In vivo evaluation the efficiency of nitazoxanide with cationic Gemini surfactant on Cryptosporidiosis
Keywords:Cationic Gemini Surfactant, Cryptosporidium, HIV patients, Immunocompromised, Nitazoxanide
Infection with cryptosporidiosis endangers the lives of many people with immunodeficiency, especially HIV patients. Nitazoxanide is one of the main therapeutic drugs used to treat cryptosporidiosis. However, it is poorly soluble in water, which restricts its usefulness and efficacy in immunocompromised patients. Surfactants have an amphiphilic character which indicates their ability to improve the water solubility of the hydrophobic drugs. Our research concerns the synthesis of new cationic Gemini surfactants that have the ability to improve the solubility of the drug Nanazoxide. So, we synthesized cationic Gemini surfactants. N1,N1,N3,N3-tetramethyl-N1,N3-bis(2-octadecanamidoethyl)propane-1,3-diaminium bromide (CGSPS18) and 2,2‘-(ethane-1,2-diylbis(oxy))bis(N-(2-octadecanamidoethyl)-N,N-dimethyl-2-oxoethane-1-aminium) dichloride (CGSES18) and the detection of their chemical composition by spectroscopic methods, as well as studying the properties of their surfaces and their toxicity. Furthermore, the efficacy of nitazoxanide in infected mice was studied in conjunction with three different doses of surfactants. To assess the effect of nitazoxanide and surfactants, the infection was parasitologically counted before and after treatment, and the intestinal, liver, and lung tissues were also examined histopathologically. In this study, it was found that the combination of the drug nitazoxanide with surfactants, especially the compound (CGSPS18) at a concentration of 25% increased the efficacy and resulted in a percentage reduction of 90.8%. Histopathological examination revealed that the group treated with the drug nitazoxanide in combination with CGSPS18 showed the best results exhibiting an almost normal villous pattern. This study demonstrated an increase in the effectiveness of nitazoxanide when combined with surfactants, and this suggests a promising future for the use of surfactants as an adjunct to enhance the effectiveness of nitazoxanide for the treatment of cryptosporidiosis in immunocompromised patients, particularly HIV patients.
Published Online First 20/4/2023
Hunter PR, Nichols G. Epidemiology and clinical features of Cryptosporidium infection in immunocompromised patients. Clin Microbiol Rev. 2002; 15(1): 145-154. https://dx.doi.org/10.1128/CMR.15.1.145-154.2002
Dong S, Yang Y, Wang Y, Yang D, Yang Y, Shi Y, et al. Prevalence of Cryptosporidium Infection in the Global Population: A Systematic Review and Meta-analysis. Acta Parasitol. 2020; 65(4): 882-889. https://dx.doi.org/10.2478/s11686-020-00230-1
Hadi AM. Isolation and Identification of Cryptosporidium sp. by Reverse Osmosis System of Tap water in Baghdad. Baghdad Sci J. 2014; 11(2): 894-899.
