R.A. Neal

Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro

A comparative study showed that 5 laboratory strains of Trypanosoma cruzi could be divided into a non-responsive group (Sonya clone and Colombiana) and a responsive group (Tulahuén, Y and Peru), based on long-term treatment of mouse infections with nifurtimox and benznidazole. In vitro sensitivity of epimastigotes and blood-stream trypomastigotes in macrophage cultures did not distinguish the strains, nor did the rate of development of nifurtimox resistance by epimastigote cultures. 7 novel anti-T. cruzi compounds also behaved similarly with respect to the 2 groups. A small decrease in sensitivity was observed in vitro by non-responsive strains of T. cruzi after re-isolation from treated mice. It is postulated that there could be an immunological component involved in successful treatment of T. cruzi infection.

Anti-leishmanial effect of allopurinol ribonucleoside and the related compounds, allopurinol, thiopurinol, thiopurinol ribonucleoside, and of formycin B, sinefungin and the lepidine WR6026

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil

Following previous studies of verapamil reversal of chloroquine resistance in malaria and multi-drug resistance in cancer cells, the effect of verapamil was investigated on nifurtimox-resistant Trypanosoma cruzi in vitro and antimony-resistant Leishmania donovani in vitro and in vivo. Verapamil alone was not active against either parasite, but in combination with nifurtimox it reversed the drug resistance of T. cruzi and in combination with sodium stibogluconate reversed the drug resistance of L. donovani.

Failure of meglumine antimoniate to cure cutaneous lesions due to Leishmania major in Algeria

On note une resurgence importante de la leishmaniose cutanee en Algerie. Cet article decrit le traitement de 400 enfants âges de 6 a 17 ans. 97 recoivent du meglumine antimoniate a raison de 60 mg/kg/jour par voie intramusculaire pendant 15 jours. 80 recoivent du metronidazole a raison de 1,5 gr par jour pour les enfants âges de 6 a 9 ans, 3 gr par jour pour ceux de plus de 9 ans par voie orale pendant 15 jours. 99 recoivent du cotrimoxazole, 108 sont des sujets controles. Les resultats sont commentes

Antileishmanial activity of the ether phospholipid ilmofosine

The ether phospholipid ilmofosine (BM 41.440) was active in vitro against amastigotes of Leishmania donovani and an antimony-resistant line of L. infantum in mouse peritoneal macrophages with ED50 values of 3.7 microM and 3.5 microM respectively. Ilmofosine was also active against L. donovani in BALB/c mice following oral and subcutaneous dosing, with an ED50 value of 10.5 mg/kg x 5 by the oral route.

Aminosidine ointments for the treatment of experimental cutaneous leishmaniasis.

A 15% aminosidine sulphate (AS)/10% urea/white soft paraffin (WSP) ointment cured all Leishmania major lesions on Balb/C mice following topical application for 10 d. Some relapses were observed 10 weeks after treatment. AS alone in WSP ointment was also highly effective. The ointment containing urea was non-irritant to mice, whereas ointments containing quaternary ammonium compounds were irritant. The 15% AS/10% urea/WSP ointment was not effective in the treatment of L. mexicana or L. panamensis lesions on Balb/C mice, no cure being observed.

Antileishmanial effects of clofazimine and other antimycobacterial agents.

In the search for more effective alternatives to the presently-used antileishmanial drugs, the activity of the major groups of antimycobacterial compounds has been examined, both in vitro and in animal models of infection. In vitro, clofazimine was the most active compound tested, with a mean ED50 of 2.3 mg l-1 against Leishmania mexicana amazonensis, 1.4 mg l-1 against L. donovani and 0.5 mg l-1 against L. major. Other active compounds were the thiosemicarbazone, thiambutosine, and salinazid, a derivative of isoniazid. Isoniazid itself was inactive, and rifampicin only partially active. In vivo, only clofazimine displayed significant activity, and it was most effective against the cutaneous infections. It is concluded that antimycobacterial activity is in general a poor predictor of antileishmanial potency.

Leishmania infecting man and wild animals in Saudi Arabia 8. The influence of prior infection with Leishmania arabica on challenge with L. major in man

A clinical trial is described of an attempt to protect against Leishmania major by prior vaccination with live L. arabica. After a single, previously leishmanin-negative, adult male volunteer was bitten by 8 Phlebotomus papatasi infected with L. arabica, no infected lesions were observed. He remained leishmanin-negative and his lymphocytes reacted weakly to antigens of L. arabica or L. major. Subsequently he and 3 other leishmanin-negative adult male volunteers were vaccinated with cultures containing 4 x 10(6) promastigotes of L. arabica. All remained leishmanin-negative but their lymphocytes showed some response to both L. arabica and L. major antigens. 96 d after vaccination these 4, and another, non-vaccinated, volunteer were challenged with 2 x 10(6) promastigotes of L. major. Active cutaneous, ulcerated lesions developed in all 5 volunteers. The lesions in 3 vaccinated volunteers were associated with marked lymphadenitis and beading, but the lesions started to heal spontaneously within 120-250 d after challenge. The lesion in the fourth vaccinated volunteer was less severe and lymphadenitis was not observed. The lesion in the unvaccinated subject developed more slowly and was smaller, but more chronic, than those in the vaccinated individuals. Marked cross-reactivity in terms of lymphocyte proliferation and interferon-gamma production was observed between L. major and L. arabica in both directions in subjects exposed first to one or the other organism. Although the procedure followed in this trial failed to give protection against L. major, further studies in volunteers should be considered.

The activity of nitrofurazone and furazolidone against Leishmania donovani, L. major and L. enriettii in vitro and in vivo.

Furazolidone and nitrofurazone showed in vitro activity against amastigotes of Leishmania donovani, L. enriettii and L. major in macrophages, at concentrations which were also toxic to the macrophages. A low grade of activity was observed against L. donovani infections in BALB/c mice by furazolidone but not with nitrofurazone. Nitrofurazone, in two concentrations, was not active when applied to the lesions of cutaneous leishmaniasis due to L. enriettii (guinea-pig infection) or L. major strain P (BALB/c mouse infection). After systemic administration to BALB/c mice infected with L. major strain JISH 252 clone 1, low-grade activity was observed at the highest level tested.

Leishmania infecting man and wild animals in Saudi Arabia 7. Partial protection of mice against Leishmania major by prior infection with L. arabica

A survey of inbred mouse strains showed that strain C3H/he was the most comparable to man in respect of its susceptibility to Leishmania major and the subsequent healing of lesions produced by this organism. L. arabica proved to have a lower virulence than L. major and prior inoculation with the former resulted in a decrease of the lesion sizes following subsequent L. major challenge. Moreover, L. major lesions that did develop in mice previously inoculated with L. arabica generally healed faster.