Pharmacokinetics and Metabolism of the Reactive Oxygen Scavenger  α-Phenyl-<i>N</i>-<i>tert</i>-butylnitrone in the Male Sprague-Dawley Rat

Trudeau-Lame, Mary E.; Kalgutkar, Amit S.; LaFontaine, Michael

doi:10.1124/dmd.31.2.147

Cited by 20 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trudeau-Lame et al reported that plasma concentrations after i.v. PBN (10 mg/kg) administration declined rapidly with a terminal halflife of 2.01 ± 0.35 h in male Sprague-Dawley rats and also total plasma clearance and volume of distribution at steady state averaged 12.37 ± 3.82 ml/min/kg and 1.74 ± 0.5 l/kg, respectively [17]. Whereas PBN has got considerably low in vivo stability and short blood residence time we prepared nanocarrier systems using different biodegradable polymers modified with PEG chain.…”

Section: Discussionmentioning

confidence: 99%

Comparative in vitro studies on PBN loaded nanoparticles prepared by biodegradable chitosan, PLGA polymers and their PEGylated block copolymers

Öztürk

Fernández-Megía

Novoa-Carballal

et al. 2014

Journal of Drug Delivery Science and Technology

View full text Add to dashboard Cite

α-phenyl-N-tert-butyl nitrone (PBN) is a neuroprotective free radical scavenger however it has low in vivo stability and blood residence time. Aim of this study is to develop a nanoparticle formulation by using different polymeric system which enhance the blood residence time and in vivo stability of PBN and characterize in terms of particle size, zeta potential, morphology, encapsulation efficiency, in vitro release profiles. Chitosan (CS), poly(D,L-lactide-co-glycolide) (PLGA) and their poly(ethylene glycol) (PEG) block copolymers were used for comparative study. Results showed that particle sizes of CS, CS-PEG, PLGA and PLGA-PEG nanoparticles are between 142-356 nm. PLGA nanoparticles and their block-copolymers' nanoparticle have greatly monodisperse distribution. CS and CS-PEG nanoparticles have zeta potential values between 17-40 mV related to amine groups, contrariwise PLGA and PLGA-PEG nanoparticles have negative zeta potential in the range of (-8) -(-19) mV. Encapsulation efficiency and loading capacity for all formulations are between 12 -54 %, 9 -68 % respectively. PLGA-PEG nanoparticles are promising for further studies due to their sufficient encapsulation efficiency and in vitro release profiles.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative in vitro studies on PBN loaded nanoparticles prepared by biodegradable chitosan, PLGA polymers and their PEGylated block copolymers

Öztürk

Fernández-Megía

Novoa-Carballal

et al. 2014

Journal of Drug Delivery Science and Technology

View full text Add to dashboard Cite

show abstract

“…However, the circulatory half-life observed for STAZN is much longer than the 2 h half-life for PBN in rats (Trudeau-Lame et al, 2003). Less than 0.5% of a dose of PBN can be found unchanged in the urine, but rather, most of this drug is metabolized in the liver (TrudeauLame et al, 2003;Lame et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Stilbazulenyl Nitrone, a Second-Generation Azulenyl Nitrone Antioxidant, Confers Enduring Neuroprotection in Experimental Focal Cerebral Ischemia in the Rat: Neurobehavior, Histopathology, and Pharmacokinetics

Ley

Vigdorchik

Belayev

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Stilbazulenyl nitrone (STAZN) is a potent lipophilic secondgeneration azulenyl nitrone antioxidant, which is highly neuroprotective in rodent models of cerebral ischemia and trauma. This study was conducted to establish whether the neuroprotection induced by STAZN persists with chronic survival and to characterize STAZNЈs pharmacokinetics. Physiologically regulated rats received a 2-h middle cerebral artery occlusion by intraluminal suture and were treated with either STAZN [four 0.6 mg/kg doses i.p. administered at 2 (i.e., onset of recirculation), 4, 24, and 48 h; n ϭ 16] or dimethyl sulfoxide vehicle (n ϭ 11). They received sequential neurobehavioral examinations followed by quantitative neuropathology at 30 days. STAZN improved neurological deficits compared with vehicle controls, beginning within Ͻ2 h of the first dose and persisting throughout a 30-day survival. Large cystic necrotic infarcts were common in vehicle-treated rats but infrequent in STAZN-treated rats, and noninfarcted forebrain tissue was increased on average by 15%. In normal rats administered 5 mg/kg STAZN i.v. in Solutol HS 15/ethanol/saline vehicle, STAZN blood levels exhibited a biexponential decline, with an initial half-life of 28 min and a subsequent slow decay with half-life of ϳ7 h. STAZN tissue levels at 2 to 3 h were, on average, 2.5% of blood levels in forebrain, 56% in myocardium, and 41% in kidney. STAZN was concentrated in liver with initial concentrations averaging 5.2-fold above blood levels and a subsequent linear decline of 40% between 24 and 72 h. These results establish that STAZN confers enduring ischemic neuroprotection, has a long circulating half-life, and penetrates well into brain and other organs-characteristics favoring its potential therapeutic utility.

show abstract

“…Two doses were used to allow for the plasma half-life of PBN (terminal half-life in rat $2 h). 31 At 240 min, animals were killed by cervical dislocation, brains rapidly removed, cerebella discarded and cerebral hemispheres frozen in liquid nitrogen. Whole hemispheres were homogenized in Trizol, total RNA extracted and cleaned using RNeasy columns (QIAGEN GmbH, Hilden, Germany).…”

Section: Microarray Analysismentioning

confidence: 99%

Induction of the cell survival kinase Sgk1: A possible novel mechanism for α-phenyl-N-tert-butyl nitrone in experimental stroke

McCaig

Ataliotis

Shtaya

et al. 2017

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Nitrones (e.g. α-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1 and Sgk1 mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1 mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline-treated Sgk1 mice. PBN-treated Sgk1 mice did not differ from saline-treated Sgk1 mice. Saline-treated Sgk1 and Sgk1 mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1 mice. Sgk3 was not augmented in Sgk1 mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia.

show abstract

Pharmacokinetics and Metabolism of the Reactive Oxygen Scavenger α-Phenyl-N-tert-butylnitrone in the Male Sprague-Dawley Rat

Abstract: ABSTRACT:The pharmacokinetics of the spin-trap ␣-phenyl-N-tert-butylnitrone (

Cited by 20 publications

References 23 publications

Comparative in vitro studies on PBN loaded nanoparticles prepared by biodegradable chitosan, PLGA polymers and their PEGylated block copolymers

Comparative in vitro studies on PBN loaded nanoparticles prepared by biodegradable chitosan, PLGA polymers and their PEGylated block copolymers

Stilbazulenyl Nitrone, a Second-Generation Azulenyl Nitrone Antioxidant, Confers Enduring Neuroprotection in Experimental Focal Cerebral Ischemia in the Rat: Neurobehavior, Histopathology, and Pharmacokinetics

Induction of the cell survival kinase Sgk1: A possible novel mechanism for α-phenyl-N-tert-butyl nitrone in experimental stroke

Contact Info

Product

Resources

About