Ephedrine treatment for autoimmune myasthenia gravis

Abstract

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity.

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis

“…The clinical results of the trial have been reported elsewhere [29]. Briefly, four patients completed three treatment cycles each containing a treatment period with ephedrine and placebo in addition to their usual medications.…”

“…Parts of Additional file 1 (the briefing document) have been published by AF Lipka et al in Neuromuscular Disorders [29]. Marcel Timmen, director of the Dutch association for neuromuscular disorders (Spierziekten Nederland), provided general support for this project.…”

“…Taken together, ephedrine for myasthenia gravis emerged as a relevant and suitable case, and we designed a protocol for a series of N-of-1 trials [25]. The clinical results have been reported elsewhere [29]. The aims of this study are: (1) to evaluate the feasibility of an N-of-1 trial protocol for determining efficacy of ephedrine as an add-on treatment in myasthenia gravis, from the trialists’ and patients’ perspective, (2) to examine whether a series of N-of-1 trials provides suitable and sufficient evidence for the NHCI to make a decision on reimbursement of the unlicensed product, and (3) to explore the suitability and sufficiency of the evidence for market authorization of ephedrine for myasthenia gravis under current regulatory pathways, based on advice from the MEB.…”

Passive transfer models of myasthenia gravis with muscle‐specific kinase antibodies

“…Drugs that activate β‐adrenergic receptors, including ephedrine and albuterol, offer a therapeutic benefit in certain forms of congenital MG . Ephedrine has also been used in autoimmune MG, and was recently successful in a small n ‐of‐1 trial . Ghazanfari et al .…”

Synaptic Homeostasis and Its Immunological Disturbance in Neuromuscular Junction Disorders

“…In addition to the promotion of presynaptic vesicle recycling [98], the effects of BDNF in the synapse are regulated by way of Wnt canonical signaling pathway [99] and activated by β2-adrenoceptor agonists (via intracellular signaling pathways, perhaps including the cyclic adenosine monophosphate, cAMP/protein kinase A/cAMP-responsive element-binding protein pathway) to maintain the structural and functional integrity of motor endplates [100]. The therapeutic pre- and postsynaptic benefits of β-adrenoceptor agonists (salbutamol and ephedrine) have been reported in MuSK MG animal models [101], neonatal myasthenia gravis (FARIS, caused by fetal AChR γ-subunit antibodies [72,73]) [102] and MG patients with nAChR antibodies [103] as well as various types of congenital myasthenic syndrome [104,105] including the patients suffering from mutations in MuSK [106] and Lrp4 [107]. …”