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CLINICAL STUDIES |
From Medical Neuroscience (Dr Nilsson), Clinical Pharmacology (Dr Cheng), Clinical Development (Mr Reinholdsson), AstraZeneca R&D Södertälje, Södertälje, Sweden; Xendo Drug Development Services, Groningen, the Netherlands (Dr Wemer); Royal Institute of Technology, Stockholm, Sweden (Dr Englund); the Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden (Dr Egberg); and the Department of Medicine, McMaster University, Hamilton, Canada (Dr Schulman).
Address for reprints: Address for correspondence: Dag Nilsson, MD, PhD, Medical Neuroscience, AstraZeneca R&D, Södertälje, SE-151 85, Sweden; e-mail: dag.nilsson{at}astrazeneca.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Acute ischemic stroke • bleeding • neuroprotectant • NXY-059 • pharmacokinetics
This highlights a significant area of unmet clinical need for patients with acute ischemic stroke. A potentially new pharmacologic treatment strategy is neuroprotection, which aims to preserve viable brain cells in the ischemic penumbra, an area of compromised tissue surrounding the area of neuronal death (infarct), and to reduce long-term disability. Preclinical studies have shown promising results for a variety of compounds, but these results have not been translated into favorable efficacy and safety for stroke patients in clinical trials.6-8 NXY-059 is a novel free radical-trapping neuroprotectant, and preclinical studies have shown that it reduces infarct size9,10 and preserves brain function in animal models of acute ischemic stroke.11-13 Recently, NXY-059 became the first neuroprotectant to demonstrate a reduction in global disability as measured by the modified Rankin Scale at last rating in a phase III clinical trial involving patients with acute ischemic stroke.14
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The present study was designed to prospectively investigate the effect of NXY-059 on hemostasis in relation to bleeding time, platelet aggregation, and platelet adhesion. The primary objective was to investigate if NXY-059 affects bleeding time in healthy volunteers, as assessed by a Surgicutt template (ITC, Edison, NJ), close to 8 hours after start of and before the end of NXY-059 infusion, at a target plasma concentration relevant to the phase III program. The secondary objectives were to assess if NXY-059 affects platelet aggregation and adhesion and to compare any observed effect with that of desmopressin. In addition, safety and tolerability of NXY-059 and desmopressin were assessed throughout the study.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Desmopressin was included as a positive control because it is known to shorten bleeding time. Volunteers were randomized to 1 of 6 different treatment sequences using a double-dummy approach so that all treatment alternatives were received; but for each of the 3 periods, every volunteer received only 1 active treatment regimen or placebo and a placebo regimen matching the other treatment (Figure 1): NXY-059 + placebo (matching desmopressin), placebo (matching NXY-059) + desmopressin; placebo (matching NXY-059) + placebo (matching desmopressin). Template bleeding time, platelet aggregation, and platelet adhesion tests were performed in each period, and the washout time of 4 to 7 days was chosen to remove any possible carryover pharmacokinetic/pharmacodynamic effects.
On day 1, volunteers received an 8-hour intravenous infusion of NXY-059 (or placebo), with a target unbound plasma concentration of 300 µmol/L, which was the highest target exposure investigated in previous phase I studies and was chosen to assure achievement of the anticipated mean target unbound concentration (260 µmol/L) in planned efficacy studies. NXY-059 (or placebo) was administered as a 1-hour loading dose, followed by a 7-hour maintenance dose, and the appropriate dose was calculated using individual creatinine clearance (CLcrea) estimated from the formula developed for males.17 Desmopressin (or placebo) was administered as a single 10-minute intravenous injection 6 hours 45 minutes ± 5 minutes after the start of infusion with NXY-059 (or placebo), at a dose of 0.3 µg/kg body weight, based on previous observations.18 If desmopressin did not have a significant shortening effect on bleeding time, the study would be considered inconclusive.
