Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-27T19:22:30.276Z Has data issue: false hasContentIssue false
  • English
  • Français

Chemotherapy of Onchocerca lienalis microfilariae in mice: a model for the evaluation of novel compounds for the treatment of onchocerciasis

Published online by Cambridge University Press:  05 June 2009

Simon Townson ,
A. Dobinson ,
C. Connelly  and
R. Muller
Simon Townson
Affiliation:
CAB International Institute of Parasitology, 395a Hatfield Road, St. Albans, Herts., AL4 0XU, UK
A. Dobinson
Affiliation:
CAB International Institute of Parasitology, 395a Hatfield Road, St. Albans, Herts., AL4 0XU, UK
C. Connelly
Affiliation:
CAB International Institute of Parasitology, 395a Hatfield Road, St. Albans, Herts., AL4 0XU, UK
R. Muller
Affiliation:
CAB International Institute of Parasitology, 395a Hatfield Road, St. Albans, Herts., AL4 0XU, UK
Get access Rights & Permissions [Opens in a new window]

Abstract

The model of Onchocerca lienalis microfilariae (mf) injected into inbred CBA/Ca mice was studied for its usefulness as an additional primary/secondary drug screen for onchocerciasis. Invermectin, DEC, suramin, flubendazole, mebendazole, levamisole, Mel W, furapyrimidone, metrifonate, amoscanate and the new Ciba-Geigy compounds CGP 6140, CGP 20'376 and CGI 17658 all significantly reduced levels of mf at a dose of 5x100 mg/kg or less. An early dosing protocol, on days 3–7 after infection, was found to be generally more effective than dosing on days 11–15, followed by necropsy on day 18. In some cases there were important differences in levels of drug activity depending on whether the drug was administered by the subcutaneous or oral route, indicating that new compounds should be tested via both routes. Ivermectin was by far the most active compound examined, virtually clearing mf from the skin at a dose of 5x0.0063 mg/kg and producing a significant mf reduction (63.5%) at 5x0.008 mg/kg following subcutaneous administration. In comparison, DEC was much less active, producing a 32.4% mf reduction at 5x25 mg/kg ranging up to a maximum of 72% reduction at 5x100 mg/kg. CGI 17658 was the most active compound examined next to ivermectin, almost 100% effective against skin mf at a dose of 5x6.25 mg/kg via the oral route while being less effective via subcutaneous administration (65% reduction). The lowest effective dose examined was 5x3.13 mg/kg (per os) which reduced mf levels by 64%. CGP 20'376 was also very active, resulting in a 46% (subcutaneous) and 62% (per os) reduction at a dose of 5x6.25 mg/kg. This mouse model has clearly identified all the known microfilaricides examined and also, to a lesser extent, those compounds considered to be principally macrofilaricides. We believe it has value as an additional drug screen for onchocerciasis, which will enable the evaluation of novel compounds against skin-dwelling Onchocerca mf at the primary/secondary level, providing complementary information to new in vitro screens using adult Onchocerca.

Keywords

Onchocerca lienalisfilaricideschemotherapydrug screeningmouse
Type
Research Papers
Information
Journal of Helminthology , Volume 62 , Issue 3 , September 1988 , pp. 181 - 194
Copyright
Copyright © Cambridge University Press 1988

