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Appropriate timing of fluoxetine and statin delivery reduces the risk of secondary bleeding in ischemic stroke rats

JOURNAL OF NEUROLOGY AND NEUROSCIENCE
Maria HH Balch,
Appropriate Timing of Fluoxetine and Statin Moner A Ragas, Danny
Delivery Reduces the Risk of Secondary Wright,Amber Hensley,
Bleeding in Ischemic Stroke Rats Kenny Reynolds, Bryce Kerr
and Adrian M Corbett
Department of Neuroscience, Cell Biology and Physiology; Wright State University; 3640 Colonel Glenn Highway; Dayton, Ohio 45435 USA Background: Ongoing clinical trials are testing the effect of fluoxetine delivered
post-stroke where a majority of patients are taking statins. This study determined the influence of the timing of administration of fluoxetine and statin on the final Corresponding author: Adrian M Corbett
infarct volume and the risk of secondary bleeding in an animal model of ischemic stroke.
Methods and findings: Ischemic strokes were induced by endothelin-1 injection
into two cortical sites of 10-12 month old female rats, targeting the forelimb motor cortex. Combined medications (5 mg/kg fluoxetine and 1 mg/kg simvastatin) were orally administered either beginning 6-12 hours or 20-26 hours after stroke Department of Neuroscience, Cell Biology induction and continued daily for 90 days. Infarct volumes were assessed at post- and Physiology; Wright State University; stroke day 91 using Nissl stained coronal brain sections. 3640 Colonel Glenn Highway; Dayton, Ohio Control animals typically had 5-13 mm3 infarct volumes following endothelin-1 induced stroke. Animals that received fluoxetine and simvastatin (FS) beginning 20- 26 hours after stroke induction showed a strong trend of reduced infarct volume (3±0.3447 mm3 SEM, P=0.0563). Earlier drug delivery (6-12 hours after stroke) resulted in significantly larger infarct volumes (15.44.260 mm3 SEM, P=0.0157) when the drug groups were directly compared. Examination of the infarcts showed that earlier drug delivery induced secondary hemorrhagic infarcts, while later delivery did not (P=0.0427; Fisher's exact test).
Conclusion: There is a danger of secondary bleeding if fluoxetine and simvastatin
are combined within 6-12 hours of ischemic stroke induction in rats resulting in larger infarct volumes. Delaying fluoxetine and simvastatin delivery to 20-26 hours after stroke induction in rats, however, reduces infarct volume and significantly lowers the risk of secondary hemorrhagic infarcts.
Keywords: Ischemic Stroke, Secondary Hemorrhagic Stroke, Fluoxetine,
Simvastatin, Infarct Volume (Assessment oF FluoxetINe In sTroke recoverY) trial in Australia, the FOCUS (Fluoxetine Or Control Under Supervision) trial in Only a small percentage of acute ischemic stroke patients the United Kingdom, and the EFFECTS (Efficacy oF Fluoxetine–a reach the hospital in time to be considered for treatment with randomizEd Controlled Trial in Stroke) trial in Sweden [4]. Since recombinant tissue plasminogen activator (rtPA),which can the majority of patients coming into the hospital are already minimize permanent brain damage and reduce the risk of long- on statins due to dyslipidemia, the purpose of this study was to term disability [1]. Fluoxetine, a selective serotonin reuptake examine whether administering fluoxetine at an earlier time- inhibitor (SSRI), has been recently shown to enhance motor point after stroke onset in combination with a statin could functional recovery after ischemic stroke [2,3]. Several ongoing improve outcomes. In this study, we measured infarct volume clinical trials are looking at the effect of Fluoxetine when differences when fluoxetine was administered either 6-12 hours given 2-15 days following stroke onset, including the AFFINITY or 20-26 hours after stroke induction in 10-12 month old rats.
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Materials and Methods
of rats showed little preference for the right or left paw during this exploration behavior. However, when rats were again tested on post-stroke day 4, they showed a preference for touching the All animal work was approved by the Institutional Animal Care wall with their ipsilateral (right) paw, while they held their left and Use Committee at Wright State University, and all procedures paw back toward their body. In this analysis we looked at the followed were in accordance with institutional guidelines. percentage of touches to the wall by right or left paw post-stroke Animals used were 10-12 month old female Sprague-Dawley rats and divided that by their pre-stroke performance percentages. (generally 300-400 grams), obtained from Harlan Laboratories Again, when the quotient was 1, the animal had fully regained (Indianapolis, IN) and fed Harlan rat chow. The specific groups pre-stroke function and when the quotient was less than 1, are indicated in Table 1.
the animal had a functional deficit in that limb. In this test in Functional tests
particular, the increased percentage of right paw use gave us values greater than 1.
