life expectancy of an infant at birth is 73 years. In Latin America, 84 infants of every l,000 live births are lost, and an infant born in those nations can expect to live 62 years. In Asia, 117 infants die of every l,000 born, and life expectancy is 58 years. In Africa, 158 of every l,000 live births are lost, and life expectancy is but 46 years. The problem is large, but we are not without solutions. One solution is the use of proven, cost-effective immunization programs in conjunction with other basic health services. Of the many alternatives for health spending, immunization offers some of the greatest benefits in relation to costs. For example, the United States measles vaccine 83

TABLE 1. INFANT MORTALITY AND LIFE EXPECTANCY BY AREA a/ Infant Area Mortality Life Expectancy Per l,000 Live Births At Birth, in Years United St 15 73 Latin America 84 62 Asia 117 58 Africa 158 46 a/ 1978 World Population Data Sheet. program conducted between 1966 and 1974 cost the Federal Government $108 million. It yielded more than a billion dollars in savings — savings in medical costs and long-term care expenses that would have been incurred if there had been no measles program. Another study esti- mated that the nation received a net benefit of $10.34 for every $1.00 of Federal money spent. Even greater returns have been realized from polio immunization programs. Although it would be inappropriate to extrapolate such benefit- cost ratios to developing countries, we can look at available data and see what an active, nationally supported system for immunization can provide. Thus, at prices currently paid by the United States govern- ment, all the necessary vaccine for a child from birth through school entry costs less than $5.00. A study in The Gambia in 1971 showed that it cost $2.40 to prevent one case, and $48 to prevent one death from measles. That was the total cost for vaccine and for its delivery. Other studies in West Africa have indicated that direct health care dollar returns far exceed investments in measles programs despite the fact that not all children with measles actually have access to a hospital or clinic. The benefit-cost ratio for smallpox vaccination will soon become the greatest for any health program as benefits continue to accrue while costs fall rapidly. Quite aside from large scale or even national campaigns, there are examples of successful immunization programs well integrated into other primary health care services. I would like to provide one example. In India, a village-based health program providing basic preventive and curative services to almost a quarter of a million people achieved 84

remarkable results in three years (Table 2). When the program was started in 1974, infant mortality was 67.6 per l,000 live births. By 1977, mortality had been reduced to 23.1 per l,000 live births. At the beginning of the program, only 2 percent of the childhood population had complete DTP immunizations. After three years, that percentage had risen to 85. The completed sequence of polio immunizations was reported for 1.5 percent of the childhood population in 1974, and for 83 percent by 1977. Immunizations were a major component of this successful program. TABLE 2. HEALTH CARE PROJECT, MIRAJ, INDIA a/ 1974 1977 Infant Mortality/l,000 Births 67.6 23.1 Maternal Mortality/l,000 Births 3.7 0.25 Complete DPt 2% 85% Complete Poliomyelitis 1.5% 83% _a/Ram, E. R., Integrated Health Services Project, Miraj, India, in Contact 44, Christian Medical Commission, World Council of Churches. Immunizations can be the cutting edge of primary health care systems because: 1. Appropriate vaccines prevent morbidity and mortality. 2. Vaccines are cost effective. 3. Vaccines provide long-1asting protection even when only limited patient contact is possible. 4. Immunization programs incorporate the general skills needed for diverse public health or community programs, thus provid- ing a vehicle for other activities. Although many vaccines are licensed or in use around the world, it would be unfair to confuse the issue or overload systems by promoting vaccine without a clear need. Tables 3 and 4 provide a partial summary of vaccines which might be considered in developing countries. Five 85

CO CO CO -H l-i •H CO CU CO cd > cd iH CU •H B P* B o 0 CO U CO O iH O C 60 C CO CO cd cxx: CX SN I-l £7 H 0 H B C CU C CO IT cd O CU O -H rH rH •H 1-i cd CU ft 1-1 CU l-l C cd IH -H -H ^j 0 ^^ -iH O cd O cd > • • * z > < rH CS1 CO Cfl CO cd -_4 *H e rH o CO cd CO •H 4-1 CO o 4J C C iH 4-1 CU •H •H CU h co 3 4J B CO •H 60 cd cu a. Si C CX c o cd O CU cu •H iH cu ^ CO Q 03 U CU 60 0 > CO cd CU 4-i • • • • > Q CO rH CN CO -* CO M co CJ •H cj 4-1 •H CO ^ C0 rH -H •H CU l-i PM CO CO CO >, CU O 3 CU CO e si CU rj rH 3 O 4J CO i-H cd CO 4-1 •H XI s cu jD 4-1 cd 1-i r- H CX H e cd CU CU CU 0 -H •H H S 0-i p f C3 H u -H CO a cd H > ^ ^ CM m .^ iO 2 § 5 u CU 4-1 cu cd 1 CO • •iH CU p~i co CU i-i -o C CX -H *o H tH 0 3 cd U CU CQ u CX M V-l cd cx o CX H > C0 <r4 Mononucleos loma venere CO •-l o u oa I-l w (0 •H -H CO •H e CO ^ CU •H CO 3 cd CO o CO i- H X CO CO C •H 0 •H •H o 3 iH cd O B CO CO jO 4J o c r4 l-i co 60 cd <9 o -H cd M CU cd CU •H rJ 4J M o u iH CX B 1-i CU u o 0 CO 4J 4J CU CO CX fi 0 4J CO e 4-l - H e o X ^> . •H CU H a CU c 0 u bn a: M rJ 0 H co co simplex luenza la/Herpes •H CO O 3 rH CD N -H C CU CO cd t4 rH e-. CU •H 4H B rH >-, rH CX 3 14 co rH c 0 cu CU CO CU O rH &_i cu iH •H x: u 4-i o O B 4H O cx iT* cd u -H CO I* 9 cu C c cx CO M o a 5 M 0 cu >, co cd h cd N cu PQ &4 H > cd u u o u X O Cd 60 x: -H 4J C CO CX o r4 U 60 o -o l-i C CU CO c I-l CU C CU 3 6n O S T> CU cd ~ rH CX >-, 4.I r- H rH O O cu jz M cu > CU CO tr_i X -H O B T3 CU -H l-i O M CU > cu fc CO cd x: xi r- H CX CX . CM PH O* cd rH IH i- H cu cu rH 60 O O i-l U Si Si CQ U CO CO CO CX 3 O CU l-i 60 C CX M CJ •H O 33 U I-l -^ >, O CX p CO rH cd cx o IH c CU *o C CU B CU u a _ cd IH cd > rJ > 86

8 >t. CO C 3 CU •» , 4-1 C co •O o N CU •H 4= C h •H rl c » -r-l ^ > 4J IH -o 1 cu o 4-1 M •H l-l rH CO ed > iH e C 3 ^ 4-J CO CO -H (3 •H CU co o o £3 •H r C .c 0 4H rH u CO •H g A a o a fa 4H 3 v_^. 4-1 iH (-; CO c ^ tH 4-J 0 0 U O CO Cfl f^ 01 4J M U CO c cu CO 4-1 4-i CO O CO co u <u co CO 6-« rH o CU CO C •H C CO T3 4J cu 0 cd u 4H M CU CU CO . *O O CU rH rH (4 ITI W 4-1 60 « rH o> •H rl O 3 rH •* >\ rH CO cd t-« 3 >, 4J T3 O CO rH Q cu 'cd CO CU CO U Q1 CU CO cd ^t ,I^ CU •o O 60 > (3 rH cd CX S U C M 06 iH 0 •4-i C CU O CU CU >> O rl 0 CX CO <d 0 CO j O -H U Q l-l 4-1 CO O rJ 3 4H S-i 3 C5 Z • >. co 1 rH PLj s-~ 4-J rl O X O CU 8~S CO ^ M cd c>0 cu ^ > O 3-S cu > -H > a u CO •H CTv § rl m fa >> 0 -Q 4-1 4-1 w u rH U S-4 4H 4J cd C cO U Q •H r? CU D >_| CO •H CU CU cu 4H 60 4-l > CU g^2 CO Sj cj e UH £5 LM iH 4H O > O cu CO CU tH 4H M U J3 CU v^/ o rH rl O cu CO 1 CO l-l Oi CU TJ CU C-O CU O 4-1 O CU U 4-l C CO rl M CO -H 60 4-1 on 9 CO 4-l 4J rl C3 O iH rH c u CO CU CO O cd U • 0 •O JO O 4-l C CO1-l • CO •H M3 •3 K/] u C O 60 CU O CO rl 4-J CO CM • Xi • CU iH 4H O E^ CO CO rl rl C S 0 • • M vO CUJ^<4Jr«CX CUiH O * 0 § CO J3 S E>^ CO CU CN rH e e e ac cu cu 4 J r*r H l-l i— 1 •H u rH CO vO l-l CO CO ^t 1 ^ ~& p -* rl M 3 o « CU C rl •> vO rl CU CU CU 5C -o »j 4-j > >, o coco cu i-4 M 4J M 4J CU MCO-HI-l-H 6CUCU> 60 «n CO C*-l CO 04 o cflcdi-iQJ4J iHcococu c O o O u i £XCUCU>-H rlOO -H « o M 0 C* CO corH-racu-o pL,T3T3ta co Cvl •" CM •° Q Z 1 3 4J CO cu CO [V] CU rH 3 <r CO cd 60 fl CN r* C CO •H C 1 00 cu 4-i CU CN CO 'J^ Q 4J CU e H (X rl — i 4-1 4-1 ^ CU 0 rH CU T3 C C W oo CU CX » < 0 rH JX, . CO cd QcJ 14 CO CO •H rH CO 4H 4H CX cd 3 • . 3 SZ rH O a C CO H cd J2 CO u co e M H w a cd CO M CU E ^f i 1 CO CX T> 3 •o •H •H at, CO iH C •H 4J T3 C O CU cu o CU cu -o O O CU cd cx •o x 4-1 0t x cd 4-1 60 •H O •H 4J 4-1 o a CO IH u H ? H r CO CO H M > 0 z Ml u O 4H CO CO 1 ^ 3 41 CO CO ^ co a H 1 •H 3 cu V CO cn £ ^ 4J C 4J cfl H a CU rl !O • iH •H CU cx tH J^ 0I iH ^ u 0 H y! Q Q 4J cX CO 0 O w cd cd • • • rJ > i-H CN CO M H < 87

