Efficacy of clofazimine and nitazoxanide combination in treating intestinal cryptosporidiosis and enhancing intestinal cellular regeneration in immunocompromised mice

Esmat, Marwa; Abdel-Aal, Amany Ahmed; Shalaby, Maisa Ahmed; Badawi, Manal Abdelmaged; El-Askary, Hala M.; Yousif, Ahmed Badawi; Fahmy, Mennat-Elrahman Ahmed

doi:10.1016/j.fawpar.2022.e00161

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…For the induction of a mouse model of immunosuppression, dexamethasone was used. Dexamethasone was used in the present study for induction of immune suppression following previous studies ( 31 , 33 , 34 , 59 , 60 ). Convincing evidence shows that EUG possesses potent antimicrobial, antifungal, antibacterial, and anti-parasitic properties ( 14–21 ), however, information about its anti-cryptosporidial properties is limited.…”

Section: Discussionmentioning

confidence: 99%

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In silico and in vivo evaluation of the anti-cryptosporidial activity of eugenol

Gattan,

Wakid,

Qahwaji

et al. 2024

Front. Vet. Sci.

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BackgroundCryptosporidiosis is an opportunistic parasitic disease widely distributed worldwide. Although Cryptosporidium sp. causes asymptomatic infection in healthy people, it may lead to severe illness in immunocompromised individuals. Limited effective therapeutic alternatives are available against cryptosporidiosis in this category of patients. So, there is an urgent need for therapeutic alternatives for cryptosporidiosis. Recently, the potential uses of Eugenol (EUG) have been considered a promising novel treatment for bacterial and parasitic infections. Consequently, it is suggested to investigate the effect of EUG as an option for the treatment of cryptosporidiosis.Materials and methodsThe in silico bioinformatics analysis was used to predict and determine the binding affinities and intermolecular interactions of EUG and Nitazoxanide (NTZ) toward several Cryptosporidium parvum (C. parvum) lowa II target proteins. For animal study, five groups of immunosuppressed Swiss albino mice (10 mice each) were used. Group I was left uninfected (control), and four groups were infected with 1,000 oocysts of Cryptosporidium sp. The first infected group was left untreated. The remaining three infected groups received NTZ, EUG, and EUG + NTZ, respectively, on the 6th day post-infection (dpi). All mice were sacrificed 30 dpi. The efficacy of the used formulas was assessed by counting the number of C. parvum oocysts excreted in stool of infected mice, histopathological examination of the ileum and liver tissues and determination of the expression of iNOS in the ileum of mice in different animal groups.Resultstreatment with EUG resulted in a significant reduction in the number of oocysts secreted in stool when compared to infected untreated mice. In addition, oocyst excretion was significantly reduced in mice received a combination therapy of EUG and NTZ when compared with those received NTZ alone. EUG succeeded in reverting the histopathological alterations induced by Cryptosporidium infection either alone or in combination with NTZ. Moreover, mice received EUG showed marked reduction of the expression of iNOS in ileal tissues.ConclusionBased on the results, the present study signified a basis for utilizing EUG as an affordable, safe, and alternative therapy combined with NTZ in the management of cryptosporidiosis.

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Section: Discussionmentioning

confidence: 99%

“…All the experimental animals were subjected to immune suppression using dexamethasone orally at a dose of 0.25 mg/g/day for 14 successive days prior to inoculation with Cryptosporidium oocysts (31). The mice continued to receive dexamethasone at the same dose throughout the experiment (32)(33)(34).…”

Section: Animals and Infectionmentioning

confidence: 99%

In silico and in vivo evaluation of the anti-cryptosporidial activity of eugenol

Gattan,

Wakid,

Qahwaji

et al. 2024

Front. Vet. Sci.

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“…The innate immune elements are the main factors that encounter the invading cryptosporidial sporozoites. They include the intestinal mechanical barriers (represented in the thick mucus layer and intestinal epithelial cells), chemokines, cytokines and antimicrobial peptides (AMPs) [57][58][59]. When the intestinal mucosa confronts self-damage or pathogen-associated molecular patterns (DAMPs or PAMPs), the immune system initiates an inflammatory status [60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Pyroptosis Tuning in Intestinal Cryptosporidiosis via the Natural Histone Deacetylase Inhibitor Romidepsin

