178 POSTER Oral in vivo pharmacokinetics of the novel orally available taxane derivative BMS-275183 in wildtype and MDR1a/b double knockout mice support that BMS-275183 is a P-glycoprotein substrate drug

2006 ◽  
Vol 4 (12) ◽  
pp. 56
Author(s):  
S. Marchetti ◽  
D. Pluim ◽  
O. Van Tellingen ◽  
L. Alland ◽  
J. Gan ◽  
...  
Keyword(s):  
Knockout Mice ◽  
The Novel ◽  
Double Knockout ◽  
P Glycoprotein ◽  
Substrate Drug ◽  
In Vivo Pharmacokinetics

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol

2021 ◽  
Vol 147 ◽  
pp. 111859
Author(s):  
Brianna J. Stubbs ◽  
Thanh Blade ◽  
Scott Mills ◽  
Jennifer Thomas ◽  
Xu Yufei ◽  
...  
Keyword(s):  
The Novel ◽  
In Vitro Stability ◽  
In Vivo Pharmacokinetics

scholarly journals TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

2011 ◽  
Vol 111 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Jarrod A. Call ◽  
James M. Ervasti ◽  
Dawn A. Lowe
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Ex Vivo ◽  
Eccentric Contraction ◽  
Mdx Mice ◽  
Double Knockout ◽  
Replacement Treatment ◽  
Generating Capacity

Previously, we demonstrated functional substitution of dystrophin by TAT-μUtrophin (TAT-μUtr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-μUtr could improve the phenotype of dystrophin and utrophin double-knockout ( mdx:utr−/−) mice. Specifically, we quantitatively compared survival and quality of life assessments in mdx:utr−/− mice receiving TAT-μUtr protein administration against placebo-treated mdx:utr−/− mice (PBS). Additionally, skeletal muscles from TAT-μUtr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-μUtr treatment extended life span 45% compared with mice administered PBS. This was attributed to significantly increased food consumption (3.1 vs. 1.8 g/24 h) due to improved ability to search for food as daily cage activities were greater in TAT-μUtr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-μUtr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm2) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-μUtr replacement treatment extend to the mdx:utr−/− double-knockout mouse and support its development as a therapy to mitigate muscle weakness in patients with Duchenne muscular dystrophy.

scholarly journals Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Hyun-Jong Cho ◽  
In-Soo Yoon
Keyword(s):  
Cytochrome P450 ◽  
Glycoprotein P ◽  
Metabolizing Enzymes ◽  
Herbal Products ◽  
P Glycoprotein ◽  
Concurrent Use ◽  
Substrate Drug ◽  
And Function

The concurrent use of drugs and herbal products is becoming increasingly prevalent over the last decade. Several herbal products have been known to modulate cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) which are recognized as representative drug metabolizing enzymes and drug transporter, respectively. Thus, a summary of knowledge on the modulation of CYP and P-gp by commonly used herbs can provide robust fundamentals for optimizing CYP and/or P-gp substrate drug-based therapy. Herein, we review ten popular medicinal and/or dietary herbs as perpetrators of CYP- and P-gp-mediated pharmacokinetic herb-drug interactions. The main focus is placed on previous works on the ability of herbal extracts and their phytochemicals to modulate the expression and function of CYP and P-gp in severalin vitroandin vivoanimal and human systems.

scholarly journals Defects in Axonal Elongation and Neuronal Migration in Mice with Disrupted tau and map1b Genes

2000 ◽  
Vol 150 (5) ◽  
pp. 989-1000 ◽  
Author(s):  
Yosuke Takei ◽  
Junlin Teng ◽  
Akihiro Harada ◽  
Nobutaka Hirokawa
Keyword(s):  
Knockout Mice ◽  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Double Knockout ◽  
Microtubule Organization ◽  
Axonal Elongation ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

Tau and MAP1B are the main members of neuronal microtubule-associated proteins (MAPs), the functions of which have remained obscure because of a putative functional redundancy (Harada, A., K. Oguchi, S. Okabe, J. Kuno, S. Terada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 1994. Nature. 369:488–491; Takei, Y., S. Kondo, A. Harada, S. Inomata, T. Noda, and N. Hirokawa. 1997. J. Cell Biol. 137:1615–1626). To unmask the role of these proteins, we generated double-knockout mice with disrupted tau and map1b genes and compared their phenotypes with those of single-knockout mice. In the analysis of mice with a genetic background of predominantly C57Bl/6J, a hypoplastic commissural axon tract and disorganized neuronal layering were observed in the brains of the tau+/+map1b−/− mice. These phenotypes are markedly more severe in tau−/−map1b−/− double mutants, indicating that tau and MAP1B act in a synergistic fashion. Primary cultures of hippocampal neurons from tau−/−map1b−/− mice showed inhibited axonal elongation. In these cells, a generation of new axons via bundling of microtubules at the neck of the growth cones appeared to be disturbed. Cultured cerebellar neurons from tau−/−map1b−/− mice showed delayed neuronal migration concomitant with suppressed neurite elongation. These findings indicate the cooperative functions of tau and MAP1B in vivo in axonal elongation and neuronal migration as regulators of microtubule organization.

scholarly journals Thymocyte-Synthesized Glucocorticoids Play a Role in Thymocyte Homeostasis and Are Down-Regulated by Adrenocorticotropic Hormone

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4163-4169 ◽  
Author(s):  
Shengjun Qiao ◽  
Sam Okret ◽  
Mikael Jondal
Keyword(s):  
Mrna Expression ◽  
Knockout Mice ◽  
Corticosterone Level ◽  
Double Knockout ◽  
Hormone Production ◽  
Down Regulation ◽  
Adult Mice ◽  
Messenger Molecule

