Welcome to the ICOPA 2022 Online Program

Abstract Body

Introduction

With an estimated 0.7 to 1 million new infections a year globally, cutaneous leishmaniasis (CL) is the most prevalent form of leishmaniasis. CL clinically manifests as a variety of skin lesions ranging from closed nodules, to plaques and ulcers. Currently recommended drugs have proved to be clinically unsatisfactory indicating the urgent need for novel safe and efficacious drugs.

Oleylphosphocholine, an alkylphoshoplipid structurally similar to miltefosine, demonstrated potent activity against Leishmania species causing visceral leishmaniasis (VL) both in vitro and in vivo. Given the discrepancies between the target product profiles of VL and CL, we here report the in vitro and in vivo efficacy of orally administered oleylphosphocholine-based formulations (two with a fast-release and two with a slow release profile) against CL-causing Leishmania species.

Materials and methods

The antileishmanial activities of OLPC and miltefosine were evaluated against intracellular amastigotes of six Leishmania species that cause CL (L. major, L. tropica, L. aethiopica, L. mexicana, L. braziliensis, L. panamensis). Following promising results, the in vivo efficacies of both drugs were investigated in two stages. First, the performance of the efficacious dose for OLPC for VL was evaluated using an experimental CL model. Secondly, the antileishmanial activity of various formulations of OLPC with diverse release profiles was investigated, including a dose response profile, using bioluminescent L. major parasites. Tissue concentrations in skin of OLPC were determined using LC-MS/MS.

Results and discussion

The in vitro activities of OLPC against CL-causing species ranged from 0.74 to 31.06 uM and are similar to those obtained for miltefosine. In the experimental CL models, OLPC administered orally at a dose of 35 mg/kg once daily for ten days was able to significantly reduce the lesion size to a similar extend as the positive control (paromomycin sulphate, ip, 50 mg/kg/day – repeated-measures ANOVA, post-hoc Tukey, p < 0.05). In contrast, the administration of miltefosine (same dose and regimen as OLPC) resulted in only a halt of the lesion size progression and was unable to decrease the lesion diameter. The second in vivo study was able to confirm these results and demonstrated a superior activity of the fast- (OLPC with lactose or cellulose carrier) over the slow-release (OLPC absorbed into a diffusion-controlled silica carrier) test formulations as measured by a significantly greater bioluminescence signal (~ parasite load) decrease when compared to the untreated controls.

Extraction of the drugs from the infected skin site 24 hours after the oral administration of 1 dose (35 mg/kg) demonstrated higher concentrations of OLPC versus miltefosine (t-test). This difference was no longer present at the end of the 10-day treatment period even though OLPC blood concentrations at the end of treatment were 2-fold higher than for miltefosine.

Conclusions

OLPC demonstrated potent activity in the intracellular macrophage model using a range of CL-causing species and was able to reduce the parasite load in an experimental L. major CL model after ten days of treatment. In a next step, the drug delivery profile into Leishmania-infected and uninfected mouse skin will be compared using skin microdialysis.

Abstract Body

It is estimated that around 40 million women living in Sub-Saharan Africa (SSA) are affected by female genital schistosomiasis (FGS), a chronic gynaecological disease caused by a waterborne parasite, Schistosoma haematobium (Sh). FGS is associated with infertility, dyspareunia and symptoms mimicking sexually transmitted infections. Awareness of the disease is largely absent in endemic communities despite growing evidence of increased prevalence of HIV and suggestion of increased cervical dysplasia, the precursor of cervical cancer (CC). Conventional FGS diagnosis is challenging, as it relies on costly equipment and high-level specialised training seldom available in resource-limited countries. Accurate estimation of disease burden is therefore hindered. To overcome these diagnostic hurdles, genital self-sampling for the community-based diagnosis of FGS compared to clinician-obtained sampling was piloted in Zambia in 2018 with excellent results (the BILHIV study). Self-sampling strategies had already been validated for the detection of oncogenic human papillomavirus (HPV) genotypes, the etiological agents of CC and HPV point-of-care diagnostic tests are now commercially available but not yet adopted across SSA. Genital self-swabs are well accepted by participants and are known to increase compliance across settings.

The ongoing Zipime Schista Study! In Zambia is a longitudinal cohort study aiming to include multiple-pathogen screening through self-sampling (Sh, HPV) and offering self-testing for HIV and STIs. This strategy is coupled with novel molecular assays that are field deployable and can provide a scalable cost-effective strategy. The study design and preliminary results will be presented.