COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)   p. 12 of 12

VI. APPENDIX B: Summary Overview of the Scientific and Technical Progress of the Special Program for Research and Training in Tropical Diseases (TDR), covering the period July 1983 to June 1984

Report of the Director, Special Program, to the Seventh Session of the Joint Coordinating Board, Bangkok, Thailand, 25-27 June 1984

(Extracted from the Draft Report of the Seventh Session of the Joint Coordinating Board)

          Dr. A. O. Lucas, Director of TDR, reported that since the Sixth Session of the Joint Coordinating Board [JCB(6)], significant advances had been made in all Components of the Special Program. He highlighted the most promising developments in the search for new ways of controlling the six diseases.

          The results had been achieved through TDR efforts carried out in close collaboration with academic and other research institutions, as well as with industry. Dr. Lucas expressed his gratitude to all the scientists and their institutions collaborating with the Program. Some of the discoveries had resulted directly from research specifically supported by TDR, and in cases where the initial discovery had been made outside the Special Program, TDR had been involved in its subsequent development into a practical tool for control of one of the diseases.

1. Malaria

          Dr. Lucas noted the significant increase in malaria, due to the growing resistance of the vector mosquitoes to chemical insecticides, and the continuing spread of drug-resistant parasites. Over the past year several new foci of chloroquine resistance had been discovered. In South-East Asia the problem had extended westwards to involve new areas, and in Africa the rapid spread of resistant strains of Plasmodium across the continent constituted a serious escalation of the problem of resistant malaria.

          TDR-supported research was producing new and improved tools to meet this challenge.

(a)  Chemotherapy

          Mefloquine, a potent antimalarial drug effective against strains of Plasmodium resistant to chloroquine and other drugs, was ready for use. It was being registered initially for use in adult males and soon would be made available for use in women and children. As mentioned by Dr. H. Mahler, Director-General, WHO, in his opening remarks to JCB(7), the development of mefloquine was an important example of the contributions industry and institutions and scientists in developing countries were making to TDR.

MALARIA

 

NEW TOOLS

STAGE OF DEVEL-

OPMENT:

ADVANCED

STAGE OF DVPTMT:

READY FOR USE

Drugs

Halofantrine
Artesunate
Others

Mefloquine
&
Combinations

Vaccines

Sporozoite
Merozoite
Gamete

 

Sensitivity

Test Kits

Sulfadoxine-

Pyrimethamine

Chloroquine

Amodiaquine
Quinine
Mefloquine
Pyritnethamine

          However, malaria parasites could acquire resistance to mefloquine, which would reduce the value of this drug. Two approaches were being used to extend the therapeutic life of mefloquine: the use of drug combinations, and controlled marketing and distribution of the drug.

          Resistant parasite strains were less likely to develop against a drug combination. Therefore, mefloquine would be administered mainly in a formulation combining mefloquine, sulfadoxine and pyrimethamine. This three-drug combination had been tested successfully in the field in TDR-supported studies.

          In agreement between WHO and the manufacturing pharmaceutical company, Hoffmann-La Roche, mefloquine and the combination drug would be sold only in those endemic countries where the parasite was not responding to chloroquine. The drugs would be sold to governments and to institutions designated by the governments. There would be no over-the-counter sales and no promotion of the drug to the public by the pharmaceutical company. In non-endemic countries mefloquine would be available only to short-term visitors to endemic areas.

          Mefloquine provided a welcome alternative for the treatment of chloroquine-resistant malaria. But one new drug was not enough. Chemically different new drugs must be found so as to reduce the risk of cross-resistance, and to give malaria control programs drugs with different biological properties, both for prevention and for treatment. TDR was pursuing these goals and was cooperating with Chinese scientists in the development of Qinghaosu and its derivatives. Also several pharmaceutical companies had invited the Program to collaborate with them in the evaluation of other promising compounds. Some of these were at the stage of initial clinical trials.