cu h C •o •H o CU • CU c 4-J c x: 1 O •H 4J U C C CO t-l ^>t iH l-i o ,— 1 CO 4-1 rH O S 4-1 CO CU o rH 4-1 O O M •H CO CO 3 <u 0J e co cd rH 4-1 Xi O 4-4 rH C M 0 C cn 1 c *4H c« o 1 a, cu 4-1 ~. CU W •H •H O •o •H Q M 4-1 CU •o a, cd CU (4 CU cu u cu i-l u rH -H CU •o 4-1 CO > O O e rH c a. at iH CO cu •H 3 cu o •H H X o CO CO (4 jj 13 l-i u ^j ^ cu » >-> \ U 1 a> o o > e M ^^ l-i O O CU PH f-I y-N •o a. x: a. o CU xi CU &.« cu cu 1 X X > 60 > 0 r* 4^ w O •H iH -H co C O Bt CO >•, 4J ^ 4-1 ^ 4-1 E CO O O *^H CO W O rH U O I-l i™H O iH rH %4 'H 3 Q -H n <U sz CU OJ J3 CU rH CO a t &-« o *4H 60 4-l 4-1 4-1 > 00 4-l *H U 60 jg I4-1 •H 4H o 4-1 O -rH HH C I-l O CU 0 0 M W od CU fa CU v^ S3 CU iH 4J Z 4J OO rH CO 5 I-l o CO co cu I4 H CA CU 60 X CU 60 4J o O CO C l-i CO C CO >^j ^, O 'H cd O -H rH co • kV h T3 O e T3 cj cu co CO • (4 -H M • •H CO O M CO g I-l CM O CO -M C 6 CU ft o •H 4-l Pi 4H 0 CU o CO S M 4-I C •4H C S CO •H vO o sa OJ O^ O -H 1 0 -H 4-1 •o rH <J- h cu ^~ CU CO > , O I-l M 3 01 1 CO I-l C0 •o co i-i h CU CU cu S3 M ;-> cu ^^ CU CU CO Cri *r~) 4J I-l r«f CU rTl CO O cu •H X! CU CO •-l -H x: cu & C co cu S3 a! I-l 4-i rH I-l 4J Cn •H •H O 4-J O a M O -H CU -H 0 •H CU -H O CO -Lj O cd •H to CO CM _Q ,J <o s *o ^ CO ^ T3 CU 3 CLj CO Xi rH CO Q o M *2 M I cu o o- o iH 60 3 1 4J CO '->• O M "S^ d 1 -H CX < M CO CO •H CU r4 60 co •H I-l -H cj CU CX^^ CO cu orf CO O 4-1 CO ^ 3 Q 4-1 4-1 60 ]U S O 3 O O CN *3 C n> £ CU 1 cd CO M [**\ 60 CO 60 ^ rH CO CO 60 h QS M 4-1 rH •H (4 O 60 OJ rH CU v^^ CU PM CO C ,—\ ^r] Q O C iH rH rH ^ /^ CO H M <: ^ U tH 4-1 <C XI rH O CJ U •o Q CU M •H •0 1 ^ 1 1 4-1 1 cu u cu co •o 3 T3 -H -H •H •H CO T3 CX *~* OS •H C li 4-i -a j-i i-J •o «H CO -H 3 U o CU o CU CU TT rH O CU C U CU •H X rl O fa a ^ > 4J CU rH CO 4-1 CU cd 4J r4 rH CO I-l ^3 X 0 •H 4J 4-1 •H C CO -^ c ca 3 O XI 60 U H H j CO CO ^ *iH £> hH O- i O- i O ^-/ ^ z n a 0 1 CJ cu CO •H 4-1 X 0 C 3 1 4-i CO 60 rH > •H C O -H CO M C cd O CO •H rH cu X! •H O O 4-1 rH cu c 4-1 C 0 • CO CU o X •H d CU O *tf H PM e O •3 S a *o U - w • CO • • 4-1 -J ^f > r-» CM C PQ 0 < • U H pq 88

tly Local & febrile ve - reactions eci- Frequent mild loca tec- reactions ft occa- bryo Local reactions dip- common. Rare CNS ccine effects with high newer vaccines ctive (common with earli' er vaccine) Occasional arth- ve ritis, peripheral 0%) neuropathy & per- plexed neuritis reported •O 4-i C U CU o CU '4-4 rH cd e o CO CU rH •H CO 4-1 CO CO -H 3 rl CU 0 rH C tH cr 4-1 J3 cx o 4_| «— j B C CO CO CU •H ov CU 4-1 CU cd CO M O CU CO cu cd > l-l 4H >% 4-1 M U T3 T3 rH CX •H rH § T> CO 4H r- H 0 M cd CU CO r- H •H CU C 4-1 cd ^ CU CU .c cu CU CX 4H cu «d CX 0 O •H U Si -H cx 60 4-1 > CX 14-l O -H > -H C K 3 O cx :>, •H 4H o < CU C 4-1 cd H 4-4 4-1 -r-l 4-1 a t3 r- H CO rH PC CU -.s CO CO 0I CO c 0 co a CO - 0 CO - o 3 l-i •H 3 M iH CU 4-1 CU CO CU 4-1 rl CO S 1 IH CO 1 T3 o 3 T3 o CU 4-1 e •o CU 4J C T3 rH 0 CU rH U CU XI cd CU .0 cd B CU CO 4-l Q i- H Cd 4-l B H •H 3 0 r? •H l-i 3 0 C 0 r? n a a CO cd cu •H cd cd CU •H > B h CO > S rl C/J 1 -^ ^ 4-1 1 •H 1 0 CO 1 CO CO O 3 1 rH G 1 i- H r< C *^H •rH t-t CU O -D O tH O >-, cd CO 3 O rl i-i -a V r- H • •H 1 -4 cd ,- H s CD .y CU rH O C CO •H cd rH ^4 X) l-i 4-1 CU CO rH « O IH co oo l-l -H o 0 4-1 Si C -H rl •H 5>i rl rl rH •H CO CO CX <-9 CU iH Cd CU TJ •H CX CO 60 iH 3 O 4-1 CO CX CO M C * l-l o cx l-l •< T3 CU 4J X C -H rl 3 CX rH CX 4-1 CU o • CU S-i CO • c 3 •H CU •H x: CU ^ CU >-> l-l rH x: co cu -*: XI 4J >> J3 CU 3 -O 1 u 4-1 CU O M " rH CU cd 60 rl • M 4-1 0) Vl rH 60 • 60 p^ cu cj h CU CO 4H CO CU CU rl rO s •H CU •H O C -H CO CU M C 0 M cd O > C -H 3 > 60 CO 3 0 ac cx ^ s CO 60 4-1 C 33 ^ 0 -H u cw > 4-1 v^ CO rH C/) O CO r- H CX ** 1 1 1 •o •H O CU 1 1 a cu 4J -o cd *o CO -H 3 cu cu TJ rH O CU 1 CO i-l 1 CX 4-1 •VJ 4-1 ^\ C > 4J CO 4-1 •H 'O >1 l-i >-. O 3 O CU CO •o CU CU •o -H 4J 4-1 -H C CO l-l CU i-H CO C l-i O cd 4J O CU > 4-1 cu J cd cd irf •H > 3 -rl 0 JS CO CU rl e cd B > v-^ CO iH 4-1 4-1 1 CM 4-i ix, u S co oo rH 3 cd , CO O rH CO H G co 0 oo S O O O ex. u 5 89

