Undermines· strongORCH-E013
Independent laboratory: chronic epothilone D and vinblastine both INCREASE isoflurane sensitivity
- what the source states
- The abstract reports that "compared with saline treatment, epothilone D and vinblastine induced a leftward (more sensitive) shift of LORR response curves (95% confidence intervals for EC50: epothilone D, 0.75[0.73, 0.77] vs. saline, 0.97[0.96, 0.98]; vinblastine, 0.74[0.73, 0.75] vs. saline, 0.98[0.97, 0.99])," while paclitaxel produced a small rightward shift (1.05[1.03, 1.06] vs. saline 0.98[0.97, 0.99]) and the opioid control morphine produced a larger rightward shift (1.16[1.15, 1.17]). Mice received the microtubule-modulating drugs for more than two weeks. The study was randomized and blinded.
- what we infer
- The most methodologically complete animal study in the case, and it runs against the theory in the form the theory is usually stated. Two features make it more informative than a single contrary data point. First, it measured full concentration–response curves rather than latency at one concentration, which is the better-specified quantity. Second, it included a destabilizer — and vinblastine shifted sensitivity in the same direction as the stabilizer epothilone D, which no account based on microtubule stability predicts, and which suggests the operative variable may be general cellular disruption. This does not refute the acute epothilone-B result (different compound, different regimen), but it does refute the generalization that stabilizing microtubules protects consciousness from anesthetics.
- limitations
- Chronic dosing (>2 weeks) versus the single acute injection of the Wellesley studies; chronic modulation invites compensatory remodeling.
- Epothilone D rather than epothilone B — and Emerson et al. found epothilone D producing resistance in tadpoles, so the compound's direction is not consistent across preparations either.
- Authors acknowledge saline was an imperfect vehicle control for poorly soluble compounds.
- LORR rather than MAC; isoflurane only; outbred CD1 mice.
- Epothilone D altered blood pH and CO₂, offering a physiological confound.