Abdul-Maksoud HF, Ismail MAM, Amer NM, EL Akkad DMH, Magdy M. Detection of Cryptosporidium-induced intestinal tissue alterations in Dexamethasone treated & un-treated mice. Egypt Soc Parasitol. 2018; 2(2): 227-249. https://doi.org/10.12816/0050453
Mccole DF, Eckmann L, Laurent F, Kagnoff MF. Intestinal epithelial cell apoptosis following Cryptosporidium parvum infection. Infect Immun. 2000; 68(3): 1710-1713. https://dx.doi.org/10.1128/IAI.68.3.1710-1713.2000
Benamrouz S, Conseil V, Chabé M, Praet M, Audebert C, Blervaque R, et al. Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model. DMM Dis Model Mech. 2014; 7(6): 693-700. https://dx.doi.org/10.1242/dmm.013292
Bhalchandra S, Lamisere H, Ward H. Intestinal organoid/enteroid-based models for Cryptosporidium. Curr Opin Microbiol. 2020; 58: 124-129. https://dx.doi.org/10.1016/j.mib.2020.10.002
Dhal A, Chinmaya P, Yun S, Mahapatra RK. An update on Cryptosporidium biology and therapeutic avenues. J Parasit Dis. 2022; 46(3): 923-939. https://dx.doi.org/10.1007/s12639-022-01510-5
Srikala SV, Santhi Priya N, Nadendla RR. Formulation, Characterization and Antihelminthic Activity Testing of Nitazoxanide Superporous Hydrogel Tablets. J Drug Deliv Ther. 2020; 10(3-s): 26-36. https://dx.doi.org/10.22270/jddt.v10i3-s.4130
Moawad HSF, Hegab MHA, Badawey MSR, Ashoush SE, Ibrahim SM, Ali AAELS. Assessment of chitosan nanoparticles in improving the efficacy of nitazoxanide on cryptosporidiosis in immunosuppressed and immunocompetent murine models. J Parasit Dis. 2021; 45(3): 606-619. https://dx.doi.org/10.1007/s12639-020-01337-y
Wuqing O, Jianjun G, Qiaoyan S. Oil-in-water-type compound nitazoxanid nanoemulsion and preparation method thereof. Published online 2012. https://patents.google.com/patent/CN102526039A/en
Salas-z R, Rodríguez-Ruiz C, Höpfl H, Morales-rojas H, Obdulia S, Rodr P. Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers. Pharm Res. 2019; 12(1): 23. https://doi.org/10.3390/pharmaceutics12010023
Zoller U. Handbook of Detergents, Part E: Applications. 1st ed. CRC Press. New York; 2008. 141: 455-468..
Burggraaf W, Leng RA. Antiprotozoal effects of surfactant detergents in the rumen of sheep. New Zeal J Agric Res. 1980; 23(3): 287-291. https://dx.doi.org/10.1080/00288233.1980.10425358
Rangel-Yagui C de O, Pessoa A, Tavares LC. Micellar solubilization of drugs. J Pharm Pharm Sci. 2005; 8(2): 147-163.
Torchilin VP. Micellar nanocarriers: Pharmaceutical perspectives. Pharm Res. 2007; 24(1): 1-16. https://dx.doi.org/10.1007/s11095-006-9132-0
Vinarov Z, Katev V, Radeva D, Tcholakova S, Denkov ND. Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure. Drug Dev Ind Pharm. 2018; 44(4): 677-686. https://dx.doi.org/10.1080/03639045.2017.1408642
Bin-Hudayb NS, Badr EE, Hegazy MA. Adsorption and corrosion performance of new cationic gemini surfactants derivatives of fatty amido ethyl aminium chloride with ester spacer for mild steel in acidic solutions. Materials (Basel). 2020; 13(12): 1-28. https://dx.doi.org/10.3390/ma13122790
Sonntag NOV. Reactions of fatty acid chlorides: II. Synthesis of monohydrazides or dihydrazides by acylation of hydrazine hydrate with saturated fatty acid chlorides. J Am Oil Chem Soc. 1968; 45(8): 571-574. https://dx.doi.org/10.1007/BF02667173
Kandeel EM, Badr EE, El-Sadek BM. Novel gemini cationic surfactants based on N, N-dimethyl fatty hydrazide and 1,3-dibromopropane: Synthesis, evaluation of surface and antimicrobial properties. J Oleo Sci. 2010; 59(12): 647-652. https://dx.doi.org/10.5650/jos.59.647