1 1 iH C CU C 0 CO 1 3 ^ M 0 0 W B « -H (-i c e w co M rH CX 0 -H C C CX iH CO O O C CO E O CO X! 4J -H -HC -H t O CO CU 4J O 4-1 4-1 O CO u O rH rH -H CU O u Ei M rH < S 4H co cog <ucd CU COCUCUCU CU 0 > 3 4-1 Z > cn -o M MO CU T3 W C_> • -H C 4H -H COCOOOrH rHM > Q QJ CUCCOCOiHcd cd0J TJiH T3 MOCUMC10O O> ,-HT3 •H CO CO-HMCUOO OCU -H C O Pd 4-1 60 CX rH »-3 •-J '-4-4 ^-- iH U Z 1 • M •H CO B-i 73 MM C o oi cx:o>>^sooi CU >-» > -H 60 >>4-1 O iH B CO > W O iH T3 tH 4-1 rH ON 4-1 O CU iH CO 4J CUCOJ3-HCOcd OCOC >-,4J U O u 4JrH CrHM ooiiH rHO o •H >, 0I -H CO QJ D CU 0I 4-14-lBO -CO) 4-i M4-l S iH 4J B > > OOO 604-l SB 4H CU u-4 iHMcdBCUCU CXMMCO -H 4-i i-l U >CU j4JO-HrHCO OCXM-i> 33CU CO 04 o M T3 U coco oiue oiuc o 1 CU CO CO M CO co-o co-o i-H cn co •HCX 3M-H 3MiH rH OX 0I 4J CU4J CU4JCO O6 O CU «>~*- 1Mcd 1Mcd CD cO r* COM 3T3 3T3 OM X CU >MO cu 4-1 c cu 4-1 c -TO -o cu O rH O4-1CO rHOCU rHOCU CU4-1 M 3 i-H4-icdM X1cOB Xicdg ai 4-J q PC! T3 COMCU CO 4-1 t: CO 4-1 E rHCOiH CU 3COJ<i -H30 -H30 OOCU 04 Xi (3OX1M MCO MCO CO.. O O C-HCOO COCOCU CO co QJ iHCUM 5 CO ^trHS >SM >BM COM>, 1 >» . CO • H >•, X MCU cox: CCO4-l co MCU 04-) O 60 C O O O C O O 4-lCOiHCO COBiH O COS O 4-J W 4-1 COMrHM CU Xj4HiH M ^. -r-t Q 4J COM MCU aI oovo o 4-1 oivocnt ^ CU MCUT3CO O*^dT3*^ CO 4J O CXiHO M 60 O .^ CU 3 X1 M rH M M CO ^ CU M M CU 3 ^J X1MCOM COOiHO rHCU C0I4-l rHCU *4H CXi CO cd H JSCX> IT <JOiHMiH <OcdiH W Q M CO S * 60 C 3 iH iH 3 •H 1 | CO 1 06 c IH c 4J T3 c a O CU •HO CUCUT3 OCUcd CUCUT3 to CX > U > 4-J CU cd4JOO > 4-1 (1I iHCO tH4J4-1 CcdM -H4J4J g H J> .JCOCO M>0 JcdCO M CJ X iH CJ CU os *o CX CU -H 3 ^ •H rH M O M O M 0 rH CO J3 CU rH CU O CO rH CX > rH > ^ CO S 3 >> CU CU CU CO H H 4-1 SH 4H T3 4-1 hJ r*^ oo CT^ •^^ §3 rH U H 90

are considered useful for universal delivery: Measles, poliomyelitis, diphtheria, tetanus, and pertussis. Others, such as yellow fever and meningococcal vaccine, would have definite regional utility. When they become available, vaccines against malaria, schistosomia- sis, dengue, and hepatitis B will also have widespread applicability. There is a definite urgency to speed development of these vaccines and to begin development of vaccines for trypanosomiasis, hepatitis A, and viral hemorrhagic fevers. We should nevertheless be aware that more than 20 percent of the mortality among children less than five years old in the developing countries can be prevented with currently avail- able vaccines. Table 5 repeats the data used by Senator Kennedy, and shows more than 82 million episodes of illness and more than 2.5 mil- lion deaths resulting annually from only four diseases. Therefore, absolute priority must be given to the delivery of available agents. What are the constraints? Dr. Perkins will discuss constraints involv- ing vaccine development, testing, and quality. I will emphasize the need to develop effective systems to deliver potent vaccines to sus- ceptible populations; that is, to make vaccines accessible. TABLE 5. ESTIMATED ANNUAL MORBIDITY AND MORTALITY OF SELECTED VACCINE PREVENTABLE DISEASES Cases Deaths Measles 72,000,000 l,500,000 Tetanus 800,000 600,000 Pertussis 8,000,000 300,000 Poliomyelitis l,800,000 200,000 Disease surveillance is the foundation on which vaccine delivery systems must be built. Quantifying disease problems and identifying populations at risk are useful for decisions regarding large-scale immunization programs and the necessary investment of personnel and resources. In most developing nations, it will be necessary to train health workers to collect and analyze such data, especially among pre- dominently rural populations. As one example: Neonatal tetanus in Bangladesh has been recognized as a health problem, but it has not been recognized as a major health problem in that country's routine report- ing system. Since cases and deaths occur at home, they are seldom brought to medical attention. A recent systematic sample of 120 rural 91

villages estimated tetanus mortality at 70,000 deaths annually; 2 tetanus deaths per 100 live births, or 20 deaths per l,000 live births. This single, vaccine-preventable disease is thus responsible for greater mortality in Bangladesh than all the causes of deaths among new- born infants in the United States put together. Studies in Africa have shown that 5-10 percent of children will die of measles. This tragic and needless loss of life is a powerful argument for placing highest priority on delivery systems for effective agents that are already available. The development of the necessary social will, a prerequisite to tackling vaccine-preventable problems, requires documentation of the size of the problem. Hence, there is need to develop surveillance systems. Decisions concerning which optional vaccines should be added to the basic core also require data generated from a surveillance system. Documentation of the effects of a vaccine program will require information systems. The lack of good data systems constitutes a major constraint on vaccine programs and on many other primary health care systems. A second major constraint involves shortages in managerial as opposed to technical skills. Any effort to improve vaccine programs must involve training health workers in planning, implementation, and evaluation of immunization and other primary health care programs. Much is now known about the various systems required to deliver vaccine. This knowledge must be communicated. In addition to social will and managerial skills, we need simpli- fication of technology. Smallpox eradication was hastened because private industry developed an effective, heat-stable, freeze-dried smallpox vaccine and an inexpensive method of vaccine administration — the bifurcated needle. Today, immunization programs need vaccines which remain stable in the field, and safe and effective methods for administering vaccines. Recent development of a relatively heat-stable measles vaccine is a step in the right direction. Further advances in heat stability are needed for other vaccines, for benefits do not result even from a well-managed program that delivers impotent vaccine to a child. Another constraint pertains to ethical and legal aspects of vaccine programs. The most frequent dilemma appears superficially as a conflict between the rights of the individual and the rights of the community. It is a long-held conviction that the rights of the individual must remain sacrosanct. With increasing insistency, however, voices are being heard on the subject of societal medical ethics. How do we pro- tect the individual's freedom of choice and simultaneously consider society's needs? How do we provide compensation for the individual who is injured as a result of participation in community immunization efforts? 92

