Nitazoxanide: In vitro and in vivo drug effects against Trichuris muris and Ancylostoma ceylanicum, alone or in combination

Abstract Our work aimed to evaluate the possible effect of Annona muricata (Graviola) leaf extract on Trichinella spiralis in in vitro and in vivo studies. Trichinella spiralis worms were isolated from infected mice and transferred to three culture media – group I (with no drugs), group II (contained Graviola) and group III (contained albendazole) – then they were examined using the electron microscope. In the in vivo study, mice were divided into five groups: GI (infected untreated), GII (prophylactically treated with Graviola for seven days before infection), GIII (infected and treated with Graviola), GIV (infected and treated with albendazole) and GV (infected and treated with a combination of Graviola plus albendazole in half doses). Drug effects were assessed by adults and larvae load beside the histopathological small intestinal and muscular changes. A significant reduction of adult and larval counts occurred in treated groups in comparison to the control group. Histopathologically, marked improvement in the small intestinal and muscular changes was observed in treated groups. Also, massive destruction of the cultured adults’ cuticle was detected in both drugs. This study revealed that Graviola leaves have potential activity against trichinellosis, especially in combination with albendazole, and could serve as an adjuvant to anti-trichinellosis drug therapy.

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Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

International Journal for Parasitology Drugs and Drug Resistance ◽

10.1016/j.ijpddr.2017.03.005 ◽

2017 ◽

Vol 7 (2) ◽

pp. 159-173 ◽

Cited By ~ 9

Author(s):

Noemi Cowan ◽

Charles Meier ◽

Anna Neodo ◽

Jennifer Keiser

Keyword(s):

Gastrointestinal Nematodes ◽

Trichuris Muris ◽

Heligmosomoides Polygyrus ◽

Albendazole Sulfoxide ◽

Oxantel Pamoate ◽

Drug Entry

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In vitro and in vivo anthelmintic efficacy of plant cysteine proteinases against the rodent gastrointestinal nematode, Trichuris muris

Parasitology ◽

10.1017/s003118200500973x ◽

2006 ◽

Vol 132 (05) ◽

Cited By ~ 51

Author(s):

G. STEPEK ◽

A. E. LOWE ◽

D. J. BUTTLE ◽

I. R. DUCE ◽

J. M. BEHNKE

Keyword(s):

Gastrointestinal Nematode ◽

Cysteine Proteinases ◽

Trichuris Muris ◽

Anthelmintic Efficacy

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Effect of combinations of marketed human anthelmintic drugs against Trichuris muris in vitro and in vivo

Parasites & Vectors ◽

10.1186/1756-3305-5-292 ◽

2012 ◽

Vol 5 (1) ◽

Cited By ~ 26

Author(s):

Jennifer Keiser ◽

Lucienne Tritten ◽

Roberto Adelfio ◽

Mireille Vargas

Keyword(s):

Trichuris Muris ◽

Anthelmintic Drugs

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New Insight to Overcome Tumor Resistance: An Overview from Cellular to Clinical Therapies

Life ◽

10.3390/life11111131 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1131

Author(s):

Giulia Mitola ◽

Paolo Falvo ◽

Francesco Bertolini

Keyword(s):

Residual Disease ◽

Drug Effects ◽

Point Of View ◽

Tumor Resistance ◽

Cancer Treatments ◽

Secondary Tumors ◽

Molecular Features ◽

Preclinical And Clinical Studies

Disease relapse caused by drug resistance still represents a major clinical hurdle in cancer treatments. Tumor cells may take advantage of different intracellular and genetic systems attenuating the drug effects. Resistant cells or minimal residual disease (MRD) cells have strong clinical relevance, as they might give rise to secondary tumors when the therapy is concluded. Thus, MRDs are crucial therapeutic targets in order to prevent tumor relapse. Therefore, several groups aim at understanding how MRDs are orginated, characterizing their molecular features, and eradicating them. In this review, we will describe MRD from a genetic, evolutionary, and molecular point of view. Moreover, we will focus on the new in vitro, in vivo, preclinical, and clinical studies that aim at eradicating tumor resistance.

