scholarly journals In Vitro Activities of Itraconazole, Methiazole, and Nitazoxanide versus Echinococcus multilocularis Larvae

2006 ◽  
Vol 50 (9) ◽  
pp. 2966-2970 ◽  
Author(s):  
Stefan Reuter ◽  
Burkhard Manfras ◽  
Marion Merkle ◽  
Georg Härter ◽  
Peter Kern
Keyword(s):  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Combined Treatment ◽  
Larval Growth ◽  
Animal Experiments ◽  
Drug Discontinuation ◽  
Mongolian Gerbils ◽  
Larval Tissue ◽  
Deadly Disease

ABSTRACT Albendazole (ABZ) and mebendazole are the only drugs licensed for treatment of human alveolar echinococcosis. In order to augment the armamentarium against this deadly disease, we tested a series of drugs for their efficacy against Echinococcus multilocularis larvae. E. multilocularis larvae grown intraperitoneally in Mongolian gerbils were transferred into tissue culture. Vesicles budded from the tissue blocks and after 6 weeks, drugs were added, and the effect on the vesicles was observed. We tested the following drugs at various concentrations: ABZ, artemether, caspofungin, itraconazole (ITZ), ivermectin, methiazole (MTZ), miltefosine, nitazoxanide (NTZ), rifampin, and trimethoprim-sulfamethoxazole. ABZ, ITZ, MTZ, and NTZ effectively destroyed parasite vesicles in this in vitro culture system. At high NTZ doses of 10 μg/ml, disintegration of all vesicles was observed after 7 days and was significantly more rapid than with ABZ at equal concentrations (21 days). After drug discontinuation, regrowth of vesicles occurred between 7 and 14 days for all four drugs, indicating a parasitostatic effect. Combination treatment with NTZ-ABZ at concentrations between 1 and 10 μg/ml for either 3 weeks, 3 months, or 6 months yielded no vesicle regrowth during 8 months after drug discontinuation. The treated larval tissue was injected intraperitoneally into gerbils, and no regrowth of larval tissue was observed, suggesting a parasitocidal effect after combined treatment. ITZ, MTZ, and NTZ are potent inhibitors of larval growth, although they proved to be parasitostatic only. The combination of NTZ plus ABZ was parasitocidal in vitro. Animal experiments are warranted for studies of dose, toxicity, and drug interactions.

scholarly journals Effect of Amphotericin B on Larval Growth of Echinococcus multilocularis

2003 ◽  
Vol 47 (2) ◽  
pp. 620-625 ◽  
Author(s):  
Stefan Reuter ◽  
Marion Merkle ◽  
Klaus Brehm ◽  
Peter Kern ◽  
Burkhard Manfras
Keyword(s):  
Amphotericin B ◽  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Larval Growth ◽  
Mongolian Gerbils ◽  
Effective Treatment Option ◽  
Destructive Effect ◽  
Promising Alternative ◽  
Vitro Effect

ABSTRACT Alveolar echinococcosis is caused by the parasitic cestode Echinococcus multilocularis. Benzimidazoles, namely, mebendazole and albendazole, are the only drugs available for the treatment of inoperable alveolar echinococcosis. At present, no therapeutic alternative is available for patients with progressive disease under treatment or for patients who are unable to tolerate the side effects of the benzimidazoles. In addition, benzimidazoles are only parasitostatic for E. multilocularis. Thus, new therapeutic options are of paramount importance. In the present study we examined the in vitro effect of amphotericin B on E. multilocularis larvae. E. multilocularis metacestodes grown in the peritoneal cavities of Mongolian gerbils were transferred into a culture system. Vesicles budded from the tissue blocks and increased in number and size during the first 5 weeks. After 6 weeks drugs were added and deleterious effects on the vesicles were observed macroscopically and microscopically. By use of this in vitro tissue culture model we demonstrated that amphotericin B effectively inhibits the growth of E. multilocularis metacestodes. This destructive effect was significantly more rapid with amphotericin B than with the benzimidazoles. Cyclic treatment was effective in suppressing parasite growth. However, amphotericin B appears to be parasitostatic for E. multilocularis larvae, and regrowth occurs even after extended periods. In summary, amphotericin B constitutes the first promising alternative for the treatment of alveolar echinococcosis in cases of intolerance or resistance to benzimidazoles. It holds promise as an effective treatment option for otherwise fatal courses of disease.