Beyond the problems we face in delivering available vaccines, we must turn our attention from the field of the possible to the field of the probable. We must work to develop vaccines for those diseases which cannot now be prevented by immunization. Those diseases for which vaccine is not yet available, but which are important enough to mandate a major effort for vaccine development, include malaria, schis- tosomiasis, African and American trypanosomiasis. Since these diseases are identified in the Tropical Disease Research Program (TDK) of the World Health Organization, they will receive increased attention in the near future. Other important diseases not included in the TDR are dengue, hepatitis A and B, and the viral hemorrhagic fevers. The American pharmaceutical industry and academic institutions can play a vital role in development of new vaccines for such important dis- eases. Their active participation has been responsible for much pro- gress in projects already underway, and in the successful completion of others. Pending development of such greatly needed new vaccines, empha- sis on effective use of currently available vaccines is important for two major reasons: (l) Vaccines can significantly and immediately improve the health of the people of the developing world; and (2) vaccine delivery, as it becomes effective, will provide a system for delivery of vaccines now under development. To reach the goal of efficient, immediate delivery of currently available vaccines, and to develop new vaccines for diseases which presently challenge us in the developing nations, we must mount a coop- erative effort unequaled in the history of public health. We must maxi- mize the potential of private industry, of academic institutions, and of governmental institutions in the United States. In view of our suc- cessful experiences both in the United States and with the recent inter- national smallpox eradication program, we have a responsibility to help developing nations maximize their potential for delivery and production of vaccine. In summary, five vaccines, now widely used in many countries, could have a significant impact on the developing world. The challenge is to develop social will, managerial skills, and simplified techniques to facilitate the universal delivery of such vaccines. Sufficient experience already exists to provide assurance that this is possible. While development of new vaccines should be urgently pursued, establishment of adequate delivery systems for currently available vac- cines with their need for surveillance systems, management, and evalua- tion would provide a solid background both for future vaccine programs, and for other primary health care services. At the same time we must emphasize that disease prevention requires a multifaceted approach of which immunization is only one aspect. Vaccines are safe, effective, and potentially accessible tools to prevent unnecessary morbidity and mortality. Whereas the challenges to 93

their successful use in developing countries seem awesome, past experience proves that we can move ahead with confidence. At the turn of the century, who could have predicted the global eradication of smallpox? Who would have envisaged the progress made against poliomye- litis since the late 1940s? Who could have foreseen the decline in measles with the advent of nationally supported immunization campaigns? The synchronized, well-managed use of these vaccines is a test of our will. If we are willing to spend ourselves and our resources to develop well-honed systems for delivery of vaccine, we will be in a position to offer to succeeding generations a more hospitable environ- ment and a childhood free from much unnecessary suffering, crippling, and death. 94

C. VACCINE PRODUCTION Frank T. Perkins There is no doubt that correct use of potent vaccines has markedly reduced the incidence of some communicable diseases. This fact is no longer disputed but in order to achieve our objective, three factors must be satisfied: 1. Vaccines must be available in adequate quantity; 2. Vaccines must be known to be potent throughout the storage period; and 3. Vaccines must be given to the majority (90 percent or more) of the target population. The purpose of this communication is to discuss the present situa- tion and future outlook for provision of potent vaccines. The Production of Vaccines Facilities for production of vaccines throughout the world can be scaled up to satisfy global requirements for those vaccines currently available against bacterial and viral diseases. At a recent meeting at WHO, Geneva, major manufacturers confirmed this impression and expressed a willingness to help the developing world to make available the quantities of vaccines to meet demands. The important point that was emphasized, however, was that there must be a global plan giving a "lead in" time of at least one year before substantial increases in demands could be satisfied. In the developing world, 90 countries are developing the infrastructure to deliver vaccine. If they are all ready for vaccine at the same time, the increase in demand will be enormous. Some developing countries are either producing particular vaccines, but rarely those against childhood diseases, or considering the possi- bility of going into production. Although WHO is willing to assist in the necessary transfer of technology, and has already written manuals for production of diphtheria, tetanus, and pertussis vaccines, we 95

question the advisability of starting with vaccine production. It seems much more logical to approach this development in three stages: 1. Establishment of a quality control facility; 2. Establishment of a vaccine blending, filling, and packaging facility; 3. Introduction of vaccine production. The reason for such a stepwise development is that each stage in development is dependent upon the previous stage having been established. Those developing countries who wish to start or increase their national vacine production face a long-term development program. For the immedi- ate or short-term programs, therefore, we must rely upon existing facil- ties, most of which are in the developed world. Far fewer manufacturers are involved in vaccine production in existing facilities in the developed world than there were ten years ago. Biologicals are not profitable to the pharmaceutical industry. A new antibiotic or a breakthrough in prophylaxis in vaccines may bring a temporary return on investment but the vaccines and sera used against childhood diseases barely repay the costs of production. Many large multinational concerns, however, have continued to produce vaccines because of continued demands and because of a policy of providing a full range of biologicals. The way in which we may see an improvement in this situation is: 1. to have a realistic estimate of future demands; 2. to collaborate with the pharmaceutical industry in fulfillment of the needs; 3. to accept a research and development component in the price; and 4. to stabilize prices by placing advanced orders. If this were done on a large but realistic scale, the industry has expressed its willingness to cooperate. In the long-term, many developing countries are contemplating vac- cine production for three reasons: 1. Purchase of vaccines from the developed world demands hard currency. 2. There is a need to maintain national employment at a high level. 96

3. The desire for self-reliance. The relative importance of each of these factors will be determined by local conditions. As a guide to the economic viability of vaccine production, it might be interesting to consider a population of 20 mil- lion with a birth rate of 30 per thousand. Such a population will need vaccine for 600,000 babies per year assuming that they all live. Such a population, therefore, will require: No. of doses given Total No. of doses Vaccine Wastage Needs Polio 3 1.8 million 50% 2.7 million BCG 1 0.6 million 50% 0.9 million Measles 1 0.6 million 30% 0.8 million DPT 3 1.8 million 30% 2.4 million Thus, total annual requirements for vaccine would be two batches of polio (oral), BCG and measles, and four batches of DPT. Any country contemplating the expenses incurred in establishing vaccine manufacture should carry out a realistic cost accounting exer- cise taking into consideration all national benefits and constraints before embarking upon the project. It will be noted that the above calculations assume that all babies live and that all children will be given all doses of vaccine. A conservative estimate is that these requirements for vaccine will be halved which makes the project less economically attractive. It may be noted that of the 152 countries in the United Nations only 34 have a population of 20 million or more. Of these, 29 are already producing and 9 are exporting vaccines. Clearly, it is neces- sary to make a very careful analysis of local conditions before encour- aging local production of vaccines. On the other hand, one country, with a population of about two million, feels it necessary to continue national production of vaccines because of the precarious position in which they find themselves in the event of international disputes. A much more attractive proposal for developing countries is to establish a national filling facility. This would requiret vaccines to be imported as bulk concentrates and then to be diluted, blended, filled, labelled, and packaged locally. 97

This is attractive to the Third World because: 1. Availability of vaccines is in the hands of the national control authority; 2. Labels can be printed in local languages; 3. Instructions on the leaflet can be checked to be in line with national immunization policies; and 4. Costs are reduced. It is important to appreciate, however, that a national facility, by becoming involved in an essential part of manufacture, will be responsible for quality control of the final product. This is a most important reason for prior establishment of a quality control facility. The established pharmaceutical industry is sympathetic to this approach because the stages from bulk production to final product are time consuming and expensive in the developed world. Furthermore, existing production facilities would be operating more efficiently. Quality Control of Vaccines The need for establishment of quality control as a primary function cannot be overemphasized. Such a control facility can: 1. Monitor quality of biologicals produced nationally or imported; 2. Monitor keeping properties of preparations (control of the cold chain); 3. Ensure that all subjects are given potent products; 4. Measure antibody responses of the community to vaccines; and 5. Measure herd immunity of a community to an infectious agent. Establishment of a national control facility, therefore, is one of the most cost effective investments that a health authority can make. This can be done in several stages from simple reading of protocols to full-quality control involving the most expensive tests. All stages of quality control are cost effective. Since production of vaccine must include an efficient filling unit, and since the final product must be subjected to quality control, it is clear why we suggest that establish- ment of a solid foundation of quality control must precede all other activities. 98

The pharmaceutical industry is most willing to transfer technology for quality control but understandably has some reservations about transfer of technology on vaccine production. This is not entirely because of guarded secrets or patent rights. With production of any vaccine, unless the process is reproduced in every detail, the products will not be similar. There is little chance that the production proce- dure will be reproduced with meticulous care in the developing world because of the constraints placed upon resources. This is why provi- sion of vaccine in bulk rather than transfer of technology in produc- tion is more attractive to all parties. The Modern Concept of Quality Control Quality control of vaccines, as practised in the developed world today, is a very complex and expensive exercise. It seems unfortunate that in almost every walk of life a tragedy has to happen before a potentially dangerous situation is fully appreci- ated. Such was the case with production of killed poliomyelitis vaccine in the Cutter incident. Where drugs are concerned, the thalidomide episode had an enormo.us impact upon the development of controls. It is equally unfortunate, however, that the outcome of such tragedies is stringent control which is always an over—reaction to the situation. These two events have been responsible for the present stringent quality control of drugs, including vaccines, and such controls demand a great number of tests involving expertise and time that is a most costly element of production and control. Our control of vaccines, therefore, is a relatively recent event of the last 25 years, whereas legislation requiring the control of biologicals is more than 50 years old. For the first 25 years the means by which such controls were effected involved neither detailed supervision nor submission of proto- cols or samples. The anomalies in quality control are somewhat disturbing. These have arisen because such requirements have been built up over a period of rapidly developing research and there has been a tendency to include every test already established for each new product irrespective of its relevance. A virus vaccine today is examined by every test known to detect an extraneous agent whether that agent is likely to be present either in the seed virus, or in the cell substrate. Poliomyelitis vaccine (oral) is a good example. In the early days of 1959 to 1965, the vaccine was made in monkey kidney cells that may be contaminated with any of 50 simian viruses identified during that period. Consequently, such vac- cine was subjected to tests capable of detecting these agents. When the virus is grown on human diploid cells that have been shown to be free from such extraneous agents, however, the virus harvest and the 99

