scholarly journals In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

PLoS ONE ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. e0178905 ◽  
Author(s):  
Jianxun Wang ◽  
Vasanth Chandrasekhar ◽  
Giovanni Abbadessa ◽  
Yi Yu ◽  
Brian Schwartz ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Noonan Syndrome ◽  
Akt Inhibitor ◽  
In Vivo Efficacy ◽  
Multiple Lentigines

scholarly journals Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines

2021 ◽  
Author(s):  
Jae-Sung Yi ◽  
Sravan Perla ◽  
Yan Huang ◽  
Kana Mizuno ◽  
Frank J. Giordano ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Transcriptome Analysis ◽  
Noonan Syndrome ◽  
Low Dose ◽  
Cardiac Fibrosis ◽  
Heart Tissue ◽  
Sh2 Domain ◽  
Autosomal Dominant Disorder ◽  
Multiple Lentigines ◽  
Dasatinib Treatment

Abstract Purpose Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11Y279C mutation. This study is performed to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a low-dose of dasatinib in NSML mice and to determine its effectiveness in ameliorating the development of HCM. Methods Dasatinib was administered intraperitoneally into NSML mice with doses ranging from 0.05 to 0.5 mg/kg. PK parameters of dasatinib in NSML mice were determined. PD parameters were obtained for biochemical analyses from heart tissue. Dasatinib-treated NSML mice (0.1 mg/kg) were subjected to echocardiography and assessment of markers of HCM by qRT-PCR. Transcriptome analysis was performed from the heart tissue of low-dose dasatinib-treated mice. Results Low-dose dasatinib exhibited PK properties that were linear across doses in NSML mice. Dasatinib treatment of between 0.05 and 0.5 mg/kg in NSML mice yielded an exposure-dependent inhibition of c-Src and PZR tyrosyl phosphorylation and inhibited AKT phosphorylation. We found that doses as low as 0.1 mg/kg of dasatinib prevented HCM in NSML mice. Transcriptome analysis identified differentially expressed HCM-associated genes in the heart of NSML mice that were reverted to wild type levels by low-dose dasatinib administration. Conclusion These data demonstrate that low-dose dasatinib exhibits desirable therapeutic PK properties that is sufficient for effective target engagement to ameliorate HCM progression in NSML mice. These data demonstrate that low-dose dasatinib treatment may be an effective therapy against HCM in NSML patients.

scholarly journals Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: Palliative treatment with a rapamycin analog

2015 ◽  
Vol 167 (4) ◽  
pp. 744-751 ◽  
Author(s):  
Andreas Hahn ◽  
Jessica Lauriol ◽  
Josef Thul ◽  
Kachina Behnke-Hall ◽  
Tushiha Logeswaran ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Noonan Syndrome ◽  
Palliative Treatment ◽  
Multiple Lentigines

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.

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