Toxin to lead: An inhibitor of factor XIa engineered from banded krait venom toxin fasxiator showed superior in vivo efficacy-safety profile compared to heparin

Toxicon ◽  
2020 ◽  
Vol 177 ◽  
pp. S27
Author(s):  
Cho Yeow Koh ◽  
Aaron Wei Liang Li ◽  
Wan Chen ◽  
Tse Siang Kang ◽  
Esther Jia En Leong ◽  
...  
Keyword(s):  
Safety Profile ◽  
In Vivo Efficacy ◽  
Venom Toxin ◽  
Factor Xia

scholarly journals PF203 CG-806, PRECLINICAL IN VIVO EFFICACY AND SAFETY PROFILE AS A PAN-FLT3/PAN-BTK INHIBITOR

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 54
Author(s):  
H. Zhang ◽  
K. Benbatoul ◽  
S. Sheng ◽  
C.-Y. Tsai ◽  
S. Howell ◽  
...  
Keyword(s):  
Safety Profile ◽  
Efficacy And Safety ◽  
In Vivo Efficacy ◽  
Btk Inhibitor

Inactivation of Factor XIa in Vivo: Studies in Chimpanzees and in Humans

1996 ◽  
Vol 76 (04) ◽  
pp. 549-555 ◽  
Author(s):  
Walter A Wuillemin ◽  
C Erik Hack ◽  
Wim K Bleeker ◽  
Bart J Biemond ◽  
Marcel Levi ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Life Time ◽  
In Vivo Studies ◽  
Clinical Samples ◽  
Plasma Samples ◽  
C1 Inhibitor ◽  
Elimination Kinetics ◽  
Factor Xia ◽  
Best Parameter

SummaryC1-inhibitor (C1Inh), antithrombin III (ATIII), α1-antitrypsin (a1AT), and α2-antiplasmin (a2AP) are known inhibitors of factor XIa (FXIa). However, their precise contribution to FXIa inactivation in vivo is not known. We investigated FXIa inactivation in chimpanzees and assessed the contribution of these inhibitors to FXIa inactivation in patients with presumed FXI activation.Chimpanzees were infused with FXIa and the various FXIa-FXIa inhibitor complexes formed were measured. Most of FXIa was complexed to C1Inh (68%), followed by a2AP (13%), a1AT (10%), and ATIII (9%). Analysis of the plasma elimination kinetics revealed a half-life time of clearance (t1/2) for the FXIa-FXIa inhibitor complexes of 95 to 104 min, except for FXIa-a1AT, which had a t1/2 of 349 min. Due to this long t1/2, FXIa-a1AT complexes were predicted to show the highest levels in plasma samples from patients with activation of FXI. This was indeed shown in patients with disseminated intravascular coagulation, recent myocardial infarction or unstable angina pectoris. We conclude from this study that in vivo C1Inh is the predominant inhibitor of FXIa, but that FXIa-a1 AT complexes due to their relatively long t1/2 may be the best parameter to assess FXI activation in clinical samples.

Are epidemiologic cut-off values predictors of the in vivo efficacy of azoles in experimental aspergillosis?

2012 ◽  
Vol 74 (2) ◽  
pp. 158-165 ◽  
Author(s):  
Enrique Calvo ◽  
F. Javier Pastor ◽  
Deanna A. Sutton ◽  
Anette W. Fothergill ◽  
Michael G. Rinaldi ◽  
...  
Keyword(s):  
In Vivo Efficacy

scholarly journals Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Santucci ◽  
Daniel J. Greenwood ◽  
Antony Fearns ◽  
Kai Chen ◽  
Haibo Jiang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Combination Chemotherapy ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Human Macrophages ◽  
Ion Microscopy ◽  
Intracellular Localisation

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

scholarly journals Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

2021 ◽  
Author(s):  
Shannon L. McArdel ◽  
Anne-Sophie Dugast ◽  
Maegan E. Hoover ◽  
Arjun Bollampalli ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Nk Cells ◽  
Red Blood Cell ◽  
Safety Profile ◽  
Nk Cell ◽  
Cell Activity ◽  
In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

scholarly journals P074 In vitro and in vivo efficacy of linezolid on Treponema pallidum, the syphilis agent

2021 ◽  
Author(s):  
L Giacani ◽  
A Haynes ◽  
M Vall Mayans ◽  
M Ubals Cazorla ◽  
C Nieto ◽  
...  
Keyword(s):  
Treponema Pallidum ◽  
In Vivo Efficacy
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