human diploid cells are not only examined for the presence of the simian viruses, but the human cells are additionally subjected to far more controls than those prepared from monkey kidney. Even today, after years of experience with vaccine production in human diploid cells that have never been shown to be contaminated, the requirements of vaccine control remain unchanged. This illustrates the inflexibili- ty of the quality control of vaccines. It is ironic that at the same time as such a situation exists, smallpox vaccines known to be contaminated continue to be licensed. The control authorities are able to defend this because of the need for large scale production for the world and because smallpox vaccine is given by the percutaneous route. The same arguments, however, cannot be used for continued production and licensing of yellow fever vaccine, known to contain some or all fowl leukosis viruses. The argument here, however, is that if it became mandatory to produce yellow fever vaccine in chick embryos known to be free from fowl leukosis viruses, then the vaccine could not be made by the developing countries where yellow fever is prevalent. Even though WHO Requirements for Yellow Fever Vaccine were revised only two years ago, it was not possible to demand that the vaccine should be free from these chicken viruses. It was of particu- lar importance, in making such a decision, that millions of subjects have been given vaccine containing fowl leukosis viruses with no record of adverse reactions due to the contaminants. There are other anomalies concerning quality control. Some tests have not contributed to the safety of the product, but no control authority is in a position to recommend their omission. This is the result of legal considerations rather than scientific argument; for, in the event of a subsequent accident with a vaccine subjected to fewer control tests, a justification for exclusion of some tests based on negative evidence would be severely criticized and possibly punished legally. This is a most serious situation that deserves more attention. The Future for Vaccines Against Tropical Diseases So far, we have been considering vaccines against the ubiquitous childhood diseases and those that have been available for some years, but the diseases that occur only in the tropics present a more serious problem. Such vaccines are, as yet, in the early stages of research. One of the major constraints to development of vaccines or drugs against such diseases is the uncertainty of being able to market the products. Today, however, the challenge before the research potential of the world is to develop biological products against these prevalent diseases. Many obstacles will need to be overcome if we are to succeed. Amongst these are: 1. A greater intensity of research into the immunology and pharma- cology of tropical diseases; 100

2. The "drugs" (including vaccines) will almost certainly be developed in countries in which the diseases do not occur, whereas clinical trials must be carried out in those areas in which the disease is prevalent; 3. An entirely new approach will be needed for quality control of prophylactic or therapeutic agents against these diseases; 4. A coordinated effort between the developed and developing world, on a scale that has not hitherto been envisaged, will be needed for success. It is important to consider in depth each of these considerations. Support by a Number of Countries is Essential The quality control of vaccines that may be developed against tropical diseases is already demanding attention. WHO is looking at controls that may be necessary for vaccines against leprosy, malaria, and dengue haemorrhagic fever. Such requirements are being formulated but they must be flexible, and subject to change as new findings accumulate. Research organizations require support to give more assis- tance in this work. It is most important to appreciate that these drugs or vaccines are urgently needed for infections that are causing millions of deaths each year. The price of efficacy, therefore, may be side reactions in a small proportion of those needing the drug or vac- cine, and the level of acceptability must be assessed in those communi- ties most in need of the products. The final equation of therapy or prophylaxis against the disease will include mortality of the disease, efficacy of the drug, reactions to the drug, and cost of the disease compared with the cost of the drug. It will be a complex formula but it will be necessary to retain an open and flexible mind on all compo- nents before the final answer is reached. Indeed, local conditions may also be the most important determinants and overrule all other factors. The necessary developments will not be achieved, however, without financial support at a realistic level and sacrifices of research time to these projects. Conclusions In providing vaccines against bacterial and viral diseases of children, there will need to be new thinking for the future. At a meet- ing in WHO, Geneva, in October 1978, it became clear that the present situation, whereby producers of the world become involved in a vicious auction to quote the lowest price, in order to be awarded large orders from international organizations, must be changed. The pharmaceutical industry cannot continue making vaccines under these conditions, 101

especially if they are also expected to carry out research and develop- ment. An alternative would be to offer each contract to more than one company but the most important consideration should be given to the involvement of governments. If governments would give part of their contribution to the developing world in the form of vaccines bought from their national producers, both producers and the developing world would benefit. Such a plan is worth serious consideration and is being examined for provision of drugs. As far as future products against tropical diseases are concerned, government support for research is essential. Provision of prepara- tions to countries where tropical diseases are prevalent, and where such countries are least able to afford such drugs or vaccines that may well be much more expensive than present day vaccines, is a problem requiring urgent attention. Stimulation of such developments is an integral component of the research needed, and the necessary support must be discussed at the beginning of any research and development program. These problems of the developing world are a tremendous challenge. The scientific world is capable of providing answers but such efforts are likely to need government financial support to give impetus to the program. A coordinated effort is essential if we are to be successful in reducing the misery caused not only by diseases for which we have satisfactory vaccines but also by tropical diseases that still remain to be conquered. No child should occupy a hospital bed with a disease that can be prevented, and our aim is to enlarge the list of preventable disease. This will be achieved only by political will, financial investment, personal sacrifices and, above all, a coordinated effort by governmment and scientific resources. 102

SELECTED PHARMACEUTICAL DEVELOPMENTS REQUIRED FOR PREVENTION OF MASSIVE BLINDNESS IN DEVELOPING COUNTRIES Barrie R. Jones Introduction The economic and social effects of blindness are such that its avoidance should surely command a priority for action. I should like to introduce the subject of blinding eye infections by giving some background and proposing an operational approach that specifies the requirements, in principle. In the developed countries the prevalence of blindness ranges from 0.05 percent to 0.2 percent of the total population. The main causes are illustrated in Table 1. This burden of blindness could be reduced at relatively high cost by preventive application of existing technolo- gy and by developments now in progress. (Symposium on Prevention of Blindness in the United Kingdom, Oxford Ophthalmological Congress, 1978 in press - Transactions Ophthalmological Society, United Kingdom) The developing countries also have these diseases, and tend to spend their resources for health by endeavouring to provide comparably sophisticated therapeutic services for privileged urban communities that constitute only a minute fraction of the total population, and an even smaller fraction of their blindness. They tend to do nothing effective about preventing the appalling additional overburden of avoid- able blindness which may be 10 to 40 times higher in their neglected rural populations (Tables 2, 3, & 4). This is partly the inevitable result of the narrow horizons of politicians and administrators, advised by persons trained through trad- itional medical schools. It is partly the result of inadequate dignity, respect, and remuneration for research, development, and service in rural community medicine, specifically in prevention of blindness. But it also results from nearly total neglect of these problems by both aca- demia and industry in the technologically advanced countries. For exam- ple, we simply do not have the drugs, the systems and the knowledge that we need to deal with onchocerciasis. This Conference may be expected to do something to mobilize resources needed to overcome these deficiencies. 103

TABLE 1. BLINDNESS IN THE UNITED KINGDOM Causes (Soresby) Percentage of Blind Persons Senile macular degeneration 27.0 Senile cataract 22.6 Glaucoma 12.0 Myopic Choroido-retinal Degeneration 8.2 Diabetic retinopathy 7.1 Optic atrophy 4.2 Vascular retinopathy 3.2 Uveitis 3.0 Retinitis pigmentosa 3.0 Dislocated lens 1.2 Retinal detachment 0.9 All other causes (each causing 0.5%) 8.6 PREVALENCE OF BINOCULAR VISUAL ACUITY <T6/60 = 0.2% OF POPULATION It is now recognized that most of the neglected rural communities with a massive overburden of avoidable blindness have a mixed harvest resulting from trachoma or onchocerciasis, or both, perhaps with mal- nutrition added — and in any case there is also, almost invariably, a high prevalence of readily remediable blindness from cataract (Tables 2, 3, & 4). This situation lends itself to a three-phase approach that: 1. Commences with initial intensive intervention that delivers a. Surgery to the community to remedy cataract and blinding distortion of the eyelids, and b. Intensive chemotherapy, on a community basis, to reduce the reservoir of infection, to block transmission, and eliminate the progression on into blindness. 104

