Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections
Abstract
:1. Introduction
2. Amphotericin B and Formulations in Clinical Use
3. Marketed Formulations of AmpB
4. Novel AmpB Parenteral Formulations in Development
4.1. Macrophage-Targeted Formulations
4.2. Nanotechnology Applications
5. Oral AmpB Formulations
5.1. Self-Emulsifying Drug Delivery Systems (SEDDS)
5.2. Self-Nanoemulsifying Drug Delivery Systems (SNEDDS)
5.3. Cochleate Formulations
5.4. Solid Lipid Nanoparticles
5.5. Polymer-Based Formulations
5.6. Pro-Drug Approach
6. Veterinary Applications of Amphotericin B
Amphotericin B in Treatment of Canine Leishmaniasis
7. Future Perspectives and Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Centers for Disease Control and Prevention Parasites-Leishmaniasis (Biology). Available online: https://www.cdc.gov/parasites/leishmaniasis/biology (accessed on 18 October 2022).
- World Health Organization. Visceral Leishmaniasis Elimination: India Gears-Up to Overcome Last-Mile Challenges. Online source: World Health Organization, Health Topics, Kala-Azar. Available online: https://www.who.int/news/item/29-07-2021-visceral-leishmaniasis-elimination-india-gears-up-to-overcome-last-mile-challenges (accessed on 18 October 2022).
- Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2015 (GBD 2015) Life Expectancy, All-Cause and Cause-Specific Mortality 1980-2015. Lancet 2016, 388, 1459–1544. [Google Scholar] [CrossRef] [Green Version]
- Okwor, I.; Uzonna, J. Social and Economic Burden of Human Leishmaniasis. Am. J. Trop. Med. Hyg. 2016, 94, 489–493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumari, S.; Kumar, V.; Tiwari, R.K.; Ravidas, V.; Pandey, K.; Kumar, A. Amphotericin B: A Drug of Choice for Visceral Leishmaniasis. Acta Trop. 2022, 235, 106661. [Google Scholar] [CrossRef]
- Sasidharan, S.; Saudagar, P. Leishmaniasis: Where Are We and Where Are We Heading? Parasitol. Res. 2021, 120, 1541–1554. [Google Scholar] [CrossRef]
- Kuhn, M.; Letunic, I.; Jensen, L.J.; Bork, P. The SIDER Database of Drugs and Side Effects. Nucleic Acids Res. 2016, 44, D1075–D1079. [Google Scholar] [CrossRef] [PubMed]
- Carolus, H.; Pierson, S.; Lagrou, K.; Van Dijck, P. Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance. J. Fungi 2020, 6, 321. [Google Scholar] [CrossRef]
- Wishart, D.S.; Feunang, Y.D.; Guo, A.C.; Lo, E.J.; Marcu, A.; Grant, J.R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; et al. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46, D1074–D1082. [Google Scholar] [CrossRef]
- Merck. The Merck Index-An Encyclopedia of Chemicals, Drugs and Biologicals, 13th ed.; O’Neil, M.J., Ed.; Merck: Whitehouse Station, NJ, USA, 2001. [Google Scholar]
- Thakur, C.P.; Singh, R.K.; Hassan, S.M.; Kumar, R.; Narain, S.; Kumar, A. Amphotericin B Deoxycholate Treatment of Visceral Leishmaniasis with Newer Modes of Administration and Precautions: A Study of 938 Cases. Trans. R. Soc. Trop. Med. Hyg. 1999, 93, 319–323. [Google Scholar] [CrossRef]
- Stevens, D.A. Overview of Amphotericin B Colloidal Dispersion (Amphocil). J. Infect. 1994, 28, 45–49. [Google Scholar] [CrossRef]
- Guo, L.S. Amphotericin B Colloidal Dispersion: An Improved Antifungal Therapy. Adv. Drug Deliv. Rev. 2001, 47, 149–163. [Google Scholar] [CrossRef]
- Adler-Moore, J.; Proffitt, R.T. AmBisome: Liposomal Formulation, Structure, Mechanism of Action and Pre-Clinical Experience. J. Antimicrob. Chemother. 2002, 49 (Suppl. 1), 21–30. [Google Scholar] [CrossRef] [PubMed]
- Bern, C.; Adler-Moore, J.; Berenguer, J.; Boelaert, M.; den Boer, M.; Davidson, R.N.; Figueras, C.; Gradoni, L.; Kafetzis, D.A.; Ritmeijer, K.; et al. Liposomal Amphotericin B for the Treatment of Visceral Leishmaniasis. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2006, 43, 917–924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thornton, S.J.; Wasan, K.M.; Piecuch, A.; Lynd, L.L.D.; Wasan, E.K. Barriers to Treatment for Visceral Leishmaniasis in Hyperendemic Areas: India, Bangladesh, Nepal, Brazil and Sudan. Drug Dev. Ind. Pharm. 2010, 36, 1312–1319. [Google Scholar] [CrossRef] [PubMed]
- Wasan, K.M. Development of an Oral Amphotericin B Formulation as an Alternative Approach to Parenteral Amphotericin B Administration in the Treatment of Blood-Borne Fungal Infections. Curr. Pharm. Des. 2020, 26, 1521–1523. [Google Scholar] [CrossRef]
- Cuddihy, G.; Wasan, E.; Di, Y.; Wasan, K. The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? Pharmaceutics 2019, 11, 99. [Google Scholar] [CrossRef] [Green Version]
- Kleinberg, M. What Is the Current and Future Status of Conventional Amphotericin B? Int. J. Antimicrob. Agents 2006, 27S, S12–S16. [Google Scholar] [CrossRef]
- Sachs-Barrable, K.; Lee, S.D.; Wasan, E.K.; Thornton, S.J.; Wasan, K.M. Enhancing Drug Absorption Using Lipids: A Case Study Presenting the Development and Pharmacological Evaluation of a Novel Lipid-Based Oral Amphotericin B Formulation for the Treatment of Systemic Fungal Infections. Adv. Drug Deliv. Rev. 2008, 60, 692–701. [Google Scholar] [CrossRef]
