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Justin A Zivin

Publications and source records attributed to Justin A Zivin.

18 recordsLinked to original sources
PubMed2006

Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial.

BACKGROUND AND PURPOSE: NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings. METHODS: We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days. RESULTS: NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02). CONCLUSIONS: NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.

Aged↗
PubMed2006

High-dose atorvastatin after stroke or transient ischemic attack.

BACKGROUND: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established. METHODS: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. RESULTS: The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. CONCLUSIONS: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. (ClinicalTrials.gov number, NCT00147602 [ClinicalTrials.gov].).

Adult↗
PubMed2006

NXY-059 for acute ischemic stroke.

BACKGROUND: NXY-059 is a free-radical-trapping agent that is neuroprotective in animal models of stroke. We tested whether it would reduce disability in humans after acute ischemic stroke. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 1722 patients with acute ischemic stroke who were randomly assigned to receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours after the onset of the stroke. The primary outcome was disability at 90 days, as measured according to scores on the modified Rankin scale for disability (range, 0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound, requiring constant care). RESULTS: Among the 1699 subjects included in the efficacy analysis, NXY-059 significantly improved the overall distribution of scores on the modified Rankin scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test). The common odds ratio for improvement across all categories of the scale was 1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of serious and nonserious adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured according to the National Institutes of Health Stroke Scale (NIHSS): the difference between the two groups in the change from baseline scores was 0.1 point (95 percent confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed according to the Barthel index (P=0.14). In a post hoc analysis of patients who also received alteplase, NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036). CONCLUSIONS: The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).

Acute Disease↗
PubMed2006

Reasons why few patients with acute stroke receive tissue plasminogen activator.

Despite the US Food and Drug Administration's approval in 1996, tissue plasminogen activator (tPA) therapy for acute ischemic stroke remains substantially underused. We reviewed 3 potential reasons for low rates of tPA use: poor patient education, physicians' perceived risk of legal liability from negative patient outcomes, and insufficient reimbursement. The recent addition of diagnosis-related grouping code 559 will provide higher payment for stroke patients treated with tPA, creating a natural experiment to examine our third reason.

Drug Utilization↗
PubMed2004

SLOW-MAG.

Explore the source record for details and available documents.

Calcium Channel Blockers↗
PubMed2004

Transcranial infrared laser therapy improves clinical rating scores after embolic strokes in rabbits.

BACKGROUND AND PURPOSE: Because photon energy delivered using a low-energy infrared laser may be useful to treat stroke, we determined whether transcranial laser therapy would improve behavioral deficits in a rabbit small clot embolic stroke model (RSCEM). METHODS: In this study, the behavioral and physiological effects of laser treatment were measured. The RSCEM was used to assess whether low-energy laser treatment (7.5 or 25 mW/cm2) altered clinical rating scores (behavior) when given to rabbits beginning 1 to 24 hours postembolization. Behavioral analysis was conducted from 24 hours to 21 days after embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a treatment is considered beneficial if it significantly increases the P50 compared with the control group. RESULTS: In the present study, the P50 value for controls were 0.97+/-0.19 mg to 1.10+/-0.17 mg; this was increased by 100% to 195% (P50=2.02+/-0.46 to 2.98+/-0.65 mg) if laser treatment was initiated up to 6 hours, but not 24 hours, postembolization (P50=1.23+/-0.15 mg). Laser treatment also produced a durable effect that was measurable 21 days after embolization. Laser treatment (25 mW/cm2) did not affect the physiological variables that were measured. CONCLUSIONS: This study shows that laser treatment improved behavioral performance if initiated within 6 hours of an embolic stroke and the effect of laser treatment is durable. Therefore, transcranial laser treatment may be useful to treat human stroke patients and should be further developed.

Animals↗
PubMed2004

Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits.

