Residual virulence of Brucella abortus in the absence of the cytochromebc1 complex in a murine model in vitro and in vivo

2000 ◽  
Vol 29 (3) ◽  
pp. 191-200 ◽  
Author(s):  
Jinkyung Ko ◽  
Gary A Splitter
Keyword(s):  
Murine Model ◽  
Brucella Abortus ◽  
Cytochromebc1 Complex ◽  
Residual Virulence

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

scholarly journals Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo

2021 ◽  
Vol 12 (38) ◽  
pp. 12719-12725
Author(s):  
Maria Varghese ◽  
Rae S. Rokosh ◽  
Carolyn A. Haller ◽  
Stacy L. Chin ◽  
Jiaxuan Chen ◽  
...  
Keyword(s):  
Murine Model ◽  
Protamine Sulfate ◽  
Clotting Time ◽  
Risk Of Bleeding ◽  
Increased Risk

Heparin mimicking sulfated poly-amido-saccharides (sulPASs) are anticoagulants resistant to heparanases and reversed by protamine sulfate. In an in vivo murine model, sulPASs extend clotting time without the increased risk of bleeding.

scholarly journals Quantitation of Candida albicans Ergosterol Content Improves the Correlation between In Vitro Antifungal Susceptibility Test Results and In Vivo Outcome after Fluconazole Treatment in a Murine Model of Invasive Candidiasis

2000 ◽  
Vol 44 (8) ◽  
pp. 2081-2085 ◽  
Author(s):  
Beth A. Arthington-Skaggs ◽  
David W. Warnock ◽  
Christine J. Morrison
Keyword(s):  
Murine Model ◽  
Invasive Candidiasis ◽  
Clinical Laboratory ◽  
Antifungal Susceptibility ◽  
Resistant Isolate ◽  
National Committee ◽  
Ergosterol Content ◽  
In Vitro Antifungal Susceptibility

ABSTRACT MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by “trailing” growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by C. albicansisolates which were trailers (M27-A MICs at 24 and 48 h, ≤1.0 and ≥64 μg/ml, respectively; SQM MIC, ≤1.0 μg/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, ≤1.0 μg/ml) and fluconazole resistant (M27-A MIC, ≥64 μg/ml; SQM MIC, 54 μg/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.

scholarly journals Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 371-379 ◽  
Author(s):  
Mariateresa Fulciniti ◽  
Pierfrancesco Tassone ◽  
Teru Hideshima ◽  
Sonia Vallet ◽  
Puru Nanjappa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Murine Model ◽  
Severe Combined Immunodeficiency ◽  
Neutralizing Antibody ◽  
Nuclear Factor Κb ◽  
Bone Lesions ◽  
Wnt Inhibitor

Abstract Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)–hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated β-catenin level while down-regulating nuclear factor-κB (NF-κB) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth.

scholarly journals 1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S411-S412
Author(s):  
Edward P Garvey ◽  
Andrew Sharp ◽  
Peter Warn ◽  
Christopher M Yates ◽  
Robert J Schotzinger
Keyword(s):  
Antifungal Activity ◽  
Invasive Aspergillosis ◽  
Murine Model ◽  
Pathogenic Fungi ◽  
Rational Drug Design ◽  
Fungal Burden ◽  
Delayed Treatment ◽  
Rational Drug

Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.

scholarly journals Efficacy of Humanized High-Dose Meropenem, Cefepime, and Levofloxacin against Enterobacteriaceae Isolates Producing Verona Integron-Encoded Metallo-β-Lactamase (VIM) in a Murine Thigh Infection Model

2015 ◽  
Vol 59 (11) ◽  
pp. 7145-7147 ◽  
Author(s):  
Islam M. Ghazi ◽  
Jared L. Crandon ◽  
Emil P. Lesho ◽  
Patrick McGann ◽  
David P. Nicolau
Keyword(s):  
Murine Model ◽  
Infection Model ◽  
High Dose ◽  
Content Type ◽  
High Mics

ABSTRACTWe aimed to describe thein vivoactivity of humanized pharmacokinetic exposures of meropenem and comparators against Verona integron-encoded metallo-β-lactamase (MBL) (VIM)-producingEnterobacteriaceaein a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despitein vitroresistance, high-dose meropenem may be a possible option against infections caused byEnterobacteriaceaeproducing MBL-type carbapenemases.

scholarly journals Identification of Group A Streptococcus Antigenic Determinants Upregulated In Vivo