- Singh, O.P.; Hasker, E.; Sacks, D.; Boelaert, M.; Sundar, S. Asymptomatic Leishmania Infection: A New Challenge for Leishmania Control. Clin. Infect. Dis. 2014, 58, 1424–1429. [Google Scholar] [CrossRef]
- Lanza, J.S.; Pomel, S.; Loiseau, P.M.; Frézard, F. Recent Advances in Amphotericin B Delivery Strategies for the Treatment of Leishmaniases. Expert Opin. Drug Deliv. 2019, 16, 1063–1079. [Google Scholar] [CrossRef]
- Vyas, S.P.; Gupta, S. Optimizing Efficacy of Amphotericin B through Nanomodification. Int. J. Nanomed. 2006, 1, 417–432. [Google Scholar] [CrossRef]
- Sundar, S.; Pandey, K.; Thakur, C.P.; Jha, T.K.; Das, V.N.R.; Verma, N.; Lal, C.S.; Verma, D.; Alam, S.; Das, P. Efficacy and Safety of Amphotericin B Emulsion versus Liposomal Formulation in Indian Patients with Visceral Leishmaniasis: A Randomized, Open-Label Study. PLoS Negl. Trop. Dis. 2014, 8, e3169. [Google Scholar] [CrossRef] [PubMed]
- Tuon, F.F.; Dantas, L.R.; de Souza, R.M.; Ribeiro, V.S.T.; Amato, V.S. Liposomal Drug Delivery Systems for the Treatment of Leishmaniasis. Parasitol. Res. 2022, 121, 3073–3082. [Google Scholar] [CrossRef] [PubMed]
- Tonin, F.S.; Steimbach, L.M.; Borba, H.H.; Sanches, A.C.; Wiens, A.; Pontarolo, R.; Fernandez-Llimos, F. Efficacy and Safety of Amphotericin B Formulations: A Network Meta-Analysis and a Multicriteria Decision Analysis. J. Pharm. Pharmacol. 2017, 69, 1672–1683. [Google Scholar] [CrossRef] [PubMed]
- Prasanna, P.; Kumar, P.; Kumar, S.; Rajana, V.K.; Kant, V.; Prasad, S.R.; Mohan, U.; Ravichandiran, V.; Mandal, D. Current Status of Nanoscale Drug Delivery and the Future of Nano-Vaccine Development for Leishmaniasis—A Review. Biomed. Pharmacother. 2021, 141, 111920. [Google Scholar] [CrossRef] [PubMed]
- Roatt, B.M.; de Oliveira Cardoso, J.M.; De Brito, R.C.F.; Coura-Vital, W.; de Oliveira Aguiar-Soares, R.D.; Reis, A.B. Recent Advances and New Strategies on Leishmaniasis Treatment. Appl. Microbiol. Biotechnol. 2020, 104, 8965–8977. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Ke, X.; Voo, Z.X.; Yap, S.S.L.; Yang, C.; Gao, S.; Liu, S.; Venkataraman, S.; Obuobi, S.A.O.; Khara, J.S.; et al. Biodegradable Functional Polycarbonate Micelles for Controlled Release of Amphotericin B. Acta Biomater. 2016, 46, 211–220. [Google Scholar] [CrossRef] [Green Version]
- Iman, M.; Huang, Z.; Alavizadeh, S.H.; Szoka, F.C.; Jaafari, M.R. Biodistribution and In Vivo Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl-Sn-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B. Antimicrob. Agents Chemother. 2017, 61, e02525-16. [Google Scholar] [CrossRef] [Green Version]
- Iman, M.; Huang, Z.; Szoka, F.C.; Jaafari, M.R. Characterization of the Colloidal Properties, In Vitro Antifungal Activity, Antileishmanial Activity and Toxicity in Mice of a Distigmasterylhemisuccinoyl-Glycerophosphocholine Liposome-Intercalated Amphotericin B. Int. J. Pharm. 2011, 408, 163–172. [Google Scholar] [CrossRef] [Green Version]
- Van de Ven, H.; Paulussen, C.; Feijens, P.B.; Matheeussen, A.; Rombaut, P.; Kayaert, P.; Van den Mooter, G.; Weyenberg, W.; Cos, P.; Maes, L.; et al. PLGA Nanoparticles and Nanosuspensions with Amphotericin B: Potent in Vitro and in Vivo Alternatives to Fungizone and AmBisome. J. Control. Release 2012, 161, 795–803. [Google Scholar] [CrossRef] [PubMed]
- Jain, K.; Verma, A.K.; Mishra, P.R.; Jain, N.K. Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development and In Vitro and In Vivo Evaluation. Antimicrob. Agents Chemother. 2015, 59, 2479–2487. [Google Scholar] [CrossRef]
- Asthana, S.; Gupta, P.K.; Jaiswal, A.K.; Dube, A.; Chourasia, M.K. Targeted Chemotherapy of Visceral Leishmaniasis by Lactoferrin-Appended Amphotericin B-Loaded Nanoreservoir: In Vitro and in Vivo Studies. Nanomedicine 2015, 10, 1093–1109. [Google Scholar] [CrossRef] [PubMed]
- Caldeira, L.R.; Fernandes, F.R.; Costa, D.F.; Frézard, F.; Afonso, L.C.C.; Ferreira, L.A.M. Nanoemulsions Loaded with Amphotericin B: A New Approach for the Treatment of Leishmaniasis. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2015, 70, 125–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dos Santos, D.C.M.; de Souza, M.L.S.; Teixeira, E.M.; Alves, L.L.; Vilela, J.M.C.; Andrade, M.; Carvalho, M. das G.; Fernandes, A.P.; Ferreira, L.A.M.; Aguiar, M.M.G. A New Nanoemulsion Formulation Improves Antileishmanial Activity and Reduces Toxicity of Amphotericin B. J. Drug Target. 2018, 26, 357–364. [Google Scholar] [CrossRef] [PubMed]
- Rochelle do Vale Morais, A.; Silva, A.L.; Cojean, S.; Balaraman, K.; Bories, C.; Pomel, S.; Barratt, G.; do Egito, E.S.T.; Loiseau, P.M. In-Vitro and in-Vivo Antileishmanial Activity of Inexpensive Amphotericin B Formulations: Heated Amphotericin B and Amphotericin B-Loaded Microemulsion. Exp. Parasitol. 2018, 192, 85–92. [Google Scholar] [CrossRef]