Tenecteplase (TNK) was engineered to have increased fibrin specificity and an increased half-life compared to Alteplase. Although Tenecteplase is currently being tested in a Phase II clinical trial in acute ischemic stroke patients, little is known about the pharmacology and dose-response or therapeutic window for Tenecteplase in embolic stroke models. In the present study, we compared Tenecteplase with Alteplase on behavioral outcome in rabbits with embolic strokes. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into the middle cerebral artery (MCA) via a catheter. The rabbit small clot embolic stroke model (RSCEM) was used for a dose-response profile analysis of Tenecteplase (0.1 mg/kg-3.3 mg/kg) and Alteplase (0.9 mg/kg-3.3 mg/kg) given intravenously 1 h following embolization. In additional studies, Tenecteplase (0.9 mg/kg) or Alteplase (3.3 mg/kg) was administered 3 (or 6) h following embolization to determine the therapeutic window for the thrombolytics. For both studies, behavioral analysis was conducted 24 h following embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a drug is considered beneficial if it significantly increases the P50 compared with the control group. The P50 of controls 24 h after embolization was 1.13 +/- 0.15 mg. Rabbits treated 1 h post-embolization with Tenecteplase (0.1, 0.25, 0.9, 1.5 or 3.3 mg/kg) had P50 values of 1.48 +/- 0.33, 2.20 +/- 0.44, 2.76 +/- 0.37, 2.15 +/- 0.29 and 2.78 +/- 0.31 mg, respectively. In Alteplase-treated rabbits, only the 3.3 mg/kg dose significantly increased the group P50 by 189% compared to control. Tenecteplase was also effective at increasing the P50 value to 2.21 +/- 0.43 mg if there was a 3-h delay following embolization, but not if there was a 6-h delay before administration. Alteplase was only effective if administered 1 h following embolization where it significantly increased the P50 value to 3.27 +/- 0.40 mg. This study indicates that Tenecteplase has a wide therapeutic range, a therapeutic window of at least 3 h and a durable effect. Moreover, the safety profile for Tenecteplase is similar to that of Alteplase. Tenecteplase does not increase the rate of intracerebral hemorrhage (ICH) above that produced by Alteplase. However, the therapeutic range and window for Alteplase is more limited than that for Tenecteplase. Our preclinical studies suggest that Tenecteplase has a better pharmacological profile than Alteplase and supports further investigation of Tenecteplase in randomized double-blinded clinical trials in stroke patients.

Animals↗
PubMed2004

Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores.

Currently, the only FDA-approved treatment for acute ischemic stroke (AIS) is the thrombolytic, tissue plasminogen activator (tPA; alteplase; activase). It has been proposed that both the spin trap agent NXY-059 (cerovive) and tenecteplase (TNK-tPA), which are currently in phase II clinical trials, may also be useful for the treatment of ischemic stroke. However, there is little information available concerning the dose-response profiles or therapeutic window for NXY-059 in a validated embolic stroke model, nor is there information available pertaining to the effects of combining NXY-059 with tenecteplase. Thus, we determined the pharmacological profile of NXY-059 on behavioral outcome following small clot embolic strokes in rabbits when administered alone or in combination with tenecteplase. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059 (0.1-100 mg/kg) was infused intravenously (IV), 1 h following embolization, whereas control rabbits received infusions of saline. We also determined the therapeutic window for NXY-059 by administering the drug 1, 3, or 6 h following embolic strokes. Lastly, in combination studies, NXY-059 was given concomitantly with tenecteplase 1 or 6 h following embolization. In the vehicle control group, the P(50) value (milligrams of clots that produce behavioral deficits in 50% of the rabbits) measured 24 h following embolism was 1.20 +/- 0.15 mg, and this was increased by 100-134% if NXY-059 (1-100 mg/kg) was administered following embolization. If NXY-059 was administered beginning 3 or 6 h following embolization, there was no significant behavioral improvement. If NXY-059 (100 mg/kg) and tenecteplase (0.9 mg/kg) were administered concomitantly 1 h postembolization, we did not measure any additional behavioral improvement compared to either drug alone. However, if the drugs were administered 6 h following embolization, we measured a statistically significant reduction of behavioral deficits. This study shows that NXY-059 is neuroprotective over a wide range if administered early following an embolic stroke. In addition, the study shows that NXY-059 can be administered in combination with tenecteplase to provide additional behavioral improvement at extended delays following embolization.

Animals↗
PubMed2004

Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence.

Caffeinol is currently being tested in acute ischemic stroke patients. However, little is known about the pharmacology or safety of caffeinol in preclinical embolic stroke models. We determined the pharmacological effects of caffeinol administration on clinical rating scores in rabbits following small clot embolic strokes (RSCEM). Male New Zealand white rabbits were embolized by injecting blood clots into the cerebral circulation via a carotid catheter. Behavioral analysis was conducted 24 h following embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. In the current study, the P50 values for the control groups were 1.32 +/- 0.23 and 1.66 +/- 0.29 mg for the bolus-injected and infused groups, respectively. Rabbits treated with caffeinol (bolus) starting 15 min following embolization had a P50 value of 1.70 +/- 1.18 mg. Caffeinol-infused rabbits had a P50 value of 2.05 +/- 0.47 and 1.67 +/- 0.48 mg for low- and high-dose ethanol, respectively. In tPA-treated rabbits (0.9 mg/kg), the group P50 was 1.58 +/- 0.43 mg. In caffeinol (bolus) and tPA-treated rabbits, we measured a decrease in the P50 value to 0.70 +/- 0.30 mg and an increase in the rate of intracerebral hemorrhage compared to control. This primary finding of this study indicates that neither bolus-injected nor infused caffeinol affects behavioral deficits following embolic strokes in rabbits. Moreover, the combination of caffeinol plus low-dose tPA does not improve behavioral deficits. However, our study suggests that there is the potential for exacerbation of stroke-induced behavioral deficits following caffeinol administration in combination with a thrombolytic that may be related to increased intracerebral hemorrhage.