Study Population and Treatment
We planned to recruit 30 healthy male volunteers aged between 20 and 45 years, who had a platelet count of 
140 x 109/L, a template bleeding time of 180 seconds but 
600 seconds, and a CLcrea in the normal age-adjusted range (85 mL/min estimated according to Cockcroft and Gault17). All volunteers provided written informed consent, and trial approval was obtained from the Independent Ethics Committee of Uppsala University, Uppsala, Sweden. The study followed the Declaration of Helsinki and was consistent with the International Conference on Harmonisation and Good Clinical Practice guidelines.
Volunteers were excluded if they had a history of a bleeding or thrombotic disorder or a history of excessive scar formation. They were not allowed to use prescribed medication or medication interfering with hemostasis. Volunteers could be discontinued from treatment voluntarily at any time or at the discretion of the investigator for safety reasons, if they had severe noncompliance to the protocol, if they were incorrectly enrolled or randomized at the start of the study, if they tested positive for alcohol or drug abuse during the study, if the treatment code was broken prematurely, or if exclusion criteria developed.
Assessments
Template bleeding time. Bleeding time tests were performed at the enrollment visit (baseline) and just before the end of infusion. A blood pressure cuff was inflated and kept at 40 mm Hg on the arm to be tested, which was not the arm used for either injection or infusion. Using the Surgicutt template (ITC),19 a horizontal incision 1 mm deep and 5 mm wide was made on the volar aspect of the forearm parallel to the elbow crease and about 5 cm distally from the cubital fossa, without applying pressure on the skin. The time elapsed from incision until no blood was absorbed with a filter paper was measured with a stopwatch. If the bleeding had not stopped within 900 seconds, which is a cutoff normally used in the clinical setting, the test was stopped and the value >900 seconds was recorded.
Platelet aggregation. Blood samples were collected within 15 minutes after the bleeding test from the arm that was not used for either injection or infusion of the investigational product, and the platelet aggregation test was performed within 3 hours of sampling. At each assessment time, 4 x 5-mL samples were collected into test tubes containing 1/10 volume of 0.129 mol/L sodium citrate as an anticoagulant by venipuncture of an antecubital or other peripheral vein and centrifuged at 150g for 12 minutes at room temperature to obtain platelet rich plasma (PRP). The remaining blood was recentrifuged at 2057g for 15 minutes at room temperature to obtain platelet poor plasma (PPP). Before testing, PRP was diluted with PPP to obtain a standardized platelet count of 250 x 109/L. A dose-titration approach involving the agonists adenosine diphosphate (ADP) and collagen was used to determine the ED50, which is the agonist concentration inducing 50% of maximum aggregation.
Platelet adhesion. For platelet adhesion, 10 mL blood was collected without addition of anticoagulant from an antecubital or other peripheral vein close to 8 hours after the start of investigational product administration, from the arm that was not used for injection or infusion of placebo or the active treatments, using 2 Becton-Dickinson 20-mL syringes (5 mL in each; Franklin Lakes, NJ). The test was performed with the ADEPLAT instrument (Marscia Brunelli Spa, Milan, Italy) within 60 seconds of blood sampling using ADEPLAT S and T glass bead columns.
Coagulation tests. Coagulation tests were used to monitor different aspects of the coagulation pathway including factor VIII activity (kinetic chromogenic assay), von Willebrand factor activity (ristocetin cofactor activity), fibrinogen concentration (v Clauss type clotting assay), activated partial thromboplastin time (Cephotest, Medinor AS, Oslo, Norway), and prothrombin time (Stago Prothrombin Assay, Stago, Asnières, France). Blood samples were collected immediately prior to desmopressin (or placebo) injection.
Pharmacokinetics
Blood samples of 5 mL for assessment of total plasma concentration of NXY-059 were taken just before the start of the loading infusion and at 3 time points (6, 7, and 8 hours) during infusions. One extra blood sample (5 mL) was taken at 8 hours for assessment of unbound plasma concentration of NXY-059.