TABLE 2. RURAL BLINDNESS IN SOUTHERN IRAN: VILLAGE OF SAR RIG 6.3% of population blind from trachoma 1.4% of population blind from cataract PREVALENCE OF BLINDNESS BINOCULAR VISUAL ACUITY -< CF @ 1M = 8.6% TABLE 3. BLINDNESS IN AN AFRICAN SAVANNA VILLAGE l/ 2.7% of population blind from onchocerciasis 9.4% of population blind from trachoma 0.3% of population blind from uncomplicated cataract PREVALENCE OF BLINDNESS BINOCULAR VISUAL ACUITY <C CF @ 3M = 3.3% TABLE 4. BLINDNESS IN AN AFRICAN RAIN FOREST VILLAGE l/ 1% of population blind from onchocerciasis 0.6% of population blind from cataract PREVALENCE OF BLINDNESS BINOCULAR VISUAL ACUITY ^ CF @ 3M = 1.6% 2. This must be followed by - saturation availability in every family of relevant eye ointment, etc. - education and assistance for improved personal hygiene, community sanitation, or environmental control, as required. 105

3. This attack on eliminating avoidable blindness needs to be planned with, and integrated into, development of primary rural health care, and strengthening of district eye services. But it must be appreciated that in these neglected communities it is the perception of benefit from (l) that makes credible and attractive the effort and expenditure for (2) and (3). Hyperendemic Blinding Eye Infections Although there are great differences between Chlamydia trachomatis and Onchocerca volvulus, their transmission and the diseases they pro- duce, the similarities between the factors leading to "blinding tra- choma" JJ/ and the factors leading to "blinding onchocerciasis" are striking. In each case man harbours the reservoir of infection, and in each case blindness only results from living in a community with an exceed- ingly high pressure of transmission of infection. In each case we need safe chemotherapy that can be easily administered by medical assistants, that will reliably produce a large reduction of the reservoir of infec- tion, with much diminished transmission, and will give rapidly perceived benefit to the treated individuals. If these requirements are met it does not matter if the course of treatment takes some weeks to complete, provided medical assistants can safely and effectively administer it on the required scale. Chemotherapy for Hyperendemic Blinding Trachoma For trachoma control the currently recommended chemotherapy is a tetracycline or macrolide eye ointment applied twice daily for 5 con- secutive days once monthly for 6-24 months. This is somewhat irritat- ing, messy, vision-blurring, and of middling efficacy. It takes a long time to yield perceived benefit, and relapse of shedding of C. trachoma- tis may occur if the treatment course is not protracted; but it can be safely administered by medical assistants or by family members, and so is widely used. We have investigated oral chemotherapy with doxycycline 5 mg/kg given twice weekly for 3 weeks. Benefit was rapidly perceived and the prevalence of active trachoma in that whole village community, includ- ing babies originally too young to be treated and new immigrants, reduced progressively for two years. Not until the third year was there an upswing of transmission with a concomitant increase in preva- lence of severe active trachoma. Doxycycline dosage every 3 days for 3 weeks should be even more effective. 106

We are now investigating the effects of 3 single weekly doses of Kelfizine W (Sulfametopyrazine) in a trachomatous population on the Island of Hormoz. So far, no serious adverse effects have arisen and the early effects look encouraging, but problems remain of ensuring adequate large-scale supervision of oral dosage, avoidance of overdosage and the possible uncertainties concerning late effects of any high dosage tetra- cycline therapy on infants, children, and potentially pregnant women who are precisely the persons harboring most of the reservoir of C. trachomatis in these communities. Furthermore, there may be anxie- ties about the possibilities for emergence of resistant enteric, respiratory and other bacteria. Ocular Therapeutic Systems for Trachoma The principle of continuous controlled delivery of chemotherapy to the eye from a drug-delivery platform that resides in the conjuncti- val sac, as developed by ALZA Research, would seem to offer the advan- tages of continuous protracted effective therapy without problems of cost and uncertainties inherent in prolonged systemic chemotherapy. The original design of "Ocusert (§) " delivering pilocarpine for glaucoma, can be retained reasonably well by most patients, with appropriate training. But retention was quite unsatisfactory in hyper- endemic eye disease without training. Nevertheless, pilot trials of various such devices delivering erythromycin for trachoma, chlorampheni- col for acute bacterial conjunctivities, or disodium cromoglycate for allergic vernal conjunctivities yielded slightly higher immediate effi- cacy than the corresponding ointment or eye drop preparations. The new principle of supratarsal delivery platforms provides secure and comforable lodgement in a potential space above the upper tarsus. Medial or lateral falling out is prevented by lodgement on the respective canthal ligament. The performance is remarkably good in small numbers of volunteers, even when wearing these inserts for peri- ods up to 2 years. Larger scale trials will shortly confirm or refute these promising pilot studies of continuous, non-irritant chemotherapy for 3-4 weeks at a time from a single insertion in each eye, and which could be carried out by medical assistants. Time does not permit discussion of the choice of antibiotic, and the attractions of rifampicin, possibly combined with erythromycin. Instead, we must consider the much more difficult problems of onchocerciasis. 107

Prevention of Blindness and Control of Onchocerciasis Elimination of onchocerciasis from Kenya was achieved, and control of the disease in the Volta River Basin is being attempted on a vast scale, by control of the Simulium fly vector. Much progress has been made; but repopulation is a problem since the flies can fly 100-200 miles. Additionally, the longevity of adult Onchocerca volvulus in man means that the extremely costly vector control program will have to be maintained over vast areas for 15-20 years to allow the reservoir of 0. volvulus to die out in the control area. Professor Peters has discussed the paucity and shortcomings of drugs available for onchocerciasis. He has emphasized the difficulties in screening new compounds for activity, in the absence of in vitro systems or animal models of infection with 0. volvulus. I should like to illustrate two ways in which ocular studies can contribute. Direct Demonstration of Activity Against Microfilariae in the Cornea Curled-up, living microfilariae of 0. volvulus are near the lower limit of what can be observed clinically in man with a good binocular biomicroscope. This enables drug effects to be observed directly in corneae heavily loaded with microfilariae. Drs. Anderson, Fuglsang, and I have shown that the following pattern consistently occurs with all drugs known to kill onchocercal microfilariae (mf): 1. increased migration of mfs. 2. straightening, immobilization, and opacification of mfs. 3. granular disintegration amidst reaction around many, but not all mfs. In addition, a highly characteristic sequence of acute inflammatory events rapidly develops in the peripheral cornea and limbus, comprised of: 1. peripheral corneal and limbal globular infiltrates 2. limbitis 3. suppurative perivasculitis (if the reaction is severe) This sequence has been observed afater oral therapy with diethylcarba- mazine (DEC), metrifonate, and suramin, and it has been studied quanti- tatively in response to topically applied DEC.9/ 108

Within the constraints of prior animal work and volunteer studies to ensure acceptably low toxicity and ocular irritancy, and within constraints of solubilities permitting formulation for ocular absorp- tion, it is possible to use these characteristic phenomena to demon- strate activity, or lack of activity against microfilariae of 0. volvulus.10/ Progressively increasing in half-1og steps from 0.0001 percent concentrations through 0.0003 percent, 0.001 percent, etc. to reach 1 percent and even 3 percent, we have cautiously applied DEC 3 times in a day, or in half-a-day. This enables us to observe the very earliest signs of action on microfilariae, and of adverse drug effects on the eye. The purpose of this investigation has not been a search for new anti-microfilarial drugs, but to demonstrate efficacy against 0. volvu- lus in classes of compounds that may have macrofilaricidal activity and which are safer for systemic use in man than is suramin. In this way, we have demonstrated the activity of levamisole 10/ and amoscanate (CGP 450). No activity could be shown with mebendazole (possibly because of its extremely low solubilities), thiabendazole, econazole, miconazole, clotrimazole, dibromopropamidine isethionate, or trifluorothymidine. The ethical acceptability of such studies, when carried out in an area of blinding hyperendemic onchocerciasis by an expert team under guidance of an investigator who is a national of the country concerned, rests on the following considerations: 1. Patients with severe corneal onchocerciasis need a lowering of their load of corneal microfilareae. 2. Any adverse reactions are detected very early at their onset, and occur in noncritical tissues of the peripheral cornea and conjuctiva. 3. No patient is placed at risk of visual damage by reactions in the critical tissues of the optic nerve or retina, as may be the case with ill-advised systemic therapy with existing drugs. 4. Furthermore, the precision of direct microscopic examinations of these effects from coded treatments, with right/left placebo con- trols, requires only a few patients to receive very small quantities of drug in one eye for l-3 days. Used strictly in this way, we believe that this is a safe and potentially useful method of generating early confirmation or refuta- tion of activity against 0. volvulus in its microfilarial form, and which could contribute materially in the search for better drugs. 109