Quah JX, Ambu S, Lim YAL, Mahdy MAK, Mak JW. Molecular identification of Cryptosporidium parvum from avian hosts. Parasitology. 2011; 138(5): 573-577. https://dx.doi.org/10.1017/S0031182010001691
Madbouly Taha N, Salah A. Yousof HA, El-Sayed SH, Younis AI, Ismail Negm MS. Atorvastatin repurposing for the treatment of cryptosporidiosis in experimentally immunosuppressed mice. Exp Parasitol. 2017; 181: 57-69. https://dx.doi.org/10.1016/j.exppara.2017.07.010
Garba A, Tohon Z, Sidiki A, Chippaux JP, Chabalier F de. Efficacité et tolérance du praziquantel chez l’enfant d’âge scolaire en zone hyper-endémique à Schistosoma haematobium (Niger, 1999). Bull Soc Pathol Exot. 2001; 94(1): 42-45. http://dx.doi.org/10.3390/pharmaceutics12010023
Carter KC, Baillie AJ, Mullen AB. The cured immune phenotype achieved by treatment of visceral leishmaniasis in the BALB/c mouse with a nonionic surfactant vesicular formulation of sodium stibogluconate does not protect against reinfection. Clin Diagn Lab Immunol. 1999; 6(1): 61-65. https://dx.doi.org/10.1128/cdli.6.1.61-65.1999
Barnes JM, Paget GE. 2 Mechanisms of Toxic Action. Prog Med Chem. 1965; 4(C): 18-38. https://dx.doi.org/10.1016/S0079-6468(08)70166-8
Rasmussen KR, Healey MC. Experimental Cryptosporidium parvum infections in immunosuppressed adult mice. Infect Immun. 1992; 60(4): 1648-1652. https://dx.doi.org/10.1128/iai.60.4.1648-1652.1992
Tarazona R, Blewett DA, Carmona MD. Cryptosporidium parvum infection in experimentally infected mice: Infection dynamics and effect of immunosuppression. Folia Parasitol (Praha). 1998; 45(2): 101-107.
Henriksen S A, Pohlenz JFL. Staining of cryptosporidia by a modified Ziehl-Neelsen technique. Acta Vet Scand. 1981; 22: 594-596. https://dx.doi.org/10.1186/BF03548684
Penido MLDO, Nelson DL, Vieira LQ, Coelho PMZ. Schistosomicidal Activity of Alkylaminooctanethiosulfuric Acids. Mem Inst Oswaldo Cruz. 1994; 89(4): 595-602. https://doi.org/10.1590/S0074-02761994000400017
Day CE. Histopathology: Methods and Protocols. 1st ed Humana Press; 2014. 1180: 31-43. https://link.springer.com/book/10.1007/978-1-4939-1050-2
Hui E. Learn R for Applied Statistics With Data Visualizations, Regressions, and Statistics. 1st ed. APress; 2019. 173-236.
Labena A, Hegazy MA, Horn H, Müller E. Sulfidogenic-corrosion inhibitory effect of cationic monomeric and gemini surfactants: Planktonic and sessile diversity. RSC Adv. 2016; 6(48): 42263-42278. https://dx.doi.org/10.1039/c6ra02393b
Labena A, Hegazy MA, Kamel WM, Elkelish, A. &, Hozzein WN. Enhancement of a cationic surfactant by capping nanoparticles: Synthesis, characterization and multiple applications. Molecules. 2020; 25(9): 2007. https://doi.org/10.3390/molecules25092007
Ezzat AO, Tawfeek AM, Al-Lohedan HA. Synthesis and application of novel gemini pyridinium ionic liquids as demulsifiers for arabian heavy crude oil emulsions. Colloids Surfaces A Physicochem Eng Asp. 2022; 634: 127961. https://dx.doi.org/10.1016/j.colsurfa.2021.127961
Pillai P, Pal N, Mandal A. Synthesis, characterization, surface properties and micellization behaviour of imidazolium‐based ionic liquids. J Surfactants Deterg. 2017; 20(6): 1321-1335. https://doi.org/10.1007/s11743-017-2021-1
Alazrak SM, Awad S, Khalil AA, El-Dougdoug W. Synthesis and evaluation of new cationic polymeric surfactant based on n-phthalimidomethyl methacrylate. Egypt J Chem. 2021; 64(7): 3861-3872. https://dx.doi.org/10.21608/ejchem.2021.54791.3224
Kareem SH, Zead LA. CMC Determination and Thermodynamic Micellisation Of NPE Surfactant In Aqueous And CH 3 OH – H 2 O Solvents. Baghdad Sci J. 2013; 10(3): 1050-1056.
