Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis

A series of compounds containing 2-substituted imidazoles has been synthesized from imidazole and tested for its biological activity against human African trypanosomiasis (HAT). The 2-substituted 5-nitroimidazoles such as fexinidazole (7a) and 1-[4-(1-methyl-5-nitro-1H-imidazol-2-ylmethoxy)-pyridin-2-yl-piperazine (9e) exhibited potent activity against T. brucei in vitro with low cytotoxicity and good solubility. The presence of the NO₂ group at the 5-position of the imidazole ring in 2-substituted imidazoles is the crucial factor to inhibit T. brucei.     

Spatial distribution of Culicoides species in Portugal in relation to the transmission of African horse sickness and bluetongue viruses

Surveillance of Culicoides (Diptera: Ceratopogonidae) biting midge vectors was carried out at 87 sites within a 50 x 50 km grid distributed across Portugal, using light trap collections at the time of peak midge abundance. Culicoides imicola (Kieffer) made up 66% of the 55 937 Culicoides in these summer collections. It was highly abundant in the central eastern portion of Portugal, between 37 degrees 5' N and 41 degrees 5' N, and in a band across to the Lisbon peninsula (at around 38 degrees 5' N). Of all the complexes, its distribution was most consistent with that of previous outbreaks of Culicoides-borne disease, suggesting that it may remain the major vector in Portugal. Its distribution was also broadly consistent with that predicted by a recent climate-driven model validating the use of remote sensing datasets for modelling of Culicoides distribution. Adult C. imicola were found to have overwintered at 12 of 20 sites re-surveyed in winter but it did so in very low numbers. Culicoides obsoletus (Meigen) and Culicoides pulicaris (Linnaeus) complex midges were widespread despite their low summer abundance. The observed coincidence of high abundances of C. imicola and high abundances of C. pulicaris in summer lead us to suggest that C. imicola could bring African horse sickness virus or bluetongue virus into contact with C. pulicaris and the latter complex, together with C. obsoletus, could then transmit these viruses across much wider areas of Europe. The fact that adult C. pulicaris are present in high abundances in winter may provide a mechanism by which these viruses can overwinter in these areas.     

Use of sleeping trees by black and white Colobus monkeys (Colobus guereza) in the Kakamega Forest,Kenya

Groups of black and white colobus monkeys, or guerezas (Colobus guereza), observed in the Kakamega Forest, Kenya, had weak fidelity for sleeping sites. Groups often slept in trees near commonly used food sources, which might reduce the time and energetic costs of travel. Although the home range of each group overlapped with four to seven others, groups seemed to avoid sleeping near other groups, which would give them immediate and exclusive access to nearby food sources in the morning. The number of times a species of tree was slept in was positively correlated with its density. This may have occurred because so many suitable sites were available that proximity to feeding trees could be obtained whether or not groups slept in the feeding trees. Groups slept in tall trees, which provide stable sleeping sites and which may provide protection from both aerial and ground predators. Groups were more tightly clustered on nights with greater visibility, which might reduce the risk of predation. Am. J. Primatol. 45:281–290, 1998. © 1998 Wiley-Liss, Inc.     

Common use of sleeping sites by two primate species in Tana River, Kenya

Choice of sleeping sites by two species of primates sharing two adjacent patches of gallery forest in Tana River, Kenya, was studied between August 1992 and February 1993. One group each of the Tana crested mangabey, Cercocebus galeritus galeritus Peters, and yellow baboon, Papio cynocephalus cynocephalus L., interchangeably shared nine sleeping sites distributed among four tree species, Acacia robusta Burch., Ficus sycomorus L., Abizzia gummifera (J. F. Gmel.) E. A. Sm. and Pachystela msolo (Engl.) Engl. The trees used by both species as sleeping sites were mainly tall trees with canopy level or emergent crowns. The trees had relatively larger crowns and lower percentage canopy cover compared to other trees at the site and were characterized by poor to moderate accessibility. Overlap in use of sleeping sites was never simultaneous and baboons occasionally supplanted mangabeys. Site choice by these two primates appeared to be influenced by predation risk, the feeding area used in the late afternoon, daily range and the availability of trees with the preferred structural characteristics. Sleeping sites appeared to be limited during and immediately after the wet season, when the frequency of supplantings increased. This observation is attributed to an increase in percentage canopy cover.     

IL-10 is up regulated in early and transitional stages in vervet monkeys experimentally infected with Trypanosoma brucei rhodesiense

IL-10 has been suggested as a possible parameter for human African trypanosomiasis stage determination. However, conclusive experimental studies have not been carried out to evaluate this, which is a prerequisite before a potential test can be validated in humans for diagnostic purposes. We used the vervet monkey model of trypanosomiasis to scrutinize IL-10 in blood and cerebrospinal fluid (CSF). Five adult males were experimentally infected with T. b. rhodesiense. The infected animals became anemic and exhibited weight loss. Parasitemia was patent after 3 days and fluctuated around 3.7 × 10⁷ trypanosomes/ml throughout the experimental period. The total CSF white cell counts increased from pre-infection means around 3 cells/μl to a peak of 30 cells/μl, 42 days post-infection (DPI). IL-10 was not detectable (< 2 pg/ml) in serum prior to infection. IL-10 serum concentrations increased to 273 pg/ml 10 DPI coinciding with the first peak of parasitemia. Thereafter the levels declined to a mean value of 77 pg/ml 34 DPI followed by a significant rise to a second peak of 304 pg/ml (p < 0.008) 42 DPI. There was no detectable IL-10 in CSF. IL-10 synthesis is thus stimulated both in the early and transitional stages of experimental trypanosomiasis. That IL-10 is produced in early stage disease is an interesting finding unlikely to be detected in humans where it is difficult to determine the exact time of infection. The IL-10 peak observed on day 42 of infection might indicate onset of parasite neuroinvasion coinciding with a peak in white blood cell counts in the blood and CSF.     

Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro

The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC₅₀ 5?nM), is not cytotoxic (HeLa CC₅₀?>?25,000?nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC₅₀ 8120?nM, P. falciparum EC₅₀ 3624?nM).