Biochemical changes in cerebrospinal fluid of Chlorocebus aethiops naturally infected with zoonotic Meningonema peruzzii.

BACKGROUND: Thirty-four wild Chlorocebus aethiops monkeys were trapped for research purposes. METHODS: During routine quarantine check-up, cerebrospinal fluid (CSF) and blood were microscopically examined for parasites. Estimations of CSF protein levels were made by the biuret method and the white cell counts by the hemocytometer. RESULTS: Seven monkeys demonstrated microfilariae in blood and CSF. This was accompanied by a two- and ninefold increase in CSF total protein and white cell counts, respectively. Necropsy of one of the blood and CSF microfilariae-positive animals revealed the presence of adult worms in the brain meninges. The parasites were identified as the zoonotic filaroid nematode Meningonema peruzii. CONCLUSIONS: Wild C. aethiops monkeys developed CSF changes resulting, most probably, from infection with M. peruzii. Moreover, the monkeys could be acting as an important reservoir. The study highlights the need for epidemiological and pathogenological studies of this parasite, which is of public health significance. Moreover, C. aethiops proved to be a useful primate model for the study of this zoonotic infection.

The story of CGP 40 215: studies on its efficacy and pharmacokinetics in African green monkey infected with Trypanosoma brucei rhodesiense.

CGP 40 215 is an inhibitor of S-adenosylmethionine decarboxylase, a key enzyme in trypanosomal polyamine biosynthesis. It is highly active against Trypanosoma brucei rhodesiense and T. b. gambiense in vitro and in the corresponding rodent models, and therefore was a promising candidate for further development as a new drug against human African trypanosomiasis. We conducted initial pharmacokinetic and efficacy studies in African green monkeys: based on two dose-finding studies, an infection-treatment and a pharmacokinetic study in eight monkeys infected with T. b. rhodesiense in the 1st stage of infection. PK analysis revealed curative drug levels in the serum but complete absence of the drug in the cerebrospinal fluid. No adverse effects of the drug were observed, although in rats CGP 40 215 had caused hypotension. The following PK parameters were calculated using a two-compartment model: t1/2=1.8 h, VSS/f=0.4 l/kg, CL/f=3.0 ml/min x kg and AUC=21 900 ng x h/ml. Six of the eight monkeys were cured, one animal relapsed on day 222 and one animal died of unknown reasons, but was aparasitaemic. The study confirmed the curative potential of CGP 40 215 for 1st stage T. b. rhodesiense infection. Unfortunately, it was also found that the compound did not pass the blood-brain barrier, a pre-requisite for cure of 2nd stage (CNS) infection. As the majority of sleeping sickness patients seeking treatment are in the 2nd stage of the disease, further development of the compound was stopped.

The role of the polyamine inhibitor eflornithine in the neuropathogenesis of experimental murine African trypanosomiasis.

The treatment of late-stage human African trypanosomiasis is complicated by a post-treatment reactive encephalopathy, also referred to as a 'reactive arsenical encephalopathy', that may be fatal. This study used a well established experimental mouse system to assess the use of the trypanostatic drug, eflornithine, in the management of this post-treatment reaction. Female CD-1 mice infected with an eflornithine-resistant trypanosome stabilate and treated with the trypanocidal compound diminazene aceturate on or after day 21 post-infection develop a reactive encephalopathy and relapsing parasitaemia. If these animals are re-treated with diminazene aceturate, a severe encephalopathy develops histologically comparable with that of human cases and characterized by a severe meningoencephalitis and astrogliosis. Histopathological and immunocytochemical examination shows that administration of eflornithine before or after the development of this reactive encephalopathy prevented or ameliorated the inflammatory reaction. Since an eflornithine resistant stabilate was used, this effect appears to be independent of the drug's trypanostatic action and illustrates an important, previously unrecognized, pharmacological property of eflornithine. Consideration can now be given to the use of eflornithine for the management of human trypanosomiasis cases, even where trypanosome resistance to eflornithine exists.

Trypanosoma brucei rhodesiense: use of an antigen detection enzyme immunoassay for evaluation of response to chemotherapy in infected vervet monkeys (Cercopithecus aethiops).

Thirty eight Trypanosoma brucei rhodesiense-infected vervet monkeys (Cercopithecus aethiops) in the late (meningoencephalitic) stage of disease, treated with various trypanocidal drugs, were monitored for a period of more than 600 days to assess the rate of clearance of trypanosome antigens from serum and cerebrospinal fluid (CSF). There was a complete but gradual reduction in antigen titres, as assessed by ELISA, in animals treated intravenously with melarsoprol, the standard drug for the late stage disease. In 8 of the 9 monkeys treated with melarsoprol, the antigen titres, as assessed by optical density values, dropped by 50% within 252 days (mean value 68 days for antigens in CSF and 116 for serum) following treatment. The remaining animal in this group, that displayed persistent antigenaemia, had been treated with a sub-curative drug dosage level. Thus, if time to 50% reduction in antigen levels were to be taken as an index to predict cure, the follow-up period after melarsoprol treatment could have been reduced from 600 to 252 days for 8 of the 9 animals, leaving only one animal for further follow up. The animals treated with experimental drug combinations displayed a variable picture. Five monkeys showed a persistence of antigens in both serum and CSF throughout the observation period, suggesting failure of the drugs to cure the infection. Parasitologically confirmed relapse of the infection was indeed observed in all the five monkeys. In some monkeys, the parasite antigens eventually cleared from serum and CSF completely, but this took a longer time duration than in the melarsoprol treated animals; others showed persistence of parasite antigens in serum, but the parasites were not detected in blood or CSF throughout the entire follow-up period. These results suggest that the experimental drug combinations used were not effective in clearing the parasites from cryptic foci and hence the persistence of antigens in serum and/or CSF.(ABSTRACT TRUNCATED AT 250 WORDS)