Shalaby,

Shoheib,

Yassin

et al. 2024

Parasite Immunology

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Cryptosporidium is an opportunistic protozoan, with many species of cross‐human infectivity. It causes life‐threatening diarrhoea in children and CD4‐defective patients. Despite its limited efficacy, nitazoxanide remains the primary anti‐cryptosporidial drug. Cryptosporidium infects the intestinal brush border (intracellular–extracytoplasmic) and down‐regulates pyroptosis to prevent expulsion. Romidepsin is a natural histone deacetylase inhibitor that triggers pyroptosis. Romidepsin's effect on cryptosporidiosis was assessed in immunocompromised mice via gasdermin‐D (GSDM‐D) immunohistochemical expression, IFN‐γ, IL‐1β and IL‐18 blood levels by ELISA, and via parasite scanning by modified Ziehl–Neelsen staining and scanning electron microscopy (SEM). Oocyst deformity and local cytokines were also assessed in ex vivo ileal explants. Following intraperitoneal injection of romidepsin, oocyst shedding significantly reduced at the 9th, 12th and 15th d.p.i. compared with infected‐control and drug‐control (nitazoxanide‐treated) mice. H&E staining of intestinal sections from romidepsin‐treated mice showed significantly low intestinal scoring with marked reduction in epithelial hyperplasia, villous blunting and cellular infiltrate. SEM revealed marked oocyst blebbing and paucity (in vivo and ex vivo) after romidepsin compared with nitazoxanide. Regarding pyroptosis, romidepsin triggered significantly higher intestinal GSDM‐D expression in vivo, and higher serum/culture IFN‐γ, IL‐1β and IL‐18 levels in romidepsin‐treated mice than in the control groups. Collectively, in cryptosporidiosis, romidepsin succeeded in enhancing pyroptosis in the oocysts and infected epithelium, reducing infection and shifting the brush border towards normalisation.

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“…19 Clofazimine, an orally administered antimicrobial approved by the US Food and Drug Administration (FDA) to treat leprosy and a "Group B" drug recommended by the World Health Organization to treat multidrug-resistant (MDR) tuberculosis (TB), was shown to be effective in controlling Cryptosporidium infection in preclinical in vitro and in vivo models. [20][21][22] Although clofazimine's PK and safety profiles had been studied in healthy volunteers, leprosy patients, and MDR-TB patients, no study had been conducted for cryptosporidiosis patients until a phase IIa trial was conducted in Malawi in HIV-infected adults. [23][24][25][26][27] The trial employed a unique two-part design by which clofazimine PK data were collected from HIV-infected adults with or without Cryptosporidium infection matched based on weight, sex, and age.…”

Section: How Might This Change Drug Discovery Development And/or Ther...mentioning

confidence: 99%

“…It was estimated that Cryptosporidium infection resulted in more than 48,000 deaths and more than 4.2 million disability‐adjusted life‐years lost in 2016 alone 19 . Clofazimine, an orally administered antimicrobial approved by the US Food and Drug Administration (FDA) to treat leprosy and a “Group B" drug recommended by the World Health Organization to treat multi‐drug‐resistant (MDR) tuberculosis (TB), was shown to be effective in controlling Cryptosporidium infection in preclinical in vitro and in vivo models 20–22 . Although clofazimine's PK and safety profiles had been studied in healthy volunteers, leprosy patients, and MDR‐TB patients, no study had been conducted for cryptosporidiosis patients until a phase IIa trial was conducted in Malawi in HIV‐infected adults 23–27 .…”

Section: Introductionmentioning

confidence: 99%

Clofazimine pharmacokinetics in HIV‐infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics

Zhang,

Conrad,

Hermann

et al. 2024

CPT Pharmacom & Syst Pharma

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Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea‐associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)–infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea‐associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV‐infected adults with/without Cryptosporidium infection using nonlinear mixed‐effects modeling. Covariates describing cryptosporidiosis‐associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two‐compartment model with lag time and first‐order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h−1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

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Efficacy of clofazimine and nitazoxanide combination in treating intestinal cryptosporidiosis and enhancing intestinal cellular regeneration in immunocompromised mice

Cited by 8 publications

References 52 publications

In silico and in vivo evaluation of the anti-cryptosporidial activity of eugenol

In silico and in vivo evaluation of the anti-cryptosporidial activity of eugenol

Pyroptosis Tuning in Intestinal Cryptosporidiosis via the Natural Histone Deacetylase Inhibitor Romidepsin

Clofazimine pharmacokinetics in HIV‐infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics

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