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Awadzi, K., Dadzie, K. Y., Schulz-Key, H., Gilles, H. M., Fulford, A. J. & Aziz, M. A. (1986) The chemotherapy of onchocerciasis XI. A double-blind comparative study of ivermectin, diethylcarbamazine and placebo in human onchocerciasis in Northern Ghana. Annals of Tropical Medicine and Parasitology, 80, 433–442.Google Scholar
Awadzi, K. & Gilles, H. M. (1980) The chemotherapy of onchocerciasis III. A comparative study of diethylcarbamazine (DEC) and metrifonate. Annals of Tropical Medicine and Parasitology, 74, 199–210.Google Scholar
Awadzi, K., Schulz-Key, H., Howells, R. E., Haddock, D. R. W. & Gilles, H. M. (1982) The chemotherapy of onchocerciasis VIII. Levamisole and its combination with the benzimidazoles. Annals of Tropical Medicine and Parasitology, 76, 459–471.Google Scholar
Aziz, M. A., Diallo, S., Diop, I. M., Lariviere, M. & Porta, M. (1982) Efficacy and tolerance of ivermectin in human onchocerciasis. Lancet ii, 171–173.Google Scholar
Bianco, A. E., Ham, P. J., El-Sinnary, K. & Nelson, G. S. (1980) Large scale recovery of Onchocerca microfilariae from naturally infected cattle and horses. Transactions of the Royal Society of Tropical Medicine and Hygiene, 74, 109–110.Google Scholar
Bianco, A. E., Nwachukwu, M. A., Townson, S., Doenhoff, M. J. & Muller, R. L. (1986) Evaluation of drugs against Onchocerca microfilariae in an inbred mouse model. Tropical Medicine and Parasitology, 37, 39–45.Google Scholar
Campbell, W. C. (1982) Efficacy of the avermectins against filarial parasites: a short review. Veterinary Research Communications, 5, 251–262.Google Scholar
Carlow, C. K. & Bianco, A. E. (1987) Resistance to Onchocerca lienalis microfilariae in mice conferred by egg antigens of homologous and heterologous Onchocerca species. Parasitology, 94, 485–496.Google Scholar
Copeman, D. B. (1979) An evaluation of the bovine Onchocerca gibsoni—Onchocerca gutturosa model as a tertiary screen for drugs against Onchocerca volvulus in man. Tropenmedizin und Parasitologie, 30, 469–474.Google Scholar
Court, J. P., Martin-Short, M. & Lees, G. M. (1986) A comparison of the response of Dipetalonema viteae and Brugia pahangi adult worms to antifilarial agentsin vitro. Tropical Medicine and Parasitology, 37, 375–380.Google Scholar
Court, J. P., Stables, J. N., Lees, G. M., Martin-Short, M. R. & Rankin, R. (1988) Dipetalonema viteae and Brugia pahangi transplant infections in gerbils for use in antifilarial screening. Journal of Helminthology, 62, 1–9.Google Scholar
Denham, D. A. (1979) A review of methods for testing compounds for filaricidal activity. Journal of Helminthology, 53, 175–187.Google Scholar
Denham, D. A. (1982) The effects of some avermectins on the growth of Brugia pahangi. Methods and Findings in Experimental Clinical Pharmacology, 4, 347–350.Google Scholar
Devaney, E. & Howells, R. E. (1984) The microfilaricidal activity of ivermectin in vitro andin vivo. Tropenmedizin und Parasitologie, 35, 47–49.Google Scholar
Duke, B. O. L. (1968) The effects of drugs on Onchocerca volvulus. III. Trials of suramin at different dosages and a comparison of the brands Antrypol, Moranyl and Naganol. Bulletin of the World Health Organization, 39, 157–167.Google Scholar
Duke, B. O. L. (1974) Further trial of trichlorophone (metrifonate) against West African forest strain ofOnchocerca volvulus. Annals of Tropical Medicine and Parasitology, 68, 241–242.Google Scholar
Friedheim, E. A. H. (1961) Quelques observations concernent le pentylthiarsaphenyl-melamine (Mel W) dans le traitement des filarioses a O. volvulus et W. bancrofti. Annals de la Société Belge de Médicine Tropicale, 41, 367–373.Google Scholar
Howells, R. E., Mendis, A. M. & Bray, P. G. (1983) The mode of action of suramin on the filarial worm Brugia pahangi, Parasitology, 87, 29–48.Google Scholar
