A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model

Wasan, Ellen K.; Gershkovich, Pavel; Zhao, Jinmin; Zhu, Xiaohua; Werbovetz, Karl A.; Tidwell, Richard R.; Clement, John G.; Thornton, Sheila J.

doi:10.1371/journal.pntd.0000913

Cited by 56 publications

(53 citation statements)

References 7 publications

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“…Ranitidine, topotecan and amprenavir had the lowest predicted LogP (ALOGPS) at 0.79, 1.84, and 1.85, respectively. Amprenavir (72)(73)(74) C) [36] and ranitidine (69-70 C) have low melting points. Topotecan has a melting point of 213-218 C .Based on the above mentioned general rule, topotecan would be better formulated as an amorphous solid dispersion.…”

Section: Solubility Profiles Of Fda Approved Drugs In Lbddsmentioning

confidence: 99%

Review and analysis of FDA approved drugs using lipid-based formulations

Savla

Browne

Plassat³

et al. 2017

Drug Development and Industrial Pharmacy

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180

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Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule. ARTICLE HISTORY

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Section: Solubility Profiles Of Fda Approved Drugs In Lbddsmentioning

confidence: 99%

Review and analysis of FDA approved drugs using lipid-based formulations

Savla

Browne

Plassat³

et al. 2017

Drug Development and Industrial Pharmacy

Self Cite

180

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“…By applying structural clustering and secondary assays to determine potency and selectivity, 70 compounds were identified that possessed 50% effective concentrations (EC 50 s) below 1 M and that did not inhibit the growth of mammalian epithelial cancer cells at this concentration. Given the need for a new small-molecule candidate for the oral treatment of leishmaniasis and our continuing efforts in this area (42)(43)(44), we decided to study selected members from the set of 70 antileishmanial molecules reported by Sharlow et al to determine whether any were candidates for further development as antileishmanial drug candidates. Several of the molecules that we evaluated displayed activity against intracellular Leishmania in vitro, and members of one class showed efficacy in a murine VL model.…”

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confidence: 99%

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Zhu

Pandharkar

Werbovetz

2012

Antimicrob Agents Chemother

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A previous screen of ϳ200,000 compounds from the PubChem database identified 70 compounds possessing 50% effective concentrations (EC 50 s) below 1 M against Leishmania major promastigotes that were not toxic to mammalian epithelial cancer cells at this concentration (E. Combinations of existing antileishmanial drugs have also been studied. Different combinations of treatment with single-dose liposomal amphotericin B followed by short courses of miltefosine were extremely effective, with a single dose of liposomal amphotericin B at 5 mg/kg of body weight followed by a 10-day course of miltefosine resulting in a cure rate of 98% (32). This combination was evaluated together with other combinations consisting of (i) a single dose of 5 mg/kg liposomal amphotericin with a 10-day course of paromomycin and (ii) a 10-day course of both paromomycin and miltefosine, with all of these combinations providing a cure rate of 97% or greater (33). When given in a single 10 mg/kg dose, liposomal amphotericin B was shown to be highly effective against VL, producing a cure rate of 95.7% (30). Single-dose liposomal amphotericin B is proposed to play a central role in a VL elimination program in India, Nepal, and Bangladesh (12).SharlowDespite these improvements in VL treatment on the Indian subcontinent, unmet needs in leishmaniasis chemotherapy still exist. In Africa, only the antimonial drug sodium stibogluconate and liposomal amphotericin B are registered for treating VL. Antimonial compounds, which have been replaced by the drugs listed above for treating VL on the Indian subcontinent due to widespread antimonial resistance (31), have been used for many years against leishmaniasis, and their use is plagued by the long duration of therapy and by the associated side effects (15,18,23,31). Liposomal amphotericin B appears to be less effective against VL in Brazil (1) and in Africa (1, 14, 26) compared to India, and the expense of liposomal amphotericin B also limits its widespread use (9). Paromomycin is inexpensive and is thus a good candidate for VL treatment in African countries, but a 15 mg/kg/day regimen of paramomycin for 21 days was inferior to standard treatment with sodium stibogluconate (20 mg/kg

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“…The formulation, named ICo-010, retained AmpB in simulated gastric and intestinal fluids and exhibited a significant antileishmanial activity in a VL-infected murine model. 75,76 ICo-010, currently being developed by iCo therapeutics, was granted orphan drug status by the FDA, but recent data from the company website do not show any further improvement from preclinical evaluations. 197 A NE loaded with doxorubicin (NE-DOX) was further grafted with phosphatidylserine (PS) to enhance the cellular uptake.…”

Section: Nanoemulsions (Nes) and Niosomesmentioning

confidence: 99%

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

Bruni¹,

Stella²,

Giraudo³

et al. 2017

IJN

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Leishmaniasis is a vector-borne zoonotic disease caused by protozoan parasites of the genus Leishmania , which are responsible for numerous clinical manifestations, such as cutaneous, visceral, and mucocutaneous leishmaniasis, depending on the site of infection for particular species. These complexities threaten 350 million people in 98 countries worldwide. Amastigotes living within macrophage phagolysosomes are the principal target of antileishmanial treatment, but these are not an easy target as drugs must overcome major structural barriers. Furthermore, limitations on current therapy are related to efficacy, toxicity, and cost, as well as the length of treatment, which can increase parasitic resistance. Nanotechnology has emerged as an attractive alternative as conventional drugs delivered by nanosized carriers have improved bioavailability and reduced toxicity, together with other characteristics that help to relieve the burden of this disease. The significance of using colloidal carriers loaded with active agents derives from the physiological uptake route of intravenous administered nanosystems (the phagocyte system). Nanosystems are thus able to promote a high drug concentration in intracellular mononuclear phagocyte system (MPS)-infected cells. Moreover, the versatility of nanometric drug delivery systems for the deliberate transport of a range of molecules plays a pivotal role in the design of therapeutic strategies against leishmaniasis. This review discusses studies on nanocarriers that have greatly contributed to improving the efficacy of antileishmaniasis drugs, presenting a critical review and some suggestions for improving drug delivery.

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A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model

Cited by 56 publications

References 7 publications

Review and analysis of FDA approved drugs using lipid-based formulations

Review and analysis of FDA approved drugs using lipid-based formulations

Identification of New Antileishmanial Leads from Hits Obtained by High-Throughput Screening

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

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