Pharmaceuticals for Developing Countries Conference Proceedings (1979) / Chapter Skim
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MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS
MAJOR DISEASE PROBLEMS OF DEVELOPING COUNTRIES--THE CURRENT STATUS OF PREVENTIVE, PROPHYLACTIC, DIAGNOSTIC, AND THERAPEUTIC AGENTS
Pages 29-120
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From page 30... ...
and urban populations are far greater than between similar population groups in industrialized countries. The health problems of rural and peri-urban populations are dominated by the diseases characteristic of poverty in wan temperatures, and by parasitic diseases, while the diseases of affluence (alcoholism, coronary heart disease, degenerative and malignant diseases)
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From page 31... ...
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.
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From page 32... ...
Plasmodium falciparum resistant to chloroquine now occurs in areas with a population of over 45 million and populations of 90 million are at grave risk. And one-third of all malaria control programs are facing problems of insecticide resistance.
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From page 33... ...
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 sexually transmitted diseases -- are common and important in most tropical countries, particularly in impoverished rural or peri-urban populations.
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From page 34... ...
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, meningococcal meningitis, etc. Apart from existing vaccines and the few infections important enough in industrialized countries to make vaccine development economically attractive (e^£«, respiratory syncytial virus infections)
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From page 35... ...
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 engendered 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 schistosomiasis and the wearing of shoes that of ancylostomiasis.
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From page 36... ...
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.
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From page 37... ...
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)
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From page 38... ...
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)
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From page 39... ...
If this success is to be maintained in the longer term, however, much more attention must be given to establishing the ability of the countries themselves to sustain a control program 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 certain cities of South East Asia dengue haemorrhagic fever/shock syndrome 39
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From page 40... ...
However, Winslow concluded that industrial absenteeism had been substantially reduced by malaria control programs in the Philippines and southern Africa and by yaws control programs in Haiti.^/ A World Bank study of construction and rubber 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.
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From page 41... ...
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)
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From page 42... ...
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 episodes 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.
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From page 43... ...
weapons are going to be delivered to their targets in rural areas. A proportion of the respiratory infections are preventable by immunization programs (diphtheria, pertussis, measles)
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From page 44... ...
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 construction force, and for active surveillance and appropriate health provisions for the population living in and servicing the development (^.£., usually expected to service the interest on the loans with which it was financed)
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From page 45... ...
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.
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From page 46... ...
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.
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From page 47... ...
Guyer B, Atangana S: Bull Wld Hlth Org 55:633, 1977 17. Hawking F: Trop Dis Bull 73:967, 1976 18.
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192, 1971 37. World Health Organization: Wld Hlth Org Off Rec, No.
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3. A third strategy designed to selectively destroy the pathogens after invasion by chemotherapeutic agents or by specific immunotherapy.
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in this column indicates that a reservoir host is known to play an important role in transmission. d/A cross (+)
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From page 52... ...
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 dermatophytoses, tinea versicolor, and superficial Candida infections respond very well to these very safe and widely available drugs.
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From page 53... ...
There are at least four serious protozoal diseases against which satisfactory chemotherapeutic agents have not yet been found or developed; namely, the various leishmaniases, African and South American trypanosomiasis, and toxoplasmosis. Here again, it is easy in theory but almost impossible in practice in most countries to decrease the incidence of these endemic diseases by manipulations of the environment.
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From page 54... ...
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 discovery 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.
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From page 55... ...
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)
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From page 56... ...
. 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.
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From page 57... ...
satisfactory chemotherapy exists against 22; (4) unsatisfactory chemotherapy exists against another 22; and (5)
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From page 59... ...
More specific to developing countries are those diseases caused by parasites, and it is drugs used specifically for prevention or treatment of these conditions on which this paper will focus. Parasitic diseases will be considered in two main groups, those caused by protozoa, and those caused by helminths.
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From page 60... ...
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 afflicting man, and a major cause of mortality. In 1976, it was estimated that 848 million people still lived in areas where transmission continued 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)
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From page 61... ...
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.
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From page 62... ...
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 statistical data.
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From page 63... ...
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 education is worthless except where the level of social discipline is exceptionally 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.
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From page 64... ...
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.
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From page 65... ...
SIMPLIFIED LIFE CYCLE OF MALARIA PARASITE TO SHOW POINTS OF ACTION OF DIFFERENT TYPES OF ANTIMALARIAL DRUGS MOSQUITO SPORONTOCIDES P foiciporum P
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From page 66... ...
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.
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From page 67... ...
pyrimethamine Blood schizontocides _b/ chloroquine + amodiaquine + quinine cj + mef loquine d/ + pyrimethamine-sulfa -- + doxine (=Fansidar (§)
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From page 68... ...
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)
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From page 69... ...
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 problems that are far from being resolved while.
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From page 70... ...
