The therapeutic time window--theoretical and practical considerations.

The length of time during which neuroprotectants can be expected to be effective is likely to vary from drug to drug and depends on an individual drug's specific mechanism of action. Glutamate-induced toxicity is a very early event during the acute phase of ischemic stroke, which means that glutamate antagonists are likely to be effective as neuroprotectants for only a short time (perhaps as little as 1 to 2 hours). Neurotrophic growth factors, however, begin to appear a few hours after the onset of ischemia, and their production may continue for weeks. Drugs aimed at protecting neurons against reperfusion injury, however, may need to be given for 1 to 2 days. Similarly, caspases, the key enzymes in apoptosis, reach a peak 1 to 2 days after the onset of ischemia. Consequently, caspase inhibitors would need to be given for at least 2 days. Drugs with very short therapeutic time windows will be difficult to examine in phase III clinical trials because of the difficulty in completing the formalities for entry to the trial. There is also a potential problem in achieving adequate concentrations of the drug in the brain if the time window is short, especially if the drug enters the central nervous system slowly. One factor that determines the way in which the drug will be used is the slope of the dose-response curve. If the curve is steep, it is easy to undershoot or overshoot the target plasma concentration. Another practical consideration is controlling physiologic and biochemical parameters. The effects of drugs that alter blood pressure or blood glucose, for example, will need to be taken into account in developing treatment regimens. Short durations of treatment are simpler to administer. Drugs or regimens that increase the level of nursing care will require changes to management practices-for example, checking that an infusion is running properly or that a large fluid load has not triggered congestive heart failure. If a treatment requires the patient to be immobile for a prolonged period, the risk of venous thrombosis, for example, will increase. Such risks will have to be balanced against the benefit the drug provides. In general, the magnitude of benefit will tend to diminish with time after the onset of stroke, whereas the risk of adverse phenomena increases with time. The utility of the drug will therefore change with the length of time the treatment needs to be given.