Models

Global

Focal

Complete

Incomplete

Multifocal

Proximal/MCAO

Cardiac arrest Aortic occlusion

Hemorrhage Intracranial

Emboli-patchy CBF MCAO+carotid

Photochemical thrombosis

Neck cuff hypertension 2 VO

Intraluminal filament Permanent reperfusion

Cephalic artery occlusion 4 VO

Permanent reperfusion

Abbreviations: VO, vessel occlusion; MCAO, middle cerebral artery occlusion; CBF, cerebral blood flow.

10 mmHg. Tirilazad in doses of 0.25, 1.0, or 2.5 mg/kg were compared to placebo in a randomized, blinded study, using nuclear magnetic resonance spectroscopy measurements of brain intracellular pH and bicarbonate as outcome measures. With cerebral ischemia, intracellular brain pH and bicarbonate decreased markedly with all doses of drug or placebo (approximate reductions from 7.2 to 5.7 mM and from 16 to 3 mM, respectively) but returned faster and to higher levels in the drug-treated groups in a dose-dependent fashion. Similarly, somatosensory-evoked potentials were reduced to zero during ischemia but returned in a dose-dependent fashion to approximately 50% of control with tirilazad during reperfusion. Unfortunately, however, not all drugs act in a dose-response fashion, and, in fact, some may have unusual dose-response curves. In addition, the finding that a drug works well in a dose-response fashion in animals does not guarantee that the same dose range will work well in humans. A dose of 10 mg in mice, which is protective, may not be the correct effective dose in humans. Clearly, performing dose-response curves in several animal species is important, if for no other reason than to determine which general range appears to have significant neuroprotective effects. However, even armed with this knowledge, we may not know the best possible dose to use in humans.

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