Adverse Effects from Chemotherapy of Severe Ocular Onchocerciasis Systemic therapy of severe onchocerciasis with diethylcarbamazine i».§.».5.»Z»-l?/ or suramin .2.»A».§.»Z».ii».i3/ regularly gives rise to unplea- sant cutaneous, ocular or systemic reactions. The dangers are much increased in very heavily parasitized persons. Deaths have occurred, especially following suramin from which the adverse effects are not necessarily entirely related to the parasiticidal effects. Suramin therapy seems especially likely to precipitate or exacerbate onchocer- cal iritis and possibly optic nerve disease requiring expert additional management to avert blindness.2j_ We have studied quantitatively both the direct anti-microfilarial, and the adverse inflammatory effects of topically applied DEC in oncho- cerca-1oaded cornea.j?/ When therapy is expressed in terms of average day-time delivery rates, DEC produces: anti-microfilarial effects at 0.l-0.3 ug/hr. mild inflammatory effects at 1 ug/hr. substantial or severe inflammatory effects at 3-30 ug/hr. There appears to be a therapeutic range of delivery rates within which DEC can kill mfs without causing substantial adverse effects. Furthermore, it appears that after a period of carefully controlled delivery rates, it may be possible for the treated eye to withstand the ordinary highly pulsed doses of DEC without adverse effects. Appli- cation of this principle may make it acceptable to use DEC to reduce the microfilarial load, thereby increasing the safety of administration of subsequent suramin therapy.J/ Our work in progress in the Southern Sudan has confirmed that the same adverse inflammatory sequelae occur with ordinary regimens of sura- min therapy, including uveitis and severe suppurative perivasculitis in the cornea. Preliminary studies have shown that these adverse inflammatory sequelae in the eye are not prevented by ordinary intensive day-time administration of various anti-inflammatory drugs or combinations including prednisolone, anti-histamine, anti-serotonin, anti-prostaglan- din synthetase, or "anti-allergic" compounds that block release of mediators; namely, disodium cromoglycate, ketotifen, isoproterenol with diethylcarbamazine, or 2-deoxyglucose. There is therefore an important requirement to study the effects of therapy using various round-the-clock non-pulsed delivery rates of DEC from supratarsal ocular therapeutic systems, to determine whether there really is a therapeutic range of controlled delivery rates within which DEC can kill 0. volvulus mfs without exciting substantial adverse 110

inflammatory reactions. One must also study the effects of combined therapy using anti-filarial and anti-inflammatory drugs of various sorts, and sequences of drug administration under conditions of steady state drug delivery to obviate the overwhelming adverse effects that appear related to peak drug delivery. The speed and precision of microscopic examination in the eye, under coded conditions, coupled with the right/left internal control opportunity which obviates so many interpersonal variables, offers a very attractive situation in which to study these phenomena which appear to apply to all drugs that kill the microfilariae, including the macrofilaricidal drug, suramin. It is likely that a modest investment in this application of continous controlled ocular drug delivery could provide data with which to write specifications for drug delivery rates for systemic and topi- cal drug delivery, that may ultimately open the door to safe and bene- ficial administration, by medical assistants, of effective programmed chemotherapy for onchocerciasis. Ill

REFERENCES 1. Anderson J, Fuglsang H: Collapse during treatment of onchocercia- sis with diethylcarbamazine. Tr Roy Soc Trop Med Hyg 68:72-73, 1974 2. Anderson J, Fuglsang H: Further studies on the treatment of ocular onchocerciasis with diethylcarbamazine and suramin. Brit J Ophthal 62:450-457, 1978 3. Anderson J, Fuglsang H, Marshall TFdeC: Effects of diethylcarbama- zine on ocular onchocerciasis. Tropenmed u Parasitol 27: 263-278, 1976 4. Anderson J, Fuglsang H, Marshall TFdeC: Effects of suramin on ocular onchocerciasis. Tropenmed u Parasitol 27:279-296, 1976 5. Bryceson ADM, Warrrell DA, Pope HM: Dangerous reactions to treat- ment of onchocerciasis with diethylcarbamazine. Brit Med J i: 742-744, 1977 6. Budden FH: Onchocerciasis therapy. Trans Roy Soc Trop Med Hyg 118-119, 1959 7. Duke BOL: Effects of drugs on Onchocerca volvulus. 3. Trials of suramin at different dosages and a comparison of the brands antry- pol, moranyl, and naganol. Bull Wld Hlth Org 38: 157-167, 1968 8. Jones BR: Prevention of blindness from trachoma. Trans Ophthal Soc UK 95:16-33, 1975 9. Jones BR, Anderson J, Fuglsang H: Effects of various concentra- tions of diethylcarbamazine citrate applied as eye drop in ocular onchocerciasis, and the possibilities of improved therapy from continuous non-pulsed delivery. Brit J Ophthal 62: 428-439, 1978 10. Jones RB, Anderson J, Fuglsang H: Evaluation of microfilaricidal effects in the cornea from topically applied drugs in ocular oncho- cerciasis: trials with levamisole and mebendazole. Brit J Ophthal 62:440-444, 1978 11. Nelson GS: A preliminary report on the out-patient treatment of of onchocerciasis with antrypol in the West Nile District of Uganda. E Afr Med J 32: 413-450, 1955 112

12. Oomen AP: Fatalities after treatment of onchocerciasis with diethylcarbamazine. Trans Roy Soc Trop Med & Hyg 63:548, 1969 13. Satti MH, Kirk R: Observations on the chemotherapy of onchocercia- sis in Bahr El Ghazal Province, Sudan. Bull Wld Hlth Org 16:53l-540, 1957 113

DISCUSSION: MAJOR DISEASE PROBLEMS OF THE DEVELOPING COUNTRIES; THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS DR. LEIGHTON CLUFF, referring to Professor Smith's statement concerning the paucity of reliable statistical information available from less developed countries, wondered about the importance of estab- lishing systems for collecting appropriate, reliable data to identify problems and assess impacts of various interventions on improvement of health status. DR. GORDON SMITH replied that precise data on worldwide prevalences were not what was needed now; it would suffice — but this is important — to obtain within particular countries accurate information about the distribution, prevalence, and incidence of diseases against an accurate demographic background. Such information is essential for purchase and distribution of pharmaceuticals or vaccines among large populations, especially when relying on untrained people. Thus, the success of a large-scale vaccination program necessarily depends upon planning based on accurate data including, for example, projections of the size and distribution of the population in the youngest age groups for estimates concerning the amount of vaccine and the distribution effort needed. DR. TAG MANSOUR asked Dr. Smith if poor communication among the scientific community in developing countries slowed drug research and development efforts. DR. SMITH noted that he had not been referring to information on drugs, but to information on health and the effects of behavior on health practices. Here, his concern focussed on two problems of com- munication: (l) how to reach the large majority of the population and inform them about disease, such as hookworm; and (2) communication within the scientific community to disseminate new knowledge. The prob- lem of keeping up with the information explosion is bad enough in devel- oped countries. In countries where resources are scarce, and where only a limited number of scientific journals arrive, the difficulty is com- pounded by the lack of expertise available to interpret the knowledge to its potential users, and to devise applicable solutions. This prob- lem has been exacerbated by the drain of the best scientists to devel- oped countries. DR. WALLACE FOX (British Medical Research Council) offered examples from his own experience to show that precise prevalence data may not always be necessary. Thus, the WHO delayed tuberculosis therapy in Africa for several years in the 1950s while sophisticated sampling sur- veys were performed. The prevalence data thus obtained merely con- firmed that there was a tuberculosis problem; little new was added. In 114

this particular case, statistical information derived through sophisti- cated methodology was not necessary; a treatment program only required approximate data concerning the numbers of people who might come to the health centers for treatment. DR. SMITH commented that the problems of therapy differ from problems of prevention. The example of tuberculosis is only useful for specific situations, such as in countries with an adequate number of treatment centers. He agreed that unncessary delay is bad. However, to conduct an effective, long-term preventive program, one needs to know the size and preferred age group for vaccination of the popula- tions likely to be at risk, and therefore their demographic constitu- tion and dynamics. DR. JOHN BRYANT (Office of International Health, DHEW) referring to comments by Drs. McDermott and Smith, asked how close the linkage is between health improvements and improved living conditions. He noted that an increase in population worldwide means an increase in the abso- lute numbers of people moving into circumstances of poverty, even though their proportion may be decreasing in relative terms. Are there unused or underutilized resources at the community level that can be used to improve health status? Can we afford to wait for the socio- economic level to improve? Is absolute poverty an obstacle to health improvement? DR. WALSH McDERMOTT noted that the People's Republic of China has shown that labor-intensive methods can be very effective in situations where the society is mobilized toward common goals. There is a large cultural component to the success or failure of labor—intensive pro- jects. Much of our technical knowledge cannot be applied without simul- taneously working to remedy the socio-economic problems. As to utilizing technology in circumstances where poverty prevails, DR. McDERMOTT believes that it is not realistic to expect people to wash their hands frequently if they have to haul water over long dis- tances. Despite this general limiting principle, some examples can be cited where technology can control diseases linked to poverty without addressing the poverty issue directly — so-called "technological fixes." DR. CLUFF requested Dr. McDermott to extend his previous comments about the effects of applying medical technology in conditions where poverty remains unchanged. DR. McDERMOTT referred to the introduction of chemotherapy for tuberculosis in Wales and in New York City that produced precipitous declines in the tuberculosis rates among the white population, and among Black males in New York City. These changes in the incidence of tuberculosis occurred without noticeable improvements in socio-economic conditions, illustrating two instances where medical technology alone 115

