Search for Macro-filaricidal drugs

Ivermectin mass-treatment of villages along the Vina valley in Northern Cameroon:

In 1987, we proposed to WHO to carry out the first mass-treatment by ivermectin in the hyperendemic villages along the river Vina du Nord. This was to be the first ivermectin trial outside the OCP-vector-controlled areas in West-Africa. No major  intervention by vector-control or chemotherapy had yet been carried out in this river valley, but entomological data on the intensity of onchocerciasis transmission had been collected in 1974 by Brian Duke and his team from Kumba (Duke, Anderson & Fuglsang 1975) and by Alfons Renz and his team from 1976 to 1978 and again from 1985 to today (see Publications and Entomology-Results). This river valley was therefore most suited to study the effects of eliminating the microfilariae reservoir  in the village populations by ivermectin mass-treatments on the intensity of O. volvulus L3 transmission. In particular, the question was – and is still – whether annual treatment at the standard dose is sufficient to eliminate the arasite from the human reservoir:

Figure from Seidenfaden et al. 2002, design A. Renz

Ivermectin treatments started 1987 (distributed by a medical team from Centre Pasteur, Yaoundé, headed by Dr. Jacques Prodhon), and gradually reached all villages along the river Vina du Nord from the Adamaoua mountains to the border to Tchad. Mectizan was and is still given today at an annual regime to the local village populations (ca. 70% treatment coverage). This treatment very successfully reduced onchocerciasis endemicity, but it could not eliminate the parasite reservoir in former hyperendemic villages, so that transmission still continues at a level, high enough to maintain endemicity:

photo Renz, data Seidenfaden et al. 2001

Today (2011), after over 20 years after the start of the treatment, infective larvae of O. volvulus are still present in man-biting Simulium damnosum s.l. flies and transmission still continues:

In conclusion, ivermectin mass-treatments have efficiently cleared the human population from the skin-dwelling microfilariae and have strongly reduced the intensity of onchocerciasis. There is little risk of eye-lesions in the thus exposed populations, but as long, as the parasite has not finaly been eliminated, there is a risk of recrudescence of the disease, as soon as resistance to ivermectin shall develop.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Search for antifilarial treatment and new drugs in the bovine Onchocerca ochengi model (1992-2002)

Starting in 1987, Goetz Wahl investigated the prevalence and epizootiology of bovine onchocercosis (Wahl et al. 1994). In collaboration with collegues from Liverpool (Prof. Sandy Trees) and IRAD Wakwa (Drs. Daniel Achukwi, Mbah and Vincent Tanya) we started 1991 developing the bovine O. ochengi model as a screen for testing new filaricidal drugs (‘Macrofil‘). These new compounds came out from the WHO/TDR effords to find new macrofilaricidal drugs (Renz et al. 1995).

The bovine O. ochengi model (photographies and design A. Renz)

 

Literature:

Renz et al. 1995, Trees et al., 2000.

To start and to evaluate this new model in comparison to O. volvulus in man, we tested a number of old-known drugs (Suramin, Ivermectin, Mel-Cy) and new compounds, that were given to us by WHO/OCT. Whilst we could confirm the filaricide action of the known adulticides, none of the new compounds proved to be of any advantage. However, interesting results come from new avermectin compounds, in particular when given at a higher and more frequent therapy schedule:

• the prophylactic action of monthly doses of  ivermectines (Tchakoute et al. 1999),
• the prolonged sterilisation of adult female worms by repeated high doses of avermectins (Bronsvoort et al. 2005),

The most important finding, however, was based on a very unexpected observation, by Alfons Renz, that high doses of tetracycline apparently had killed adult Onchocerca worms (reported to WHO/OCT by A. Renz in 1996). He then developed the idea that this might be due to the bactericide action of tetracyclince:  This antibiotic is well known to act against intracellular bacteria (Rickettsiales). And Onchocerca worms were known to harbour  intracellular Rickettsia-like bacteria (Kozek & Figueroa, 1977).  In combination, this lead him to the hypothesis, that these endobacteria must be in fact endosymbionts and that their killing would cause the death of the worm host. This hypothesis was tested in a controlled experiment with 6 cattle in 1997 and again showed that Wolbachia-endosymbionts area valid targets for antifilarial treatment  (Langworthy et al. 2000).

 

At that time this idea – very revolutionary at this time – did not interest many people, when Alfons Renz promoted it first: No reaction from WHO, and our veterinarian colleague from the Liverpool School of Tropical Medicine even argued “if this really worked, than we would have known this since longtime, because tetracycline is in use since may years”. Nevertheless, together with the project veterinarian Dr. Mark Bronsvoort, we decided to repeat the trial and added 6 oxytetracycline-treated cattle in the next trial round, aimed to test Moxidectin (1997). Again, all worms died (Langworthy et al. 2000). At the same time, Prof. Dieter Büttner and Dr. Achim Hoerauf from the Bernhard Nocht Institute in Hamburg, who had learned from our success with tetracycline during a filariasis meeting in Woods Hole, repeated the experiment with a rodent filaria, Litomosoides sigmodontis. Again, these filarial worms, which also harbour endobacteria, were killed by tetracycline treatment. Now, it became clear, these these ‘Rickettsia-like-bacteria’ (since known to be Wolbachia species) must be truely endosymbiotic partners of the filaria, which cannot survive without them

Tetracycline kills Onchocerca worms ! (1996)

 

 

 

 

 

 

This is the Since this discovery in 1996, a wealth of publications and most interesting new findings have come out with view to the chemotherapy, pathology and molecular biology of Wolbachia symbionts. But one should never forget, that at the beginning, it was a just an unexpected and very disturbing observation from a ‘misbehaving’ animal in an untreated control group.  In most cases, one would just have forgotten about this “strange observation”.original slide (photo A. Renz) of those remaining dead ‘nodules’ in the tetracycline-treated cow no. 17. The nodules were removed post-mortem by Mark Bronsvoort and A. Renz in Ngaoundéré in January 1996 and were examined at the Institute of Pathology  in Tübingen (Thanks to Prof. Kaiserling, whose technical assistant did the histology).

It is also worth while reporting, why this particular cattle was treated with such high doses of tetracycline for so long: From a purely economic point of view, the costs of treatments largely exceeded the value of the cattle, and is was just one of the six control cows.  So no particular reason why this animal should be saved. But is was a matter of honor for the Irish vet to prove, that modern medicine is superior to traditional traetment: As it is seen on the figure above, the inguinal region of this animal was severely affected by dermatophilosis, caused by the bacterium Dermatophilus congolensis. The belly was just one open sore.  We just had finished palpating the animal for its Onchocerca nodules (you can see a shaved region, where we looked for a tattooed nodule). But instead of releasing the cow, the herdsman Abbo (our oldest and most experienced!) put his hand behind the cow and started smearing fresh cattle feces on the open wounds: This is our traditional was of treating this disease. Very shocked, Mark Bronsvoort interrupted him, saying: We now have much better and more efficient modern drug. So Abbo stopped, saying not a single word, but having a long look on Mark.  This was reason enough for the latter to put all modern veterinary art into the treatment of this animal. To make a long story short, it did not succeed, and cow no 17 had to be euthanized because of this incurable infection.

 

 

 

 

 

 

 

 

More on Dermatophilus in Cameroon and filarial co-infections see  Diplomarbeit Konstanze Lay.

Sources: onchocerciasis:  WHO; bovine model and transmission A. Renz; illustrations by Alfons Renz