Montoya staircase: Rats were fasted overnight and then placed Surgery for stroke induction
on a restricted diet consisting of 85% of their ad lib rat chow while they were trained to pick up sucrose pellets on the Montoya Anesthesia was induced with 5% isoflurane, and then the animals Staircase [5]. The Montoya Staircase consists of a raised platform were maintained on 2-2.5% isoflurane using an anesthesia mask with seven stairwells on each side containing sucrose pellets on the stereotactic apparatus (Stoelting Co., USA). The basic (three per stairwell) on each side of the platform, allowing left surgical procedures are as described in a previous study[6], and right forelimb function to be assessed. Training occurred with the following modifications: two holes were drilled in during the dark-phase and consisted of 15 minute trials inside the skull, with positions relative to Bregma of (0.0 mm A.P., the Montoya Staircase with sucrose pellets that have been 2.5 mm M.L.) and (1.5 mm A.P., and 2.5 mm M.L.). The needle painted with maple extract; the maple odor helps the rats locate containing endothelin-1 was inserted into both holes in the skull, the sucrose pellets on the stair wells. Training generally lasts then lowered to a depth of 2 mm. One and one-half microliters anywhere from 10-14 days. At the end of the training period, the of endothelin-1 (600 pmol) was injected into each hole over a period of about 5 minutes. These positions were chosen to target rat's pre-stroke performance was determined by the best overall the forelimb motor cortex in rats [7].
performance (total pellets taken) during the last three days of training. Animals must have learned to pick up at least 9 pellets Treatment conditions
with both their left and right forepaws or they were excluded Two different time-points were chosen for initiating 5 mg/ from the Montoya Staircase analysis. The majority of animals kg fluoxetine and 1 mg/kg simvastatin after stroke induction: learned to retrieve between 15-18 pellets with both paws. At 3-5 6-12 hours (12 animals per group) and 20-26 hours (8 animals days post-stroke the rats were tested on the Montoya Staircase per group). Animals were randomly assigned to either drug or again, and their best performance (total pellets taken) was used control group after the surgery, but before the baseline stroke as a measure of their post-stroke baseline performance. To deficit was determined using either Montoya Staircase or normalize their performance, we divided the number of pellets Forelimb Asymmetry tests. After drug treatment was begun, it taken by each paw post-stroke by the number of pellets taken by was continued daily for a period of 90 days, using voluntary oral each paw pre-stroke. Thus, when the quotient was 1, the animal administration of the drugs [8]. Briefly, this involves putting the had fully regained pre-stroke function in a particular limb and drugs in a 4 gram ball of sugar cookie dough and allowing the when the quotient was less than 1, the animal had a functional animals to eat it. Control animals receive the 4 gram ball of sugar deficit in that limb. Animals that failed to reach training criteria cookie dough with no drugs added.
on Montoya Staircases were tested on Forelimb Asymmetry.
Forelimb asymmetry: Animals were placed in a clear vertical Histology
cylinder and videotaped for 5 minutes. Rats would rear up and The animal was anesthetized with 100mg/kg, i.p. pentobarbital touch the walls of the cylinder with their right and left forepaws (Euthasol®), then euthanized by cardiac perfusion with phosphate- to explore their environment. Normally, pre-stroke, the majority buffered saline followed by 4% paraformaldehyde in phosphate Table 1 Characteristics of treatment groups. FS refers to fluoxetine and statin groups.