Abstract Thymocytes from adult mice synthesize glucocorticoids (GCs), and some data indicate a role for this hormone production in thymic homeostasis. Here we present further support for this view by showing that the dramatic increase in thymocyte number seen after adrenalectomy (ADX) does not correlate with the decrease in systemic GCs but rather with an ACTH-mediated down-regulation of GC synthesis in thymocytes. High ACTH concentrations caused by ADX in wild-type mice down-regulated CYP11B1 mRNA expression, encoding the last enzyme required for corticosterone synthesis and as a consequence reduced GC synthesis in thymocytes. This was not seen in IL-1β/IL-18 double-knockout mice unable to respond to ADX with high ACTH levels. However, if ADX IL-1β/IL-18 double-knockout mice were treated with ACTH, this led to a down-regulation of CYP11B1 and GC synthesis in thymocytes. In addition, in vivo treatment of mice with the CYP11B1 antagonist metyrapone, without affecting the systemic corticosterone level, increased thymocyte numbers and in vitro treatment of isolated thymocytes prevented thymocyte loss. Furthermore, in vitro experiments showed that both ACTH and its receptor-induced second-messenger molecule cAMP down-regulated mRNA expression of critical enzymes in GC steroidogenesis and GC synthesis in thymocytes. We conclude that thymocyte-produced GCs are important for the homeostasis of adult mouse thymocytes and that high ACTH level, in contrast to stimulating GC synthesis in the adrenal glands, has the opposite effect in thymocytes.

scholarly journals Hypothalamic-Pituitary Cytokine Network

Endocrinology ◽  
2004 ◽  
Vol 145 (1) ◽  
pp. 104-112 ◽  
Author(s):  
Anastasia Kariagina ◽  
Dmitry Romanenko ◽  
Song-Guang Ren ◽  
Vera Chesnokova
Keyword(s):  
Hpa Axis ◽  
Knockout Mice ◽  
Single Gene ◽  
Pituitary Cells ◽  
Mrna Levels ◽  
Acth Secretion ◽  
Double Knockout ◽  
Cytokine Network ◽  
Human Pituitary

Abstract Cytokines expressed in the brain and involved in regulating the hypothalamus-pituitary-adrenal (HPA) axis contribute to the neuroendocrine interface. Leukemia inhibitory factor (LIF) and LIF receptors are expressed in human pituitary cells and murine hypothalamus and pituitary. LIF potently induces pituitary proopiomelanocortin (POMC) gene transcription and ACTH secretion and potentiates CRH induction of POMC. In vivo, LIF, along with CRH, enhances POMC expression and ACTH secretion in response to emotional and inflammatory stress. To further elucidate specific roles for both CRH and LIF in activating the inflammatory HPA response, double-knockout mice (CRH/LIFKO) were generated by breeding the null mutants for each respective single gene. Inflammation produced by ip injection of lipopolysaccharide (1 μg/mouse) to double CRH and LIF-deficient mice elicited pituitary POMC induction similar to wild type and markedly higher than in single null animals (P < 0.0.01). Double-knockout mice also demonstrated robust corticosterone response to inflammation. High pituitary POMC mRNA levels may reflect abundant TNFα, IL-1β, and IL-6 activation observed in the hypothalamus and pituitary of these animals. Our results suggest that increased central proinflammatory cytokine expression can compensate for the impaired HPA axis function and activates inflammatory ACTH and corticosterone responses in mice-deficient in both CRH and LIF.

scholarly journals Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H10Replacement Subtype

2001 ◽  
Vol 21 (23) ◽  
pp. 7933-7943 ◽  
Author(s):  
Yuhong Fan ◽  
Allen Sirotkin ◽  
Robert G. Russell ◽  
Julianna Ayala ◽  
Arthur I. Skoultchi
Keyword(s):  
Knockout Mice ◽  
Knockout Mouse ◽  
Embryonic Stem ◽  
Mouse Development ◽  
Double Knockout ◽  
Linker Histones ◽  
Deficient Mice ◽  
Mouse Lines

ABSTRACT H1 linker histones are involved in facilitating the folding of chromatin into a 30-nm fiber. Mice contain eight H1 subtypes that differ in amino acid sequence and expression during development. Previous work showed that mice lacking H10, the most divergent subtype, develop normally. Examination of chromatin in H10−/− mice showed that other H1s, especially H1c, H1d, and H1e, compensate for the loss of H10 to maintain a normal H1-to-nucleosome stoichiometry, even in tissues that normally contain abundant amounts of H10 (A. M. Sirotkin et al., Proc. Natl. Acad. Sci. USA 92:6434–6438, 1995). To further investigate the in vivo role of individual mammalian H1s in development, we generated mice lacking H1c, H1d, or H1e by homologous recombination in mouse embryonic stem cells. Mice lacking any one of these H1 subtypes grew and reproduced normally and did not exhibit any obvious phenotype. To determine whether one of these H1s, in particular, was responsible for the compensation present in H10−/− mice, each of the three H1 knockout mouse lines was bred with H10 knockout mice to generate H1c/H10, H1d/H10, or H1e/H10double-knockout mice. Each of these doubly H1-deficient mice also was fertile and exhibited no anatomic or histological abnormalities. Chromatin from the three double-knockout strains showed no significant change in the ratio of total H1 to nucleosomes. These results suggest that any individual H1 subtype is dispensable for mouse development and that loss of even two subtypes is tolerated if a normal H1-to-nucleosome stoichiometry is maintained. Multiple compound H1 knockouts will probably be needed to disrupt the compensation within this multigene family.

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