Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis

Sansone, Valeria; Burge, J.; McDermott, Michael P.; Smith, Paula V.; Herr, Barbara E.; Tawil, Rabi; Pandya, Shree; Kissel, John T.; Ciafaloni, Emma; Shieh, Perry B.; Ralph, Jeffrey W.; Amato, Antony; Cannon, Stephen C.; Trivedi, Jaya; Barohn, Richard J.; Crum, Brian A.; Mitsumoto, Hiroshi; Pestronk, Alan; Meola, G.; Conwit, Robin; Hanna, Michael G.; Griggs, Robert C.

doi:10.1212/wnl.0000000000002416

Cited by 59 publications

(71 citation statements)

References 36 publications

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“…A second randomised placebo controlled trial with a one year open label extension phase attempting to ascertain if benefit was maintained in the longer-term was reported in 2016 36 .…”

Section: Phase III Trialsmentioning

confidence: 99%

“…However the dosage of DCP used in glaucoma, 50 mg every 6 hours, was twice the average dosage used in studies demonstrating the efficacy of DCP for the treatment of PP 35,36 . In the 2016 study of DCP in periodic paralysis 18% of participants taking DCP withdrew due to adverse events, the majority in the long-term extension phase 36 .…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…In the 2016 study of DCP in periodic paralysis 18% of participants taking DCP withdrew due to adverse events, the majority in the long-term extension phase 36 . Although paraesthesia was the most common side effect occurring in 47% of those taking DCP it was never the cause of withdrawal.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…The development of renal calculi is often a concern when using long-term CAIs. Of the 53 participants (39 hypoPP, 14 hyperPP) who underwent renal tract assessment at the end of the trial eight developed new renal calculi (7 hypoPP, 1hyperPP) and two hypoPP participants had an increase in size of pre-existing calculi 36 . One participant withdrew because of painful calculi but it is unclear if the others were symptomatic or if treatment was necessary.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

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Dichlorphenamide efficacy in the primary periodic paralyses

Matthews

Hanna

2017

Expert Opinion on Orphan Drugs

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“…A second randomised placebo controlled trial with a one year open label extension phase attempting to ascertain if benefit was maintained in the longer-term was reported in 2016 36 .…”

Section: Phase III Trialsmentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

See 2 more Smart Citations

Dichlorphenamide efficacy in the primary periodic paralyses

Matthews

Hanna

2017

Expert Opinion on Orphan Drugs

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“…The frequency of attacks in this group of diseases, which present with attacks, can be reduced by carbonic anhydrase inhibitors (acetazolamide and diclorphenamide) or potassium-sparing diuretics (1). Sansone et al (2) showed in their randomized, multi-center, doubleblind, placebo-controlled trial that diclorphenamide can be used in the treatment of PP with an evidence level of class 1. Fortyfour patients with HYP and 21 with HOP were included in the trial.…”

mentioning

confidence: 99%

An Approved Treatment in Periodic Paralyses: Diclorphenamide

Sezgi̇n¹

2016

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Periodic paralyses (PP) are autosomal inherited muscle diseases that are directly associated with changes in serum potassium levels. Classified as channelopathies, PP are often triggered by exercise. Hyperkalemic periodic paralysis (HYP) is associated with mutations in SCN4A gene, and hypokalemic periodic paralysis (HOP) is associated with mutations in a calcium channel gene called CACNA1S and a sodium channel gene called SCN4A. PP becomes symptomatic in the first decade of life. The frequency of attacks in this group of diseases, which present with attacks, can be reduced by carbonic anhydrase inhibitors (acetazolamide and diclorphenamide) or potassium-sparing diuretics (1). Sansone et al. (2) showed in their randomized, multi-center, doubleblind, placebo-controlled trial that diclorphenamide can be used in the treatment of PP with an evidence level of class 1. Fortyfour patients with HYP and 21 with HOP were included in the trial. Two randomized, double-blind, placebo-controlled trials lasted 9 weeks, followed by a 1-year extension phase in which all participants received dichlorphenamide (DCP). The median attack rate, frequency of severe attacks, and the duration of attacks were lower in ptients with HYP on DCP. The median attack rate was also lower in patients with HOP on DCP compared with placebo, but without reaching statistical significance. There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events were paresthesia, confusion, cognitive decline, and kidney stones. The median attack rate and frequency of severe attacks were increased in one patient with HOP on DCP with the NaV1.4pR222W mutation who had not previously used a carbonic anhydrase inhibitor; DCP treatment was stopped and the patient was excluded from the trial. The main shortcomings of these trials mentioned by the authors were the lack of comparison between DCP and acetazolamide and the limited number of participants, which precluded analysis by genetic subgroup. Finally, the Food and Drug Administration approved the use of DCP in HYP and HOP in August 2015. EthicsPeer-review: Internal peer-reviewed.

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Central Role of Subthreshold Currents in Myotonia

Metzger

Dupont

Voss

et al. 2019

Annals of Neurology

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It is generally thought that muscle excitability is almost exclusively controlled by currents responsible for generation of action potentials. We propose that smaller ion channel currents that contribute to setting the resting potential and to subthreshold fluctuations in membrane potential can also modulate excitability in important ways. These channels open at voltages more negative than action potential threshold and are thus termed subthreshold currents. As subthreshold currents are orders of magnitude smaller than the currents responsible for the action potential, they are hard to identify and easily overlooked. Discovery of their importance in regulation of excitability opens new avenues for improved therapy for muscle channelopathies and diseases of the neuromuscular junction.

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Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis

Abstract: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

Cited by 59 publications

References 36 publications

Dichlorphenamide efficacy in the primary periodic paralyses

Dichlorphenamide efficacy in the primary periodic paralyses

An Approved Treatment in Periodic Paralyses: Diclorphenamide

Central Role of Subthreshold Currents in Myotonia

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