          Simple kits for testing the sensitivity of malaria parasites to commonly-used drugs had been developed and extensively tested by the Program. These kits were now widely used by national malaria control programs and provided them with a rational basis for decisions on the best use of antimalarial drugs.

(b) Immunology

          Research towards the development of malaria vaccines was advancing rapidly and it appeared that one or more vaccines would be available soon for preliminary testing in man. Major advances had occurred in the identification of protective malaria antigens at the different stages of the parasite (sporozoite, merozoite, gamete), and these antigens could now be produced in quantity by recombinant DNA technology or by polypeptide synthesis.

          An important development in solving the remaining technical problems has been the interest shown by industry in participating in the development of malaria vaccines. Their resources and know-how should further accelerate the rapid progress that has been made in recent years. The Program was actively seeking to expand its collaboration with the pharmaceutical industry, the United States Agency for International Development, and other agencies and institutions working to develop malaria vaccines.

          If malaria vaccines become available, they could provide malaria control programs with a powerful addition to their existing armamentarium. Deployed in combination with other control measures, vaccines could help to reverse the deteriorating trend in the global picture of malaria control.

2. Filariasis

          The Filariasis Component of TDR, in collaboration with the Onchocerciasis Chemotherapy group, had accorded the highest priority to the development of new drugs, especially for the treatment of onchocerciasis. Currently available drugs were of limited efficacy and frequently caused unpleasant and dangerous side effects. In collaboration with industry, major advances have been made in the search for safe and effective drugs.

          The most promising compound, ivermectin, was undergoing clinical trials; preliminary results were very encouraging. If these results on safety and efficacy were confirmed, ivermectin would represent a major advance in the chemotherapy of onchocerciasis.

FILARIASIS

NEW TOOLS

STAGE OF DEVELOPMENT:
ADVANCED                            READY FOR USE

Drugs

Ivermectin*

Flubendazole**
CGP 6l40***
CGP 20376***

*Merck, Sharp and Dohme

**Janssen Pharmaceutica

***Ciba-Geigy

          Other drugs were also under development. In a study carried out in Mexico, flubendazole produced a marked, sustained fall in the worm count of onchocerciasis patients. However the injection was painful and the drug was being reformulated by Janssen Pharmaceutica to reduce this reaction. Two promising compounds developed by Ciba-Geigy, CGP 6140 and CGP 20376, were ready for Phase I clinical trials.

3. Chagasí Disease

          The prevention and treatment of Chagasí disease were hampered by lack of suitable drugs. For example, the transmission of the infection in association with blood transfusion was a public health problem in some parts of endemic areas. A new screening technique, developed through the Program, had identified over 20 candidate compounds that could sterilize blood infected with the causative organism, Trypanosoma cruzi. These were undergoing further testing to identify a safe and effective agent.

CHAGASí DISEASE

NEW TOOLS

STAGE OF DEVEL-

OPMENT:

 ADVANCED

STAGE OF DVPMENT:

READY FOR USE

USE

Drugs

Trypanocides for stored blood

 

Reference sera

 

Diagnostic tests

Rapid screening of stored blood

 

 

Vector Control

Insecticidal
paints

 

 

Taxonomy

DNA probes

 

 

          Diagnostic techniques for Chagasí disease had been standardized by a network of laboratories and technical agreement among investigators had been raised to over 90%. One important factor in improving comparability and reliability had been the provision of standard reference sera. Several thousand specimens of this reference material had been provided to investigators for quality control in their laboratories. In addition, two new diagnostic tests had been developed and were being evaluated within the network.

          One approach to control of the triatomid bug that transmitted Chagasí disease was the use of paint containing an insecticide. This approach had proved effective in initial trials and field studies were being conducted to make the paint more attractive to the inhabitants of affected housing.