Animals↗
PubMed2004

Neuroprotection for ischemic stroke: two decades of success and failure.

Alteplase (rt-PA) is the first therapy successfully developed for acute stroke therapy. The success of rt-PA spurred development of new avenues for acute stroke management. For the last two decades, a great deal of attention has been paid to neuroprotective therapies. Initial preclinical studies demonstrated numerous drugs are effective for treating acute stroke in animal models; however, subsequent clinical trials have been frustrating, and none of the agents has proven effective. The various outcomes of preclinical and clinical trials have been the subject of much discussion. In this article, we review some key neuroprotective trials and the possible reasons for their failures. By identifying the discrepancies between preclinical studies and clinical trials, we may be able to set guidelines for future effective trials.

Animals↗
PubMed2003

Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator.

BACKGROUND AND PURPOSE: It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute ischemia stroke. Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has glutathione peroxidase-like and anti-inflammatory properties in embolic stroke models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator (tPA), the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke. METHODS: Male New Zealand White rabbits were embolized by injection of a suspension of small blood clots into the middle cerebral artery via a catheter. Five minutes after embolization, ebselen (10 to 50 mg/kg) was infused intravenously. Control rabbits received infusions of the vehicle required to solubilize ebselen. In additional rabbits, ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with tPA (0.9 or 3.3 mg/kg tPA). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. RESULTS: A drug is considered neuroprotective if it significantly increases the P50 compared with the vehicle-treated control group. The P50 of controls 24 hours after embolization was 1.35+/-0.30 mg. Rabbits treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P50 values of 2.12+/-0.56, 2.82+/-0.75 (P<0.05), and 0.49+/-0.54 mg, respectively. A significant neuroprotective effect was observed with the 20-mg/kg dose, but not if there was a 60-minute delay before administration (P50=1.69+/-0.32 mg). When tPA (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P50=2.98+/-0.18 mg) or 60 (P50=3.60+/-0.79 mg) minutes, there was no additional neuroprotective effect compared with tPA alone (P50=3.38+/-0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (0.9 mg/kg) 60 minutes after embolization, the P50 was 3.52+/-0.73 mg (P<0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P50=1.69+/-0.32 and 1.54+/-0.36 mg, respectively). CONCLUSIONS: This study indicates that ebselen may be neuroprotective when administered shortly after an embolic stroke, but the time- and dose-response analyses suggest that it has a narrow therapeutic window. Nevertheless, ebselen may be beneficial if administered concomitantly with a thrombolytic because it significantly enhanced the neuroprotective activity of low-dose tPA.

Animals↗
PubMed2003

Effects of intrathecal administration of a cell permeant caspase inhibitor, boc-D-fluoromethylketone (BDFMK), on behavioral deficits following spinal cord ischemia: a dose-response analysis.

Caspase inhibition has been proposed as a target to attenuate ischemia-induced neurodegeneration and behavioral dysfunction. The present study evaluated the pharmacological effects of a single dose of an irreversible cell permeant general (nonselective) caspase inhibitor, Boc-D-fluoromethylketone (BDFMK) administered intrathecally (i.t.) in a reversible spinal cord ischemia model (RSCIM). Quantal analysis indicated that the P(50) (represents the duration of ischemia that produces permanent paraplegia in 50% of the animals in a group) of the control group was 25.08+/-4.71 min. Using the RSCIM, neuroprotection is observed if a drug significantly prolongs the P(50) compared to the control group. The P(50) values for the BDFMK-treated groups were 27.21+/-2.62, 27.28+/-3.29 and 28.98+/-2.32 min, for the three dose groups studied. There were no statistically significant changes when measured 18 or 48 h following ischemia. Biochemical analysis of cell extracts from the caudal lumbar spinal cord indicated that there was increased production of the 120-kDa fragment of fodrin suggesting enhanced caspase-3 activity, an increase that was reduced by i.t. BDFMK administration. Moreover, in caudal lumbar spinal cord extracts from a set of paraplegic rabbits (25-50 min occlusion), we measured a 32-42% decrease of caspase-3 activity in BDFMK-treated rabbits. The present study shows that i.t. administration of BDFMK reduced caspase-3 activity, but the inhibition did not translate into a significant behavioral improvement. Our results suggest that administration of a single dose of the caspase inhibitor BDFMK is insufficient to attenuate ischemia-induced behavioral deficits following aortic occlusion.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Inter-relationships between spinal cord blood flow, neuronal death and neurological function in rabbit spinal cord ischemia.

