Abstract：
:CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Durmus S,Xu N,Sparidans RW,Wagenaar E,Beijnen JH,Schinkel AHdoi
10.1016/j.phrs.2013.06.009subject
Has Abstractpub_date
2013-10-01 00:00:00pages
9-16eissn
1043-6618issn
1096-1186pii
S1043-6618(13)00106-0journal_volume
76pub_type
杂志文章abstract：:The ataxin-2 binding protein 1 (A2BP1) gene is reported to be one of the susceptibility genes in schizophrenia, autism, and obesity. The aim of this study was to explore the association of A2BP1 gene polymorphisms with antipsychotic induced weight gain (AIWG) in Chinese Han population. Three hundred and twenty-eight p...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2015.06.003
更新日期：2015-09-01 00:00:00
abstract：BACKGROUND:We examined the influence of diabetes mellitus (DM) on the healing of HCl-induced gastric lesions and the healing promoting effect of IGF-1 on these lesions. METHODS:Experiments were performed on rats injected with streptozotocin (STZ, 70 mg kg(-1), i.p.) 5 weeks prior to the experimental session. Diabetic ...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1999.0581
更新日期：2000-02-01 00:00:00
abstract：:This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1 microgml(-1)) for 18 h, the endothelial cells irregularly aggregated wit...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2006.05.006
更新日期：2006-10-01 00:00:00
abstract：:Adaptive responses to stress are critical to enhance physical and mental well-being, but excessive or prolonged stress may cause inadaptability and increase the risks of psychiatric disorders, such as depression. GABABR signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. K...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2020.105355
更新日期：2021-01-01 00:00:00
abstract：:Previous studies have suggested additional beneficial effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors including the lipid-lowering effect; however, results on lipid profile are controversial. Thus, this meta-analysis aimed to determine the effect of SGLT2 inhibitors treatment on lipid levels in patients ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2020.105068
更新日期：2020-10-01 00:00:00
abstract：:Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a major phosphatase involved in several cellular processes. In recent years, SHP2 has been the focus of significant attention in human diseases, particular in cancer. Several studies have shown that SHP2 plays an important role in regulating immune cel...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2019.104595
更新日期：2020-02-01 00:00:00
abstract：:Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis and arteriolar hypertrophy. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but previous studies have demonstrated that angiotensin II (Ang II), the pri...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2002.0959
更新日期：2002-05-01 00:00:00
abstract：:Carbon-based nanomaterials have unique physicochemical properties relevant to the diagnosis and treatment of various diseases. There have been many reports indicating that carbon nanomaterials (CNMs) can interact and perturb biomolecules such as proteins and amyloid structures. This review is an attempt to reflect the...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2019.03.023
更新日期：2019-05-01 00:00:00
abstract：:The antitumour and immunosuppressive activities of spermine dialdehyde (SDA), a synthetic, oxidized form of spermine, were examined using L1210 cell lines and murine bone marrow cells. SDA acted as a high affinity substrate for aldehyde dehydrogenase (ADH) derived from different sources, with kinetic profiles similar ...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/1043-6618(92)90675-2
更新日期：1992-05-01 00:00:00
abstract：:Transdermal iontophoresis (TI) is a physical enhancement technique to facilitate the delivery of primarily charged molecules across the skin. TI of peptides is influenced by a complex interplay of several factors and one of the main issues in optimizing iontophoretic delivery of peptides is to improve the transport ef...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(03)00080-x
更新日期：2003-08-01 00:00:00
abstract：:Cardiovascular diseases (CVD) are among the main causes of death globally and in this context hypertension represents one of the key risk factors for developing a CVD. It is well established that the peripheral renin-angiotensin system (RAS) plays an important role in regulating blood pressure (BP). All components of ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.06.016
更新日期：2017-11-01 00:00:00
abstract：:The gut microbiota and its short chain fatty acid (SCFA) metabolites have been established to play an important protective role against neurodegenerative diseases. Our previous study demonstrated that cerebral ischemic stroke triggers dysfunctional gut microbiota and increased intestinal permeability. In this study, w...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2019.104403
更新日期：2019-10-01 00:00:00
abstract：:Levosulpiride is the (-)-enantiomer of sulpiride. It has shown greater central antidopaminergic activity, antiemetic and antidyspeptic effects and lower acute toxicity than both the racemic and dextro forms. Several clinical studies indicate that levosulpiride has therapeutic efficacy in depressive and somatoform diso...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/1043-6618(95)80053-0
更新日期：1995-02-01 00:00:00
abstract：:Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels sugge...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.02.011
更新日期：2017-05-01 00:00:00