James, E. R., Smith, B. & Donnelly, J. (1986) Invasion of the mouse eye by Onchocerca microfilariae. Tropical Medicine and Parasitology, 37, 359–360.Google Scholar
Jones, B. R., Anderson, J. & Fuglsang, H. (1978) Evaluation of microfilaricidal effects in the cornea from topically applied drugs in ocular onchocerciasis: trials with levamisole and mebendazole. British Journal of Opthalmology, 62, 440–444.CrossRefGoogle Scholar
Kale, O. O. (1982) Further trials of mebendazole and metrifonate in the treatment of onchocerciasis. Bulletin of the World Health Organization, 60, 109–113.Google Scholar
Kozek, W. J. & Figueroa, H. (1982) Attempts to establish O. volvulus infection in primates and small laboratory animals. Acta Tropica, 39, 317–321.Google Scholar
Rivas-Alcala, A. R., Greene, B. M., Taylor, H. R., Domiguez-vazquez, A., Ruvalcaba-macias, A. M., Lugo-PfeiffeR, C., Mackenzie, C. D. & Beltran, F. (1981) Chemotherapy of onchocerciasis: a controlled comparison of mebendazole, levamisole and diethylcarbamazine. Lancet, 5 September, 485–490.Google Scholar
Shandong Institute Of Parasitic Disease And Institute Of Parasitic Disease Of Chinese Academy Of Medical Science. (1982) Therapeutic effect of furapyrimidone on Bancroftian filariasis. Chinese Journal of Internal Medicine, 21, 419–420.Google Scholar
Striebel, H. P. (1986) Filariasis. In: Experimental Models in Antimicrobial Chemotherapy. (editors.Zak, o. & Sande, M.A.), Vol. 3, pp. 281–332. Academic Press, London.Google Scholar
Strote, G. (1987) In vitro study on the effect of the new chemotherapeutic agents CGP 6140 and CGP 20,376 on the microfilariae of Onchocerca volvulus. Tropical Medicine and Parasitology, 38, 211–213.Google Scholar
Suswillo, R. R., Nelson, G. S., Muller, R., Mcgreevy, P. B., Duke, B. O. L. & Denham, D. A. (1977) Attempts to infect jirds (Meriones unguiculatus) with Wuchereria bancrofti, Onchocerca volvulus, Loa loa loa and Mansonella ozzardi. Journal of Helminthology, 51, 132–134.Google Scholar
Townson, S. & Bianco, A. E. (1982) Experimental infection of mice with the microfilariae of Onchocerca lienalis. Parasitology, 85, 283–293.Google Scholar
Townson, S., Bianco, A. E. & Owen, D. (1981) Attempts to infect small laboratory animals with the infective larvae of Onchocerca lienalis. Journal of Helminthology, 55, 247–249.CrossRefGoogle Scholar
Townson, S., Connelly, C., Dobinson, A. & Muller, R. (1987a) Drug activity against Onchocerca gutturosa males in vitro: a model for chemotherapeutic research on onchocerciasis. Journal of Helminthology, 61, 271–281.Google Scholar
Townson, S., Dobinson, A., Connelly, C. & Muller, R. (1987b) Screening antifilarial compounds against Onchocerca lienalis microfilariae in mice. Tropical Medicine and Parasitology, 38, 74.Google Scholar
Who (1979) Report of the Fourth Meeting of the Scientific Working Group on Filariasis. Progress in the Immunology of Filariasis. Published by the World Health Organization TDR/FIL-SWG (4) 79.3.Google Scholar
Who (1985a) Report of the 11th meeting of the scientific working group on filariasis on review of filaricide screening methods and results in relation to synthetic chemistry, biochemistry and toxicology held jointly with the Onchocerciasis Chemotherapy Project. Published by the World Health Organization TDR/FIL-SWG (11) 85.3.Google Scholar
Who (1985b) Origins and progress of the Onchocerciasis Chemotherapy Project (OCT). Publ. by the World Health Organization. OCP/85.3.Google Scholar
Who (1987) Tropical Disease Research: a global partnership. Eighth Programme Report. Filariasis. pp 61–74. Publ. by the World Health Organization, Geneva.Google Scholar
Zahner, H., Sanger, I., Lammler, G. & Muller, H. A. (1987) Effect of ivermectin in Dipetalonema viteae and Litomosoides carinii infections of Mastomys natalensis. Tropical Medicine and Parasitology, 38, 117–122.Google Scholar