Following rabbit spinal cord ischemia we measured histology, neurological outcome and spinal cord blood flow to investigate relationships between these quantities over a range of ischemia durations. Rabbits underwent reversible spinal cord ischemia induced by temporary aortic artery occlusion for zero to 65 min. In one cohort, surviving spinal cord cells were counted after 4 days of reperfusion using computer image analysis (n=23). Neurological outcome (paraplegic or non-paraplegic) was assessed in another group (n=381) after 18 h of reperfusion. A third group (n=8) had spinal cord blood flow measured by radioactive tracer immediately after ischemia. Histological analysis showed fewer motor neurons and astrocytes surviving as ischemia duration increased. Following 13 min (95% confidence interval (CI), 6 to 27) of ischemia 50% of low lumbar cord motor neurons remained alive; 50% of rabbits were paraplegic following 28.4 (26.7 to 30.0) min of ischemia; 28% (17% to 48%) of low lumbar motor neurons survived at this duration; 5% of rabbits were permanently paraplegic following 13.6 (10.6 to 16.1) min of ischemia, although only 52% (30% to 87%) of lower spinal cord motor neurons survived. Low lumbar cord blood flow was reduced to 2% of flow in non-ischemic thoracic cord after 25 and 60 min of ischemia (0.52 and 0.59 ml/100 g/min, respectively). These data support a fundamental hypothesis on which experimental ischemia is based: that substantial neuronal death follows directly from reversible ischemia and leads to permanent neurological deficit.

Animals↗
PubMed2002

Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator.

BACKGROUND AND PURPOSE: It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemic stroke. However, there is little information concerning the neuroprotective properties of NXY-059 when administered after an embolic stroke. Moreover, there is no information available concerning the combination of NXY-059 with the only Food and Drug Administration-approved pharmacological agent for the treatment of acute stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on behavioral outcome after an embolic stroke when administered alone or in combination with tPA. METHODS: Male New Zealand White rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059G (100 mg/kg) was infused intravenously 5 minutes or 3 hours after embolization, whereas control rabbits received infusions of the saline vehicle. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes or 3 hours after embolization (3.3 mg/kg). In combination studies, NXY-059G was given 5 minutes after embolization, followed by the administration of tPA beginning either 60 minutes or 3 hours after embolization. Behavioral analysis was conducted 24 hours after embolization. RESULTS: In the vehicle control group, the ES50 value (calculated as the amount of microclots [milligrams] that produce neurological dysfunction [impairment] in 50% of the rabbits within a specific treatment group) measured 24 hours after embolism was 1.04+/-0.31 mg, and this was increased by 153% to 2.54+/-0.72 mg if NXY-059G was administered beginning 5 minutes after embolization. However, if NXY-059G was administered beginning 3 hours after embolization, the ES50 was 2.01+/-0.40 mg. The rabbits treated with tPA alone had an ES50 of 2.64+/-0.66 or 0.63+/-0.35 mg if tPA administration started 60 minutes or 3 hours after embolization, respectively. If tPA was administered after NXY-059G (started at 5 minutes), the ES50 values were 3.15+/-0.50 or 2.66+/-0.82 if tPA administration started 60 minutes or 3 hours after embolization, respectively. CONCLUSIONS: This study suggests that NXY-059G is neuroprotective and can increase behavioral ratings if administered early after an embolic stroke. In addition, the study shows that NXY-059G can be used in combination with tPA without negative side effects. The drug combination can improve behavioral function and increase ES50 values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.

Animals↗
PubMed2002

Effects of the spin trap agent disodium- [tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit Large clot embolic stroke model: combination studies with tissue plasminogen activator.