2005 ◽  
Vol 73 (9) ◽  
pp. 6026-6038 ◽  
Author(s):  
Kowthar Y. Salim ◽  
Dennis G. Cvitkovitch ◽  
Peter Chang ◽  
Darrin J. Bast ◽  
Martin Handfield ◽  
...  
Keyword(s):  
Murine Model ◽  
Vibrio Vulnificus ◽  
Group A Streptococcus ◽  
Hypothetical Protein ◽  
Invasive Disease ◽  
Antigenic Determinants ◽  
Expression Library ◽  
Group A

ABSTRACT Group A Streptococcus (GAS) causes a range of diseases in humans, from mild noninvasive infections to severe invasive infections. The molecular basis for the varying severity of disease remains unclear. We identified genes expressed during invasive disease using in vivo-induced antigen technology (IVIAT), applied for the first time in a gram-positive organism. Convalescent-phase sera from patients with invasive disease were pooled, adsorbed against antigens derived from in vitro-grown GAS, and used to screen a GAS genomic expression library. A murine model of invasive GAS disease was included as an additional source of sera for screening. Sequencing DNA inserts from clones reactive with both human and mouse sera indicated 16 open reading frames with homology to genes involved in metabolic activity to genes of unknown function. Of these, seven genes were assessed for their differential expression by quantitative real-time PCR both in vivo, utilizing a murine model of invasive GAS disease, and in vitro at different time points of growth. Three gene products—a putative penicillin-binding protein 1A, a putative lipoprotein, and a conserved hypothetical protein homologous to a putative translation initiation inhibitor in Vibrio vulnificus—were upregulated in vivo, suggesting that these genes play a role during invasive disease.

scholarly journals Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

2015 ◽  
Vol 59 (6) ◽  
pp. 3645-3647 ◽  
Author(s):  
Carolina B. Moraes ◽  
Karen L. White ◽  
Stéphanie Braillard ◽  
Catherine Perez ◽  
Junghyun Goo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Murine Model ◽  
Therapeutic Benefit ◽  
Racemic Mixture ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTWith the aim of improving the available drugs for the treatment of Chagas disease, individual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in theirin vitroactivity against a panel ofTrypanosoma cruzistrains;in vivoefficacy in a murine model of Chagas disease;in vitrotoxicity and absorption, distribution, metabolism, and excretion characteristics; andin vivopharmacokinetic properties. There is unlikely to be any therapeutic benefit of an individual nifurtimox enantiomer over the racemic mixture.

Tissue Engineered Human Septal Cartilage in a Murine Model

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P87-P88
Author(s):  
Angela Chang ◽  
Sage August ◽  
Barbara L Schumacher ◽  
Williams Gregory ◽  
Robert L Sah ◽  
...  
Keyword(s):  
Cell Viability ◽  
Murine Model ◽  
Three Dimensional ◽  
Alginate Beads ◽  
Septal Cartilage ◽  
Hematoxylin And Eosin ◽  
Matrix Production ◽  
Nasal Septal Cartilage

Problem Tissue engineering of human nasal septal cartilage represents an alternative technique for creating large quantities of autologous material for use in reconstructive surgery of the head and neck. Septal neocartilage constructs developed in vitro by the alginate method have demonstrated cartilaginous extracellular matrix production, but their biocompatibility and development in vivo remains largely unknown. Methods A murine model was used to examine the behavior of neocartilage constructs in vivo. Chondrocytes collected from donors undergoing septoplasty were expanded in monolayer and suspended in alginate beads for three-dimensional culture in media containing human serum and growth factors. After in vitro incubation for 5 weeks, the neocartilage constructs were implanted subcutaneously in the dorsum of athymic mice for 30 days (n=3). The mice were sacrificed and the constructs were explanted for assessment of cell viability, gross morphology, and histology. Results The mice survived and tolerated the implant well. Infection and extrusion were not observed. Neocartilage constructs maintained their general shape and size, and demonstrated cell viability after implantation. Explanted constructs were firm and opaque, sharing closer semblance to native septal tissue relative to the gelatinous, translucent pre-implant constructs. On hematoxylin and eosin staining, the explanted constructs exhibited distinct morphologies characteristic of native tissue, which were not observed in pre-implant constructs. Conclusion Neocartilage constructs are viable in an in vivo murine model. The morphologic and histologic features of explanted constructs more closely resemble native septal tissue when compared to pre-implant constructs. Significance Septal neocartilage constructs are biocompatible and demonstrate potential for in vivo maturation with eventual clinical application.

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