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Kidney-based in vitro models for drug-induced toxicity testing

Archives of Toxicology ◽

10.1007/s00204-019-02598-0 ◽

2019 ◽

Vol 93 (12) ◽

pp. 3397-3418 ◽

Cited By ~ 10

Author(s):

João Faria ◽

Sabbir Ahmed ◽

Karin G. F. Gerritsen ◽

Silvia M. Mihaila ◽

Rosalinde Masereeuw

Keyword(s):

Adverse Effects ◽

Drug Disposition ◽

Drug Effects ◽

Toxicity Testing ◽

Cell Types ◽

In Vitro Assays ◽

Vascular Effects ◽

Drug Induced

Abstract The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs’ microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

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NMR-Based Metabolomics in Metal-Based Drug Research

Molecules ◽

10.3390/molecules24122240 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2240 ◽

Cited By ~ 6

Author(s):

Federica De Castro ◽

Michele Benedetti ◽

Laura Del Coco ◽

Francesco Paolo Fanizzi

Keyword(s):

Drug Exposure ◽

Drug Research ◽

Tumor Response ◽

Drug Effects ◽

Platinum Complexes ◽

Ruthenium Compounds ◽

Biological Substrates ◽

Metabolomic Approach

Thanks to recent advances in analytical technologies and statistical capabilities, the application field of metabolomics has increased significantly. Currently, this approach is used to investigate biological substrates looking for metabolic profile alterations, diseases markers, and drug effects. In particular, NMR spectroscopy has shown great potential as a detection technique, mainly for the ability to detect multiple (10s to 100s) metabolites at once without separation. Only in recent years has the NMR-based metabolomic approach been extended to investigate the cell metabolic alterations induced by metal-based antitumor drug administration. As expected, these studies are mainly focused on platinum complexes, but some palladium and ruthenium compounds are also under investigation. The use of a metabolomics approach was very effective in assessing tumor response to drugs and providing insights into the mechanism of action and resistance. Therefore, metabolomics may open new perspectives into the development of metal-based drugs. In particular, it has been shown that NMR-based, in vitro metabolomics is a powerful tool for detecting variations of the cell metabolites induced by the metal drug exposure, thus offering also the possibility of identifying specific markers for in vivo monitoring of tumor responsiveness to anticancer treatments.

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Lenalidomide Reduces Survival of Chronic Lymphocytic Leukemia Cells in Primary Co-Cultures by Altering the Myeloid Microenvironment

Blood ◽

10.1182/blood.v120.21.3894.3894 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3894-3894

Author(s):

Angela Schulz ◽

Claudia Dürr ◽

Thorsten Zenz ◽

Stephan Stilgenbauer ◽

Peter Lichter ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Drug Effects ◽

Surface Expression ◽

Lymphocytic Leukemia ◽

Cell Surface Expression ◽

Clinical Activity ◽

Altered Expression

Abstract Abstract 3894 Chronic lymphocytic leukemia (CLL) cells are highly dependent on their microenvironment. External stimuli provided by bone marrow stromal cells or non-malignant leukocytes are required for their survival and proliferation. Interestingly, peripheral blood-derived monocytes differentiate in the presence of CLL cells to so-called Nurse-like cells (NLCs), which are round or fibroblast-shaped adherent cells that were shown to promote survival of CLL cells in vitro and to exist in lymph nodes of CLL patients. In search of new therapeutic options for patients with CLL, the immunomodulatory drug lenalidomide turned out to have significant clinical activity in CLL. Lenalidomide does not induce apoptosis in CLL cells directly, but is rather believed to act via the microenvironment. Several studies described that it alters cytokine levels and the activation status of the cells. Further, a CLL-specific T-cell defect was shown to be repaired by lenalidomide, which might represent a major activity of this drug in CLL. However, its mechanism of action seems to be complex and is not well understood. As monocytes as well as NLCs are very effective in maintaining survival of CLL cells, we aimed to investigate whether lenalidomide interferes with these supportive cell-cell interactions. To do this, we established primary co-cultures of monocytes and CLL cells in the presence or absence of lenalidomide and observed a significantly decreased viability of CLL cells after 14 days of treatment, suggesting an impact of this drug on the survival support of NLCs. Therefore, we analyzed the immunophenotype of NLCs by flow cytometry, as well as the secretion of cytokines in the co-cultures by ELISA and antibody-coupled bead arrays. Among the effects induced by lenalidomide, we observed reduced cell surface expression of the MHC II protein HLA-DR on NLCs as well as lower levels of the chemokine CCL2, but higher levels of IL-10 in the culture supernatant, indicating an altered inflammatory milieu in the co-cultures. The enhanced IL-10 levels resulted in an increase in STAT1 phosphorylation in CLL cells as measured by Western blot analysis. As a consequence, enhanced expression of the adhesion molecule ICAM-1 (CD54) and an altered expression of cytoskeletal genes (e.g. RHOC and CORO1B) were observed in CLL cells after lenalidomide treatment. Chemotaxis assays using transwell culture dishes and SDF1-α as chemoattractant revealed an impaired migratory potential of lenalidomide-treated CLL cells, which was not due to reduced expression of the SDF1-α receptor CXCR4. In summary, our data show that lenalidomide reduces the survival support of NLCs for CLL cells in vitro, suggesting that this drug effects the myeloid microenvironment in CLL in vivo. Furthermore, lenalidomide impairs the migratory potential of CLL cells which may affect circulation and homing of CLL cells in vivo. Disclosures: No relevant conflicts of interest to declare.