BACKGROUND AND PURPOSE: It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemia and stroke. To date, there is little information concerning the safety of NXY-059 when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on hemorrhage and infarct rate and volume when administered alone or in combination with tPA. In addition, we determined whether NXY-059G affected 2 physiological variables, blood glucose levels and body temperature. METHODS: Male New Zealand White rabbits were embolized by injecting a large blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, NXY-059G (100 mg/kg) was infused intravenously; control rabbits received infusions of saline, the vehicle required to solubilize NXY-059G. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes after embolization (20% bolus injection/80% infusion over 30 minutes). Body temperature and blood glucose levels were measured throughout the study. Postmortem analysis included assessment of hemorrhage and infarct rate, size, and location. RESULTS: In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 52% (n=23), and this was increased by 67% if tPA was administered (n=15). The rabbits treated with NXY-059G in the absence of tPA had a 79% incidence of hemorrhage (n=19), an increase of 52% over the control group. In the combination drug-treated groups, the NXY-059G/tPA group had a 47% incidence of hemorrhage (n=15). There was a decrease of hemorrhage volume in the NXY-059G+tPA group compared with the other 3 groups included in the study. There was no significant effect of NXY-059G either alone or in combination with tPA on infarct rate or volume. NXY-059G did not significantly alter the physiological variables that were measured. CONCLUSIONS: This study suggests that NXY-059G may affect the integrity of the cerebral vasculature when administered immediately after an embolic stroke, as evidenced by an increase in hemorrhage rate. However, when NXY-059G is administered in combination with tPA, it may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. The mechanism(s) involved in the NXY-059G-induced increase in hemorrhage rate and reduction of tPA-induced hemorrhage rate remains to be elucidated.

Animals↗
PubMed2002

Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits.

BACKGROUND AND PURPOSE: It has been proposed that the novel thrombolytic microplasmin may be useful in the treatment of ischemic stroke. In the present study the effects and safety profile of microplasmin were evaluated in 2 rabbit embolic stroke models that have been used successfully to develop tissue plasminogen activator (tPA) as the only Food and Drug Administration-approved treatment for stroke. The rabbit small clot embolic stroke model (RSCEM) and rabbit large clot embolic stroke model (RLCEM) were used to determine the potential neuroprotective properties and safety profile of microplasmin, respectively, after an embolic stroke. METHODS: Rabbits were embolized by injecting small blood clots (RSCEM) or large blood clots (RLCEM) into the cerebral circulation. For the RSCEM, 126 rabbits were included, with behavioral analysis conducted 24 hours later, allowing for determination of the effective stroke dose (ES50) or clot amount (milligrams) that produces severe neurological deficits in 50% of rabbits. For RLCEM safety study analysis, 47 rabbits were included, with postmortem analyses consisting of assessment of hemorrhage and infarct rate and size. In test animals microplasmin was infused intravenously 60 minutes after embolization, whereas control rabbits were given infusions of the saline/Plasma-Lyte vehicle with all assessments performed in a blinded fashion. RESULTS: In the RSCEM, a drug is considered neuroprotective if it significantly increases the ES50 compared with the vehicle-treated control group. The ES50 of the vehicle-treated control group 24 hours after embolization was 1.36+/-0.42 mg (n=38). Microplasmin, infused starting 60 minutes after embolization, increased the ES50 to 2.32+/-0.57 (n=21), 1.89+/-0.48 (n=21), 2.81+/-0.55 (n=22), and 1.89+/-0.28 mg (n=24) for the 1-, 2-, 4-, and 8-mg/kg doses, respectively. There was a statistically significant behavioral improvement in the 4-mg/kg dose arm (P=0.040). The microplasmin dose of microplasmin that was statistically significant (4 mg/kg) was subsequently determined to be safe in the RLCEM because it did not increase the incidence of hemorrhages (56%) compared with vehicle-treated rabbits (63%), nor did it significantly alter hemorrhage volume, infarct rate, or infarct volume. CONCLUSIONS: The present study shows that microplasmin improves behavioral rating scores in the RSCEM when administered 60 minutes after embolization, at a dose that does not increase hemorrhages in the RLCEM. This is in contrast to tPA, which significantly enhances the hemorrhage rate in the RLCEM.

Animals↗
PubMed2002

The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke.

BACKGROUND AND PURPOSE: Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke. METHODS: One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. RESULTS: In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5- and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume. CONCLUSIONS: This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhibitor must be administered to produce a beneficial effect. Overall, on the basis of our results, we hypothesize that the increased rate of intracerebral hemorrhage observed after tPA administration may be partly due to increased reocclusion of cerebral vessels following lysis of the emboli and that reocclusion can be controlled by administration of a platelet inhibitor.

Animals↗