Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2001;32:2433-2438
doi: 10.1161/hs1001.096009
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horn, J.
Right arrow Articles by Limburg, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horn, J.
Right arrow Articles by Limburg, M.
Related Collections
Right arrow Animal models of human disease
Right arrow Acute Cerebral Infarction
Right arrow Neuroprotectors

(Stroke. 2001;32:2433.)
© 2001 American Heart Association, Inc.

Comments, Opinions, and Reviews

Nimodipine in Animal Model Experiments of Focal Cerebral Ischemia

A Systematic Review

J. Horn, MD; R.J. de Haan, PhD; M. Vermeulen, MD; P.G.M. Luiten, PhD M. Limburg, MD

From the Department of Neurology (J.H., M.V.), the Department of Clinical Epidemiology and Biostatistics (R.J.d.H.), and the Department of Medical Informatics (M.L.), Academical Medical Center, University of Amsterdam, and the Department of Animal Physiology (P.G.M.L.), University of Groningen, Groningen, the Netherlands.

Correspondence to J. Horn, MD, Department of Neurology, AMC, PO Box 22700, 1100 DE, Amsterdam, Netherlands. E-mail jhorn{at}wxs.nl


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose—— Based on the results of animal experiments, clinical trials were performed with nimodipine, which did not demonstrate a beneficial effect on outcome after stroke. The aim of this study was to determine whether the evidence from animal experiments with nimodipine supported the use of nimodipine in clinical trials.

Methods—— We performed a systematic review of animal experiments with nimodipine in focal cerebral ischemia. Studies were identified by searching Medline and Embase. We assessed whether these studies showed a beneficial effect of active treatment. In-depth analyses were performed on infarct size and amount of edema, and subgroup analyses were performed on the length of the time window to the initiation of treatment and the methodological quality of the studies.

Results—— Of 225 identified articles, 20 studies were included. The methodological quality of the studies was poor. Of the included studies, 50% were in favor of nimodipine. In-depth analyses showed statistically significant effects in favor of treatment (10 studies). No influence of the length of time to the initiation of treatment or of the methodological quality on the results was found.

Conclusions—— We conclude that the results of this review did not show convincing evidence to substantiate the decision to perform trials with nimodipine in large numbers of patients. There were no differences between the results of the animal experiments and clinical studies. Surprisingly, we found that animal experiments and clinical studies ran simultaneously.


Key Words: animal models • calcium channel blockers • cerebrovascular disorders • nimodipine • meta-analysis


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The recognition of the existence of a penumbral zone in ischemic stroke, as described by Astrup and Siesjo,1 was a major trigger in the search for an effective neuroprotective agent. Massive calcium influx into cells was found to be a final common pathway leading to cell death. Therefore, calcium channel blockers might protect the penumbral zone from becoming necrotic. Early steps on the road toward neuroprotective treatments in stroke were, as usual, in the form of animal experiments. Positive results of treatment with nimodipine, an L-type calcium channel blocker, in animal models of acute focal ischemia were reported, and investigations of this agent were started in patients in the early 1980s. In 1988, a randomized controlled trial in stroke patients showed a beneficial effect.2 On the basis of these promising results, calcium antagonists in stroke were studied in more clinical trials,3–6 in which, finally, 7665 patients were randomized. These trials failed to confirm the beneficial effect of active treatment,7 but in a meta-analysis of 9 trials with nimodipine in acute ischemic stroke, a statistically significant effect in favor of nimodipine was found when treatment was started within 12 hours of stroke onset.8 This again raised hope for neuroprotective treatment in stroke patients. However, in a recent systematic review performed for the Cochrane collaboration7 on the effects of calcium antagonists in stroke, this positive effect of early treatment could not be confirmed.

Similar discrepancies between initial successful experimental animal data and lack of effect in clinical application have been reported for a variety of potentially neuroprotective drugs. These agents either evoked unacceptable adverse reactions or did not have any beneficial effect.9–12 These disappointing results have raised doubts about the interpretation and validity of the results of animal stroke models with respect to subsequent clinical research.

The aim of the present investigation was to determine whether the evidence from animal experiments was in favor of nimodipine, which would mean that these models were inadequate in the prediction of treatment response in patients or that the data were inconclusive, which would mean that the clinical trials were based on insufficient evidence.