- Ribeiro, T.G.; Chávez-Fumagalli, M.A.; Valadares, D.G.; França, J.R.; Rodrigues, L.B.; Duarte, M.C.; Lage, P.S.; Andrade, P.H.R.; Lage, D.P.; Arruda, L.V.; et al. Novel Targeting Using Nanoparticles: An Approach to the Development of an Effective Anti-Leishmanial Drug-Delivery System. Int. J. Nanomed. 2014, 9, 877–890. [Google Scholar] [CrossRef] [Green Version]
- Ribeiro, T.G.; Ribeiro, J.R.; Fuscaldi, L.L.; Santos, M.L.; Duarte, M.C.; Lage, P.S.; Martins, V.T.; Costa, L.E.; Fernandes, S.O.A.; Cardoso, V.N.; et al. An Optimized Nanoparticle Delivery System Based on Chitosan and Chondroitin Sulfate Molecules Reduces the Toxicity of Amphotericin B and Is Effective in Treating Tegumentary Leishmaniasis. Int. J. Nanomed. 2014, 9, 5341–5353. [Google Scholar] [CrossRef] [Green Version]
- Jain, V.; Gupta, A.; Pawar, V.K.; Asthana, S.; Jaiswal, A.K.; Dube, A.; Chourasia, M.K. Chitosan-Assisted Immunotherapy for Intervention of Experimental Leishmaniasis via Amphotericin B-Loaded Solid Lipid Nanoparticles. Appl. Biochem. Biotechnol. 2014, 174, 1309–1330. [Google Scholar] [CrossRef]
- Singh, P.K.; Jaiswal, A.K.; Pawar, V.K.; Raval, K.; Kumar, A.; Bora, H.K.; Dube, A.; Chourasia, M.K. Fabrication of 3-O-Sn-Phosphatidyl-L-Serine Anchored PLGA Nanoparticle Bearing Amphotericin B for Macrophage Targeting. Pharm. Res. 2018, 35, 60. [Google Scholar] [CrossRef]
- Doroud, D.; Vatanara, A.; Zahedifard, F.; Gholami, E.; Vahabpour, R.; Rouholamini Najafabadi, A.; Rafati, S. Cationic Solid Lipid Nanoparticles Loaded by Cystein Proteinase Genes as a Novel Anti-Leishmaniasis DNA Vaccine Delivery System: Characterization and in Vitro Evaluations. J. Pharm. Pharm. Sci. 2010, 13, 320. [Google Scholar] [CrossRef] [Green Version]
- Sarwar, H.S.; Sohail, M.F.; Saljoughian, N.; Rehman, A.U.; Akhtar, S.; Nadhman, A.; Yasinzai, M.; Gendelman, H.E.; Satoskar, A.R.; Shahnaz, G. Design of Mannosylated Oral Amphotericin B Nanoformulation: Efficacy and Safety in Visceral Leishmaniasis. Artif. Cells Nanomed. Biotechnol. 2018, 46, 521–531. [Google Scholar] [CrossRef]
- Shahnaz, G.; Edagwa, B.J.; McMillan, J.; Akhtar, S.; Raza, A.; Qureshi, N.A.; Yasinzai, M.; Gendelman, H.E. Development of Mannose-Anchored Thiolated Amphotericin B Nanocarriers for Treatment of Visceral Leishmaniasis. Nanomedicine 2017, 12, 99–115. [Google Scholar] [CrossRef] [PubMed]
- Francis, A.P.; Gurudevan, S.; Jayakrishnan, A. Synthetic Polymannose as a Drug Carrier: Synthesis, Toxicity and Anti-Fungal Activity of Polymannose-Amphotericin B Conjugates. J. Biomater. Sci. Polym. Ed. 2018, 29, 1529–1548. [Google Scholar] [CrossRef] [PubMed]
- Zaioncz, S.; Khalil, N.M.; Mainardes, R.M. Exploring the Role of Nanoparticles in Amphotericin B Delivery. Curr. Pharm. Des. 2017, 23, 509–521. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Q.; Li, X.; Xia, D.; Yu, H.; Chen, D.; Fan, W.; Gan, Y. Lipid-Based Formulations for Oral Drug Delivery: Effects on Drug Absorption and Metabolism. Curr. Drug Metab. 2015, 16, 200–210. [Google Scholar] [CrossRef]
- Asthana, S.; Gupta, P.K.; Jaiswal, A.K.; Dube, A.; Chourasia, M.K. Overexpressed Macrophage Mannose Receptor Targeted Nanocapsules- Mediated Cargo Delivery Approach for Eradication of Resident Parasite: In Vitro and In Vivo Studies. Pharm. Res. 2015, 32, 2663–2677. [Google Scholar] [CrossRef]
- Gupta, P.K.; Jaiswal, A.K.; Asthana, S.; Teja, B.V.; Shukla, P.; Shukla, M.; Sagar, N.; Dube, A.; Rath, S.K.; Mishra, P.R. Synergistic Enhancement of Parasiticidal Activity of Amphotericin B Using Copaiba Oil in Nanoemulsified Carrier for Oral Delivery: An Approach for Non-Toxic Chemotherapy. Br. J. Pharmacol. 2015, 172, 3596–3610. [Google Scholar] [CrossRef] [Green Version]
- Thanki, K.; Prajapati, R.; Sangamwar, A.T.; Jain, S. Long Chain Fatty Acid Conjugation Remarkably Decreases the Aggregation Induced Toxicity of Amphotericin B. Int. J. Pharm. 2018, 544, 1–13. [Google Scholar] [CrossRef]
- Wasan, K.M.; Sivak, O.; Bartlett, K.; Wasan, E.K.; Gershkovich, P. Novel Oral Amphotericin B Formulation (ICo-010) Remains Highly Effective against Murine Systemic Candidiasis Following Exposure to Tropical Temperature. Drug Dev. Ind. Pharm. 2015, 41, 1425–1430. [Google Scholar] [CrossRef]
- Ling Tan, J.S.; Roberts, C.J.; Billa, N. Mucoadhesive Chitosan-Coated Nanostructured Lipid Carriers for Oral Delivery of Amphotericin B. Pharm. Dev. Technol. 2019, 24, 504–512. [Google Scholar] [CrossRef]
- Kaur, K.; Kumar, P.; Kush, P. Amphotericin B Loaded Ethyl Cellulose Nanoparticles with Magnified Oral Bioavailability for Safe and Effective Treatment of Fungal Infection. Biomed. Pharmacother. 2020, 128, 110297. [Google Scholar] [CrossRef]
- Ludwig, D.B.; de Camargo, L.E.A.; Khalil, N.M.; Auler, M.E.; Mainardes, R.M. Antifungal Activity of Chitosan-Coated Poly(Lactic-Co-Glycolic) Acid Nanoparticles Containing Amphotericin B. Mycopathologia 2018, 183, 659–668. [Google Scholar] [CrossRef] [PubMed]
- Mohamed, H.A.; Radwan, R.R.; Raafat, A.I.; Ali, A.E.-H. Antifungal Activity of Oral (Tragacanth/Acrylic Acid) Amphotericin B Carrier for Systemic Candidiasis: In Vitro and in Vivo Study. Drug Deliv. Transl. Res. 2018, 8, 191–203. [Google Scholar] [CrossRef] [PubMed]