scholarly journals Immune response of mice to Echinococcus multilocularis infection after therapy with amphotericin B colloidal dispersion

2007 ◽  
Vol 44 (2) ◽  
pp. 47-56 ◽  
Author(s):  
J. Porubcová ◽  
E. Dvorožňáková ◽  
Z. Ševčíková
Keyword(s):  
Immune Response ◽  
Amphotericin B ◽  
Echinococcus Multilocularis ◽  
Proliferative Response ◽  
Larval Growth ◽  
Colloidal Dispersion ◽  
Cell Subpopulation ◽  
Th2 Immune Response ◽  
Ifn Γ

AbstractThe effect of amphotericin B colloidal dispersion (ABCD) on selected immunological parameters and growth of the larval cysts in mice infected intraperitoneally with Echinococcus multilocularis protoscoleces was observed. ABCD was administered at a dose 10 mg/kg body weight twice a week from week 5 to 10 post infection (p.i.). The Echinococcus infection suppressed the proliferative response of splenic T lymphocytes to nonspecific mitogen concanavalin A throughout almost the whole course of the experiment and ABCD administration did not affect this inhibittion. The increase in the proliferative response of B lymphocytes to lipopolysaccharide was found in infected mice with ABCD treatment from week 6 to 10 p.i. ABCD induced a significant rise of the splenic CD4 T cell subpopulation in infected mice only on week 6 p.i. The CD8 T subpopulation was not influenced by the therapy. The level of serum Th1 cytokine IFN-γ in infected and ABCD treated mice was elevated only at week 8 p.i., while the level of serum Th2 cytokine IL-5 was not influenced by the therapy. The ABCD treatment inhibited the IFN-γ production by splenocytes in vitro from week 6 to 10 p.i. On the contrary, the IL-5 production in vitro was stimulated at weeks 8 and 12 p.i. None antiparasitic effect of ABCD on larval growth was determined.Results suggest that amphotericin B colloidal dispersion did not affect the inhibited Th1 immune response after parasite infection. On the contrary, ABCD advanced the Th2 immune response development, which allows the progressive growth of the parasite.

Long-term (35 years) cryopreservation of Echinococcus multilocularis metacestodes

Parasitology ◽  
2020 ◽  
Vol 147 (9) ◽  
pp. 1048-1054
Author(s):  
Teivi Laurimäe ◽  
Philipp A. Kronenberg ◽  
Cristian A. Alvarez Rojas ◽  
Theodor W. Ramp ◽  
Johannes Eckert ◽  
...  
Keyword(s):  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Geographic Origin ◽  
Experimental Animals ◽  
Long Term Storage ◽  
Term Maintenance ◽  
Term Storage

AbstractThe metacestode of Echinococcus multilocularis is the etiological agent of alveolar echinococcosis. The metacestode stage used for research is maintained in rodents by serial passages. In order to determine whether cryopreservation of E. multilocularis metacestodes would be suitable for long-term maintenance and replace serial passages, isolates of different geographic origin were cryopreserved in 1984–1986. The aim of the current study was to test the viability of cryopreserved isolates following long-term cryopreservation (up to 35 years) and to determine the phylogenetic clades these isolates belonged to. Cryopreserved isolates were tested for viability in vitro and in vivo in gerbils. In vitro results of 5 isolates indicated protoscolex survival in 13 of 17 experiments (76%) and metacestode survival in 5 of 12 (42%) in vivo experiments. In vivo results showed ‘abortive lesions’ in 13 of the 36 animals, 15 were negative and 8 harboured proliferating metacestode tissue containing protoscoleces. Genetic analysis confirmed the isolates belonged to European, Asian and North-American clades. In conclusion, the results of the current study indicate that metacestodes of E. multilocularis are able to survive long-term cryopreservation. Therefore, cryopreservation is a suitable method for long-term storage of E. multilocularis metacestode isolates and reduces the number of experimental animals.

scholarly journals A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

2019 ◽  
Author(s):  
Justin Komguep Nono ◽  
Manfred B. Lutz ◽  
Klaus Brehm
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Larval Stage ◽  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Activin A ◽  
Dependent Manner ◽  
Cell Type