*    Materials and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Literature Search and Inclusion Criteria
Our literature search for the present review was restricted to published results of animal studies, which were identified by searching Medline (1966 to 1999) and Embase (1980 to 1999) with the use of the search terms "nimodipine" (limited to "animal") and "cerebral ischemia." Reference lists of identified articles were also searched.

Studies were included if they fulfilled the following criteria: (1) the study assessed the effect of nimodipine on focal cerebral ischemia; (2) a group of control animals was described; (3) nimodipine was administered after the induction of ischemia; (4) the effect of nimodipine was assessed in animals or in whole brains, not in slices or samples of brain tissue; (5) nimodipine was not tested in combination with other neuroprotective agents; (6) there was a restriction to the original study results (reviews and duplicate publications were excluded); and (7) the studies were published in English, French, or German. The selection of trials (unblinded) was performed (by J.H.) on the basis of title and abstract. In case of doubt, the whole publication was evaluated.

Data Extraction
From the included studies, the following data were extracted: animal species; number of animals in treated and control groups; method of allocation to treatment group; method to induce ischemia; method, dosage, and time of drug administration; method to assess efficacy (blinded assessment); and results of treatment.

Methodological Quality of Studies
On the basis of recommendations published in 1999,13 we designed an 8-point rating system to assess the methodological quality of the included animal experimental studies. One point was attributed for each of the following characteristics: (1) the dose/response relationship that was investigated, (2) randomization of the experiment, (3) optimal time window of the treatment investigated, (4) monitoring of physiological parameters, (5) blinded outcome assessment, (6) assessment of at least 2 outcomes (infarct size and 1 functional outcome), (7) outcome assessment in the acute phase (1 to 3 days), and (8) outcome assessment in the chronic phase (7 to 30 days). The points were granted when in the study report these items were mentioned. Studies scoring <4 points were graded as "poor methodological quality," and studies with >=4 points were scored as "good methodological quality."

Outcome Assessment and Statistical Analyses
For each study, we defined whether a positive (nimodipine beneficial) or negative (no difference between active and placebo treatment or deleterious effect of nimodipine) result was reported.

Analysis in depth was possible only for a limited selection of trials, which reported data on the impact of nimodipine on infarct size or amount of edema. Per study, we calculated the effect size (the mean of the treatment group minus the mean of the control group divided by the pooled standard deviation of the 2 groups) and pooled the individual effect sizes accordingly. Because our data was shown to be heterogeneous, we used a random-effects model.14 Statistical uncertainty was expressed in 95% CIs.

Subgroup Analyses
In view of the common opinion that treatment has to be started as soon as possible after the induction of ischemia,15 we performed a subgroup analysis on data from studies in which nimodipine was started within or later than 1 hour after ischemia. Difference in the frequency of treatment results was analyzed with the Fisher exact test. Finally, we investigated whether study methodology influenced the results of the experiments.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Description of Studies
We identified 225 articles. On the basis of predefined criteria, 205 articles were excluded (a list of these studies is available from the author). Table 1 lists the various reasons for exclusion. Many studies were excluded because they described the effect of nimodipine in global ischemia models or because nimodipine was administered before the induction of ischemia. We also identified several duplicate publications.16–24


View this table:
[in this window]
[in a new window]
  		Table 1. Reasons for Exclusion of Articles (Total 205)

Twenty studies fulfilled the inclusion criteria; the characteristics of these studies are listed in Table 2, in which the studies are ordered by increasing length of the time interval between the induction of ischemia and the initiation of treatment. In total, 234 animals were treated with nimodipine (216 animals served as controls) after the induction of focal cerebral ischemia. In all studies, the animals were anesthetized during the surgical procedures, only 1 study explicitly reported that the animals were allowed to recover before the induction of ischemia.25 Parameters such as body temperature, blood glucose levels, and blood pressure were maintained within strict limits in most animal experiments.