- Desai, J.V.; Urban, A.; Swaim, D.Z.; Colton, B.; Kibathi, L.W.; Ferrè, E.M.N.; Stratton, P.; Merideth, M.A.; Hunsberger, S.; Matkovits, T.; et al. Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis. Antimicrob. Agents Chemother. 2022, 66, e00308-22. [Google Scholar] [CrossRef] [PubMed]
- Thornton, S.J.; Wasan, K.M. The Reformulation of Amphotericin B for Oral Administration to Treat Systemic Fungal Infections and Visceral Leishmaniasis. Expert Opin. Drug Deliv. 2009, 6, 271–284. [Google Scholar] [CrossRef] [PubMed]
- Grace, E.; Asbill, S.; Virga, K. Naegleria Fowleri: Pathogenesis, Diagnosis, and Treatment Options. Antimicrob. Agents Chemother. 2015, 59, 6677–6681. [Google Scholar] [CrossRef] [Green Version]
- Belkherroubi-Sari, L.; Adida, H.; Seghir, A.; Boucherit, Z.; Boucherit, K. New Strategy for Enhancing the Therapeutic Index of Fungizone®. J. Mycol. Med. 2013, 23, 3–7. [Google Scholar] [CrossRef]
- Pham, T.T.H.; Barratt, G.; Michel, J.P.; Loiseau, P.M.; Saint-Pierre-Chazalet, M. Interactions of Antileishmanial Drugs with Monolayers of Lipids Used in the Development of Amphotericin B–Miltefosine-Loaded Nanocochleates. Colloids Surf. B Biointerfaces 2013, 106, 224–233. [Google Scholar] [CrossRef]
- Stone, N.R.H.; Bicanic, T.; Salim, R.; Hope, W. Liposomal Amphotericin B (AmBisome®): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions. Drugs 2016, 76, 485–500. [Google Scholar] [CrossRef] [Green Version]
- Lister, J. Amphotericin B Lipid Complex (Abelcet®) in the Treatment of Invasive Mycoses: The North American Experience. Eur. J. Haematol. 1996, 56, 18–23. [Google Scholar] [CrossRef]
- Clemons, K.V.; Stevens, D.A. Comparative Efficacies of Four Amphotericin B Formulations-Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet-Against Systemic Murine Aspergillosis. Antimicrob. Agents Chemother. 2004, 48, 1047–1050. [Google Scholar] [CrossRef]
- Wasan, K.M.; Wasan, E.K.; Gershkovich, P.; Zhu, X.; Tidwell, R.R.; Werbovetz, K.A.; Clement, J.G.; Thornton, S.J. Highly Effective Oral Amphotericin B Formulation against Murine Visceral Leishmaniasis. J. Infect. Dis. 2009, 200, 357–360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leon, C.G.; Lee, J.; Bartlett, K.; Gershkovich, P.; Wasan, E.K.; Zhao, J.; Clement, J.G.; Wasan, K.M. In Vitro Cytotoxicity of Two Novel Oral Formulations of Amphotericin B (ICo-009 and ICo-010) against Candida Albicans, Human Monocytic and Kidney Cell Lines. Lipids Health Dis. 2011, 10, 144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ibrahim, F.; Sivak, O.; Wasan, E.K.; Bartlett, K.; Wasan, K.M. Efficacy of an Oral and Tropically Stable Lipid-Based Formulation of Amphotericin B (ICo-010) in an Experimental Mouse Model of Systemic Candidiasis. Lipids Health Dis. 2013, 12, 158. [Google Scholar] [CrossRef] [Green Version]
- Wasan, E.K.; Gershkovich, P.; Zhao, J.; Zhu, X.; Werbovetz, K.; Tidwell, R.R.; Clement, J.G.; Thornton, S.J.; Wasan, K.M. A Novel Tropically Stable Oral Amphotericin B Formulation (ICo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model. PLoS Negl. Trop. Dis. 2010, 4, e913. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gershkovich, P.; Sivak, O.; Wasan, E.K.; Magil, A.B.; Owen, D.; Clement, J.G.; Wasan, K.M. Biodistribution and Tissue Toxicity of Amphotericin B in Mice Following Multiple Dose Administration of a Novel Oral Lipid-Based Formulation (ICo-009). J. Antimicrob. Chemother. 2010, 65, 2610–2613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wasan, K.M.; Wasan, E.K.; Hnik, P. Assessing the Safety, Tolerability, Pharmacokinetics, and Biodistribution of Novel Oral Formulations of Amphotericin B following Single- and Multiple-Dose Administration to Beagle Dogs. Antimicrob. Agents Chemother. 2020, 64, e01111-20. [Google Scholar] [CrossRef]
- Sivak, O.; Gershkovich, P.; Lin, M.; Wasan, E.K.; Zhao, J.; Owen, D.; Clement, J.G.; Wasan, K.M. Tropically Stable Novel Oral Lipid Formulation of Amphotericin B (ICo-010): Biodistribution and Toxicity in a Mouse Model. Lipids Health Dis. 2011, 10, 135. [Google Scholar] [CrossRef] [Green Version]
- Hnik, P.; Wasan, E.K.; Wasan, K.M. Safety, Tolerability, and Pharmacokinetics of a Novel Oral Amphotericin B Formulation (ICo-019) Following Single-Dose Administration to Healthy Human Subjects: An Alternative Approach to Parenteral Amphotericin B Administration. Antimicrob. Agents Chemother. 2020, 64, e01450-20. [Google Scholar] [CrossRef]
- Hnik, P.; Wasan, E.K.; Wasan, K.M. Phase Ia and Ib Double-Blind Randomized Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of a Novel Oral Amphotericin B Formulation (iCo-019) in Healthy Human Subjects. AAPS PharmSci360, Clinical Pharmacology. 2020 (Published Abstract). Available online: https://www.eventscribe.com/2020/PharmSci360/fsPopup.asp?Mode=posterinfo&PosterID=290734 (accessed on 10 October 2022).