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Anthelmintic action of plant cysteine proteinases against the rodent stomach nematode,Protospirura muricola,in vitroandin vivo

Parasitology ◽

10.1017/s0031182006001302 ◽

2006 ◽

Vol 134 (1) ◽

pp. 103-112 ◽

Cited By ~ 37

Author(s):

G. STEPEK ◽

A. E. LOWE ◽

D. J. BUTTLE ◽

I. R. DUCE ◽

J. M. BEHNKE

Keyword(s):

Detrimental Effect ◽

Gastrointestinal Nematodes ◽

Cysteine Proteinases ◽

Trichuris Muris ◽

Kiwi Fruit ◽

Heligmosomoides Polygyrus ◽

Anthelmintic Efficacy ◽

Papaya Latex

Cysteine proteinases from the fruit and latex of plants, including papaya, pineapple and fig, were previously shown to have a rapid detrimental effect,in vitro, against the rodent gastrointestinal nematodes,Heligmosomoides polygyrus(which is found in the anterior small intestine) andTrichuris muris(which resides in the caecum). Proteinases in the crude latex of papaya also showed anthelmintic efficacy against both nematodesin vivo. In this paper, we describe thein vitroandin vivoeffects of these plant extracts against the rodent nematode,Protospirura muricola, which is found in the stomach. As in earlier work, all the plant cysteine proteinases examined, with the exception of actinidain from the juice of kiwi fruit, caused rapid loss of motility and digestion of the cuticle, leading to death of the nematodein vitro. In vivo, in contrast to the efficacy againstH. polygyrusandT. muris, papaya latex only showed efficacy againstP. muricolaadult female worms when the stomach acidity had been neutralized prior to administration of papaya latex. Therefore, collectively, our studies have demonstrated that, with the appropriate formulation, plant cysteine proteinases have efficacy against nematodes residing throughout the rodent gastrointestinal tract.

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In vitro anthelmintic effects of cysteine proteinases from plants against intestinal helminths of rodents

Journal of Helminthology ◽

10.1017/s0022149x0786408x ◽

2007 ◽

Vol 81 (4) ◽

pp. 353-360 ◽

Cited By ~ 19

Author(s):

Gillian Stepek ◽

Ann E. Lowe ◽

David J. Buttle ◽

Ian R. Duce ◽

Jerzy M. Behnke

Keyword(s):

Rapid Development ◽

Intestinal Helminths ◽

Cysteine Proteinases ◽

Trichuris Muris ◽

Heligmosomoides Polygyrus ◽

Development Of Resistance ◽

Taxonomic Groups ◽

Gi Helminths

AbstractInfections with gastrointestinal (GI) nematodes are amongst the most prevalent worldwide, especially in tropical climates. Control of these infections is primarily through treatment with anthelmintic drugs, but the rapid development of resistance to all the currently available classes of anthelmintic means that alternative treatments are urgently required. Cysteine proteinases from plants such as papaya, pineapple and fig are known to be substantially effective against three rodent GI nematodes, Heligmosomoides polygyrus, Trichuris muris and Protospirura muricola, both in vitro and in vivo. Here, based on in vitro motility assays and scanning electron microscopy, we extend these earlier reports, demonstrating the potency of this anthelmintic effect of plant cysteine proteinases against two GI helminths from different taxonomic groups – the canine hookworm, Ancylostoma ceylanicum, and the rodent cestode, Rodentolepis microstoma. In the case of hookworms, a mechanism of action targeting the surface layers of the cuticle indistinguishable from that reported earlier appears to be involved, and in the case of cestodes, the surface of the tegumental layers was also the principal location of damage. Hence, plant cysteine proteinases have a broad spectrum of activity against intestinal helminths (both nematodes and cestodes), a quality that reinforces their suitability for development as a much-needed novel treatment against GI helminths of humans and livestock.

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