Weight at Stroke
Drugs (oral)
Age at Stroke
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buffered saline. The brain was dissected out, the left hemisphere performance in Montoya Staircase and Forelimb Asymmetry was marked, and the brain post-fixed 24 hours in 4% paraformaldehyde assessed. To be included in the functional analysis, rats had to pick in phosphate buffered saline. The brain was then put into a 30% up at least 9 sucrose pellets with each forepaw in the Montoya sucrose solution for three days, in preparation for cryosectioning. Staircase test and show at least a 20% functional deficit. The rats Fifty micron coronal slices were cut on a cryostat and collected displayed similar post-stroke function in the contralateral paw into phosphate buffered saline. For infarct measurement, these in each of the time groups: in the 6-12 hours treatment groups, sections were mounted onto gel-subbed slides, then stained with the mean contralateral function was 0.30±0.32 (mean±SD) in Nissl stain [6], dehydrated and coverslipped with DPX mountant the FS group and 0.33±0.28 in the control group. In the 20-26 (Sigma-Aldrich). hours treatment groups, the post-stroke mean contralateral function was 0.525±0.31 for the FS group and 0.37±0.27 for the control group. There was no statistical difference in the functional Brightfield images were taken of the sections using a 4X deficits on the contralateral forepaw between the drug and objective, then montaged using Adobe Photoshop 7.0 (Adobe control groups. In some cases, we would see a bilateral deficit, Systems Inc, San Jose CA, USA) into a complete picture of any and when those infarcts were examined, the infarcts generally damaged regions of the brain. Area of the infarct was determined involved a portion of the corpus callosum. Infarcts were induced with ImageJ software from NIH. We determined infarct area with endothelin-1 injections at the forelimb motor cortex, and (mm2) for every third or fourth slice, then multiplied by the slice drug treatment with 5 mg/kg fluoxetine and 1 mg/kg simvastatin thickness (mm) and either 3 or 4 respectively, to determine the was begun either 6-12 hours OR 20-26 hours after stroke complete infarct volume in mm3. Individuals determining the induction. These drug dosages correlate to approximately a 40 infarct volume were blinded to the animal group (control group mg fluoxetine dose and a 10 mg dose of simvastatin in humans or fluoxetine-simvastatin group). We lost four brains in the [15]. This amount of fluoxetine is about twice what is currently fluoxetine-simvastatin treated group for 6-12 hour administration being used in on-going clinical trials [3,4].
and two of the fluoxetine-simvastatin treated group (20-26 hour administration) due to damage while cutting the brains on the Exclusions
microtome (shattering), which made the brain slices impossible to mount on slides or damage to brain while dissecting that made In this study, we examined infarct sizes in all animals that determination of complete infarct volume impossible. underwent stroke and also displayed at least a 20% contralateral deficit in the Montoya Staircase or Forelimb Asymmetry. In our endothelin-1 induced stroke method, we positioned a needle An unpaired t-test with Welch's correction for unequal variances with endothelin-1 at a depth of 2 mm from the cortical surface was used for statistical comparison of the infarct volumes (Prism before injecting 600 pmoles of endothelin-1 into the site. This 6.0, GraphPad Software Inc. San Diego, USA). Figure 1 shows movement of the needle through the cortex sometimes nicks a
means and standard error of the means, with individual infarct blood vessel and causes some bleeding, which the endothelin-1 volumes given by closed symbols clustered around means. will generally stop for an interval. One of the animals in the control Sample sizes are given in the figure legends. The online relative group had substantial bleeding due to this needle damage of risk calculator from the MedCalc site (www.medcalc.org/calc/ blood vessels (Figure 3; Panel A: positive control for hemorrhagic
relative_risk.php) was used to determine the relative risk of the infarcts), which produced secondary hemorrhagic damage in this stroke rats developing secondary hemorrhagic stroke due to drug animal and a huge infarct that spread far anterior and posterior combination administration time and Fisher's exact test (two- compared to our normal infarcts (total infarct volume of 53.20 tailed) was used to determine if there was a statistical difference mm3). Because this damage was due to a surgical artifact, and in the occurrence of secondary hemorrhagic infarcts between the not due to the endothelin-1 induced ischemic damage, it was not two delivery times.
included in this study. The only other reason that a rat brain was excluded from this analysis was if the brain was damaged either during dissection or during the cryostat sectioning, such that we could not mount the individual slices or could not accurately Functional assessment
determine the entire infarct volume. Female Sprague-Dawley rats (10-12 months old, 300-400 grams) Infarct volumes vary with timing of fluoxetine,
were initially trained to pick up sucrose pellets in the Montoya Staircase [5] and also tested for forelimb bias using the Forelimb statin administration
Asymmetry Test [6]. We chose old rats as an animal model to In Figure 1, infarct volumes were calculated on post-stroke day
better model the human stroke population, as neurogenesis is 91, with animals either receiving fluoxetine and simvastatin (FS decreased in both humans and animals with age [9,10], and the in figure, 5 mg/kg, and 1 mg/kg, respectively) or vehicle control, drugs chosen would work to increase neurogenesis [11-14]. Three beginning either 6-12 hours or 20-26 hours after stroke induction days prior to the stroke, the rats were introduced to the vehicle and continuing daily through post-stroke day 90. In Panel A, that would contain their drugs or serve as a vehicle control (4 we see a strong trend toward a reduction in infarct size in the grams of sugar cookie dough, Pillsbury®) to allow them to get FS group (3.051±0.3447 mm3, mean±SEM; squares) compared over their avoidance of novel foods; their pre-stroke baseline to control (6.277±0.14 mm3, mean±SEM; circles) when the Copyright iMedPub Find this article in: www.jneuro.c 3
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Figure 1 Infarct volume varies with timing of fluoxetine and simvastatin delivery after ischemic stroke.
