Progesterone pharmacokinetics in the mouse: implications for potential stroke therapy

Wong, Raymond; Ray, David; Kendall, David A.

doi:10.1111/j.2042-7158.2012.01537.x

Cited by 17 publications

(18 citation statements)

References 51 publications

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“…The accumulation of PROG after its intraperitoneal administration is reported to be higher in the brain than in plasma [28]. Thus, high levels of PROG are quickly found in the brain after injection, allowing a rapid action of this steroid in the brain.…”

Section: Discussionmentioning

confidence: 98%

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

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Section: Discussionmentioning

confidence: 98%

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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“…While our estimates suggest that doses below 8 mg/kg/day may be more effective in humans, only an empirically-based dose optimization in a Phase IIB trial under defined conditions (vehicle, route, dose, and schedule) can determine what dose or doses are optimal (Fig. 1 2,6,7,17–19 ).…”

Section: Overview Of the Phase II Clinical And Preclinical Reportsmentioning

confidence: 88%

“…The dosing is comparable to the median serum level (335 ng/mL, 2 days after initial dose) used in the SyNAPSe clinical trial. 2 The trajectories for the preclinical dosing are representative of two studies: a pharmacokinetic report showing PROG concentration in mice treated with 8 mg/kg/d of PROG delivered by implanted osmotic minipumps (simulating continuous infusion) 17 and the strong inverse relationship observed between serum PROG levels and percent cerebral edema following TBI in rats. 7 There are numerous reports that a dose of 8 mg/kg/d is effective for restoring behavioral functions in rodent models of TBI and stroke.…”

Section: Overview Of the Phase II Clinical And Preclinical Reportsmentioning

confidence: 99%

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury

Howard

Sayeed

Stein

2017

Journal of Neurotrauma

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To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

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“…Our previous pharmacokinetic study demonstrated that progesterone delivered via i.p. injection has a very short half-life in both plasma and brain [ 27 ] but high progesterone concentrations in the brain can be achieved via mini pump infusion. There have only a few studies, involving progesterone and experimental stroke, which have reported infusion delivery in rats [ 4 ] and mice [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…The aim of the current study was to evaluate if progesterone would be effective in conferring neuroprotection after the onset of experimental stroke when administered via osmotic mini-pump in adult mice. In a prior study from our laboratory, the pharmacokinetics of progesterone in mice using this dosing method were investigated, and found it to be effective in delivering progesterone to the target area of the brain [ 27 ]. The delivery of progesterone via osmotic mini-pumps in an experimental stroke model, induced via middle cerebral artery occlusion (MCAO), has not been demonstrated previously; mini-pump delivery could offer a more suitable dosing method with the advantages of reducing peaks and troughs in drug levels, the stress associated with repeated injections, and diminishing levels of release over time as seen with pellet implants.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice

et al. 2014

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BackgroundProgesterone is neuroprotective in numerous preclinical CNS injury models including cerebral ischaemia. The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals.ResultsAnimals underwent transient middle cerebral artery occlusion. At the onset of reperfusion, mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide). Adult and aged C57 Bl/6 mice were dosed additionally with subcutaneous infusion (1.0 μl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Mice were allowed to survive for up to 7 days post-ischaemia and assessed for general well-being (mass loss and survival), neurological score, foot fault and t-maze performance. Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia. In hypertensive animals, progesterone treatment lowered neurological deficit [F(1,6) = 18.31, P = 0.0001], reduced contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and time taken to complete trials [F(1,2) = 15.92, P = 0.0009] for t-maze.ConclusionPost-ischemic progesterone administration via mini-pump delivery is effective in conferring functional improvement in a transient MCAO model in adult mice. Preliminary data suggests such a treatment regimen was not effective in producing a protective effect in aged mice. However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

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Progesterone pharmacokinetics in the mouse: implications for potential stroke therapy

Abstract: A bolus intraperitoneal loading dose of progesterone followed by continuous delivery via osmotic minipump is an effective way of delivering progesterone to the brain.

Cited by 17 publications

References 51 publications

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury

Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice

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