ABSTRACTBackgroundAlveolar echinococcosis (AE), caused by the metacestode larval stage of the fox-tapeworm Echinococcus multilocularis, is a chronic zoonosis associated with significant modulation of the host immune response. A role of regulatory T-cells (Treg) in generating an immunosuppressive environment around the metacestode during chronic disease has been reported, but the molecular mechanisms of Treg induction by E. multilocularis remain elusive so far.Methodology/Principal findingsWe herein demonstrate that excretory/secretory (E/S) products of the E. multilocularis metacestode promote the formation of Foxp3+ Treg from CD4+ T-cells in vitro in a TGF-β-dependent manner. We also show that host T-cells secrete elevated levels of the immunosuppressive cytokine IL-10 in response to metacestode E/S products. Within the E/S fraction of the metacestode we identified an E. multilocularis activin A homolog (EmACT) that displays significant similarities to mammalian Transforming Growth Factor-β (TGF-β)/activin subfamily members. EmACT obtained from heterologous expression promoted host TGF-β-driven CD4+ Foxp3+ Treg conversion in vitro. Furthermore, like in the case of metacestode E/S products, EmACT-treated CD4+ T-cells secreted higher levels of IL-10. These observations suggest a contribution of EmACT in the in vitro expansion of Foxp3+ Treg by the E. multilocularis metacestode. Using infection experiments we show that intraperitoneally injected metacestode tissue expands host Foxp3+ Treg, confirming the expansion of this cell type in vivo during parasite establishment.Conclusions/SignificanceIn conclusion, we herein show that E. multilocularis larvae secrete a factor with clear structural and functional homologies to mammalian activin A. Like its mammalian homolog, this protein induces the secretion of IL-10 by T-cells and contributes to the expansion of TGF-β-driven Foxp3+ Treg, a cell type that has been reported crucial for generating a tolerogenic environment to support parasite establishment and proliferation.AUTHOR SUMMARYThe metacestode larval stage of the tapeworm E. multilocularis grows infiltratively, like a malignant tumor, within the organs of its human host, thus causing the lethal disease alveolar echinococcosis (AE). Immunosuppression plays an important role in both survival and proliferation of the metacestode, which mainly depends on factors that are released by the parasite. These parasite-derived molecules are potential targets for developing new anti-echinococcosis drugs and/or improving the effectiveness of current therapies. Additionally, an optimized use of such factors could help minimize pathologies resulting from over-reactive immune responses, like allergies and autoimmune diseases. The authors herein demonstrate that the E. multilocularis metacestode releases a protein, EmACT, with significant homology to activin A, a cytokine that might support host TGF-β in its ability to induce the generation of immunosuppressive regulatory T-cells (Treg) in mammals. Like its mammalian counterpart, EmACT was associated with the expansion of TGF-β-induced Treg and stimulated the release of elevated amounts of immunosuppressive IL-10 by CD4+ T-cells. The authors also demonstrate that Treg are locally expanded by the metacestode during an infection of mice. These data confirm an important role of Treg for parasite establishment and growth during AE and suggest a potential role of EmACT in the expansion of these immunosuppressive cells around the parasite.

scholarly journals In VitroandIn VivoActivities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

2013 ◽  
Vol 57 (8) ◽  
pp. 3829-3835 ◽  
Author(s):  
Tatiana Küster ◽  
Nadja Kriegel ◽  
David W. Boykin ◽  
Chad E. Stephens ◽  
Andrew Hemphill
Keyword(s):  
Active Compound ◽  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Treatment Options ◽  
Efficient Treatment ◽  
Content Type ◽  
Core Group

ABSTRACTAlveolar echinococcosis (AE) is a disease predominantly affecting the liver, with metacestodes (larvae) of the tapewormEchinococcus multilocularisproliferating and exhibiting tumor-like infiltrative growth. For many years, chemotherapeutical treatment against alveolar echinococcosis has relied on the benzimidazoles albendazole and mebendazole, which require long treatment durations and exhibit parasitostatic rather than parasiticidal efficacy. Although benzimidazoles have been and still are beneficial for the patients, there is clearly a demand for alternative and more efficient treatment options. Aromatic dications, more precisely a small panel of di-N-aryl-diguanidino compounds, were screened for efficacy againstE. multilocularismetacestodesin vitro. Only those with a thiophene core group were active against metacestodes, while furans were not. The most active compound, DB1127, was further investigated in terms ofin vivoefficacy in mice experimentally infected withE. multilocularismetacestodes. This diguanidino compound was effective against AE when administered intraperitoneally but not when applied orally. Thus, thiophene-diguanidino derivatives with improved bioavailability when administered orally could lead to treatment options against AE.