- Kontogiannidou, E.; Meikopoulos, T.; Virgiliou, C.; Bouropoulos, N.; Gika, H.; Vizirianakis, I.S.; Müllertz, A.; Fatouros, D.G. Towards the Development of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) Containing Trimethyl Chitosan for the Oral Delivery of Amphotericin B: In Vitro Assessment and Cytocompatibility Studies. J. Drug Deliv. Sci. Technol. 2020, 56, 101524. [Google Scholar] [CrossRef]
- Kontogiannidou, E.; Meikopoulos, T.; Gika, H.; Panteris, E.; Vizirianakis, I.S.; Müllertz, A.; Fatouros, D.G. In Vitro Evaluation of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) Containing Room Temperature Ionic Liquids (RTILs) for the Oral Delivery of Amphotericin B. Pharmaceutics 2020, 12, 699. [Google Scholar] [CrossRef]
- Fernández-García, R.; Muñoz-García, J.C.; Wallace, M.; Fabian, L.; González-Burgos, E.; Gómez-Serranillos, M.P.; Raposo, R.; Bolás-Fernández, F.; Ballesteros, M.P.; Healy, A.M.; et al. Self-Assembling, Supramolecular Chemistry and Pharmacology of Amphotericin B: Poly-Aggregates, Oligomers and Monomers. J. Control. Release 2022, 341, 716–732. [Google Scholar] [CrossRef] [PubMed]
- Maji, I.; Mahajan, S.; Sriram, A.; Medtiya, P.; Vasave, R.; Khatri, D.K.; Kumar, R.; Singh, S.B.; Madan, J.; Singh, P.K. Solid Self Emulsifying Drug Delivery System: Superior Mode for Oral Delivery of Hydrophobic Cargos. J. Control. Release 2021, 337, 646–660. [Google Scholar] [CrossRef] [PubMed]
- Papahadjopoulos, D.; Vail, W.J.; Jacobson, K.; Poste, G. Cochleate Lipid Cylinders: Formation by Fusion of Unilamellar Lipid Vesicles. Biochim. Biophys. Acta-Biomembr. 1975, 394, 483–491. [Google Scholar] [CrossRef]
- Pawar, A.; Bothiraja, C.; Shaikh, K.; Mali, A. An Insight into Cochleates, a Potential Drug Delivery System. RSC Adv. 2015, 5, 81188–81202. [Google Scholar] [CrossRef]
- Lipa-Castro, A.; Legrand, F.-X.; Barratt, G. Cochleate Drug Delivery Systems: An Approach to Their Characterization. Int. J. Pharm. 2021, 610, 121225. [Google Scholar] [CrossRef]
- Skipper, C.P.; Atukunda, M.; Stadelman, A.; Engen, N.W.; Bangdiwala, A.S.; Hullsiek, K.H.; Abassi, M.; Rhein, J.; Nicol, M.R.; Laker, E.; et al. Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of Amphotericin B. Antimicrob. Agents Chemother. 2020, 64, e00838-20. [Google Scholar] [CrossRef]
- Santangelo, R.; Paderu, P.; Delmas, G.; Chen, Z.; Mannino, R.; Zarif, L.; Perlin, D.S. Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis. Antimicrob. Agents Chemother. 2000, 44, 2356–2360. [Google Scholar] [CrossRef] [Green Version]
- Delmas, G.; Park, S.; Chen, Z.W.; Tan, F.; Kashiwazaki, R.; Zarif, L.; Perlin, D.S. Efficacy of Orally Delivered Cochleates Containing Amphotericin B in a Murine Model of Aspergillosis. Antimicrob. Agents Chemother. 2002, 46, 2704–2707. [Google Scholar] [CrossRef] [Green Version]
- Zarif, L.; Graybill, J.R.; Perlin, D.; Mannino, R.J. Cochleates: New Lipid-Based Drug Delivery System. J. Liposome Res. 2000, 10, 523–538. [Google Scholar] [CrossRef]
- Lu, R.; Hollingsworth, C.; Qiu, J.; Wang, A.; Hughes, E.; Xin, X.; Konrath, K.M.; Elsegeiny, W.; Park, Y.D.; Atakulu, L.; et al. Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis. mBio 2019, 10, e00724-19. [Google Scholar] [CrossRef]
- Pham, T.T.H.; Gueutin, C.; Cheron, M.; Abreu, S.; Chaminade, P.; Loiseau, P.M.; Barratt, G. Development of Antileishmanial Lipid Nanocomplexes. Biochimie 2014, 107, 143–153. [Google Scholar] [CrossRef] [PubMed]
- Lipa-Castro, A.; Nicolas, V.; Angelova, A.; Mekhloufi, G.; Prost, B.; Chéron, M.; Faivre, V.; Barratt, G. Cochleate Formulations of Amphotericin b Designed for Oral Administration Using a Naturally Occurring Phospholipid. Int. J. Pharm. 2021, 603, 120688. [Google Scholar] [CrossRef] [PubMed]
- Lipa Castro, A.; Pomel, S.; Cailleau, C.; Fournier, N.; Dennemont, I.; Loiseau, P.M.; Barratt, G. Pharmacokinetics, Biodistribution, and Activity of Amphotericin B-Loaded Nanocochleates on the Leishmania Donovani Murine Visceral Leishmaniasis Model. Int. J. Pharm. 2022, 624, 121985. [Google Scholar] [CrossRef]
- Aigner, M.; Lass-Flörl, C. Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached? J. Fungi 2020, 6, 66. [Google Scholar] [CrossRef] [PubMed]
- Mehnert, W.; Mäder, K. Solid Lipid Nanoparticles. Adv. Drug Deliv. Rev. 2012, 64, 83–101. [Google Scholar] [CrossRef]
