Use of TRH analogues in motorneurone disease

Abstract

TRH analogues have a longer half-life than does TRH and enhanced neuropharmacological actions. In motorneurone disease (MND), no benefit was reported with MK771 and DN1417. Focal, transient, and slight improvements in weakness and spasticity were described with CG3509. A controlled trial with a single intravenous dose of RX 77368 showed improvements in dysarthria, tongue movements, respiration, swallowing, and spasticity lasting up to 72 hours. Changes in muscle force were of no functional significance. There was an acute 25-30% increase in mean corrected fiber density and in mean macro-EMG parameters in biceps, but no change in amplitude or area of single macro-EMG motor units followed during the 2-hour infusions. An acute, direct or indirect, central effect of RX77368 on recruitment order or on activation threshold of pathological motor units is suggested. In a subacute open trial with repeated intravenous infusions of RX77368 (median 2 weeks), improvement in bulbar function in 8 of 12 responders, cramps (5 of 9), and spasticity (5 of 8) were maintained for medians of 18, 14, and 7 days, respectively. Side effects were prominent with doses above 0.2 mg/kg. Disease progression has not been halted with any analogue, but whether it may be usefully slowed down with RX77368 is worth investigating.