Efficacy and tolerability of oleylphosphocholine (OlPC) in a laboratory model of visceral leishmaniasis

Abstract

Objectives: The alkylphospholipid oleylphosphocholine (OlPC) is a structural analogue of miltefosine and may represent a potential therapeutic backup for the treatment of visceral leishmaniasis (VL). This laboratory study compared the in vitro and in vivo activity profile of both OlPC and miltefosine. Methods:The in vitro potency of OlPC was compared with that of miltefosine, amphotericin B, paromomycin and pentavalent antimony (Sb V ) using the intracellular amastigote assay on different Old World and New World Leishmania species. The in vivo efficacy was dose titrated in the Leishmania infantum hamster model after infection with 2×10 7 amastigotes (day 0) and oral treatment at day 21 using an aqueous (OlPC/H 2 O) and liposomal formulation of OlPC in single and repeated (5 day) oral dosing regimens. The amastigote reductions in the liver, spleen and bone marrow were assessed (day 35).Results: The in vitro activity of OlPC against Leishmania donovani, L. infantum, Leishmania tropica, Leishmania mexicana and Leishmania panamensis showed mean IC 50 values ,5 mM, while the IC 50 values for Leishmania major and Leishmania braziliensis were 7.7 and 13.5 mM, respectively. These results are fairly similar to those obtained for miltefosine. In the hamster model, treatment with 20 and 40 mg/kg for 5 days proved that both OlPC formulations were equipotent and showed a markedly higher efficacy compared with miltefosine. A single dosing of 100 mg/kg of OlPC/H 2 O or OlPC liposomes reduced the parasite burdens by 96. 2% and 99.3% in liver, 99.8% and 99.9% in spleen, and 87.6% and 96.9% in bone marrow, respectively. No signs of toxicity or adverse drug-related effects were noted.Conclusions: These data suggest that OlPC may become a promising candidate to improve and simplify current case management of VL. Additional pharmacological and pharmacokinetic studies are ongoing to assess the full potential of OlPC as a 'drug candidate'.

In Vivo Selection of Paromomycin and Miltefosine Resistance in Leishmania donovani and L. infantum in a Syrian Hamster Model

“…For MIL, in vitro selection on intracellular amastigotes failed to induce a susceptibility shift in most L. donovani and L. infantum isolates (4). Previous experiments already indicated that treatment relapses can be evoked in the Syrian golden hamster, which provides an ideal tool to validate our in vitro selection results in vivo, hereby more closely mimicking the actual field situation (10). Since the Syrian hamster model also has fairly good predictive value for human VL, it was logically selected for our drug resistance selection design in vivo (21,22).…”

“…To validate these unexpected in vitro findings and in an alternative attempt to obtain MIL-resistant strains, the present study in hamsters established a resistance selection process on in vivo amastigotes. This model was chosen based on the previous observations that Syrian golden hamsters do not fully clear Leishmania infection after MIL treatment at 40 mg/kg of body weight orally for 5 days (10) and that intraperitoneal PMM treatment at 150 mg/kg for 5 days only resulted in 80% reduction of amastigote burdens (S. Hendrickx, unpublished data); this is in contrast to the study performed by Sane et al (11). Since these two treatment regimens resulted in incomplete parasite clearance, this treatment approach was exploited in the present study to monitor relapse and recurrence of disease in treated animals and assess the effect of successive treatment cycles on drug susceptibility, thereby fully mimicking clinical drug use in the patient.…”

Direct Comparison of the Efficacy and Safety of Oral Treatments with Oleylphosphocholine (OlPC) and Miltefosine in a Mouse Model of L. major Cutaneous Leishmaniasis

“…Based on data accumulated so far in two independent rodent models of leishmaniasis, namely L. infantum visceral infection in Golden hamsters [9] and L. major cutaneous infection here in BALB/c mice, OlPC has greater in vivo efficacy and superior safety profile compared to miltefosine when compared at equivalent dose regimen. In addition, although no direct comparison with miltefosine was performed, the clinical efficacy of OlPC against L. infantum canine leishmaniasis (CanL) was also demonstrated in naturally infected dogs using a 14-day regimen of 4 mg/kg/day [16], a daily dose exceeding the maximum tolerated dose of miltefosine in that species (recommended miltefosine regimen in dogs: 2 mg/kg for 28 days).…”

“…While OlPC and miltefosine demonstrate comparable activity in vitro , OlPC revealed to be of higher efficacy in vivo when tested in a predictive hamster model of visceral leishmaniasis [9]. This study evaluates the value of OlPC for the treatment of Old World CL (OWCL) by testing it in laboratory models of L. major infected-mice.…”

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

“…was similar to the profile of MF, with IC 50 values in the low micromolar range, except for L. major and L. braziliensis. 165 When tested on a VL hamster model with L. infantum, OlPC was found to be more potent than MF after multiple or single oral dosing. Furthermore, short oral treatment with OlPC improves clinical signs of canine L. infantum leishmaniasis.…”