- Jansook, P.; Pichayakorn, W.; Ritthidej, G.C. Amphotericin B-Loaded Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carrier (NLCs): Effect of Drug Loading and Biopharmaceutical Characterizations. Drug Dev. Ind. Pharm. 2018, 44, 1693–1700. [Google Scholar] [CrossRef]
- Bianco, M.A.; Gallarate, M.; Trotta, M.; Battaglia, L. Amphotericin B Loaded SLN Prepared with the Coacervation Technique. J. Drug Deliv. Sci. Technol. 2010, 20, 187–191. [Google Scholar] [CrossRef]
- Liu, Y.; Jiang, Z.; Hou, X.; Xie, X.; Shi, J.; Shen, J.; He, Y.; Wang, Z.; Feng, N. Functional Lipid Polymeric Nanoparticles for Oral Drug Delivery: Rapid Mucus Penetration and Improved Cell Entry and Cellular Transport. Nanomed. NBM 2019, 21, 102075. [Google Scholar] [CrossRef]
- Chalasani, K.B.; Russell-Jones, G.J.; Jain, A.K.; Diwan, P.V.; Jain, S.K. Effective Oral Delivery of Insulin in Animal Models Using Vitamin B12-Coated Dextran Nanoparticles. J. Control. Release 2007, 122, 141–150. [Google Scholar] [CrossRef]
- Singh, A.; Yadagiri, G.; Parvez, S.; Singh, O.P.; Verma, A.; Sundar, S.; Mudavath, S.L. Formulation, Characterization and in Vitro Anti-Leishmanial Evaluation of Amphotericin B Loaded Solid Lipid Nanoparticles Coated with Vitamin B12-Stearic Acid Conjugate. Mater. Sci. Eng. C 2020, 117, 111279. [Google Scholar] [CrossRef]
- Parvez, S.; Yadagiri, G.; Gedda, M.R.; Singh, A.; Singh, O.P.; Verma, A.; Sundar, S.; Mudavath, S.L. Modified Solid Lipid Nanoparticles Encapsulated with Amphotericin B and Paromomycin: An Effective Oral Combination against Experimental Murine Visceral Leishmaniasis. Sci. Rep. 2020, 10, 12243. [Google Scholar] [CrossRef] [PubMed]
- Parvez, S.; Yadagiri, G.; Arora, K.; Javaid, A.; Kushwaha, A.K.; Singh, O.P.; Sundar, S.; Mudavath, S.L. Coalition of Biological Agent (Melatonin) With Chemotherapeutic Agent (Amphotericin B) for Combating Visceral Leishmaniasis via Oral Administration of Modified Solid Lipid Nanoparticles. ACS Biomater. Sci. Eng. 2021. [Google Scholar] [CrossRef] [PubMed]
- Parvez, S.; Karole, A.; Mudavath, S.L. Transport Mechanism of Hydroxy-Propyl-Beta-Cyclodextrin Modified Solid Lipid Nanoparticles across Human Epithelial Cells for the Oral Absorption of Antileishmanial Drugs. Biochim. Biophys. Acta-Gen. Subj. 2022, 1866, 130157. [Google Scholar] [CrossRef] [PubMed]
- Thanki, K.; Date, T.; Jain, S. Improved Oral Bioavailability and Gastrointestinal Stability of Amphotericin B through Fatty Acid Conjugation Approach. Mol. Pharm. 2019, 16, 4519–4529. [Google Scholar] [CrossRef]
- Thanki, K.; Date, T.; Jain, S. Enabling Oral Amphotericin B Delivery by Merging the Benefits of Prodrug Approach and Nanocarrier-Mediated Drug Delivery. ACS Biomater. Sci. Eng. 2021. [Google Scholar] [CrossRef] [PubMed]
- Schultz, R.M.; Johnson, E.G.; Wisner, E.R.; Brown, N.A.; Byrne, B.A.; Sykes, J.E. Clinicopathologic and Diagnostic Imaging Characteristics of Systemic Aspergillosis in 30 Dogs. J. Vet. Intern. Med. 2008, 22, 851–859. [Google Scholar] [CrossRef] [PubMed]
- Graupmann-Kuzma, A.; Valentine, B.A.; Shubitz, L.F.; Dial, S.M.; Watrous, B.; Tornquist, S.J. Coccidioidomycosis in Dogs and Cats: A Review. J. Am. Anim. Hosp. Assoc. 2008, 44, 226–235. [Google Scholar] [CrossRef]
- O’Brien, C.; Krockenberger, M.; Martin, P.; Wigney, D.; Malik, R. Long-Term Outcome of Therapy for 59 Cats and 11 Dogs with Cryptococcosis. Aust. Vet. J. 2006, 84, 384–392. [Google Scholar] [CrossRef]
- Gremião, I.; Schubach, T.; Pereira, S.; Rodrigues, A.; Honse, C.; Barros, M. Treatment of Refractory Feline Sporotrichosis with a Combination of Intralesional Amphotericin B and Oral Itraconazole. Aust. Vet. J. 2011, 89, 346–351. [Google Scholar] [CrossRef]
- Oliva, G.; Gradoni, L.; Ciaramella, P.; de Luna, R.; Cortese, L.; Orsini, S.; Davidson, R.N.; Persechino, A. Activity of Liposomal Amphotericin B (AmBisome) in Dogs Naturally Infected with Leishmania Infantum. J. Antimicrob. Chemother. 1995, 36, 1013–1019. [Google Scholar] [CrossRef]
- Legendre, A.M.; Rohrbach, B.W.; Toal, R.L.; Rinaldi, M.G.; Grace, L.L.; Jones, J.B. Treatment of Blastomycosis with Itraconazole in 112 Dogs. J. Vet. Intern. Med. 1996, 10, 365–371. [Google Scholar] [CrossRef] [PubMed]
- Foy, D.S.; Trepanier, L.A. Antifungal Treatment of Small Animal Veterinary Patients. Vet. Clin. N. Am. Small Anim. Pract. 2010, 40, 1171–1188. [Google Scholar] [CrossRef] [PubMed]
- Boothe, D. Polymyxins. Available online: https://www.merckvetmanual.com/pharmacology/antibacterial-agents/polymyxins (accessed on 31 August 2022).
