Assessment of tegumental damage to Schistosoma mansoni and S. haematobium after in vitro exposure to ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy

Buchter, Valentin; Hess, Jeannine; Gasser, Gilles; Keiser, Jennifer

doi:10.1186/s13071-018-3132-x

Cited by 18 publications

(20 citation statements)

References 20 publications

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“…For both prodigiosin and obatoclax, worm motility was not restored even after 72 hours recovery, contrasting significantly with results seen after praziquantel treatment where juvenile worms were found to have significantly better recovery after drug treatment than adult worms [48,49]. Imaging of prodigiosin and obatoclax treated worms revealed that both drugs resulted in significant damage to the tegument, with numerous areas of blebbing and separation from the worm body (Fig 3), a phenotype previously seen in with other anti-schistosomal drugs, and associated with increased ion flow across the tegument, exposure to host immune system, and eventual loss of viability [50,51].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 76%

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Ehrenkaufer

Stebbins

et al. 2020

PLoS Negl Trop Dis

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Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the PLOS NEGLECTED TROPICAL DISEASES

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Section: Plos Neglected Tropical Diseasesmentioning

confidence: 76%

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Ehrenkaufer

Stebbins

et al. 2020

PLoS Negl Trop Dis

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“…This background inflammation is seen near veins and sinusoids, probably because of abundance of Schistosoma antigens following the treatment. The burst of antigens is a known phenomenon that may occur after treatment of schistosomiasis with anti-schistosomal drugs [37,38] or, similarly, filariasis treated with diethylcarbamazine [39]. In the placebo-treated mice there was a huge granulomatous inflammatory response that eventually led to mouse mortality (data not shown).…”

Section: Discussionmentioning

confidence: 98%

Oral Administration of Artemisone for the Treatment of Schistosomiasis: Formulation Challenges and In Vivo Efficacy

et al. 2020

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Artemisone is an innovative artemisinin derivative with applications in the treatment of malaria, schistosomiasis and other diseases. However, its low aqueous solubility and tendency to degrade after solubilisation limits the translation of this drug into clinical practice. We developed a self-microemulsifying drug delivery system (SMEDDS), which is easy to produce (simple mixing) with a high drug load. In addition to known pharmaceutical excipients (Capmul MCM, Kolliphor HS15, propylene glycol), we identified Polysorb ID 46 as a beneficial new additional excipient. The physicochemical properties were characterized by dynamic light scattering, conductivity measurements, rheology and electron microscopy. High storage stability, even at 30 °C, was achieved. The orally administrated artemisone SMEDDS formulation was highly active in vivo in S. mansoni infected mice. Thorough elimination of the adult worms, their eggs and prevention of the deleterious granuloma formation in the livers of infected mice was observed even at a relatively low dose of the drug. The new formulation has a high potential to accelerate the clinical use of artemisone in schistosomiasis and malaria.

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“…For comparison, by the same incubation time, juvenile S. mansoni incubated with 100 μM OXA and the control group showed no difference in the viability, confirming previous studies of OXA being only slightly active in vitro and against juvenile stages of the parasite. 9,24 Only by 72 h of incubation, where the derivatives had long exerted their activity, we found a 38% reduction of the viability of OXA respect to the control worms.…”

Section: Resultsmentioning

confidence: 65%

“…In vitro studies Fc-CH 2 -OXA, Rc-CH 2 -OXA and Ph-CH 2 -OXA previously demonstrated promising activity as drug candidates in vitro against adult S. mansoni and S. haematobium and first stage of the larval development (NTS: newly transformed schistosomula) and in vivo in adult S. mansoni infected mice. 22,24 In order to test the full potential of our compounds, we first elucidated the in vitro activity of the OXA derivatives against 28-day-old juvenile S. mansoni worms since one of the important drawbacks of PZQ is its missing activity against this developmental stage. All three compounds killed all the worms within 24 h of incubation at a concentration of 100 μM (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis

Buchter¹,

Ong²,

Mouvet³

et al. 2020

Preprint

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<div>Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its </div><div>strengths and weaknesses, is the only treatment available. We previously reported 3 lead </div><div>compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene‐containing </div><div>(Fc‐CH2‐OXA), ruthenocene‐containing (Rc‐CH2‐OXA) and benzene‐containing (Ph‐CH2‐OXA). </div><div>These derivatives showed excellent in vitro activity against both Schistosoma mansoni and S. </div><div>haematobium larvae and adult worms, and in vivo against S. mansoni. Encouraged by these </div><div>promising results, we followed a guided drug discovery process and report in this investigation on </div><div>metabolic stability studies, in vivo studies, computational simulations, and formulation studies. </div><div>Molecular dynamics simulations supported the in vitro results on the target protein. Though all </div><div>three compounds were poorly stable within an acidic environment, they were only slightly cleared </div><div>in the in vitro liver model. This is likely the reason as to why the promising in vitro activity did not </div><div>translate to in vivo activity. This limitation could not be saved by the formulation of lipid </div><div>nanocapsules as an intent to improve the in vivo activity. Further studies should focus on increasing </div><div>the compound’s bioavailability, in order to reach an active concentration in the parasite’s </div><div>microenvironment. </div>

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Assessment of tegumental damage to Schistosoma mansoni and S. haematobium after in vitro exposure to ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy

Cited by 18 publications

References 20 publications

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Oral Administration of Artemisone for the Treatment of Schistosomiasis: Formulation Challenges and In Vivo Efficacy

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis

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