abstract：:This paper discusses the discovery of ligands for orphan receptors and the identification of the natural endogenous ligands for those receptors in physiology. The central thesis is that orphan seven transmembrane receptors (7TMRs) are allosteric conduits of chemical information exchange from extracellular ligands to i...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2016.01.022
更新日期：2016-12-01 00:00:00
abstract：:We have recently synthesized a new series of 4,5-dihydrobenzo-oxa-cycloheptapyrazole derivatives with the aim to discover novel CB1 antagonist agents characterized by anti-obesity activity comparable to that of SR141716A but with reduced adverse effects such as anxiety and depression. Within the novel class, the CB1 a...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2013.06.001
更新日期：2013-08-01 00:00:00
abstract：:Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we comp...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2016.10.031
更新日期：2017-01-01 00:00:00
abstract：:Mitochondria are best known for their role in ATP generation. However, studies over the past two decades have shown that mitochondria do much more than that. Mitochondria regulate both necrotic and apoptotic cell death pathways, they store and therefore coordinate cellular Ca2+ signaling, they generate and metabolize ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2018.08.010
更新日期：2018-12-01 00:00:00
abstract：:Secretion of matrix metalloproteinases (MMPs) by macrophages and smooth muscle cells (SMC) may impair atherosclerotic cap integrity leading to atherosclerosis complications. Selective estrogen receptor modulators (SERMs) have favourable impact on plasma lipid levels, but their role in the prevention of atherosclerosis...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2007.05.004
更新日期：2007-08-01 00:00:00
abstract：:Breast cancer, the most prevalent cancer in women, remains the second in the list of cancer mortality, the majority of these fatalities resulted from estrogen receptor alpha (ERα) positive disease. ERα is well known for its function on breast cancer initiation and development and has become the most successful biomark...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2019.104294
更新日期：2019-08-01 00:00:00
abstract：:An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physi...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2003.11.017
更新日期：2004-10-01 00:00:00
abstract：:The investigation was aimed at investigating whether the dopaminergic projection arriving at the nucleus septi lateralis (NSL) is involved in the facilitatory effect of vasopressin (AVP) on memory retrieval. The bilateral 6-OHDA lesions to the NSL were made in 20 male Wistar rats before testing the intracerebroventric...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1997.0280
更新日期：1998-02-01 00:00:00
abstract：:The activity of short porcine galanin (Gal) analogues was tested in vitro using rat gastric fundus strips. The peptides contracted longitudinal smooth muscle in a concentration-dependent manner with the following order of potency: Gal(1-29) >[Cit(14)]Gal(1- 15) >[Asp(14)]Gal(1- 15) >[Dab(14)]Gal(1- 15) >[Nle(14)] Gal(...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2001.0827
更新日期：2001-07-01 00:00:00
abstract：:Cetyl myristoleate (CM) was reported by Diehl and May [J Pharm Sci 83 (1994) 296] to block inflammation and prevent adjuvant-induced arthritis in rats. To verify this earlier work, we have synthesized pure CM and tested its anti-arthritic properties in a collagen-induced arthritis model in DBA/1LacJ mice. Multiple int...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(02)00239-6
更新日期：2003-01-01 00:00:00
abstract：:The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2016.07.038
更新日期：2016-09-01 00:00:00
abstract：:The antiepileptic drug vigabatrin (GVG) is known to decrease significantly the serum concentration of concurrently administered phenytoin (PHT) in epileptic patients. To assess a possible mechanism for this interaction, the effect of GVG on the intestinal absorption of PHT was investigated by means of circulation expe...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(05)80133-1
更新日期：1992-09-01 00:00:00
abstract：:The effects of the angiotensin-converting enzyme (ACE) inhibitor monopril and the angiotensin II receptor blocker losartan on serum glucose, protein levels and some serum lipid components were compared in normal and diabetic rats receiving oral antidiabetic drugs 'repaglinide or gliclazide'. The two antihypertensive a...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2003.12.019
更新日期：2004-08-01 00:00:00
abstract：:Macroscale delivery systems that can be locally implanted on the tumor tissue as well as avoid all the complications associated to the systemic delivery of therapeutics have captured researchers' attention, in recent years. Particularly, the microneedle-based devices can be used to efficiently deliver both small and m...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2019.104438
更新日期：2019-10-01 00:00:00
abstract：:The role of the angiotensin AT1 receptors in certain behavioural effects of angiotensin II (Ang II), using their selective antagonist losartan (DuP 753), was assessed. Ang II, given intracerebroventricularly (ICV) at the dose of 1 nmole, significantly improved object recognition, learning of conditioned avoidance resp...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1996.0073
更新日期：1996-09-01 00:00:00
abstract：:Accumulation of amyloid-β peptides (Aβ) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in Aβ clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food ...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2014.02.008
更新日期：2014-03-01 00:00:00