View this table:
[in this window]
[in a new window]
  		Table 2. Characteristics of 20 Included Studies (Ordered by Length of Time Interval Between Ischemia and Start of Treatment)

In 12 of 19 studies, treatment was started within 1 hour after the induction of ischemia.16,21,25–34 One study did not state the length of this interval.35 The methodological quality of the included studies was poor (median 2.85 points, range 1 to 5). Only 2 studies mentioned randomization of the animals,27,33 and in 6 studies, the outcome was assessed by a blinded assessor.21,25,26,28,32,36 One study reported "double-blind" assessment of effectiveness.37 Although 9 studies assessed 2 outcome measurements (functional and histopathologic),18,25,27,32,35–39 only 3 studies assessed outcome in the chronic phase.18,32,36

Outcome
Of the 20 included studies, 10 reported a positive effect of nimodipine, and 10 did not. In 7 studies, exact data about infarct size were presented21,28–31,36,37 (Figure 1). The pooled effect size in favor of nimodipine was -1.2 (95% CI -1.7 to -0.7).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Results of in-depth analysis on infarct size. SMD indicates standardized mean difference (effect size).

Extracting data regarding the amount of edema was possible in 3 studies18,27,34 (Figure 2), revealing a pooled effect size of -0.6 (95% CI -1.2 to -0.1) in favor of nimodipine.



View larger version (10K):
[in this window]
[in a new window]
  		Figure 2. Results of analysis on amount of edema.

Subgroup Analysis
Additional analysis of the studies in which treatment was started within 1 hour after the induction of ischemia resulted in 4 positive and 8 negative studies. Treatment that was started >=1 hour after the induction of ischemia resulted in 5 positive and 2 negative studies (P=0.17).

In the 4 studies with a good methodological quality,25,32,36,37 2 showed an effect in favor of nimodipine, and 2 did not.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present investigation, we focused on whether the evidence from animal experiments was in favor of nimodipine, which would mean that these models were inadequate to predict the treatment response in patients or that the data from animal experiments were inconclusive, which would mean that the clinical trials were based on insufficient evidence. The selected studies did not provide an answer regarding the efficacy of treatment with nimodipine (50% of the studies were in favor of nimodipine). Nor did subgroup analyses on the length of the time window to treatment and the methodological quality of the studies demonstrate beneficial treatment results. Because we had no information that time window to treatment would differ between different animal models, we decided not to speculate and performed the rough time analysis as presented. More detailed subgroup analyses on the effects of different doses of nimodipine or infusion periods could not be performed because of the small number of included studies. In-depth analyses on the effect of nimodipine on infarct size and the amount of edema showed statistically significant beneficial results. These data could be extracted only from a small subsample of publications, which turned out mainly to be reports with positive treatment results. However, this supports the fact that both infarct size and functional outcome should be assessed in animal experiments of focal ischemia.

We found that the methodological quality of the included studies was poor. Issues such as randomization, masked treatment allocation, blinded outcome assessment, and intention to treat analyses, which are very important issues and are now generally required in clinical studies, were especially neglected in these animal experiments.40 Surprisingly, 1 study reported a double-blind assessment of effectiveness.

We realize that systematic reviews carry hazards such as publication bias and a bias for good quality studies.41,42 Evaluating "old" studies from the early 1980s increases these hazards. Because most experiments were performed >10 years ago, we did not approach the authors for detailed information about their studies. We considered it to be unlikely that the authors either possessed or would remember the data required. By limiting our search strategy to the electronic databases and the reference lists of articles, we were unable to estimate the number of unpublished manuscripts. For clinical trials with calcium antagonists in ischemic stroke, we found that at least 18% of all studies remained unpublished.7 In these unpublished trials, results were significantly worse for patients in the treatment group. One might assume that in experimental animal research, this percentage would not be different. If such a publication bias for negative animal experiments exists, this would result in an even more "negative" conclusion of the present review. Other possible sources for bias are selection of studies and data extraction. The fact that this was done by 1 author might have increased this risk; however, criteria for study inclusion and data extraction were strict. The number of manuscripts written in a "foreign language" (ie, Chinese, Japanese, Russian, or Polish) was limited (2%). We assumed that translating these manuscripts would not result in more useful data.

