Increasing nerve agent treatment efficacy by P-glycoprotein inhibition

Joosen, Marloes J.A.; Vester, Stefanie M.; Hamelink, Jouk; Klaassen, Steven D.; Berg, R.M. van den

doi:10.1016/j.cbi.2016.06.012

Cited by 22 publications

(18 citation statements)

References 30 publications

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“…Small molecules with a molecular weight of less than 500 can pass through the BBB. However, relatively lipophilic compounds are reportedly effluxed from the CNS by p-glycoprotein and other mechanisms [ 165 ]. Therefore, the physicochemical properties of these compounds must be optimized.…”

Section: Discussionmentioning

confidence: 99%

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

2017

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P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD.

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Section: Discussionmentioning

confidence: 99%

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

2017

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“…Abcb1 inhibition with tariquidar causes an increase in the peripheral tissue concentration of several target substrates: docetaxel, 55 verapamil, 30 bortezomib, 25 and others. 26,56,57 The addition of tariquidar to botryllamide G significantly increased the brain exposure of lapatinib through 1 h due to rapid early botryllamide G distribution. Yet, over a 24 h period, tariquidar (in the presence of low botryllamide G exposure) counterintuitively decreased lapatinib plasma and brain AUC.…”

Section: Discussionmentioning

confidence: 99%

“…22 Accordingly, much research has recently focused on the inhibition of one or both of these transporters to prolong the mean residence time of anti-cancer therapies in the brain. [23][24][25][26][27][28][29][30][31][32] However, there has been no sustainable clinical improvement in this field; thus, the search continues for a new class of ABCB1 and/or ABCG2 inhibitors. Furthermore, many targeted small molecule-or chemotherapeutics are substrates for more than one transporter.…”

Section: Introductionmentioning

confidence: 99%

Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain

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Sissung

et al. 2019

Cancer Biology & Therapy

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Introduction: Transporters comprising the blood-brain barrier complicate delivery of many therapeutics to the central nervous system. The present study ascertained whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. Methods: Wild-type and Mdr1a/Mdr1b (-/-) mice were treated with botryllamide G and lapatinib ("doublet therapy"), and while a separate cohort of wild-type mice was treated with botryllamide, tariquidar and lapatinib ("triplet therapy"). Results: Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the in vitro IC 50 of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In Mdr1a/ Mdr1b (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 h*ng/mL vs 4007 h*ng/mL; P = .031), but not plasma exposure (P = .15). No significant differences were observed after 24 h. Lapatinib brain exposure was greater through 1 h when wild-type mice were administered triplet therapy (298 h*pg/mg vs 120 h*pg/mg; P < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 h*pg/mg vs 4461hr*ng/mL; P < .001) and did not alter the brain:plasma ratio. Conclusions: In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking Abcb1, although the combination of botryllamide G and tariquidar increases brain exposure in wild-type mice only briefly (1 h). Additional research is needed to find analogs of this compound that have better pharmacokinetics and pharmacodynamic effects on ABCG2 inhibition.

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“…[23][24][25] There are several limitations imposed by the BBB which includes molecule size, hydrophilicity, polarity, substrate specicity, and active efflux mechanisms. [26][27][28][29] These properties however, are lacking in most oxime structures. Therefore, the development of effective measures to counteract the problem of BBB penetration by oximes in order to treat OP poisoning remains a challenging issue.…”

Section: Introductionmentioning

confidence: 99%

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

et al. 2020

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Increasing nerve agent treatment efficacy by P-glycoprotein inhibition

Cited by 22 publications

References 30 publications

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

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