Infarct volumes were assessed in rats at post-stroke day 91, and drug-treated rats received 5 mg/kg fluoxetine and 1 mg/ kg simvastatin daily in vehicle, beginning at the time indicated in the panel. FS in the figure refers to animals receiving fluoxetine and simvastatin. Panel A: Panel shows infarct volumes assessed in rats receiving either vehicle control (circles, N=8) and or drugs in vehicle (squares, N=6) beginning 20-26 hours after ischemic stroke induction and continuing daily until the end of study. Infarct volumes showed a strong trend of reduction, but just missed a significant difference (P=0.0563, Welch's t-test) for the fluoxetine and simvastatin group. Panel B: Panel shows infarct volumes when either vehicle control (circles, N=8) or drugs in vehicle (squares, N=11) was delivered 6-12 hours after ischemic stroke induction and continued daily until the end of study. Infarct volumes showed no statistical difference (P=0.1347; Welch's t-test). Panel C: Panel shows direct comparison of infarct volumes for the group receiving fluoxetine and simvastatin with different delivery times after stroke induction. The timing of delivery after stroke produced a significant difference in infarct volumes (P=0.0157; Welch's t-test), with the earlier timing producing a much larger infarct.
fluoxetine and simvastatin drug combination is administered infarct size was enlarged.
beginning 20-26 hours after the stroke (P=0.0569; Welch's correction on unpaired t-test with unequal variance), which was Histological evidence of secondary hemorrhagic
an unexpected result. We did not think drug administration this transformation in rats receiving fluoxetine and
late after stroke induction would have any effect on the infarct statin at an early time point
volume. The reduction in infarct volume has also correlated with In Figure 2, infarcts are shown (outlined with dashed lines) in
an increase in motor functional recovery, referenced in some of representative coronal brain sections for each of the relevant our previous work [6]. We next tested whether an earlier time groups. The endothelin-1 injection site was usually clearly seen point for drug delivery would result in further reduction of infarct at the dorsal portion of the cortex as it is generally a hole in volume and greater functional recovery, administering the drugs the tissue at 91 days post-stroke, since it was the origin of the 6-12 hours after stroke induction, a time period over which the infarct. In control animals (Panels A and C), we have generally majority of stroke patients have been shown to arrive at the seen additional damage to the right side of this injection point, hospital [1]. In Panel B, we see that drug delivery at an earlier time representing perhaps reperfusion damage when the endothelin-1 point actually resulted in larger infarct volumes (15.24±4.26 mm3; was metabolized or eliminated, allowing blood flow to return mean±SEM; squares) which were not statistically different from after approximately 24 hours [16]. Areas with very small surface control infarct volumes (9.775±2.786 mm3; mean±SEM; circles) damage were not included in outlined infarcts just for clarity in (P=0.1347; Welch's correction for unpaired t-test with unequal this figure, but they were included in the infarct analysis above. In variance). In panel C, we directly compared the infarct volumes general, we did not see evidence of any secondary hemorrhagic in the two groups that received fluoxetine and simvastatin, just stroke in control animals, whether or not the control vehicle was looking at the effect the difference in delivery time (noted on the delivered at 6-12 hours after stroke (Panel A) or 20-26 hours after X axis) had on the infarct volume. This data was simply taken from stroke (Panel C). panels A and B, re-plotted on the same scale and then compared Panel D shows the infarct size (largest in a series of brain sections) for statistical difference. Earlier delivery (6-12 hours after stroke) from an animal given fluoxetine and simvastatin 20-26 hours after resulted in statistically larger infarcts (circles; mean of 15.24 stroke induction. You only see the original damage associated with mm3) compared to later delivery times (20-26 hours after stroke; the endothelin-1 injection at the core of the infarct, but the rest squares; 3.051 mm3 mean) (P=0.017; Welch's correction of of the cortex appears to have normal Nissl staining. In contrast to unpaired t-test with unequal variance). Since this was a surprising control animals, there does not appear to be damage to the right result, we examined the infarcts closely to determine why the of the original site, perhaps indicating that reperfusion damage 4Copyright iMedPub Find this article in: www.jneuro.com
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Representative images showing coronal brain sections with infarcts from groups shown in
Figure 2 Figure 1.