scholarly journals The susceptibility analysis of Echinococcus multilocularis protoscoleces tubulin to mebendazole and RNA interference

2020 ◽  
Author(s):  
Qiqi Shi ◽  
Lele Huo ◽  
Bin Jiang ◽  
Haijun Gao ◽  
Jinxin Zheng ◽  
...  
Keyword(s):  
Rna Interference ◽  
Echinococcus Multilocularis ◽  
Drug Target ◽  
Alveolar Echinococcosis ◽  
Molecular Level ◽  
Benzimidazole Derivatives ◽  
Flame Cell ◽  
Reverse Transcription Pcr ◽  
Transmission Electron

ABSTRACTAlveolar echinococcosis, caused by the larval (metacestode) stage of the tapeworm Echinococcus multilocularis, is a lethal parasitosis of the liver prevalent in the Northern Hemisphere. For chemotherapy the benzimidazole derivatives mebendazole and albendazole were introduced, which were found to disrupt the microtubules by inhibition of the polymerization of tubulin into microtubules, and β-tubulin was determined to be the drug target molecule. In the present study, we evaluated the chemosensitivity of E. multilocularis protoscoleces tubulin to mebendazole and RNA interference in vitro, and to explore whether the molecular level and ultrastructure of E. multilocularis protoscoleces microtubules change post-mebendazole and RNA interference. We identified that mebendazole is parasitostatic to E. multilocularis protoscoleces through suppression the tubulin expression and change the flame cell morphology in molecular level, besides RNA interference indicated that β 2 tubulin is probably one of the vital tubulin gene to form the flame cell and the protonephridial system tubules (collective tubes) of E. multilocularis protoscoleces. Molecular level and ultrastructure detection were performed by reverse transcription-PCR, western blotting and transmission electron microscope. The RNA interference would be probably as a parasitocidal method to disrupt the survival of PSCs, extend that the relevant tubulin maybe as potential target for drug development against AE.

scholarly journals In Vitro Activities of Benzimidazoles against Echinococcus multilocularis Metacestodes

1998 ◽  
Vol 42 (5) ◽  
pp. 1052-1056 ◽  
Author(s):  
Heike Jura ◽  
Augustinus Bader ◽  
Matthias Frosch
Keyword(s):  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Survival Rates ◽  
Meriones Unguiculatus ◽  
Benzimidazole Derivatives ◽  
Reverse Transcription Pcr ◽  
Clinical Observations ◽  
Vitro Model ◽  
First Time

ABSTRACT Alveolar echinococcosis, caused by the larval (metacestode) stage of the tapeworm Echinococcus multilocularis, is a lethal parasitosis of the liver prevalent in the Northern Hemisphere. For chemotherapy the benzimidazole derivatives mebendazole and albendazole were introduced, and their use has resulted in a significant improvement in the survival rates. However, data from experiments with animals and clinical observations indicate that these drugs elicit only parasitostatic activity and in most cases are not able to completely eliminate the parasitic metacestode tissue. In the present study, we applied a culture system for the in vitro growth and proliferation ofE. multilocularis metacestodes to analyze the parasitostatic and parasitocidal potential of mebendazole. Here, we demonstrate for the first time that at concentrations of >0.1 μM, i.e., at concentrations used for therapy of human alveolar echinococcosis, this antihelminth drug is parasitocidal in vitro. Viability assessment was performed by infection experiments withMeriones unguiculatus and mebendazole-treated metacestode tissue and by reverse transcription-PCR for the detection of E. multilocularis mRNA. The E. multilocularis in vitro model proved to be a valuable tool for the analysis of the potential of antihelminth drugs.

scholarly journals Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae

2021 ◽  
Vol 12 ◽  
Author(s):  
Zijing Wang ◽  
Ruopeng Cai ◽  
Gang Wang ◽  
Zhimin Guo ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Effect ◽  
Combined Treatment ◽  
Animal Experiments ◽  
Opportunistic Pathogen ◽  
Drug Resistant ◽  
Carbapenem Resistant ◽  
Acute Pneumonia