4. African Trypanosomiasis

          New technologies had recently become available for the control of African sleeping sickness and others were at an advanced stage of development. These included simple diagnostic tests and new methods of vector control, including the use of traps. The simple Card Agglutination Trypanosomiasis Test (CATT) had been extensively evaluated in the field and proved to be a practical screening test. Scientists in different parts of Africa had devised a variety of traps, including impregnation with natural and synthetic odors as bait for capturing and thereby controlling tsetse flies. A number of these activities had begun outside the Program, and TDRís role had been to coordinate the efforts of the scientists, many of whom had been working in isolation. In West Africa, a ground-spraying technique based on the use of agricultural sprays had been developed and validated.

AFRICAN TRYPANOSOMIASIS

 

NEW TOOLS

STAGE OF DEVELOPMENT
ADVANCED                                       READY FOR USE

 

Diagnostic tests

Mini-column                                         CATT test

 

Vector control

New traps                                            Biconical traps

Odor baits

          These new developments have been incorporated into a new strategy for the control of African sleeping sickness in West Africa.

5. Leprosy

          The Scientific Working Group on the Chemotherapy of Leprosy (THELEP) had conducted surveys on the distribution of Dapsone resistance in leprosy patients and had supported research to define the best multidrug treatment regimens. A WHO Study Group on Chemotherapy of Leprosy for Control Programs had based its recommendations for practical multidrug treatment schedules largely on the findings of THELEP. The multidrug treatment schedules had three advantages. They reduced the risk of drug-resistant strains emerging, they rendered patients non-infectious in a relatively short time, and they substantially reduced the duration of treatment. Combinations of chemotherapy and immunotherapy using killed M. leprae plus BCC in conjunction with multidrug chemotherapy had given promising results in early studies.

LEPROSY

NEW TOOLS

STAGE OF

DEVELOPMENT:

ADVANCED

STAGE OF DVPMENT:

READY FOR USE

 

Drug treatment

Immunotherapy

Multidrug regimens

 

Vaccine

Killed M. leprae

 

Diagnostic

Specific antigens & antibodies

 

          Evaluation of the leprosy vaccine developed by the Program had reached the stage of pre-vaccination studies in preparation for large-scale trials of the vaccine. The complex protocols required for these trials were at an advanced stage of planning.

          Remarkable progress had been made in the development of diagnostic tests for leprosy. Monoclonal antibodies that recognized M. leprae-specific epitopes had been identified and were being developed into immunodiagnostic tests. These tests should facilitate the diagnosis of leprosy in early cases before clinical signs of the disease are present.

6. Biological Control of Vectors

          Bacillus thuringiensis var. israeliensis (B.t. var israeliensis) had been deployed at an operational level for the control of the Simulium vectors of onchocerciasis (river blindness) in West Africa. It was also effective against the larvae of the mosquito vectors of malaria, but the short duration of the effect might limit its practical value for this purpose. A non-sporing mutant of B. thuringiensis had been discovered and was being investigated to determine if it had advantages over the standard strain.

BIOLOGICAL CONTROL OF VECTORS

NEW TOOLS

STAGE OF DVPMENT:
ADVANCED

STAGE OF DVPMENT:
READY FOR USE

Bacteria

B. sphaericus

B. thuringiensis (Asporogenic)

B

Thuringiensis (H-14)

 

 

 

 

Fungi

L. giganteum

 

 

          New strains of Bacillus sphaericus were showing considerable promise in the control of mosquitoes. These new strains were effective in polluted waters and their action persisted for periods varying from six weeks to several months. Industry was showing interest in developing these new strains in collaboration with the Program.

7. Conclusion

          Dr. Lucas stressed that his presentation was confined to just a few examples of products arising through TDR support that were ready or nearly ready for use. Never before in the long struggle against these parasitic and infectious diseases had their challenge been matched by such exciting opportunities. With the foundations laid, there was every reason to expect that over the next few years there would be a steady stream of new products -- drugs, vaccines, new diagnostic techniques and innovative methods of controlling these diseases -- emerging from the activities sponsored and coordinated by the Special Program.



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