Total plasma concentrations of NXY-059 were determined by a column-switching high-performance liquid chromatographic method, using an external standard. The ultraviolet absorbance of NXY-059 at 299 nm was used for detection and quantification of the substance. The limit of quantification (LOQ) was 0.2 µmol/L, with a coefficient of variation (CV) of <12.7% in the plasma concentration range 0.4 to 750 µmol/L. Unbound plasma concentrations of NXY-059 were determined by ultrafiltration. The LOQ was 1.0 µmol/L ultrafiltrate, with a CV <3.1% in the concentration range 80 to 500 µmol/L (total concentration). The bioanalyses were performed at Analytical Services, Quintiles AB, Uppsala, Sweden, according to the procedures in agreement with AstraZeneca R&D Södertälje.
The fraction unbound in plasma (fu) was calculated for each subject from the ratio between the unbound plasma concentration, that is, the concentration in the ultrafiltrate and the total concentration in plasma at 8 hours. The steady-state plasma concentration (Css) was calculated for each subject by taking the mean of the plasma concentrations at 6, 7, and 8 hours. The corresponding unbound steadystate plasma concentration (Cuss) was calculated by multiplying Css with fu.
Safety and Tolerability
The incidence and nature of adverse events were collected for all volunteers who participated in at least 1 study period. An adverse event was defined as the development of an undesirable medical condition or the deterioration of an existing medical condition following or during exposure to a pharmaceutical product, whether or not causally related to the product. Adverse events were recorded just prior to the first investigational product administration and throughout the study. Adverse events were rated as 1 for mild (aware of symptoms but easily tolerated), 2 for moderate (discomfort sufficient to interfere with normal activities), and 3 for severe (unable to perform normal activities).
A serious adverse event was defined as an adverse event that occurred during any study phase and at any dose of NXY-059, desmopressin, or placebo and resulted in death, was immediately life-threatening, resulted in hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital abnormality, or was an important medical event that may either jeopardize the subject or require medical intervention to prevent one of the previous outcomes. The causality of serious adverse events and their relationship to study treatment were also assessed.
Physical examination, electrocardiogram (ECG), vital signs (pulse, blood pressure), and laboratory measurements were performed throughout the study.
Statistical Analysis
The observations on bleeding time, platelet aggregation, and platelet adhesion were analyzed in a multiplicative mixed linear model for a 3-period crossover design with fixed effects of treatment and period, and a random effect of subjects assuming independent lognormal distributed residuals, and hence the logarithms of the original values were analyzed. Carryover effects were not expected but were explored in supplementary analyses.
The effect of NXY-059 on bleeding time, compared with placebo, was evaluated using an equivalence test, with equality defined as a treatment ratio within the reference interval (0.7-1/0.7). The test was constructed using a 90% confidence interval (CI) for the treatment ratio, and if the CI fell within the reference interval, the null hypothesis of nonequality was rejected. Because the reason for including the desmopressin arm was not a major objective, it was decided to use a nonstandard, 1-sided test at the level of 10%. The hypothesis for the desmopressin was that the ratio of bleeding times during desmopressin and placebo is equal to 1.0 against the alternative that the ratio is <1.0. The alternative indicated that the bleeding time was reduced by desmopressin.
The sample size estimation in each session was based on bleeding time data using a Surgicutt (ITC) device from Buchanan et al.19 Within-subject and between-subject variations were estimated using a log-linear model with fixed effect of treatment (acetylsalicyclic acid or no acetylsalicyclic acid) and a random effect of subject. The within-subject variance of logarithmic bleeding time was estimated to be 0.116. The observed within-subject variances (on the logarithmic scale) in this study were similar to those observed by Buchanan et al,19 and hence the assumptions in the sample size estimation were fulfilled.
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The power of a level 0.05 equivalence test of NXY-059 and placebo with the reference interval (0.7-1/0.7) was at least 95%.
