In vitro and in vivo prophylactic and curative activity of the triterpene saponin PX-6518 against cutaneous Leishmania species.
OBJECTIVE
The oleanane triterpene saponin PX-6518, with known potent in vitro and in vivo activity against Leishmania donovani, was investigated for its spectrum against the cutaneous species Leishmania mexicana, Leishmania panamensis and Leishmania major.


METHODS
In vitro activity was based on the reduction of amastigotes in primary peritoneal mouse macrophages. BALB/c mice were injected with 2 × 10(6) amastigotes in the base of the tail (L. panamensis and L. major) or the foot (L. mexicana) and subcutaneously treated with PX-6518 [1-10 mg/kg body weight (BW)] or Pentostam(®) (250 mg/kg BW Sb(V) eq). Evolution of skin lesions was monitored in a prophylactic dose-finding study, and early curative [6 weeks post-infection (pi)] and late curative (>8-10 weeks pi) studies.


RESULTS
While moderate susceptibility to PX-6518 was obtained in vitro (IC(50): 1-4 µg/mL), excellent in vivo activity was demonstrated. In the prophylactic study (six administrations on alternate days, starting at 1 day pi), PX-6518 was 100% effective at 1 mg/kg BW against L. mexicana and L. panamensis, whereas L. major lesions could be prevented at 2 mg/kg BW. In the early curative (1 mg/kg BW once a week for 4 weeks) and late curative (1 mg/kg BW twice a week for 4 weeks) studies, PX-6518 completely healed L. mexicana and L. panamensis lesions, whereas L. major lesions were reduced by ∼ 50%.


CONCLUSIONS
This study demonstrates that PX-6518 possesses potent and broad-spectrum prophylactic and curative efficacy against cutaneous leishmaniasis in the BALB/c mouse model. L. major was the least susceptible species tested and parasitological cure could not be obtained.
Laboratory for Microbiology, Parasitology and Hygiene LMPH, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Raquel Andreia
RA
Inocêncio da Luz
Marieke
M
Vermeersch
Maartje
M
Deschacht
Sarah
S
Hendrickx
Tim
T
Van Assche
Paul
P
Cos
Louis
L
Maes
D000818:Animals; D019072:Antibiotic Prophylaxis; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage; D007893:Leishmania donovani / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects; D007894:Leishmania mexicana / Q000187:drug effects; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000517:prevention & control*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
C481665:PX-6518; D012503:Saponins; D014315:Triterpenes; D000967:Antimony Sodium Gluconate