Chemoprophylaxis in man is no longer considered of significant practical value with the only available compound, pentamidine, and attempts to protect cattle have been marred by drug resistance. South American Trypanosomiasis (Chagas' Disease)
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From page 71... ...
Only three groups of specific antileishmanials are available. In addition, the two drugs mentioned above in relation to Chagas' disease are undergoing clinical trials against leishmaniasis.
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From page 72... ...
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.
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From page 73... ...
Table 5 shows the compounds currently In use or undergoing clinical trials.
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From page 74... ...
H CO co 3 O 1 >; ••H -8 -' 1 O 60 cn O CU f.
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From page 75... ...
. Hycanthone was the first single-dose, injectable preparation produced, and it gave very promising results in early clinical trials.
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From page 76... ...
C9333-Go, at least, exhibits a broad spectrum of action against intestinal helminths and all three schistosome species. In summary, therefore, several effective compounds are currently available for treatment of one or another form of schistosomiasis.
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From page 77... ...
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 blindness", but the reaction to dead larvae is so severe that DEC can rarely be used in patients with this condition.
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From page 78... ...
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, £•£.
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From page 79... ...
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.
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From page 80... ...
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.
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From page 81... ...
Weller TH: The increasing impact of schistosomiasis in a changing global ecology, Development of Chemotherapeutic Agents for Parasitic Diseases. Proceedings of the International Conference, Versailles, 1l-13 June 1974.
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From page 82... ...
WHO Chronicle 32:154-155, 1978 22. WHO: Receptivity to Malaria and other Parasitic Diseases.
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From page 83... ...
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.
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From page 84... ...
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.
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From page 85... ...
4. Immunization programs incorporate the general skills needed for diverse public health or community programs, thus providing a vehicle for other activities.
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From page 86... ...
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From page 88... ...
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From page 89... ...
tly Local & febrile ve - reactions eci- Frequent mild loca tec- reactions ft occabryo Local reactions dip- common. Rare CNS ccine effects with high newer vaccines ctive (common with earli' er vaccine)
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From page 90... ...
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From page 91... ...
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 predominently rural populations.
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From page 92... ...
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.
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From page 93... ...
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 vaccines with their need for surveillance systems, management, and evaluation would provide a solid background both for future vaccine programs, and for other primary health care services.
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From page 94... ...
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?
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From page 95... ...
Some developing countries are either producing particular vaccines, but rarely those against childhood diseases, or considering the possibility 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
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From page 96... ...
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.
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From page 97... ...
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 million with a birth rate of 30 per thousand.
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From page 98... ...
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.
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From page 99... ...
This is why provision of vaccine in bulk rather than transfer of technology in production 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.
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From page 100... ...
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.
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From page 101... ...
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.
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From page 102... ...
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.
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From page 103... ...
They tend to do nothing effective about preventing the appalling additional overburden of avoidable blindness which may be 10 to 40 times higher in their neglected rural populations (Tables 2, 3, & 4)
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From page 104... ...
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 |
From page 105... ...
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 |
From page 106... ...
. Hyperendemic Blinding Eye Infections Although there are great differences between Chlamydia trachomatis and Onchocerca volvulus, their transmission and the diseases they produce, the similarities between the factors leading to "blinding trachoma" JJ/ and the factors leading to "blinding onchocerciasis" are striking.
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From page 107... ...
Furthermore, there may be anxieties 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 conjunctival sac, as developed by ALZA Research, would seem to offer the advantages of continuous protracted effective therapy without problems of cost and uncertainties inherent in prolonged systemic chemotherapy.
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From page 108... ...
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.
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From page 109... ...
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.
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From page 110... ...
Suramin therapy seems especially likely to precipitate or exacerbate onchocercal 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 onchocerca-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.
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From page 111... ...
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 topical drug delivery, that may ultimately open the door to safe and beneficial administration, by medical assistants, of effective programmed chemotherapy for onchocerciasis.
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From page 112... ...
Trans Roy Soc Trop Med Hyg 118-119, 1959 7. Duke BOL: Effects of drugs on Onchocerca volvulus.
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From page 113... ...
Trans Roy Soc Trop Med & Hyg 63:548, 1969 13. Satti MH, Kirk R: Observations on the chemotherapy of onchocerciasis in Bahr El Ghazal Province, Sudan.
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From page 114... ...
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.
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From page 115... ...
referring to comments by Drs. McDermott and Smith, asked how close the linkage is between health improvements and improved living conditions.
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From page 116... ...
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 therefore lower export prices possible.
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From page 117... ...
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?
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From page 118... ...
interjected that debate over the effectiveness of immunization programs is meaningless unless the analysis is undertaken within a framework that embraces the economic 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.
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From page 119... ...
He did cite another negative side effect from vaccination programs: mothers who perceive the benefits of a program blame the government for not continuing it.
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