Panel A: Control vehicle 6-12 hours after stroke induction. Coronal right hemisphere clearly
shows injection site for endothelin-1 and then enlarged infarct continuing from this initial area of damage (outlined with dashed lines).
Panel B: Fluoxetine and simvastatin 6-12 hours after stroke induction. Coronal right
hemisphere shows posterior portion of injection infarct (near top of cortex, enclosed by dashed lines) as well as a completely dissociated secondary hemorrhagic infarct (lower portion of right hemisphere, enclosed with dashed lines). In a majority of images from this group, we found evidence of secondary hemorrhagic infarcts appearing in either the right or left hemisphere, which accounts for the larger infarct volumes associated with this group. Panel C: Control vehicle 20-26 hours after stroke induction. Infarct size was similar to that
seen in Panel A; we just show the portion of the cortex with the infarct (outlined by dashed Panel D: Fluoxetine and simvastatin 20-26 hours after stroke induction. This figure shows
the largest damage in a coronal section from this group, with the infarct centered around the injection site (enclosed in dashed lines). The scale bar represents 500 microns. was minimized. Alternatively, the fluoxetine and simvastatin are 6-12 hours after stroke (Panel B), we found more evidence of both known to increase growth factors in the brain, and we have secondary hemorrhagic stroke, clearly dissociated from the shown in a previous study [6] that one of these growth factors, original endothelin-1 injection site (e.g. ventral location, location brain derived neurotrophic factor (BDNF), is elevated around in other hemisphere, far anterior or posterior to original injection the site of the original infarct; this may allow tissue around the site): Six of the original 11 animals in the early delivery FS original infarct to survive.
group showed signs of secondary infarcts. The relative risk was calculated to be 4.36 (95% CI=0.64-29.5) for these small groups Out of 12 control animals with vehicle delivered at 6-12 hours, (6 positive outcomes and 5 negative outcomes) for the treated we saw two that had possible signs of secondary hemorrhagic group to have a bad outcome compared to control (1 positive and infarcts (infarcts were located either far anterior or far posterior 7 negative). and dissociated away from the original infarct). One of these substantial bleeding occurred when lowering the needle into the Discussion
cortex, so was an artifact of the surgical procedure. An example of this is shown in Figure 3, panel A, illustrating the extensive A number of animal studies have looked at fluoxetine
bleed from surgical artifact compared to a possible secondary administration in stroked animals or traumatic brain injury animals hemorrhagic transformation. One control animal did show some and many have failed to see any positive effect of the fluoxetine posterior lateral damage, which may have been caused by a [17-19]. In several of these studies, neurogenesis is examined in secondary hemorrhagic infarct, so we did include this animal when the dentate gyrus, with only cursory examination of neurogenesis we compared relative risk of secondary hemorrhagic infarcts. In in lateral ventricles that are very posterior in the brain (to the side contrast, when we examined fluoxetine and simvastatin delivery Copyright iMedPub Find this article in: www.jneuro.c 5
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Hemorrhagic infarcts in control rats.
Figure 3 Panel A: Positive control shows hemorrhagic infarct induced by excessive bleeding during the
stroke induction surgery (needle hit a blood vessel). Note that the secondary hemorrhagic infarct (red arrow) is very posterior to our normal injection site infarct (black arrow) and is completely dissociated from any cortical injury at the dorsal cortical surface. Panels B and C show anterior and posterior sections, respectively, from our one control
rat that appeared to have a secondary hemorrhagic transformation. Possible secondary hemorrhagic infarcts are marked with red arrows, while the endothelin-1 induced infarct is marked by a black arrow.
