Possible reasons for lesser efficacy of antioxidants in clinical studies
| • Current theories about mode of drug action in arresting propagation of neuronal damage in the ischemic territory are inappropriate. |
| • Current experimental models of ischemia are inappropriate to human stroke. |
| • Effective neuroprotection by drug in the models cannot predict success in the human illness. |
| • Drug that inhibits one parameter of injury might be insufficient to inactivate other parallel pathways of the ischemic destructive cascade. |
| • Stroke is associated with several injuries induced by various mechanisms. Single treatment might miss the “time window” opportunity, e.g., glutamate toxicity may occur early and last only a short time. |
| • Antioxidants should be given in very narrow range of therapeutic dosages. As with vitamins, antioxidants given in high doses in a certain redox situation might become pro-oxidants and toxic. |
| • Inadequate circulation in collateral vessels preventing adequate delivery of the drug to a major portion of the ischemic tissue. |
| • Inadequate penetration into salvageable portion of the ischemic zone that maintains BBB integrity. |
| • Genetic, environmental, age, and dietary background differences between the study trials. |
| • Source of supplementation: natural vs. synthetic agents might influence the study outcome. |
| • The high heterogeneity of the brain damage size and neurological outcome in human stroke patients, making it difficult to obtain statistically significant effects of therapeutic agents. |
| • Brain structure, function, and vascular anatomy of humans and animals differ. |