Was the animal model used suitable to predict the effectiveness of nimodipine in stroke patients? Several authors have discussed the discrepancies between the results of animal models in stroke and the results of clinical studies.43–48 A possible explanation for these discrepancies was the difference in the age of the patients. Older stroke patients often have comorbidity, such as diabetes and hypertension. Furthermore, in animal experiments, physiological parameters (blood pressure, [brain] temperature, and blood glucose levels) can be kept within strict limits, and neuroprotective treatment can be started immediately or shortly after the induction of ischemia. Finally, major differences exist in the assessment of the effectiveness of animal experiments measuring histopathologic parameters compared with trials measuring functional ability in stroke patients.

Results of animal experiments with nimodipine in focal cerebral ischemia were reported until 1997, which was 15 years after the first clinical study. It is surprising that these animal experiments ran a course parallel to several clinical studies, because it is reasonable to assume that the clinical studies are preceded by animal studies. However, as early as 1982, the first results of clinical studies on the effect of nimodipine on cerebral blood flow in stroke patients were reported.49 On the basis of the hypothesis of the calcium-dependent final common pathway in cell death and his previous experiments, an author started a "single-blind" pilot study, which showed that treatment with nimodipine was promising.50 In 1988, the same author reported the results of a placebo-controlled, double-blind, randomized clinical trial.2 In the introduction to his article, results of animal experiments with nimodipine were quoted. Only 1 experiment dealt with focal cerebral ischemia28; others concerned global ischemia or the use of nimodipine before the induction of ischemia. The authors concluded that nimodipine was statistically significantly better than placebo regarding mortality and changes in neurological deficit (modified Mathew scale). However, repeat analysis of data on the functional outcome of patients in this trial, by dichotomizing the score on the disability item in the modified Mathew scale, shows a difference that was not statistically significant.7 The supposedly positive results of this first randomized controlled trial were followed by a small trial,51 which showed similar results. In the introduction to that article, the authors refer to an animal experiment by Germano et al.52 Subsequent reports on larger clinical trials3,4,53,54 refer in the introduction to a single positive animal experiment, to the proven effectiveness of nimodipine in the treatment of subarachnoid hemorrhage, and primarily to the positive results of the first randomized controlled trial with nimodipine in ischemic stroke.

We conclude that the results of the animal experiments reviewed in the present investigation did not show convincing empirical evidence to substantiate the decision for trials with nimodipine in stroke patients. In fact, there were no differences between the results of animals experiments and clinical studies. Surprisingly, we found that animal experiments and clinical studies ran simultaneously.


*    Acknowledgments
 
We want to thank Dr P.J. Assendelft for critically reading the manuscript and giving advice.

