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Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.

Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC - BMC Neurol (2004)

Bottom Line: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally.Minocycline did not significantly affect hemodynamic and physiological variables.A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Medical College of Georgia, Augusta GA, 30912, USA. lxu@mail.mcg.edu

ABSTRACT

Background: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens.

Methods: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats.

Results: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.

Conclusions: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.

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Serum Levels of Minocycline. A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998).
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Figure 1: Serum Levels of Minocycline. A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998).

Mentions: A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998, Figure 1). Peak concentrations averaged 3.6, 13.0 and 28.8 mg/L with 3, 10 and 20 mg/kg doses respectively. The serum levels of MC at a 3 mg/kg dose (3.6 mg/L) were similar to that reported in humans after a standard 200 mg dose [14].


Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.

Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC - BMC Neurol (2004)

Serum Levels of Minocycline. A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC415551&req=5

Figure 1: Serum Levels of Minocycline. A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998).
Mentions: A linear relationship was observed between peak concentration and dose over the dose range studied (r = 0.998, Figure 1). Peak concentrations averaged 3.6, 13.0 and 28.8 mg/L with 3, 10 and 20 mg/kg doses respectively. The serum levels of MC at a 3 mg/kg dose (3.6 mg/L) were similar to that reported in humans after a standard 200 mg dose [14].

Bottom Line: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally.Minocycline did not significantly affect hemodynamic and physiological variables.A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Medical College of Georgia, Augusta GA, 30912, USA. lxu@mail.mcg.edu

ABSTRACT

Background: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens.

Methods: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats.

Results: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.

Conclusions: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.

Show MeSH
Related in: MedlinePlus