Effectiveness of Miltefosine Nanoemulsion Concerning the Treatment of Acute and Chronic Toxoplasmosis: In Vivo Study
-
Gholam Reza Valizadeh
,
Mohammad Mahdi Mahboubian
,
Amir Housein Maghsood
,
Fatemeh Mirzaei
,
Seyedmousa Motavalli Haghi
,
Faezeh Forooghi Parvar
,
Mohammad Fallah
Abstract
Background: Toxoplasma gondii is one of the most common parasites worldwide. It is of great importance to identify new potential drugs that are effective and less harmful in pregnant women and newborns. We investigated nanoemulsion miltefosine (NEM) in treating experimental acute and chronic toxoplasmosis.
Methods: A combination of triacetin, Tween 80, and ethanol (1:2) was used for the development of NEM formulations. The size of NEM was calculated to be 17.463 nm by DLS and TEM. To investigate the performance of miltefosine (MLF), NEM, sulfadiazine (SDZ), and pyrimethamine (PYR) (positive control) in vivo, acute toxoplasmosis was induced in mice by an intraperitoneal injection of RH strain tachyzoites. After five days, the mice were examined for the number and condition of tachyzoites and histopathological changes in the liver and spleen. Chronic toxoplasmosis was investigated in rats and the number and size of brain cysts along with histopathological changes were assessed in different groups.
Results: The results of the in vivo assessment of drugs in acute toxoplasmosis showed the following order regarding a decrease in the number of tachyzoites and an increase in survival rate: SDZ&PYR > NEM > MLF. The effects of drugs on chronic toxoplasmosis showed a significant effect of NEM (50%) on reducing the number of cysts compared to SDZ&PYR (10%) and MLF (12%) and reducing the size of NEM brain cysts (21%) compared to SDZ&PYR (5 %) and MLF (8%).
Conclusion: Increasing the penetration of NEM through the blood-brain barrier (BBB) and subsequently reducing the number and size of T. gondii tissue cysts is a promising new drug in treating chronic toxoplasmosis.
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2. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965-76.
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5. Pandey P, Gulati N, Makhija M, Purohit D, Dureja H. Nanoemulsion: A Novel Drug Delivery Approach for Enhancement of Bioavailability. Recent Pat Nanotechnol. 2020;14(4):276-293.
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7. Polat ZA, Obwaller A, Vural A, Walochnik J. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters. Parasitol Res. 2012;110(2):515-20.
8. Garg R, Tremblay MJ. Miltefosine represses HIV-1 replication in human dendritic cell/T-cell cocultures partially by inducing secretion of type-I interferon. Virology. 2012;432(2):271-6.
9. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012;67(11):2576-97.
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11. Advisory Committee on Safety of Medicinal Products (ACSoMP): Measures to minimize the risk of ocular adverse events with miltefosine Internet Document: 12 Apr 2023.
12. Latifi A, Mohebali M, Yasami S, Soleimani M, Rezaian M, Kazemirad E. Comparing cytotoxicity and efficacy of miltefosine and standard antimicrobial agents against Acanthamoeba trophozoites and cyst forms: An in vitro study. Acta Trop. 2023;247:107009.
13. Najafian HR, Mohebali M, Rezayat SM, et al. Nanoliposomal miltefosine for the treatment of cutaneous leishmaniasis caused by Leishmania major (MRHO/IR/75/ER): The drug preparation and in vitro study. IJPRAS, 2016, 5(3):97-107.
14. Mohebali M, Fotouhi A, Hooshmand B, et al. Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop. 2007;103(1):33-40.
15. Esmaeili J, Mohebali M, Edrissian GH, et al. Evaluation of miltefosine against Leishmania major (mrho/ir/75/er): in vitro and in vivo studies. Acta Med Iran. 1970;46(3):191-196.
16. Valizadeh GR, Mahboobian MM, Maghsood AH, et al. Development and evaluation of miltefosine-loaded nanoemulsions on in vitro culture of Toxoplasma gondii. Nanomed J. 2024;11(2):172-86.
17. Ebrahimzadeh MA, Taheri MM, Ahmadpour E, et al. Anti-Toxoplasma Effects of Methanol Extracts of Feijoa sellowiana, Quercus castaneifolia, and Allium paradoxum. J Pharmacopuncture. 2017;20(3):220-226.
18. Romand S, Pudney M, Derouin F. In vitro and in vivo activities of the hydroxynaphthoquinone atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, or minocycline against Toxoplasma gondii. Antimicrob Agents Chemother. 1993;37(11):2371-8.
19. Eissa MM, Barakat AM, Amer EI, Younis LK. Could miltefosine be used as a therapy for toxoplasmosis? Exp Parasitol. 2015;157:12-22.