Received December 21, 2000; revision received May 22, 2001; accepted June 15, 2001.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Astrup J, Siesjo BK. Thresholds in cerebral ischaemia: the ischemic penumbra. Stroke. 1981; 12: 723–725.[Free Full Text]
  2. Gelmers HJ, Gorter K, De Weerdt CJ, Wiezer HJA. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988; 318: 203–207.[Abstract]
  3. Clinical trial of nimodipine in acute ischemic stroke: The American nimodipine study group. Stroke. 1992; 23: 3–8.[Abstract/Free Full Text]
  4. Trust Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet. 1990; 336: 1205–1209.[Medline] [Order article via Infotrieve]
  5. Franke CL, Palm R, Dalby M, Schoonderwaldt HC, Hantson L, Eriksson B, Lang-Jenssen L, Smakman J. Flunarizin in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands. Acta Neurol Scand. 1996; 93: 56–60.[Medline] [Order article via Infotrieve]
  6. Azcona A, Lataste X. Isradipine in patients with acute ischaemic cerebral infarction: an overview of the ASCLEPIOS programme. Drugs. 1990; 40: 52–57.
  7. Horn J, Limburg M. Calcium antagonists for acute ischemic stroke. Cochrane Database Syst Rev. 2000: CD001928.
  8. Mohr JP, Orgogozo JM, Harrison MJG, Hennerici M, Wahlgren NG, Gelmers HJ, Martinez-Vila E, Dycka J, Tettenborn D. Meta-analysis of oral nimodipine trials in acute ischemic stoke. Cerebrovasc Dis. 1994; 4: 197–203.
  9. Davis SM, Albers GW, Diener HC, Lees KR, Norris J. Termination of Acute Stroke Studies Involving Selfotel Treatment: ASSIST Steering Committee. Lancet. 1997; 349: 32.[Medline] [Order article via Infotrieve]
  10. Diener HC. Multinational randomised trial of Lubeluzole in acute ischaemic stroke. Cerebrovasc Dis. 1998; 8: 172–181.[Medline] [Order article via Infotrieve]
  11. Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, Orgogozo JM, Whitehead J. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial: GAIN International Investigators. Lancet. 2000; 355: 1949–1954.[Medline] [Order article via Infotrieve]
  12. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J. Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke. 2000; 1: 347–354.
  13. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999; 30: 2752–2758.[Abstract/Free Full Text]
  14. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7: 177–188.[Medline] [Order article via Infotrieve]
  15. The European Ad Hoc Consensus Group. Neuroprotection as initial therapy in acute stroke: third report of an Ad Hoc Consensus Group Meeting. Cerebrovasc Dis. 1998; 8: 59–72.[Medline] [Order article via Infotrieve]
  16. Meyer FB, Anderson RE, Yaksh TL, Sundt TM. Effect of nimodipine on intracellular brain pH, cortical blood flow, and EEG in experimental focal cerebral ischemia. J Neurosurg. 1986; 64: 617–626.[Medline] [Order article via Infotrieve]
  17. Meyer FB. Intracellular brain pH and ischemic vasoconstriction in the white New Zealand rabbit. Stroke. 1990; 21 (suppl IV): IV-117–IV-119.
  18. Hara H, Onodera H, Nagasawa H, Kogure K. Effect of nimodipine on ischemia-induced brain edema and mortality in a novel transient middle cerebral artery occlusion model. Jpn J Pharmacol. 1990; 53: 247–253.[Medline] [Order article via Infotrieve]
  19. Hara H, Nagasawa H, Kogure K. Nimodipine prevents postischemic brain damage in the early phase of focal cerebral ischemia. Stroke. 1990; 21 (suppl IV): IV-102–IV-104.
  20. Hara H, Nagasawa H, Kogure K. Nimodipine attenuates both ischaemia-induced brain oedema and mortality in a rat novel transient middle cerebral artery occlusion model. Acta Neurochir Suppl (Wien). 1990; 51: 251–253.[Medline] [Order article via Infotrieve]
  21. Greenberg JH, Uematsu D, Araki N, Hickey WF, Reivich M. Cytosolic free calcium during focal cerebral ischemia and the effects of nimodipine on calcium and histologic damage. Stroke. 1990; 21 (suppl IV): IV-72–IV-77.
  22. Greenberg JH, Uematsu D, Araki N, Reivich M. Intracellular calcium and pathophysiological changes in cerebral ischemia. Arzneimittelforschung. 1991; 41: 324–332.[Medline] [Order article via Infotrieve]
  23. Uematsu D, Greenberg JH, Hickey WF, Reivich M. Nimodipine attenuates both increase in cytosolic free calcium and histologic damage following focal cerebral ischemia and reperfusion in cats. Stroke. 1989; 20: 1531–1537.[Abstract/Free Full Text]
  24. Uematsu D, Araki N, Greenberg JH, Sladky J, Reivich M. Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology. 1991; 41: 88–94.[Abstract/Free Full Text]
  25. Lyden PD, Zivin JA, Kochhar A, Mazzarella V. Effects of calcium channel blockers on neurologic outcome after focal ischemia in rabbits. Stroke. 1988; 19: 1020–1026.[Abstract/Free Full Text]
  26. Snape MF, Baldwin HA, Cross AJ, Green AR. The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat. Neuroscience. 1993; 53: 837–844.[Medline] [Order article via Infotrieve]
  27. Deng W, Feng Y. Effect of dl-3-n-butylphthalide on brain edema in rats subjected to focal cerebral ischemia. Chin Med Sci J. 1997; 12: 102–106.[Medline] [Order article via Infotrieve]
  28. Gotoh O, Mohamed AA, McCulloch J, Graham DI, Harper AM, Teasdale GM. Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1986; 6: 321–331.[Medline] [Order article via Infotrieve]
  29. Berger L, Hakim AM. Calcium channel blockers correct acidosis in ischemic rat brain without altering cerebral blood flow. Stroke. 1988; 19: 1257–1261.[Abstract/Free Full Text]
  30. Berger L, Hakim AM. Nimodipine prevents hyperglycemia-induced cerebral acidosis in middle cerebral artery occluded rats. J Cereb Blood Flow Metab. 1989; 9: 58–64.[Medline] [Order article via Infotrieve]
