Efficacy of AR-R15896AR in the rat monofilament model of transient middle cerebral artery occlusion

Bialobok, Paul; Cregan, Edward F.; Sydserff, S G; Eisman, Mark S.; Miller, Jerry A.; Cross, A.J.; Simmons, Roy D.; Gendron, Patricia; McCarthy, Dennis J.; Palmer, Gene C.

doi:10.1016/s1052-3057(99)80046-9

Cited by 9 publications

(17 citation statements)

References 24 publications

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“…These two test parameters were, in turn, highly correlated with the degree of deficits observed in neurological scores from 1–21 days post‐MCAO, as well as with the degree of deficiencies in contralateral forepaw dexterity occurring at 30 and 60 days post‐MCAO. The degree of neurological damage following induction of transient MCAO with the intraluminal suture technique in rats is strain sensitive 2. Wistar rats have in general been the strain of choice because of good survivability rates and consistent lesion volumes observed to two hours of MCAO 1–4,6,8.…”

Section: Discussionmentioning

confidence: 99%

“…During surgery and recovery care was taken to prevent any central or peripheral hypothermia. Motor impairment was rated on a scale of 0 (no impairment) to 4 (severe circling or forelimb deficits) 1,2,6–8 T 2 ‐weighted MR images were taken at two and seven days post‐MCAO 1…”

Section: Methodsmentioning

confidence: 99%

“…However, in the emergency room the physician is faced with an unknown situation(s), such as, the timing of the occurrence, the exact location of the occluded artery(s), the completeness of the occlusion, state of consciousness, the condition, age, and health of the patient, and other underlying diseases. Previously, we1,2 and others3,4 have successfully employed the monofilament suture model of middle cerebral artery occlusion (MCAO) in the Wistar rat in order to evaluate promising compounds for advancement to clinic trials. However, when we attempted to develop a similar model in the Sprague Dawley strain of rat, we noticed that despite the use of rigid controls for the experimental conditions, the size of the ensuing cortical infarcts as assessed with T 2 ‐weighted magnetic resonance imaging (MRI) and ultimately histopathology varied considerably among animals.…”

Section: Introductionmentioning

confidence: 99%

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T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

Palmer

Peeling

Corbett

et al. 2001

Annals of the New York Academy of Sciences

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The intraluminal suture model of transient middle cerebral artery occlusion (MCAO) in the Sprague Dawley strain of rats characteristically results in an inconsistently sized brain lesion. The purpose of the investigation reported here was to determine whether there were strong point‐to‐point correlations between the degree of cortical lesion size, as assessed in vivo using T2‐weighted magnetic resonance imaging (MRI) and corresponding cortical lesion size using routine histopathological techniques. Moreover, we aimed to investigate if cortical lesion size as determined by these two modalities correlates with neurological and/or skilled motor deficits observed in individual animals. Baseline behavioral scores were obtained on the animals prior to receiving 60 min of transient MCAO. Following MCAO, animals were tested for 1–21 days for neurological deficits. T2‐weighted MRIs of the cortex were taken at two and seven days post‐MCAO. At 30 and 60 days the rats were retested for forelimb dexterity in the staircase test. Subsequently, the cortex was examined for histopathological damage. Indeed, there were highly significant correlations between lesion size determined by MRI and histopathology. The degree of cortical damage observed in the T2‐weighted MRI, as well as the size of the histopathological lesions were, in turn, highly correlated with the degrees of deficiencies observed in the composite neurological assessments and with the deficits involving skilled use of the contralateral forepaw (damaged side).

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

Palmer

Peeling

Corbett

et al. 2001

Annals of the New York Academy of Sciences

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“…AR-R15896AR (15 mg/kg IV, then 25 mg/kg per day SC for 7 days) was also active in reducing cortical infarct size in the monofilament model of MCAO (2 hours of ischemia). 18 In another model of "excitotoxic" lesion in which malonic acid is injected directly into the rat striatum, AR-R15896AR (either 9 mg/kg SC or 200 nmol intrastriatal) significantly reduced the striatal lesion volume. In the cat MCAO model (90 minutes of ischemia), infarct volume (MRI T2W imaging) was reduced by 80% after infusion of AR-R15896AR (175 g · kg Ϫ1 · min Ϫ1 for 15 minutes) commenced at 30 minutes after the onset of ischemia.…”

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confidence: 99%

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

Lees

Dyker

Sharma

et al. 2001

Stroke

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Background and Purpose-AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. Methods-This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, nϭ36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (nϭ33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (nϭ59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (nϭ42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. Results-Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524Ϯ536 ng/mL at the end of the 250-mg loading infusion and were 1847Ϯ478 ng/mL at steady state after the 9 maintenance doses of 120 mg. Conclusions-The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain. (Stroke. 2001;32:466-472.)

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“…There are at least three principal objectives to sampling: (1) proof of exposure; (2) adequate experimental design—timing of pharmacodynamic assessment in relation to drug bioavailability, and halflife; and (3) facilitation of comparison across species, especially from animals to humans. In this review, the role of pharmacokinetic factors in response to the experimental drug AR‐R15896 is evaluated as a case study, using published literature 1–7. Details of the pharmacology and clinical potential of AR‐R15896 are to be found in earlier publications in this series,8–9 as well as in a recent clinical paper 10…”

Section: Introductionmentioning

confidence: 99%

On the Relationship Between Plasma Concentrations of Drugs and Outcome of Stroke Studies in Laboratory Animals

Curry

2001

Annals of the New York Academy of Sciences

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In assessing plasma concentrations of drugs in relation to neuroprotective effect, emphasis should be placed on measured or calculated concentrations during the window of opportunity for effect, rather than at the end of the experiment. Unbound (plasma free) concentrations should be especially considered as should brain penetration to the stroked area. Problem‐solving exercises should include post hoc assessment of dosing residues and proof of exposure. The shape of the graph of response versus concentration in plasma is very steep, giving the impression of an all‐or‐none effect. Although higher doses lead to greater effects, attempts to statistically correlate plasma level and infarct size are likely to be unsuccessful. There is strong evidence that the pharmacokinetic properties of drugs are affected by the physiological consequences of ischemia.

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Efficacy of AR-R15896AR in the rat monofilament model of transient middle cerebral artery occlusion

Cited by 9 publications

References 24 publications

T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

On the Relationship Between Plasma Concentrations of Drugs and Outcome of Stroke Studies in Laboratory Animals

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Efficacy of AR-R15896AR in the rat monofilament model of transient middle cerebral artery occlusion

Cited by 9 publications

References 24 publications

T2‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

T2‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

On the Relationship Between Plasma Concentrations of Drugs and Outcome of Stroke Studies in Laboratory Animals

Contact Info

Product

Resources

About

T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model

T₂‐Weighted MRI Correlates with Long‐Term Histopathology, Neurology Scores, and Skilled Motor Behavior in a Rat Stroke Model