Platelet aggregation ED50 and the percentage of retained platelets (platelet adhesion) were compared pairwise between treatments. Hence, the ratio of the logarithms of original values was analyzed using a 2-sided t test at a 5% significance level. The coagulation test variables were not part of the formal statistical comparison and only descriptive statistics were used for the evaluation. The pharmacokinetic variables for Css, Cuss, and fu were summarized using n, mean, standard deviation, CV, median, minimum, and maximum values.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Bleeding Time
The estimate of the ratio of bleeding times between NXY-059 and placebo was 1.015, and equivalence was established on the 5% level, as the 2-sided 90% CI (92%-112%) was within the interval (0.7-1/0.7 [=70%-143%]; Table II). Hence, it was concluded that NXY-059 did not shorten or prolong bleeding time compared with placebo.
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As expected, desmopressin met the predefined criteria for a significant decrease in bleeding time compared with placebo according to the prespecified 1-sided test on the level 10% (P = .057), thus confirming the validity of the methodology (Table II). Desmopressin also decreased bleeding time compared with NXY-059 (P = .034). The mean bleeding times for the 3 different treatment periods are presented in Table III, and individual values of bleeding time in all subjects are presented in Figure 3. It was observed both during the NXY-059 and placebo periods that the subjects in general had a slightly longer bleeding time at infusion (mean, 370 seconds [SD, 125] and 369 seconds [SD, 136], respectively) compared to enrollment (mean, 324 seconds [SD, 98]).
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Platelet Aggregation
NXY-059 did not cause any significant difference in the platelet aggregation induced by ADP relative to placebo (ratio estimate, 0.992; P = .937), whereas a significant increase in the ED50 value relative to placebo was seen after desmopressin injection (Table IV). It was estimated that desmopressin increased the ED50 value by 23% over placebo (ratio estimate, 1.228; P = .036 for a difference from 1) and 24% over NXY-059 (ratio estimate, 1.238; P = .030). Equivalence was found for the ratio of NXY-059 to placebo (ratio estimate, 0.992; P = .937; 95% CI, 82%-120%).
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For collagen-induced platelet aggregation, neither NXY-059 nor desmopressin promoted an ED50 value significantly different from that for placebo (Table IV). The ratio estimates of the ED50 values for platelet aggregation induced by collagen for NXY-059 and desmopressin over placebo were estimated to 1.183 (P = .079; 95% CI, 98%-143%) and 1.193 (P = .065; 95% CI, 99%-144%), respectively.
Platelet Adhesion
For the ADEPLAT S and T tests, there was no significant difference between placebo and NXY-059 (Table V). Desmopressin induced a significant increase in platelet adhesion over placebo and NXY-059 according to both the ADEPLAT S and T tests (Table V). According to the ADEPLAT S test, it is estimated that there was a 19% increase in platelet adhesion for desmopressin over placebo (ratio estimate, 1.189; P = .027) and a 30% increase over NXY-059 (ratio estimate, 1.297, P = .001). The ADEPLAT T test showed a significant increase for desmopressin over placebo by 150% with a ratio estimate of 2.508 (P < .001) and over NXY-059 by 164% with a ratio estimate of 2.638 (P < .001).
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Coagulation Parameters
Although not part of the formal statistical comparison for evaluating pharmacodynamic variables, there were no differences among treatment with NXY-059 or placebo in terms of an effect on factor VIII activity, von Willebrand factor activity, fibrinogen concentration, activated partial thromboplastin time, or prothrombin time.
Pharmacokinetics
The mean fu of NXY-059 was 0.66 (median, 0.62; minimum, 0.52; maximum, 0.92; CV, 18.1%). The mean Cuss of NXY-059 was 335 µmol/L (median, 326 µmol/L; minimum, 241 µmol/L; maximum, 433 µmol/L; CV, 13.5%). The target exposure of NXY-059 (Cuss of 300 µmol/L) was achieved.
Safety and Tolerability
Treatment with NXY-059 was generally well-tolerated, and no serious adverse events were reported. One volunteer discontinued from the study prior to receiving NXY-059 because of pharyngitis, rhinitis, and headache. Of the 29 volunteers in the NXY-059 group, 16 reported a total of 26 adverse events (17 mild, 9 moderate); of 30 volunteers in the desmopressin group, 23 reported a total of 37 adverse events (23 mild, 14 moderate); and of 30 volunteers who received placebo, 11 reported a total of 14 adverse events (11 mild, 3 moderate). There were no clinically significant differences in the incidence of adverse events among the 3 treatment groups. The most commonly reported adverse events were as follows: NXY-059, headache (14) and rhinitis (5); desmopressin, flushing (12), headache (8), and rhinitis (6); and for placebo, headache (10) (Table VI).