can make a difference. The same effects of tuberculosis chemotherapy were noted among the aboriginals and among the people of European descent in New Zealand. DR. McDERMOTT indicated that not enough attention has been paid to investigate the pathogenetic chains of the diseases of poverty, to look for weak points that could be attacked. In this context, he observed that the medical care system had a delivery system long before it had technology (the reverse of the usual situation — where technology pre- cedes the establishment of the system for its delivery). The tendency of the medical profession is to find an effective agent, plug it into the system, and then move on to something else, instead of perfecting the technology. DR. SMITH commented that the experience with tuberculosis in New York City cannot be extrapolated to less developed countries. In New York City and other urban areas, access to care was concentrated in a small area. The example of polio vaccine in the developing world should also be considered a very special case, for the large market in the industrialized countries made cheaper production costs and there- fore lower export prices possible. DR. BARRIE JONES commented on Dr. McDermott's experiences with the Navajo in controlling infectious disease. Mass chemotherapy with sul- fonamides for trachoma hs been considered a failure because it resulted in little reduction in prevalence of the infection. It is much more meaningful to consider the prevalence of a potentially blinding sever- ity of disease which relates to duration of life in a community with very high pressure of eye-to-eye transmission of infection. Viewed in this light, sulfonamide chemotherapy in the Navajo was followed by very great reduction in severity of disease and, later, abolition of further blindness from trachoma, despite a continuing but diminishing preva- lence of very mild trachoma. DR. JOYCE LASHOFF (Office of Technology Assessment) referred to Dr. McDermott's comments on China, since she had recently spent three weeks in that country. She believes that the political organization of the population, which emphasizes education, sanitation, and assumption of responsibility, is an essential component to the successes of the Chinese health care system, much more so than any cultural factor. She pointed out that education in relation to sanitation has been excep- tionally successful, even under adverse conditions. As a rather extreme and somewhat humorous example, she cited the toilet training of water buffaloes in the effort to control the spread of schistosomiasis. DR. FRANZ ROSA (former Chief of Maternal and Child Health, WHO) wished to introduce, for the record, consideration of the problem of pregnancy and pharmaceuticals. He mentioned the need to find agents to aid in the appropriate spacing of births, and which would not interfere with breast-feeding. 116

DR. DIETER KOCH-WESER (Department of Preventive Medicine, Harvard University) reiterated Dr. McDermott's comment that health delivery systems antedated technology in the United States. Agreeing that the health care delivery system was very important, he asked whether its lack was not the major problem in less developed countries. DR. McDERMOTT noted that it is difficult to generalize; the sudden introduction of particular technologies into the industrialized world has had devastating effects on delivery systems. Health delivery sys- tems vary widely among — and even within — less developed countries, from traditional healers to Western-trained physicians. Most delivery systems in less developed countries can handle non-toxic drugs, while highly toxic drugs require very sophisticated systems. No matter what the system, however, the putative healer must have something to deliver. DR. CLUFF cautioned that any delivery system introduced into less developed countries be appropriate to the available technology. DR. McDERMOTT suggested that the "technological substrate" — or the demographic pattern of diseases in a particular country — be con- sidered when examining the possibilities of introducing a new technology or increasing the availability of the old. For example, if one looks at myocardial infarctions in United States, many of those stricken never reach the doctor because they die first. Such individuals do not figure in the "technological substrate." DR. EDWARD CROSS (Agency for International Development) asked who has the responsibility for translating research findings into a health care program, if not the researcher. DR. SMITH replied that it was not necessarily the duty of the researcher to see to implementation of his findings. This responsibili- ty belongs to disease control or health care administrators. However, researchers often fail to communicate effectively with those responsi- ble and use jargon to excess, which limits understanding and applica- tion of their findings. DR. CLUFF asked Dr. Perkins why an effective immunization program must reach 90 percent of the population. Should this figure be a goal for all vaccination programs, and is there any evidence to support the need for such a large effort? DR. FRANK PERKINS, noting that hard evidence was scarce, cited the recent outbreaks of pertussis in the United Kingdom, which were linked to low vaccination rates. Over the last three years, the percentage of the target group to have been vaccinated had fallen from 85 to 35. He mentioned the psychological importance of setting a target of 90 per- cent to reach an actual rate of 80 percent. 117

MS. BARBARA STOCKING (University of Sussex) requested continued discussion about delivery systems for vaccines in developing countries. In the absence of delivery systems, how can vaccination programs reach the majority of the population? DR. WILLIAM FOEGE replied that it is best to use a primary health care system for a vaccination program if one exists in a particular country. In those vast areas where primary health care centers do not exist, however, mobile teams delivering vaccines to primary health care centers might be a better solution. DR. CLUFF wondered whether WHO "team" immunization programs have reached immunization rates of 90 percent. DR. FOEGE replied that the question cannot be answered as precise- ly as it was posed, and that 90 percent should not be seen as a univer- sal epidemiological target. In the smallpox program, for example, pop- ulations were immunized in specific outbreaks. In other programs, each percentage increase of coverage costs more; the additional costs must be balanced against the available resources, and against the mar- ginal rate of return. Worldwide, however, 90 percent coverage has been achieved many times in immunization programs. DR. OSCAR GISH (University of Michigan) interjected that debate over the effectiveness of immunization programs is meaningless unless the analysis is undertaken within a framework that embraces the econo- mic situation, political environment, and etiology of diseases. He asked whether some of the advances in disease control over the last few decades, for example, smallpox eradication, have made any real impact on living conditions overall. Some studies suggest that the Indian population is less healthy today than ten years ago. DR. WALLACE PETERS responded by citing a personal anecdote illustrative of the improvements in overall living conditions produced by a specific disease control program. He related the case of a jungle village in Nepal, which had long been rendered uninhabitable by endemic malaria. Thirteen years after the introduction of a malaria control program, the area had been transformed into a thriving agricultural region with noticeable improvement in the residents' quality of life. Other examples among many should include yaws and malaria control in Liberia. DR. CLUFF observed that the record is replete with evidence that the control or eradication of a single disease has changed the history of mankind. DR. SMITH asked that Drs. Foege or Perkins provide information on two potentially undesirable effects which may have been caused by the introduction of measles vaccination programs in Africa: (l) the country cannot sustain the effort following withdrawal of foreign 118

assistance, increasing the likelihood of the virus' return with greater force than ever; (2) the country feels obliged to sustain the immuniza- tion program following withdrawal of foreign assistance, and thus skews the spending of the health budget in that direction. DR. FOEGE replied that much has been learned from the measles programs in West Africa. In The Gambia, measles transmission was inter- rupted for three years, thus freeing hospital beds for other purposes. The return of measles following cessation of the program has not been more virulent than before the program. Overall, results are mixed, and some countries could not sustain a comprehensive measles vaccination program. DR. PERKINS commented that immunized individuals enjoy permanent protection against the virus. He did cite another negative side effect from vaccination programs: mothers who perceive the benefits of a pro- gram blame the government for not continuing it. DR. CLUFF asked Drs. Janssen and Jones about the proximate utility of the new pharmaceutical agents and techniques they discussed for developing countries today, especially since successful application depends upon a well-developed personal health care delivery system. DR. PAUL JANSSEN noted that some agents are easy to administer at low cost. It is possible to eradicate roundworms, for example, with- out changes in hygiene at the (low) cost of ten cents per person per year. DR. JONES noted that although fungal diseases of the eye can now be effectively treated in advanced medical centers, management is pro- tracted and difficult to carry out in rural communities of humid tropical developing countries where the problem is probably greatest. Prophylactic ointments now have to be developed, with guidance from local microbiologic studies. Prophylaxis covering the main fungal and bacterial threats, used after all eye injuriess, should be more cost- effective than the individual treatment of a few established cases. He also described the training received by many physicians in developing countries as often irrelevant to the conditions and the health needs in their countries, and noted this as another barrier to successful appli- cation of prophylactic and therapeutic agents. 119

Next: CURRENT PROGRAMS FOR DEVELOPMENT OF PHARMACEUTICALS »
Pharmaceuticals for Developing Countries: Conference Proceedings Get This Book
×
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF
  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!