Amifampridine for the Management of Lambert-Eaton Myasthenic Syndrome: A New Take on an Old Drug

Yoon, Connie H.; Owusu-Guha, Jocelyn; Smith, A. Gordon; Buschur, Pamela

doi:10.1177/1060028019864574

Cited by 21 publications

(21 citation statements)

References 27 publications

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“…3,4-diaminopyridine (3,4-DAP) is a non-specific voltage-dependent potassium channel (Kv1.5) blocker, which causes depolarization of the presynaptic membrane at the NMJ and delays nerve repolarization, thus increasing quantal release of ACh. It is used in the treatment of Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenia ( 84 , 85 ). A recent phase IIb study in 10 adult patients with MuSK-MG, showed that it was safe and an improvement was seen across both objective measures of muscle strength and patient reported outcomes ( 86 ).…”

Section: Treatment Of Jmgmentioning

confidence: 99%

Management of Juvenile Myasthenia Gravis

2020

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Juvenile Myasthenia Gravis (JMG) is a rare disorder, defined as myasthenia gravis in children younger than 18 years of age. While clinical phenotypes are similar to adults, there are a number of caveats that influence management: broader differential diagnoses; higher rates of spontaneous remission; and the need to initiate appropriate treatment early, to avoid the long-term physical and psychosocial morbidity. Current practice is taken from treatment guidelines for adult MG or individual experience, with considerable variability seen across centers. We discuss our approach to treating JMG, in a large specialist JMG service, and review currently available evidence and highlight potential areas for future research. First-line treatment of generalized JMG is symptomatic management with pyridostigmine, but early use of immunosuppression, where good control is not achieved is important. Oral prednisolone is used as first-line immunosuppression with appropriate prevention and monitoring of side effects. Second-line therapies including azathioprine and mycophenolate may be considered where there is: no response to steroids, inability to wean to a reasonable minimum effective dose or if side-effects are intolerable. Management of ocular JMG is similar, but requires close involvement of ophthalmology in young children to prevent amblyopia. Muscle-specific tyrosine kinase (MuSK)-JMG show a poorer response to pyridostigmine and anecdotal evidence suggests that rituximab should be considered as second-line immunosuppression. Thymectomy is indicated in any patient with a thymoma, and consideration should be given in acetylcholine receptor (AChR) positive JMG allowing time for spontaneous remission. The benefit is less clear in ocular JMG and is not advised in MuSK-JMG. Children experiencing a myasthenic crisis require urgent hospital admission with access to the intensive care unit. PLEX is preferred over IVIG due to rapid onset of action, but this needs to be balanced with feasibility in very young children. Key questions remain in the management of JMG: when to initiate both first- and second-line treatments, choosing between steroid-sparing agents, and determining the optimal dose and treatment duration. We feel that given the rarity of this disease, the establishment of national registries and collaboration across groups will be needed to address these issues and facilitate future drug trials in JMG.

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Section: Treatment Of Jmgmentioning

confidence: 99%

Management of Juvenile Myasthenia Gravis

2020

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“…3,4-DAP is the FDA-approved first-line treatment for patients with Lambert-Eaton Myasthenic Syndrome (LEMS; (7)(8)(9)(10)). Although 3,4-DAP is canonically thought to mediate its effects by partially blocking presynaptic Kv channels, a previous report that millimolar concentrations of 3,4-DAP could have off-target effects on Cav1 channels led to the question of whether 3,4-DAP mechanisms of action at therapeutic concentrations (estimated to be in the low micromolar range) involve Cav1 channels.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical and animal model studies suggest that neuromuscular transmission, and subsequently muscle strength, can be improved by the use of 3,4-diaminopyridine (3,, which is a small molecule that acts as an antagonist at voltage-gated potassium (Kv) channels. 3,4-DAP was recently approved by the FDA to treat LEMS (7)(8)(9)(10) and has been shown to be effective at increasing neuromuscular strength in patients with LEMS (11)(12)(13)(14). However, 3,4-DAP has dose-dependent side effects that restrict the amount that patients take to relatively small doses, which prevents full symptomatic relief in many patients with LEMS (15,16).…”

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confidence: 99%

A high-affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

Ojala

Ginebaugh

et al. 2021

Journal of Biological Chemistry

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3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-approved treatment for neuromuscular weakness caused by Lambert–Eaton myasthenic syndrome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the presynaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-target agonist effect on the Cav1 subtype (“L-type”) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAP’s mechanism(s) of action, we first used the patch-clamp electrophysiology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-affinity (1–10 μM) partial antagonist effect of 3,4-DAP in addition to the well-known low-affinity (0.1–1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5- or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, independent of Cav1 calcium channels. Finally, we demonstrated that 1.5- or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv channels to mediate AP broadening and enhance transmitter release at the NMJ.

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“…Міастенічні синдром (МС) Ламберта-Ітона -рідкісне аутоімунне захворювання, яке впливає на вивільнення пресинаптичного ацетилхоліну, яке індукується аутоантителами проти потенціал-керованих кальцієвих каналів [1,2]. За оцінками, поширеність МС Ламберта-Ітона у всьому світі становить від 3 до 4 на мільйон населення [3,4]. Він може бути паранеопластичним (ПМС) або непаранеопластичним (НПМС).Мета: провести аналіз особливостей перебігу, діагностики та лікування синдрому Ламберта -Ітона з метою поліпшення якості онкологічної допомоги пацієнтам.Матеріали та методи: В роботі наведено результати аналізу експериментальних та клінічних досліджень в пошукових системах Scientific Indexing Services, PubMed, Elibrary, Hinari, власні клінічні спостереження і дослідження.…”

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