- Cormack, C.A.; Donahoe, S.L.; Talbot, J.J.; Beatty, J.A.; Barrs, V.R. Disseminated Invasive Aspergillosis Caused by Aspergillus Felis in a Cat. J. Vet. Intern. Med. 2021, 35, 2395–2400. [Google Scholar] [CrossRef] [PubMed]
- Plumb, D. Plumb’s Veterinary Drug Handbook, 9th ed.; PharmaVet Inc: Hoboken, NJ, USA, 2018. [Google Scholar]
- Poleschinski, J.M.; Straub, J.U.; Schmidt, V. Comparison of Two Treatment Modalities and PCR to Assess Treatment Effectiveness in Macrorhabdosis. J. Avian Med. Surg. 2019, 33, 245–250. [Google Scholar] [CrossRef] [PubMed]
- Phalen, D.N. Update on the Diagnosis and Management of Macrorhabdus Ornithogaster (Formerly Megabacteria) in Avian Patients. Vet. Clin. N. Am. Exot. Anim. Pract. 2014, 17, 203–210. [Google Scholar] [CrossRef] [PubMed]
- Purkait, B.; Kumar, A.; Nandi, N.; Sardar, A.H.; Das, S.; Kumar, S.; Pandey, K.; Ravidas, V.; Kumar, M.; De, T.; et al. Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania Donovani. Antimicrob. Agents Chemother. 2012, 56, 1031–1041. [Google Scholar] [CrossRef] [Green Version]
- Ponte-Sucre, A.; Gamarro, F.; Dujardin, J.; Barrett, M.P.; López-Vélez, R.; García-Hernández, R.; Pountain, A.W.; Mwenechanya, R.; Papadopoulou, B. Drug Resistance and Treatment Failure in Leishmaniasis: A 21st Century Challenge. PLoS Negl. Trop. Dis. 2017, 11, e0006052. [Google Scholar] [CrossRef] [Green Version]
- Oliva, G.; DVM, X.R.; Crotti, A.; Maroli, M.; Castagnaro, M.; Gradoni, L.; Lubas, G.; Paltrinieri, S.; Zatelli, A.; Zini, E. Guidelines for Treatment of Leishmaniasis in Dogs. J. Am. Vet. Med. Assoc. 2010, 236, 1192–1198. [Google Scholar] [CrossRef]
- World Health Organization. Control of the Leishmaniases: Report of a Meeting of the WHO Expert Committee on the Control of Leishmaniases; World Health Organization: Geneva, Switzerland, 2010. [Google Scholar]
- Lamothe, J. Activity of Amphotericin B in Lipid Emulsion in the Initial Treatment of Canine Leishmaniasis. J. Small Anim. Pract. 2001, 42, 170–175. [Google Scholar] [CrossRef]
- Ginel, P.J.; Lucena, R.; López, R.; Molleda, J.M. Use of Allopurinol for Maintenance of Remission in Dogs with Leishmaniasis. J. Small Anim. Pract. 1998, 39, 271–274. [Google Scholar] [CrossRef]
- Cortadellas, O. Initial and Long-Term Efficacy of a Lipid Emulsion of Amphotericin B Desoxycholate in the Management of Canine Leishmaniasis. J. Vet. Intern. Med. 2003, 17, 808–812. [Google Scholar] [CrossRef] [PubMed]
Coccidioidomycosis | Ocular aspergillosis |
Fungal infections | Refractory aspergillosis |
Histoplasmosis | Severe Coccidioidomycosis |
Invasive Aspergillosis | Severe Cryptococcosis |
Invasive Fungal Infections | Severe Fungal infection: Basidiobolus spp. |
Leishmaniasis | Severe Fungal infection: Conidiobolous spp. |
Meningitis, Cryptococcal | Severe Fungal infection: Sporotrichosis spp. |
Meningitis, Fungal | Severe Histoplasmosis |
Mucocutaneous Leishmaniasis | Severe Mucocutaneous leishmaniasis |
Mycotic endophthalmitis | Severe North American blastomycosis |
Penicillium marneffei infection | Severe Systemic candidiasis |
Visceral leishmaniasis | Ocular aspergillosis |
Candidal cystitis | Refractory aspergillosis |
Disseminated Cryptoccosis | Severe Coccidiomycosis |
Fungal osteoarticular infections | Severe Cryptococcosis |
Formulation | Excipients | PharmacokineticFeatures:t½, t1/2β, Vd | Dosage (mg/kg) | References |
---|---|---|---|---|
D-AmpB | NaDC | 24 h/ 15 days/ not reported | 0.7–1 mg/kg | Thakur et al., 1999 [11] |
Fungizone® | ||||
Anforicin® | ||||
ABLC (Abelcet®) | DMPC DMPG | 24 h/ 10 days/ 131 ± 58 L | 5 mg/kg | Stevens 1994 [12] |
ABCD (Amphotec®) | Disc-shaped AmpB cholesteryl sulfate complex | 24 h/ 4–8 weeks/ not reported | 2 mg/kg | Guo 2001 [13] |
L-AmpB | HSPC Cholesterol DSPG α-tocopherol | 24 h/ 6 days/ 18.9–49.1 L | 3 mg/kg | Adler-Moore and Proffitt 2002 [14]; Bern et al., 2006 [15] |
Liposomal AmpB | ||||
AmBisome® |
Formulation | Excipients | Advantages | Targeted Species | References |
---|---|---|---|---|