  31. Hakim AM. Cerebral acidosis in focal ischemia, II: nimodipine and verapamil normalize cerebral pH following middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1986; 6: 676–683.[Medline] [Order article via Infotrieve]
  32. Sauter A, Rudin M. Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging. Stroke. 1986; 17: 1228–1234.[Abstract/Free Full Text]
  33. Dirnagl U, Jacewicz M, Pulsinelli W. Nimodipine posttreatment does not increase blood flow in rats with focal cortical ischemia. Stroke. 1990; 21: 1357–1361.[Abstract/Free Full Text]
  34. Nishikibe M. Effect of the calcium entry blocker NB-818 on cerebral blood flow after unilateral carotid occlusion in the Mongolian gerbil. J Pharmacol Exp Ther. 1988; 246: 719–725.[Abstract/Free Full Text]
  35. Bartkowski HM, Brakel A, Mondora RA, Kutan R. Therapeutic value of a constant intravenous infusion of nimodipine for 24 hours after acute cerebral infarction. Stroke. 1988; 19: 147.Abstract
  36. Selcuklu A, Koc RK, Pasaoglu H, Kandemir O, Pasaoglu A. The effects of nimodipine, mannitol and their combination on experimental cerebral ischaemia. Turk Neurosurg. 1993; 3: 95–102.
  37. Germano IM, Bartkowski HM, Cassel ME, Pitts LH. The therapeutic value of nimodipine in experimental focal cerebral ischemia: neurological outcome and histopathological findings. J Neurosurg. 1987; 67: 81–87.[Medline] [Order article via Infotrieve]
  38. Germano IM, Bartkowski HM, Berry I, Moseley M, Brant-Zawadzki M, Pitts LH. Magnetic resonance imaging in the evaluation of nimodipine-treated acute experimental focal cerebral ischemia. Acta Radiol Suppl. 1986; 369: 49–52.[Medline] [Order article via Infotrieve]
  39. Kobayashi S, Obana W, Andrews BT, Nishimura MC, Pitts LH. Lack of effect of nimodipine in experimental regional cerebral ischemia. Stroke. 1988; 19: 147.Abstract.
  40. Wardlaw JM, Warlow CP, Sandercock P, Dennis MS, Lindley RI. Neuroprotection disappointment yet aGAIN. Lancet. 2000; 356: 597.
  41. Dickersin K. The existence of publication bias and risk factors for its occurrence. JAMA. 1990; 263: 1385–1389.[Abstract]
  42. Moher D, Pham Ba, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, Klassen TP. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998; 352: 609–613.[Medline] [Order article via Infotrieve]
  43. Molinari GF. Why model strokes? Stroke. 1988; 19: 1195–1197.[Free Full Text]
  44. Wiebers DO, Adams HP, Whisnant JP. Animal models of stroke: are they relevant to human disease? Stroke. 1990; 21: 1–3.[Free Full Text]
  45. Zivin JA, Grotta JC. Animal stroke models: they are relevant to human disease. Stroke. 1990; 21: 981–983.[Free Full Text]
  46. Millikan C. Animal stroke models. Stroke. 1992; 23: 795–797.[Free Full Text]
  47. Grotta JC. Why do all drugs work in animal models but none in stroke patients?: neuroprotective therapy. J Intern Med. 1995; 237: 89–94.[Medline] [Order article via Infotrieve]
  48. De Keyser J, Sulter G, Luiten PG. Clinical trials with neuroprotective agents in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 1999; 22: 535–540.[Medline] [Order article via Infotrieve]
  49. Gelmers HJ. Effect of nimodipine on postischemic cerebrovascular reactivity, as revealed by measuring regional cerebral blood flow (rCBF). Acta Neurochir. 1982; 63: 283–290.[Medline] [Order article via Infotrieve]
  50. Gelmers HJ. The effects of nimodipine on the clinical course of patients with acute ischemic stroke. Acta Neurol Scand. 1984; 69: 232–239.[Medline] [Order article via Infotrieve]
  51. Paci A, Ottaviano P, Trenta A, Iannone G, De Santis, Lancia G, Moschini E, Carosi M, Amigoni S, Caresia L. Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta Neurol Scand. 1989; 80: 282–286.[Medline] [Order article via Infotrieve]
  52. Germano I, Bartkowski H, Nishimura M, Cassel B, Pitts L. The effects of nimodipine in acute experimental cerebral ischemia in the rat. Stroke. 1986; 17: 144.Abstract.
  53. Wahlgren NG, MacMahon DG, De Keyser J, Indredavik B, Ryman T. Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke. Cerebrovasc Dis. 1994; 4: 204–210.
  54. Hennerici M, Kramer G, North PM, Schmitz H, Tettenborn D. Nimodipine in the treatment of acute MCA ischemic stroke: Nimodipine European Stroke trial group. Cerebrovasc Dis. 1994; 4: 189–193.
  55. de la Torre JC. Synergic activity of combined prostacyclin: dimethyl sulfoxide in experimental brain ischemia. Can J Physiol Pharmacol. 1991; 69: 191–198.[Medline] [Order article via Infotrieve]
  56. Roda JM, Carceller F, Diez-Tejedor E, Avendano C. Reduction of infarct size by intra-arterial nimodipine administered at reperfusion in a rat model of partially reversible brain focal ischemia. Stroke. 1995; 26: 1888–1892.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 StrokeHome page
J. Minnerup, J. Heidrich, J. Wellmann, A. Rogalewski, A. Schneider, and W.-R. Schabitz
Meta-Analysis of the Efficacy of Granulocyte-Colony Stimulating Factor in Animal Models of Focal Cerebral Ischemia
Stroke, June 1, 2008; 39(6): 1855 - 1861.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
N. A. Crossley, E. Sena, J. Goehler, J. Horn, B. van der Worp, P. M.W. Bath, M. Macleod, and U. Dirnagl
Empirical Evidence of Bias in the Design of Experimental Stroke Studies: A Metaepidemiologic Approach
Stroke, March 1, 2008; 39(3): 929 - 934.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
E. Sena, P. Wheble, P. Sandercock, and M. Macleod
Systematic Review and Meta-Analysis of the Efficacy of Tirilazad in Experimental Stroke
Stroke, February 1, 2007; 38(2): 388 - 394.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
R. Lemon and S. B Dunnett
Surveying the literature from animal experiments
BMJ, April 30, 2005; 330(7498): 977 - 978.
[Full Text] [PDF]