Klebsiella pneumoniae (K. pneumoniae) is an important nosocomial and community acquired opportunistic pathogen which causes various infections. The emergence of multi-drug resistant (MDR) K. pneumoniae and carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) has brought more severe challenge to the treatment of K. pneumoniae infection. In this study, a novel bacteriophage that specifically infects K. pneumoniae was isolated and named as vB_KpnM_P-KP2 (abbreviated as P-KP2). The biological characteristics of P-KP2 and the bioinformatics of its genome were analyzed, and then the therapeutic effect of P-KP2 was tested by animal experiments. P-KP2 presents high lysis efficiency in vitro. The genome of P-KP2 shows homology with nine phages which belong to “KP15 virus” family and its genome comprises 172,138 bp and 264 ORFs. Besides, P-KP2 was comparable to gentamicin in the treatment of lethal pneumonia caused by K. pneumoniae W-KP2 (K47 serotype). Furthermore, the combined treatment of P-KP2 and gentamicin completely rescued the infected mice. Therefore, this study not only introduces a new member to the phage therapeutic library, but also serves as a reference for other phage-antibiotic combinations to combat MDR pathogens.

Surgical treatment of alveolar echinococcosis: a single centre experience and systematic review of the literature

2019 ◽  
Vol 98 (4) ◽  
pp. 167-173
Keyword(s):  
Case Report ◽  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Lymphatic System ◽  
Surgical Intervention ◽  
Clinical Symptoms ◽  
Safety Margin ◽  
Surgical Removal ◽  
Single Centre Experience ◽  
Therapeutic Procedures

Introduction: Alveolar echinococcosis (AE) is a zoonosis caused by Echinococcus multilocularis. AE is primarily localised in the liver. Echinococcus multilocularis imitates tumour-like behaviour. It can metastasise through blood or lymphatic system to distant organs. Echinococcosis often remains asymptomatic due to its long incubation period and indistinct symptoms. Clinical symptoms are determined by the parasite’s location. Diagnosis of echinococcosis is based on medical history, clinical symptoms, laboratory tests, serology results, imaging methods and final histology findings. Surgical removal of the cyst with a safety margin, followed by chemotherapy is the therapeutic method of choice. Case report: We present a case report of alveolar echinococcosis in a thirty-year-old female patient in whom we surgically removed multiple liver foci of alveolar echinococcosis. The disease recurred after two years and required another surgical intervention. Conclusions: Alveolar echinococcosis is a disease with a high potential for a complete cure provided that it is diagnosed early and that the recommended therapeutic procedures are strictly adhered to.

Effects of Probiotics in the Management of Infected Chronic Wounds: From Cell Culture to Human Studies

2020 ◽  
Vol 15 (3) ◽  
pp. 193-206
Author(s):  
Brognara Lorenzo ◽  
Salmaso Luca ◽  
Mazzotti Antonio ◽  
Di M. Alberto ◽  
Faldini Cesare ◽  
...  
Keyword(s):  
Chronic Wounds ◽  
Animal Experiments ◽  
Multidrug Resistant ◽  
Preliminary Evidence ◽  
Human Studies ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Keywords Probiotics

Background: Chronic wounds are commonly associated with polymicrobial biofilm infections. In the last years, the extensive use of antibiotics has generated several antibiotic-resistant variants. To overcome this issue, alternative natural treatments have been proposed, including the use of microorganisms like probiotics. The aim of this manuscript was to review current literature concerning the application of probiotics for the treatment of infected chronic wounds. Methods: Relevant articles were searched in the Medline database using PubMed and Scholar, using the keywords “probiotics” and “wound” and “injuries”, “probiotics” and “wound” and “ulcer”, “biofilm” and “probiotics” and “wound”, “biofilm” and “ulcer” and “probiotics”, “biofilm” and “ulcer” and “probiotics”, “probiotics” and “wound”. Results: The research initially included 253 articles. After removal of duplicate studies, and selection according to specific inclusion and exclusion criteria, 19 research articles were included and reviewed, accounting for 12 in vitro, 8 in vivo studies and 2 human studies (three articles dealing with animal experiments included also in vitro testing). Most of the published studies about the effects of probiotics for the treatment of infected chronic wounds reported a partial inhibition of microbial growth, biofilm formation and quorum sensing. Discussion: The application of probiotics represents an intriguing option in the treatment of infected chronic wounds with multidrug-resistant bacteria; however, current results are difficult to compare due to the heterogeneity in methodology, laboratory techniques, and applied clinical protocols. Lactobacillus plantarum currently represents the most studied strain, showing a positive application in burns compared to guideline treatments, and an additional mean in chronic wound infections. Conclusions: Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings such as infected chronic wounds, large, long-term clinical trials are still lacking, and further research is needed.

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