Moulik SP, Rakshit AK, Naskar B. Evaluation of Non-Ambiguous Critical Micelle Concentration of Surfactants in Relation to Solution Behaviors of Pure and Mixed Surfactant Systems: A Physicochemical Documentary and Analysis. J Surfactants Deterg. 2021; 24(4): 535-549. https://dx.doi.org/10.1002/jsde.12503
Azum N, Rub MA, Asiri AM, Bawazeer WA. Micellar and interfacial properties of amphiphilic drug–non-ionic surfactants mixed systems: Surface tension, fluorescence and UV–vis studies. Colloids Surfaces A Physicochem Eng Asp. 2017; 522: 183-192. https://dx.doi.org/10.1016/j.colsurfa.2017.02.093
Bhadani A, Endo T, Sakai K, Sakai H, Abe M. Synthesis and dilute aqueous solution properties of ester functionalized cationic gemini surfactants having different ethylene oxide units as spacer. Colloid Polym Sci. 2014; 292(7): 1685-1692. https://dx.doi.org/10.1007/s00396-014-3233-9
Bhadani A, Tani M, Endo T, Sakai K, Abe M, Sakai H. New ester based gemini surfactants: the effect of different cationic headgroups on micellization properties and viscosity of aqueous micellar solution. Phys Chem Chem Phys. 2015; 17(29): 19474-19483. https://dx.doi.org/10.1039/c5cp02115d
Rosen MJ, Kunjappu JT. Surfactants and Interfacial Phenomena. 4th ed WILEY. New Jersey; 2012: 1-38. https://dx.doi.org/10.1002/9781118228920
Puvvada S, Blankschtein D. Molecular-thermodynamic approach to predict micellization, phase behavior and phase separation of micellar solutions. I. Application to nonionic surfactants. J Chem Phys. 1990; 92(6): 3710-3724. https://dx.doi.org/10.1063/1.457829
Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release. 2001; 73(2-3): 137-172. https://dx.doi.org/10.1016/S0168-3659(01)00299-1
Krishna AK, Flanagan DR. Micellar solubilization of a new antimalarial drug, β‐arteether. J Pharm Sci. 1989; 78(7): 574-576. https://dx.doi.org/10.1002/jps.2600780713
Mosmann T. Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. RSC Adv. 1983; 6(65): 55-63. https://dx.doi.org/10.1016/0022-1759(83)90303-4
Abd-El-Aziz AS, El-Ghezlani EG, Elaasser MM, Afifi TH, Okasha RM. First Example of Cationic Cyclopentadienyliron Based Chromene Complexes and Polymers: Synthesis, Characterization, and Biological Applications. J Inorg Organomet Polym Mater. 2020; 30(1): 131-146. https://dx.doi.org/10.1007/s10904-019-01295-w
El-Badry AA, Abdel Aziz IZ, Shoeib EY, Ghallab MMI. Cryptosporidium genotypes and associated risk factors in a cohort of Egyptian children. Comp Clin Path. 2017; 26(5): 1017-1021. doi:10.1007/s00580-017-2477-4
Pumipuntu N, Piratae S. Cryptosporidiosis: A zoonotic disease concern. Vet World. 2018; 11(5): 681-686. https://dx.doi.org/10.14202/vetworld.2018.681-686
Wang R jun, Li J qiang, Chen Y cai, Zhang L xian, Xiao L hua. Widespread occurrence of Cryptosporidium infections in patients with HIV/AIDS: Epidemiology, clinical feature, diagnosis, and therapy. Acta Trop. 2018; 187: 257-263. https://dx.doi.org/10.1016/j.actatropica.2018.08.018