Home page
 Obstet GynecolHome page
L. E. Mignini, P. M. Latthe, J. Villar, M. D. Kilby, G. Carroli, and K. S. Khan
Mapping the Theories of Preeclampsia: The Role of Homocysteine
Obstet. Gynecol., February 1, 2005; 105(2): 411 - 425.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
M. R. Macleod, T. O'Collins, D. W. Howells, and G. A. Donnan
Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias
Stroke, May 1, 2004; 35(5): 1203 - 1208.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
P. Pound, S. Ebrahim, P. Sandercock, M. B Bracken, and I. Roberts
Where is the evidence that animal research benefits humans?
BMJ, February 28, 2004; 328(7438): 514 - 517.
[Full Text] [PDF]

Home page
 BMJHome page
P. Pound and S. Ebrahim
Supportive evidence is lacking for report on animal studies
BMJ, November 2, 2002; 325(7371): 1038 - 1038.
[Full Text]

Home page
 StrokeHome page
D. J. Gladstone, S. E. Black, and A. M. Hakim
Toward Wisdom From Failure: Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions
Stroke, August 1, 2002; 33(8): 2123 - 2136.
[Abstract] [Full Text] [PDF]

Home page
 Eval Health ProfHome page
I. Chalmers, L. V. Hedges, and H. Cooper
A Brief History of Research Synthesis
Eval Health Prof, March 1, 2002; 25(1): 12 - 37.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horn, J.
Right arrow Articles by Limburg, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horn, J.
Right arrow Articles by Limburg, M.
Related Collections
Right arrow Animal models of human disease
Right arrow Acute Cerebral Infarction
Right arrow Neuroprotectors

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.