UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)

1996 WORKPLAN of the STEERING COMMITTEE on MACROFILARICIDAL DRUGS FOR ONCHOCERCIASIS AND LYMPHATIC FILARIASIS (MACROFIL)

Background:

The objectives of the Programme are to discover adulticidal (macrofilaricidal) drugs for onchocerciasis and lymphatic filariasis with the following profile:

. Effective (>70% Kill);

. Safe (for community use with limited medical supervision);

. Acceptable dosing regimen (oral dosing over no more than 3 days, or single intramuscular injection);

. Long shelf life (>2 years at ambient temperatures).

The value to the patient of such drugs would be:

. Permanent removal of the source of pathology (Microfilariae in onchocerciasis; adult worms in lymphatic filariasis);

. Removal of need to take ivermectin continuously.

The value to the community is:

. Control or elimination of transmission; sustaining and consolidating OCP's achievements to date in onchocerciasis control;

. Elimination of needs for, and costs of, continuous ivermectin treatment;

. Reduction in the likelihood of acquired resistance to ivermectin;

. An alternative to larviciding, which is no longer an affordable option;

. Providing a fully effective adulticidal drug to replace diethylcarbamazine in lymphatic filariasis.

Current Activities:

Two complementary strategies are being followed to discover new lead molecules:

. Characterization and validation of potential drug targets in filariae, leading to rational, computer-aided design, or identification of novel ligands by interaction with parasite receptors;

. In vivo assays (against B. pahangi and A. viteae in the gerbil) of novel molecules obtained from as wide a range of novel compounds as possible. Two compound screening centres are currently supported for these activities.

Once active molecules are identified, chemical synthesis may be supported when analogues are not available, to optimize promising leads.

Secondary evaluation of potential drugs is carried out using B. pahangi in the dog, and once pharmacokinetic results are available, against O. ochengi in cattle. Preclinical studies (Bulk chemical synthesis, analysis, formulation, pharmacokinetics, toxicology, etc.) are contracted out to specialist laboratories, but at present the programme supports two general drug assay/pharmacokinetics laboratories. Similarly, clinical studies in onchocerciasis and lymphatic filariasis are carried out by a network of centres in endemic countries.

Proposals for collaboration in any of the above activities are welcomed.

Objectives Completed in 1995

1. Amocarzine. Phase I clinical trials initiated in India.

2. Amocarzine. Extended Phase II clinical trials, using 3 mg/kg post-prandially twice a day for 3 days against onchocerciasis, initiated in Ghana.

3. Suramin clinical trial completed in Nigeria. Sera analyzed for secondary parameters of macrofilaricidal action.

4. Two new drug analytical laboratories established and validated for GLP.

5. Mutagenicity studies completed on compounds 129577, 251993 and 105666.

6. Separation of enantiomers of UMF 078 by chiral column technology. Efficacy studies initiated.

7. Efficacy studies of Lilly 269019 against B. pahangi in dog completed.

8. Work on ivermectin resistance probes reviewed and research programme modified.

9. Revision of centralized compound database and programme modifications initiated.

10. Review of molecular targets in filariae suitable for high throughput screening.

Financial support for this programme currently comes from both TDR and the Onchocerciasis Control Programme in West Africa, although the latter will be phased out at the end of 1997, when Macrofil will continue as a TDR programme.

All correspondence on Macrofilaricidal drugs for Onchocerciasis and Lymphatic Filariasis should be sent to:

Dr Colin Ginger, Manager Steering Committee on Macrofilaricidal Drugs for Onchocerciasis and Lymphatic Filariasis Special Programme for Research and Training in Tropical Diseases (TDR)

World Health Organization 20, Avenue Appia CH-1211 Geneva 27, Switzerland

Telephone: (41-22) 791.38.18 Facsimile: (41-22) 791.48.54 Email: Gingerc

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