of the hippocampus). Also, the delivery method for fluoxetine is hemorrhagic transformation at an earlier time point, but that generally one which would induce stress in the animal (surgical hemorrhagic transformation disappeared at a later time point, implantation of an osmotic pump delivering fluoxetine, daily although the drugs were exactly the same at both time points. intraperitoneal injections of fluoxetine, oral gavage of fluoxetine, However, given the results of this study and another study from etc.). We have seen increases in neurogenesis in older (10-12 this lab [6], it appears that giving fluoxetine 20-26 hours after month) rats in the subventricular zone (SVZ) of the anterior lateral stroke induction not only promotes motor functional recovery, ventricles in the presence of fluoxetine when it is given with but also reduces the infarct volume significantly compared to voluntary oral administration, thus eliminating any stress with giving the fluoxetine and simvastatin within 6-12 hours of stroke administration of the fluoxetine. We also see functional recovery, induction. which correlates well with what is being seen in clinical trials of We are currently performing studies where the rats are on the the drug in stroke patients[2,20] or traumatic brain injury patients statins prior to stroke induction, and fluoxetine is given at various [21]. Since stress has an inhibitory effect on neurogenesis and times after stroke, so that the drug delivery will correlate better fluoxetine generally has a positive effect [22,23], we believe that with what is seen during clinical trials with fluoxetine. We will care must be taken to eliminate stress when administering the directly compare fluoxetine delivery at 6-12 hours, 20-26 hours fluoxetine to animal models of disease, which our drug delivery and 48-54 hours after stroke induction, and note impact on infarct system accomplishes [8]. volume at 7 days post-stroke and any trend towards hemorrhagic Both fluoxetine and simvastatin have been shown to increase transformation. vascular endothelial growth factor (VEGF) [14,24]. In the early delivery time, the formation of VEGF may cause bleeding because Conclusion
the normal proteins involved in structural support of angiogenesis The combination of simvastatin and fluoxetine increased the are not yet available. In a study from Michael Chopp's lab, relative risk (RR=4.36, 95% CI=0.64-29.5) of bleeding after early delivery (within 1 hour of induction) of rhVEGF to middle ischemic stroke if it is given 6-12 hours after stroke induction in cerebral artery-occluded male Wistar rats showed signs of blood rats. However, delivery of simvastatin and fluoxetine 20-26 hours brain barrier leakage and hemorrhagic transformation, while after ischemic stroke in rats significantly reduces infarct size later delivery (48 hours after stroke induction) did not [25]. This compared to earlier delivery and shows a strong trend towards study may be the basis for beginning the fluoxetine post-stroke infarct reduction compared to controls. treatment no earlier than the second day post-stroke in ongoing Clinical Trials testing fluoxetine for motor recovery after stroke. Author Contribution
We do not have direct evidence for increased VEGF immediately after drug administration yet, but from previous work on these Maria HH Balch and Moner A Ragas contributed equally to this drugs, the preceding was a potential explanation for why we saw paper and should both be considered first authors.
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Source of Funding: This work was supported by a Women in State University, Dr. Jack Bantle, given to Adrian M. Corbett.
Science Giving Circle Grant to Adrian M. Corbett; an Original Work Grant to Moner A. Ragas from the Graduate Student Disclosures
Assembly at Wright State University, and internal support from None the Vice President for Research and Graduate Studies at Wright Copyright iMedPub Find this article in: www.jneuro.c 7
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Source: http://www.jneuro.com/neurology-neuroscience/appropriate-timing-of-fluoxetine-and-statin-delivery-reduces-the-risk-of-secondary-bleeding-in-ischemic-stroke-rats.pdf

2013.4.1.010_or_quynh.en.indd

Original Research Oseltamivir resistance among infl uenza viruses: surveillance in northern Viet Nam, 2009–2012Hoang Vu Mai-Phuong,a Nguyen Co Thach,a Nguyen Le Khanh Hang,a Nguyen Thi Kim Phuongb and Le Quynh MaiaCorrespondence to Hoang Vu Mai-Phuong (e-mail: [email protected] or [email protected]). Introduction: Antiviral resistance has been reported in seasonal influenza A viruses and avian influenza A(H5N1) viruses in Viet Nam, raising concerns about the efficacy of treatment.Methods: We analysed specimens from two sources during the period 2009–2012: influenza-positive samples from influenza-like illness patients at sentinel clinics in northern Viet Nam and isolates from patients with confirmed A(H5N1) infections. Pyrosequencing was used to detect mutations: H275Y [for A(H1N1) and A(H5N1)], E119V [for A(H3N2)] and I117V [for A(H5N1)]. A neuraminidase inhibition assay was used to determine the Inhibitory Concentration 50 (IC )

ordoneardentistrylibrary.org

Dr. Nikita Kareker et al . / IJRID Volume 4 Issue 5 Sep.-Oct. 2014 Available online at www.ordoneardentistrylibrary.org ISSN 2249-488X Case – report INTERNATIONAL JOURNAL OF RESEARCH IN DENTISTRY LIQUID SUPPORTED DENTURE …… A KINDER SOLUTION: A CASE REPORT Dr. Nikita Kareker*. Dr. Ashwin Mysore.