20. Al-Zanbagi NA. In vivo effect of some home spices extracts on the Toxoplasma gondii tachyzoites. J Family Community Med. 2009;16(2):59-65.
21. Chew WK, Wah MJ, Ambu S, Segarra I. Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts. Exp Parasitol. 2012;130(1):22-5.
22. Saraei M, Ghaderi Y, Mosavi T, Shahnazi M, Keshavarz H, Shojaee S. Brain cystogenesis capacity of Toxoplasma gondii, avirulent Tehran strain in mice. Asian Pac J Trop Dis. 2014;4:S739-S42.
23. Ma J, He JJ, Wang M, Hou JL, Elsheikha HM, Zhu XQ. Toxoplasma gondii induces metabolic disturbances in the hippocampus of BALB/c mice. Parasitol Res. 2021;120(8): 2805-2818.
24. Nasr ME, Abd El Hamid AH, Aly NSM, et al. Efficacy of azithromycin on experimental toxoplasmosis infected mice. J Egypt Soc Parasitol. 2020;50(2):293-299.
25. Otto, R.R. The antiparasitic effect of Hexadecylphosphocholine (Miltefosine) against Toxoplasma gondii in vitro and in vivo. Department of Medicine Charite University Medicine, Berlin. 2011. doi.org/10.17169/refubium-7485.
26. Barakat AM, El-Razik KAA, El Fadaly HAM, et al. Parasitological, Molecular, and Histopathological Investigation of the Potential Activity of Propolis and Wheat Germ Oil against Acute Toxoplasmosis in Mice. Pharmaceutics. 2023;15(2):478.
27. Khademvatan S, Yousefi E, Asadi N, Abasi E. Evaluation of In Vitro Cytotoxic and Apoptotic Effects of miltefosine on the Toxoplasma gondii RH Strain. Iran J Parasitol. 2024;19(1):52-60.
28. Dard C, Swale C, Brenier-Pinchart MP, et al. A brain cyst load-associated antigen is a Toxoplasma gondii biomarker for serodetection of persistent parasites and chronic infection. BMC Biol. 2021;19(1):25.
29. Gondim BLC, da Silva Catarino J, de Sousa MAD, et al. Nanoparticle-Mediated Drug Delivery: Blood-Brain Barrier as the Main Obstacle to Treating Infectious Diseases in CNS. Curr Pharm Des. 2019;25(37):3983-96.
30. Debache K, Hemphill A. Effects of miltefosine treatment in fibroblast cell cultures and in mice experimentally infected with Neospora caninum tachyzoites. Parasitology. 2012;139(7):934-44.
31. Benaim G, Paniz-Mondolfi A. Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular Ca2+ Homeostasis as a Rational Therapeutic Target in Leishmaniasis and Chagas Disease. Biomolecules. 2024;14(4):406.
2. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965-76.
3. Montazeri M, Mehrzadi S, Sharif M, Sarvi S, Shahdin S, Daryani A. Activities of anti-Toxoplasma drugs and compounds against tissue cysts in the last three decades (1987 to 2017), a systematic review. Parasitol Res. 2018;117(10):3045-57.
4. Montazeri M, Sharif M, Sarvi S, Mehrzadi S, Ahmadpour E, Daryani A. A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006-2016). Front Microbiol. 2017; 8:25.
5. Pandey P, Gulati N, Makhija M, Purohit D, Dureja H. Nanoemulsion: A Novel Drug Delivery Approach for Enhancement of Bioavailability. Recent Pat Nanotechnol. 2020;14(4):276-293.
6. van Blitterswijk WJ, Verheij M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des. 2008;14(21):2061-74.
7. Polat ZA, Obwaller A, Vural A, Walochnik J. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters. Parasitol Res. 2012;110(2):515-20.
8. Garg R, Tremblay MJ. Miltefosine represses HIV-1 replication in human dendritic cell/T-cell cocultures partially by inducing secretion of type-I interferon. Virology. 2012;432(2):271-6.
9. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012;67(11):2576-97.
10. Kumar, Awanish (2013). Leishmania and Leishmaniasis. Springer Science & Business Media. p. 39. ISBN 9781461488699. Archived from the original on 2017-09-10.
11. Advisory Committee on Safety of Medicinal Products (ACSoMP): Measures to minimize the risk of ocular adverse events with miltefosine Internet Document: 12 Apr 2023.
12. Latifi A, Mohebali M, Yasami S, Soleimani M, Rezaian M, Kazemirad E. Comparing cytotoxicity and efficacy of miltefosine and standard antimicrobial agents against Acanthamoeba trophozoites and cyst forms: An in vitro study. Acta Trop. 2023;247:107009.
13. Najafian HR, Mohebali M, Rezayat SM, et al. Nanoliposomal miltefosine for the treatment of cutaneous leishmaniasis caused by Leishmania major (MRHO/IR/75/ER): The drug preparation and in vitro study. IJPRAS, 2016, 5(3):97-107.