AmpB/B and AmpB/U | PEG-PBC and PEG-PUC | Less hemolytic activity | Not indicated | Wang et al., 2016 [29] |
DSHemsPC-AmpB-Lip | 1,2-Distigmasterylhemisuccinoyl-sn-glycero-3 phosphocholine DMPC DMPG | Reduced production cost and nephrotoxicity. In vivo studies in a mouse model | L. major | Iman et al., 2017 [30]; Iman et al., 2011 [31] |
PLGA-AmpB | PLGA | Dosage reduction and increased efficacy in a mouse models. | L. infantum | Van de Ven et al., 2012 [32] |
MPPIA-AmpB | Poly(propylene imine)dendrimer conjugated with mannose | Reduced toxicity. Macrophage targeting. Increased cellular uptake. | L. donovani | Jain et al., 2015 [33] |
LcPGNP-AmpB | Glycoprotein Lactoferrin PLGA | Nanoparticle formulation | L. donovani | Asthana et al., 2015 [34] |
CHOL-NE-AmpB | Medium chain triglycerides Tween80 Cholesterol α-tocopherol | Increased selectivity and stability. | L. amazonesis/L. infantum | Caldeira et al., 2015 [35]; Santos et al., 2018 [36] |
ME-AmpB | Mygliol® 812 Tween80 Lipoid® S100 | Increased efficacy and selectivity in a mouse model | L. donovani | Rochelle et al., 2018 [37] |
NQC-AmpB | Chitosan chondroitin sulfate | in vivo efficacy in a mouse model. | L. amazonesis | Ribeiro, Chavez et al., 2014 [38]; Ribeiro, Franca et al., 2014 [39] |
AmpB-C-SLNs | Chitosan stearic acid soy-phosphatidylcholineTween80 | Reduced toxicity and increased efficiency in vivo in a mouse model | L. donovani | Jain et al., 2014 [40] |
PLGA-PhoS-AmpB | PLGA decorated with 3-O-sn-Phosphatidyl-L-serine | Increased stability and efficacy in vivo in a mouse model | L. donovani | Singh et al., 2018. [41] |
Formulation | Composition | Administration Route | Targeted Species | References |
---|---|---|---|---|
MTC-AmpB | Mannose-anchored thiolated chitosan NPs for AmpB and Tween80 | oral | L. Donovani | Sarwar et al., 2018 [43,44]; Shahnaz et al., 2017 |
MPPIA-AmpB | Poly(propylene imine)dendrimer conjugated with mannose + AmpB | Intravenous | L. Donovani | Jain et al., 2015 [45] |
MnosCNc-AmpB | AmpB entrapped mannose grafted chitosan nanocapsules | Intravenous | L. Donovani | Asthana et al., 2015 [46] |
AmpB-PM | Amphotericin B and Polymannose conjugate. | Intravenous | C. Albicans | Francis et al., 2018 [47] |
MTC AmpB | mannose-anchored thiolated chitosan AmpB nanocarrier | Intravenous | L. donovani | Shahnaz et al., 2017 [48] |
Formulation | Excipients | Targeted Species | References |
---|---|---|---|
MTC-AmpB | Mannose-anchored thiolated chitosan NPs Tween80 | L. donovani | Sarwar et al., 2018 [43]; Shahnaz et al., 2017 [44] |
CopNEC-AmpB | D-α-tocopherol polyethylene glycol 1000 succinate phosphatidylcholine Copaiba oil | L. donovani | Gupta et al., 2015 [49] |
AmpB-OA | oleic acid conjugated to AmpB | not established | Thanki et al., 2018 [50] |
iCo-010 | Peceol® Gelucire® | L. donovani | Wasan et al., 2015 [51] |
ChiAmp NLC | Chitosan Tween80 lecithin | not established | Ling et al., 2019 [52] |
AmpB-EC-NPs | Ethyl cellulose | C. albicans | Kaur et al., 2020 [53] |
Chitosan coated PLGA containing AmpB | Chitosan-coated PLGA | C. albicans C. tropicalis C. glabrata | Ludwig et al., 2018 [54] |
Trag-AAc-AmpB | Tragacanth Acrylic Acid | C. albicans | Mohamed et al., 2018 [55] |
CAMB | Phosphatidylserine Calcium | C. albicans | Desai et al., 2022 [56] |
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Wasan, E.; Mandava, T.; Crespo-Moran, P.; Nagy, A.; Wasan, K.M. Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections. Pharmaceutics 2022, 14, 2316. https://doi.org/10.3390/pharmaceutics14112316
Wasan E, Mandava T, Crespo-Moran P, Nagy A, Wasan KM. Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections. Pharmaceutics. 2022; 14(11):2316. https://doi.org/10.3390/pharmaceutics14112316
Chicago/Turabian StyleWasan, Ellen, Tavonga Mandava, Pablo Crespo-Moran, Adrienne Nagy, and Kishor M. Wasan. 2022. "Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections" Pharmaceutics 14, no. 11: 2316. https://doi.org/10.3390/pharmaceutics14112316