Efficacy,Safety, and Dose of Pafuramidine,a New Oral Drug for Treatment of First Stage Sleeping Sickness,in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies

Background

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.

Methods

The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.

Findings/Conclusion

Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.     

A framework for predicting and visualizing the East African wildebeest migration-route patterns in variable climatic conditions using geographic information system and remote sensing

In the Serengeti–Mara ecosystem of East Africa, the migrating wildebeests (Connochaetes taurinus) response to food resource distribution and terrain complexity impacts their movement characteristics. This manifests in varying ways such as movement speed, direction, turning frequency, and moving distance. To investigate these characteristics, indices derived from vegetation quantity (normalized difference vegetation index, NDVI) and relief (slope) were used in our previous work to quantify the relationships between migration route location versus vegetation, relief complexity, and their combination. Least cost pathways determined using these indices were representative of approximate migration routes. The simulated routes were shown to be strongly influenced by vegetation during the dry season. However the impact of climatic change (rainfall) on route location was not investigated though known to influence vegetation recovery patterns. This paper specifically addresses the impact of climatic change on route location. The mean monthly rainfall data were used to classify the rainy and dry seasons in the Serengeti, the Western, and the Mara areas as normal, drier, or wetter than normal, over the 1986–1997 period. The classification is based on the mean monthly rainfall variability about the 11-year seasonal mean. Regression analysis showed strong linear relationships between rainfall and mean NDVI for each one of the three areas. The subsequent seasonal classification based on the corresponding habitat vegetation characteristics (NDVI) revealed the relative variation of vegetation with rainfall. Using the derived general categories, migration routes are then predicted for the various categories using a route attractivity index. The seasonal migration routes were shown to change depending on the relative abundance of the rainfall during the dry season. Dry season migration routes tended toward areas with better vegetation activity, i.e., those characterized by higher NDVI gradients. Our results showed that during the western trek, wetter dry seasons have the effect of delaying the herds movement northwestward. During the northern trek, wetter dry seasons have the effect of delaying the tendency to move westward. However the variation in rainfall conditions during the rainy and dry season had no significant influence on the southern trek route location. We assume that predicted routes based on average general category conditions for different years are representative of main migration route patterns for similar seasons, therefore they are well suited for approximate route prediction, if the climatic characteristics of the year are known.     

Effect of the intensity of host parasitemia on the vectorial competence of Glossina morsitans Westwood, 1850 (Mall) infected by Trypanosoma (Nannonmonas) congolense IL 1180

Two groups of teneral flies (aged less than 32 hours) of Glossina morsitans morsitans (Mall) were fed separately on two rats that had been infected with Trypanosoma (Nannomonas) congolense IL 1180, among which one had a low parasitaemia (antilog 5.4-5.7) and the other a high parasitaemia (antilog 7.8-8.1). Following to the two modes of parasitaemia, variations of the procyclic indexes were found between males and females. When both sexes were considered, it was found that the intestinal infection rate was relatively higher in the flies that were fed on the rat with a low parasitaemia than in those fed on the rat with a high parasitaemia. Although no significant differences in metacyclic indexes were observed between sexes, the mature infection rate was most pronounced in the flies that were fed on the rat with high parasitaemia. When both sexes were considered, the vectorial competence (VC) reached 0.5532 and 0.5521 in the flies that had been fed on the rats with low and high parasitaemia, respectively. The VC of the two modes of infectious feeding was not significantly different. However, when considering the parasitaemia of antilog 5.4-5.7, the VC was relatively more important in the females than in the males. No significant difference in VC was detected between sexes when considering the antilog 7.8-8.1 parasitaemia. It was found that there is discrepancy in the way the metacyclic infection and the VC evolve in relation to the procyclic infection, suggesting that the intensity of the parasitaemia only influences the intestinal stage.     

Simulating the East African wildebeest migration patterns using GIS and remote sensing

The Serengeti–Mara ecosystem in East Africa is a spectacular natural heritage endowed with diverse fauna and flora. The presence of the seasonally migrating wildebeest (Connochaetes taurinus) is a major boost for tourism. This migration however has enormous impacts to the ecosystem. Consequently efforts at monitoring the herd's migration trends and patterns remain a challenge to wildlife managers and ecologists in the region. In this paper, the relative influence of vegetation (normalized difference vegetation index), landscape and relief on herds migration routes are investigated and the migration routes simulated using GIS and remote sensing techniques. The results are compared with the annual mean route taken by the herds, as determined by radio tracking over the 1995–1997 period. Green vegetation availability is shown to be the major criterion in route choice. It is also shown that during the dry season phases of the migration (western trek, western corridor), the herd endures complex relief (complexity quantified based on slope and inter‐visibility) in the search for greener grass. During the season of abundance (southern trek), relief becomes critical in making route choices, with herds avoiding difficult terrain, notwithstanding their relatively more abundant vegetation. The method proposed in this paper is viable for rapid prediction of approximate routes for the migrating wildebeest in different climatic conditions.