Recommendations for standards regarding preclinical neuroprotective and restorative drug development.

The plethora of failed clinical trials with neuroprotective drugs for acute ischemic stroke have raised justifiable concerns about how best to proceed for the future development of such interventions. Preclinical testing of neuroprotective drugs is an important aspect of assessing their therapeutic potential, but guidelines concerning how to perform preclinical development of purported neuroprotective drugs for acute ischemic stroke are lacking. This conference of academicians and industry representatives was convened to suggest such guidelines for the preclinical evaluation of neuroprotective drugs and to recommend to potential clinical investigators the data they should review to reassure themselves that a particular neuroprotective drug has a reasonable chance to succeed in an appropriately designed clinical trial. Without rigorous, robust, and detailed preclinical evaluation, it is unlikely that novel neuroprotective drugs will prove to be effective when tested in large, time-consuming, and expensive clinical trials. Additionally, similar recommendations are provided for drugs with the potential to enhance recovery after acute ischemic stroke, a burgeoning new field with great potential but little currently available data. The suggestions contained in this document are meant to serve as overall guidelines that must be adapted to the individual characteristics related to particular drugs and their preclinical and clinical development needs.

[1]  S. Finklestein,et al.  Intracisternal Basic Fibroblast Growth Factor (bFGF) Enhances Behavioral Recovery following Focal Cerebral Infarction in the Rat , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  L. Wilkins.  Ancrod for the Treatment of Acute Ischemic Brain Infarction , 1994, Stroke.

[3]  J. Bogousslavsky,et al.  Cerebrovascular Disease: Pathophysiology, Diagnosis and Management , 1998 .

[4]  E. J. Green,et al.  Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats , 1992, Brain Research.

[5]  J. Garcìa,et al.  CEREBRAL INFARCTION: EVOLUTION OF HISTOPATHOLOGICAL CHANGES AFTER OCCLUSION OF A MIDDLE CEREBRAL ARTERY IN PRIMATES , 1974 .

[6]  R. P. Stroemer,et al.  Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. , 1998, Stroke.

[7]  M. E. Moseley,et al.  Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (<6.5 hour) ischemic stroke , 1998, Neurology.

[8]  K. Lees,et al.  Clinical experience with excitatory amino acid antagonist drugs. , 1995, Stroke.

[9]  M. Chopp,et al.  A New Rat Model of Thrombotic Focal Cerebral Ischemia , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  C. Beaulieu,et al.  Polynitroxyl Albumin Reduces Infarct Size in Transient Focal Cerebral Ischemia in the Rat: Potential Mechanisms Studied by Magnetic Resonance Imaging , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  S. Finklestein,et al.  Intracisternal osteogenic protein‐1 enhances functional recovery following focal stroke , 1998, Neuroreport.

[12]  Mary Elizabeth Parker,et al.  Recovery of Upper Extremity Function in Stroke Patients: The Copenhagen Stroke Study , 1995 .

[13]  J. Broderick,et al.  The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. , 1998, Stroke.

[14]  S. Snyder,et al.  Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia , 1997, Nature Medicine.

[15]  L. Symon,et al.  Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon. , 1974, Experimental neurology.

[16]  T. Waltz,et al.  Experimental acute thrombotic stroke in baboons. , 1986, Stroke.

[17]  MarcFisher.  Characterizing the Target of Acute Stroke Therapy , 1997 .

[18]  T. Jones,et al.  Use-dependent growth of pyramidal neurons after neocortical damage , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  R. Macko,et al.  Chronic reversible cerebral ischemia: evaluation of a new baboon model. , 1980, Neurosurgery.

[20]  B. Siesjö,et al.  Calcium in ischemic cell death. , 1998, Stroke.

[21]  S. Finklestein,et al.  Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Traystman,et al.  Gender-linked brain injury in experimental stroke. , 1998, Stroke.

[23]  J. Baron,et al.  Early reperfusion in the anesthetized baboon reduces brain damage following middle cerebral artery occlusion: a quantitative analysis of infarction volume. , 1997, Stroke.

[24]  D. M. Feeney,et al.  Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. , 1982, Science.

[25]  R. Traystman,et al.  Estrogen-mediated neuroprotection after experimental stroke in male rats. , 1998, Stroke.

[26]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[27]  R. Busto,et al.  Combating hyperthermia in acute stroke: a significant clinical concern. , 1998, Stroke.

[28]  Koroshetz Wj,et al.  Tissue plasminogen activator for acute ischemic stroke. , 1996, The New England journal of medicine.

[29]  M. Fisher.  Neuroprotection of Acute Ischemic Stroke: Where are We? , 1999 .

[30]  D. Graham,et al.  Focal Cerebral Ischaemia in the Rat: 1. Description of Technique and Early Neuropathological Consequences following Middle Cerebral Artery Occlusion , 1981, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  R. Ridley,et al.  Functional Benefit from Clomethiazole Treatment after Focal Cerebral Ischemia in a Nonhuman Primate Species , 1999, Experimental Neurology.

[32]  G. Clincke,et al.  Neocortical localization of tactile/proprioceptive limb placing reactions in the rat , 1992, Brain Research.

[33]  J. Baron,et al.  Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window. , 1995, Stroke.

[34]  J. Zivin,et al.  Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. , 1991, Archives of neurology.

[35]  Joakim Bjorkdahl.  Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion , 1996 .

[36]  P. Chan,et al.  Role of oxidants in ischemic brain damage. , 1996, Stroke.

[37]  T. Wieloch,et al.  Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. , 1996, Stroke.

[38]  M. Fisher,et al.  Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. , 1998, Stroke.

[39]  Fuhai Li,et al.  Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. , 1997, Stroke.

[40]  R. Nudo,et al.  Neural Substrates for the Effects of Rehabilitative Training on Motor Recovery After Ischemic Infarct , 1996, Science.

[41]  B. Kolb,et al.  Nerve growth factor treatment prevents dendritic atrophy and promotes recovery of function after cortical injury , 1997, Neuroscience.