Paul, many drugs have a "bell-shaped" curve of efficacy plotted against dose. In other words, there is often an optimal range for the drug to exert therapeutic effects. For most if not all drugs, they don't work if they do not reach a high enough concentration in the relevant space (for example, blood, spinal cord fluid, brain tissue, gut contents, etc.) For some drugs, at a certain concentration, they have the desired effect, and increasing concentration does not increase the therapeutic effect, but may increase undesirable (and even fatal) side effects. For those drugs, your "therapeutic range" limit is set on the upper end by the side effects. And for still other drugs (actually, quite a few, especially for growth factors and cytokines), increasing the concentration above a certain point will yield decreasing therapeutic effect, and once again may well get into increased side effects through the drug's effects on other biochemical pathways etc.
Another factor for not assuming that the high-dose tbi flop rules out success for the lower-dose stroke study: The processes that end in brain cell death after trauma or stroke are complex. Most drugs like Cerestat, when studied in pre-preclinical characterizations, are found to have effects on several processes in tissues. Cerestat blocks the ability of the NMDA receptor on brain nerve cells to interact with certain stimulatory compounds, that cause excess calcium to flow into the cells, which in turn pushes the cell towards death. (This is all described in Cambridge Neurosci's patents, U.S. 5,262,568 and others.) But the NMDA receptor is also involved in other nerve responses. It may well be that a beneficial effect of Cerestat caused by its presence at low to medium levels could have positive effects on stroke patients. A higher dose of the drug could have been given to TBI patients because a higher concentration is needed for an effect on one or more other pathways which were hoped to prove beneficial in brain cell death after trauma. The fact that this did not work does not imply that the lower doses won't work in stroke, where the cause of cell death is similar to that after trauma in some ways, and different in other respects. Of course, it also does not mean that the drug WILL work in stroke. |