14. Mohebali M, Fotouhi A, Hooshmand B, et al. Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop. 2007;103(1):33-40.
15. Esmaeili J, Mohebali M, Edrissian GH, et al. Evaluation of miltefosine against Leishmania major (mrho/ir/75/er): in vitro and in vivo studies. Acta Med Iran. 1970;46(3):191-196.
16. Valizadeh GR, Mahboobian MM, Maghsood AH, et al. Development and evaluation of miltefosine-loaded nanoemulsions on in vitro culture of Toxoplasma gondii. Nanomed J. 2024;11(2):172-86.
17. Ebrahimzadeh MA, Taheri MM, Ahmadpour E, et al. Anti-Toxoplasma Effects of Methanol Extracts of Feijoa sellowiana, Quercus castaneifolia, and Allium paradoxum. J Pharmacopuncture. 2017;20(3):220-226.
18. Romand S, Pudney M, Derouin F. In vitro and in vivo activities of the hydroxynaphthoquinone atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, or minocycline against Toxoplasma gondii. Antimicrob Agents Chemother. 1993;37(11):2371-8.
19. Eissa MM, Barakat AM, Amer EI, Younis LK. Could miltefosine be used as a therapy for toxoplasmosis? Exp Parasitol. 2015;157:12-22.
20. Al-Zanbagi NA. In vivo effect of some home spices extracts on the Toxoplasma gondii tachyzoites. J Family Community Med. 2009;16(2):59-65.
21. Chew WK, Wah MJ, Ambu S, Segarra I. Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts. Exp Parasitol. 2012;130(1):22-5.
22. Saraei M, Ghaderi Y, Mosavi T, Shahnazi M, Keshavarz H, Shojaee S. Brain cystogenesis capacity of Toxoplasma gondii, avirulent Tehran strain in mice. Asian Pac J Trop Dis. 2014;4:S739-S42.
23. Ma J, He JJ, Wang M, Hou JL, Elsheikha HM, Zhu XQ. Toxoplasma gondii induces metabolic disturbances in the hippocampus of BALB/c mice. Parasitol Res. 2021;120(8): 2805-2818.
24. Nasr ME, Abd El Hamid AH, Aly NSM, et al. Efficacy of azithromycin on experimental toxoplasmosis infected mice. J Egypt Soc Parasitol. 2020;50(2):293-299.
25. Otto, R.R. The antiparasitic effect of Hexadecylphosphocholine (Miltefosine) against Toxoplasma gondii in vitro and in vivo. Department of Medicine Charite University Medicine, Berlin. 2011. doi.org/10.17169/refubium-7485.
26. Barakat AM, El-Razik KAA, El Fadaly HAM, et al. Parasitological, Molecular, and Histopathological Investigation of the Potential Activity of Propolis and Wheat Germ Oil against Acute Toxoplasmosis in Mice. Pharmaceutics. 2023;15(2):478.
27. Khademvatan S, Yousefi E, Asadi N, Abasi E. Evaluation of In Vitro Cytotoxic and Apoptotic Effects of miltefosine on the Toxoplasma gondii RH Strain. Iran J Parasitol. 2024;19(1):52-60.
28. Dard C, Swale C, Brenier-Pinchart MP, et al. A brain cyst load-associated antigen is a Toxoplasma gondii biomarker for serodetection of persistent parasites and chronic infection. BMC Biol. 2021;19(1):25.
29. Gondim BLC, da Silva Catarino J, de Sousa MAD, et al. Nanoparticle-Mediated Drug Delivery: Blood-Brain Barrier as the Main Obstacle to Treating Infectious Diseases in CNS. Curr Pharm Des. 2019;25(37):3983-96.
30. Debache K, Hemphill A. Effects of miltefosine treatment in fibroblast cell cultures and in mice experimentally infected with Neospora caninum tachyzoites. Parasitology. 2012;139(7):934-44.
31. Benaim G, Paniz-Mondolfi A. Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular Ca2+ Homeostasis as a Rational Therapeutic Target in Leishmaniasis and Chagas Disease. Biomolecules. 2024;14(4):406.
| Files | ||
| Issue | Vol 19 No 3 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijpa.v19i3.16389 | |
| Keywords | ||
| Acute Chronic In vivo Miltefosine Toxoplasmosis | ||
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How to Cite
1.
Valizadeh G, Mahboubian MM, Maghsood AH, Mirzaei F, Motavalli Haghi S, Forooghi Parvar F, Fallah M. Effectiveness of Miltefosine Nanoemulsion Concerning the Treatment of Acute and Chronic Toxoplasmosis: In Vivo Study. Iran J Parasitol. 2024;19(3):314-324.