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No abnormalities in routine clinical laboratory results were observed in this study. Apart from 1 volunteer receiving desmopressin, there were no clinically significant findings for recordings of systolic and diastolic blood pressure and pulse rate in supine and standing positions. However, volunteers receiving desmopressin did have an increase in pulse and a decrease in diastolic blood pressure in standing and supine positions compared with placebo.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In the present study, there was a tendency of a shorter bleeding time at enrollment compared to during infusion with both NXY-059 and placebo. A potential explanation for this is that the enrollment test was performed when volunteers arrived from work, studies, or other activities. In contrast, the tests during the infusion days were performed in the afternoon following a calm and uneventful day at the investigation site, suggesting that there may be a significant difference between these time points with respect to physical activity versus rest and psychologic stress versus relaxation, which consequently has an effect on the level of catecholamines and therefore on hemostatic mechanisms.
Platelet activation plays a pivotal role in hemostasis; this process involves a change in cellular shape, release of granular constituents, adhesion, and aggregation.21 There have been conflicting reports of the effect of desmopressin on platelet activation with principally no effect or an increased platelet aggregation reported at pharmacologic concentrations of desmopressin.21,22 In the present study, a significant increase in the ED50 value for aggregation (indicating that the platelets are less prone to aggregate) induced by ADP was observed 1 hour after desmopressin injection compared with ED50 values obtained both during placebo and NXY-059 infusion. An unchanged or decreased ED50 after desmopressin had been expected and more in line with results from other published studies. A possible reason could be that the blood sampling for platelet aggregation was performed around 1 hour after the desmopressin injection so that platelets might have already partly aggregated and deaggregated in vivo. Alternatively, the platelets could have partly aggregated and deaggregated ex vivo in the test tubes and therefore, to some extent, were in a refractory state when stimulated to aggregate ex vivo. There was no significant difference for desmopressin in the ED50 values induced by collagen, compared with either NXY-059 or placebo. Desmopressin significantly increased platelet adhesion compared with placebo and NXY-059, which was expected, based on published observations.18
The observed mean Cuss of NXY-059 (335 µmol/L) was close to the dosing target (300 µmol/L; deviation of 11.6%), which is consistent with a previous study.16
There were no safety concerns identified during the study and no evidence that volunteers receiving NXY-059 experienced a higher incidence of adverse events compared with volunteers receiving either desmopressin or placebo. In addition, all reported adverse events were either mild or moderate. The highest number of adverse events was reported in the desmopressin group, due to 12 volunteers who experienced flushing, which is a well-known reaction during treatment with desmopressin.22 NXY-059 did not appear to have any clinically significant effect on the vital signs, ECG, or clinical chemistry variables measured, concurring with previous observations.14,16
In summary, this study showed that NXY-059 does not affect hemostasis in terms of bleeding time, platelet aggregation, or platelet adhesion at indicated therapeutic plasma concentration. In addition, the exposure of NXY-059 was well tolerated, and no safety concerns were identified during the study. These are important features of a neuroprotective agent intended to offer clinical benefit to patients suffering an acute ischemic stroke.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Dr Nilsson, Dr Cheng, and Reinholdsson are employees and shareholders of AstraZeneca. Dr Nilsson is also a shareholder of Renovis Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. World Health Organization. The World Health Report 2004. Geneva, Switzerland: The World Health Organization; 2004.
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11. Marshall JWB, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke. 2003;34: 2228-2233.
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19. Buchanan GR, Holtkamp CA. A comparative study of variables affecting the bleeding time using two disposable devices. Am J Clin Pathol. 1989;91: 45-51.[Web of Science][Medline] [Order article via Infotrieve]
20. Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke. 2003;34: 1437-1442.
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