Sosnik A, Augustine R. Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them. Adv Drug Deliv Rev. 2016; 103: 105-120. https://dx.doi.org/10.1016/j.addr.2015.12.022
Kanoje B, Patel D, Kumar V, Sahoo SK, Parikh J, Kuperkar K. Unraveling the solubilization and cytotoxicity study of poorly water-soluble anti-inflammatory drug in aqueous Gemini surfactants solution with physicochemical characterization and simulation study. Colloids Surfaces B Biointerfaces. 2019; 179: 437-444. https://dx.doi.org/10.1016/j.colsurfb.2019.03.059
Fatma N, Panda M, Ansari WH. Colloids and Surfaces A : Physicochemical and Engineering Aspects Solubility enhancement of anthracene and pyrene in the mixtures of a cleavable cationic gemini surfactant with conventional surfactants of different polarities. Colloids Surfaces A Physicochem Eng Asp. 2015; 467: 9-17. https://dx.doi.org/10.1016/j.colsurfa.2014.11.010
Gaggero A, Jurišić Dukovski B, Radić I, et al. Co-grinding with surfactants as a new approach to enhance in vitro dissolution of praziquantel. J Pharm Biomed Anal. 2020; 189: 1-12. https://dx.doi.org/10.1016/j.jpba.2020.113494
Kolenyak-Santos F, Garnero C, De Oliveira RN, De Souza AL, Chorilli M, Allegretti SM, et al. Nanostructured lipid carriers as a strategy to improve the in vitro schistosomiasis activity of Praziquantel. J Nanosci Nanotechnol. 2015; 15(1): 761-772. https://dx.doi.org/10.1166/jnn.2015.9186
Abdelhamed E, Fawzy E, Ahmed S, Zalat R, Rashed H. Effect of Nitazoxanide, Artesunate Loaded Polymeric Nano Fiber and Their Combination on Experimental Cryptosporidiosis. Iran J Parasitol. 2019; 14(2): 240-249.
Fahmy M-E, Abdelaa A, Hassan S, Shalaby M, Ismail MA, Khairy R, et al. Antiparasitic and immunomodulating effects of nitazoxanide , ivermectin and selenium on Cryptosporidium infection in diabetic mice. Rev Bras Parasitol Veterinária. 2021; 30(4): 1-16. https://dx.doi.org/10.1590/S1984-29612021087
Sadek GS, El-Aswad BE. Role of COX-2 in pathogenesis of intestinal Cryptosporidiosis and effect of some drugs on treatment of infection. Res J Parasitol. 2014; 9(2): 21-40. https://dx.doi.org/10.3923/jp.2014.21.40
El-wakil ES, Salem AE, Al-Ghandour AM. Evaluation of possible prophylactic and therapeutic effect of mefloquine on experimental cryptosporidiosis in immunocompromised mice. J Parasit Dis. 2021; 45(2): 380-393. https://dx.doi.org/10.1007/s12639-020-01315-4
Certad G, Benamrouz S, Guyot K, Mouray A, Chassat T, Flament N, et al. Fulminant Cryptosporidiosis after Near-Drowning : a Human Cryptosporidium parvum Strain Implicated in Invasive Gastrointestinal Adenocarcinoma and Cholangiocarcinoma in an Experimental Model. Appl Environ Microbiol. Published online 2012: 1746-1751. https://dx.doi.org/10.1128/AEM.06457-11
Metawae A, Bayoumy A, Ali I, Hammam O, Temsah K. Efficacy of Nitazoxanide Alone or Loaded with Silica Nanoparticle for Treatment of Cryptosporidiosis in Immunocompetent Hosts. Int J Med Arts. 2021; 3(1): 1229-1239. https://dx.doi.org/10.21608/ijma.2021.55788.1237
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