Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging.

Cerebral ischemia is the primary basis of stroke, both sharing common pathogenic origins leading to irreversible brain damage if blood supply is not restored promptly. Existing evidence indicates that carbonic anhydrase (CA) inhibitors (CAIs) may impart therapeutic benefits against ischemia-reperfusion (I/R) pathology via the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) pathway. We hypothesize that CAI and cAMP activation may enhance the therapeutic outcome against I/R conditions. In this investigation, the potential of dichlorphenamide (CAI) and the role of cAMP against ischemia-reperfusion injury were evaluated using a transient global cerebral I/R (tGCI/R) model. Swiss albino mice were subjected to bilateral common carotid artery occlusion (BCCAo) for 20 min and reperfusion (R) or sham surgery on day 1. Dichlorphenamide (DCPA, 20 mg/kg) and/or forskolin (cAMP agonist, 3 mg/kg) was administered intraperitoneally (i.p.) after BCCAo/R for 14 days. Results showed that tGCI/R impaired neurocognitive functions and lowered brain levels of cAMP and protein kinase A (PKA) that were ameliorated by DCPA and/or forskolin (FSK). DCPA and/or FSK attenuated tGCI/R-induced brain edema, blood-brain barrier dysfunction, oxidative-nitrosative stress, pro-inflammatory cytokines, acetylcholinesterase activity, cell death, and neurotransmitter imbalance (e.g., glutamate, γ-aminobutyric acid). The study showed that DCPA improved neurological and biochemical parameters against tGCI/R injury via cAMP-PKA-mediated activation of protective mechanisms. However, DCPA and FSK in combination showed much enhanced therapeutic outcomes against tGCI/R. Therefore, CA and cAMP present novel targets that may retard the progress of a transient ischemic attack to a full-blown stroke.

BACKGROUND: Hypokalemic periodic paralysis is a chronic condition characterized by sporadic attacks of weakness associated with acute hypokalemia. Attacks are typically associated with specific triggers, such as prolonged rest following exercise or consumption of a high-carbohydrate meal. Most commonly, this condition is caused by an autosomal dominant calcium channel mutation, and patients typically have an established family medical history of hypokalemic periodic paralysis. Long-term complications include the development of progressive proximal myopathy. Oral potassium chloride may be considered for the treatment of an acute attack, with administration of acetazolamide or dichlorphenamide as long-term prophylaxis. Nephrologists can play an important role in the recognition and treatment of previously undiagnosed hypokalemic periodic paralysis.
METHODS: We summarize the case of a 19-year-old white man who presented to the emergency department with undiagnosed attacks of hypokalemic periodic paralysis, and who reported, at follow-up, improvement in the severity and frequency of attacks with dichlorphenamide.
CONCLUSIONS: This case demonstrates the crucial role nephrologists can play, not only in the diagnosis of hypokalemic periodic paralysis, but also in the ongoing management of this condition. Patients should be advised to regularly follow up with their nephrology team for evaluation due to the risk of developing myopathy.

Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP).
Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies.
Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], -1.00 [P < .0001]; placebo/DCP [n = 20], -0.63 [P = .01] and DCP/DCP, -2.25 [P < .0001]; placebo/DCP, -1.69 [P = .01]). Relatively smaller median decreases in weekly attack and severity-weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; -0.14 [P = .1] and -0.24 [P = .09]) than among those switching from placebo to DCP after 9 weeks (n = 16; -1.04 [P = .049] and -2.72 [P = .08]). Common adverse events (AEs) were paresthesia and cognition-related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution.
One-year open-label DCP treatment after a 9-week randomized, controlled study confirmed long-term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition-related AEs) were manageable in most patients.

Andersen-Tawil syndrome is a rare, autosomal dominant, multisystem disorder for which the majority of cases are caused by pathogenic variants in the KCNJ2 gene. The syndrome is characterized by the clinical triad of episodic paralysis, cardiac conduction abnormalities, and dysmorphic facial and skeletal features. Treatment of Andersen-Tawil syndrome is primarily focused on management of cardiac arrhythmias and preventive management of paralytic attacks. Dichlorphenamide is approved by the US Food and Drug Administration for use in primary periodic paralysis based on several randomized, controlled trials but has not been studied in patients with Andersen-Tawil syndrome. Here, we report a case of the syndrome caused by a de novo pathogenic variant in the KCNJ2 gene (c.95_98del). The paralytic attack rate for this patient was better controlled with dichlorphenamide compared with acetazolamide, further supporting the use of dichlorphenamide in patients with Andersen-Tawil syndrome.

To get insight into the mechanism of action of carbonic anhydrase inhibitors (CAI) in neuromuscular disorders, we investigated effects of dichlorphenamide (DCP) and acetazolamide (ACTZ) on ClC-1 chloride channels and skeletal muscle excitability. We performed patch-clamp experiments to test drugs on chloride currents in HEK293T cells transfected with hClC-1. Using the two-intracellular microelectrode technique in current-clamp mode, we measured the effects of drugs on the resting chloride conductance and action potential properties of sarcolemma in rat and mouse skeletal muscle fibers. Using BCECF dye fluorometry, we measured the effects of ACTZ on intracellular pH in single rat muscle fibers. Similarly to ACTZ, DCP (100 μM) increased hClC-1 chloride currents in HEK cells, because of the negative shift of the open probability voltage dependence and the slowing of deactivation kinetics. Bendroflumethiazide (BFT, 100 μM), structurally related to DCP but lacking activity on carbonic anhydrase, had little effects on chloride currents. In isolated rat muscle fibers, 50-100 μM of ACTZ or DCP, but not BFT, induced a ~ 20% increase of the resting chloride conductance. ACTZ reduced action potential firing in mouse muscle fibers. ACTZ (100 μM) reduced intracellular pH to 6.8 in rat muscle fibers. These results suggest that carbonic anhydrase inhibitors can reduce muscle excitability by increasing ClC-1 channel activity, probably through intracellular acidification. Such a mechanism may contribute in part to the clinical effects of these drugs in myotonia and other muscle excitability disorders.

Primary periodic paralyses are rare, hereditary skeletal muscle diseases characterized by episodic muscle weakness. Dichlorphenamide was effective and well tolerated in two studies, including one with adolescents. This analysis describes effects of dichlorphenamide among adolescents and adults.
Patients with primary periodic paralyses in a double-blind, controlled, crossover study were randomized to dichlorphenamide or placebo for nine weeks, with a nine-week or longer between-treatment washout period. Attack rate and severity-weighted attack rate during the final eight weeks of each treatment phase were calculated for adolescents and adults separately.
Seven adolescents (10 to ≤17 years) and 66 adults were enrolled; five of seven adolescents were evaluable for efficacy and six for safety. Dichlorphenamide total daily dosing among adolescents was 50 mg (n = 1) or 100 mg (n = 5), and in adults was 105.7 mg (mean; n = 61). In adolescents, the median decrease from baseline in frequency of weekly attacks was greater with dichlorphenamide (-0.96) than with placebo (-0.57), similar to findings in adults (dichlorphenamide, -0.83; placebo, -0.24). Severity-weighted attack frequency was likewise reduced more with dichlorphenamide than with placebo in adolescents and adults. The most common adverse event with dichlorphenamide in adolescents was skin rash (two of six [33%]). In adults, numbness was the most common adverse event (26 of 54 [48%]); skin rash occurred less frequently (10 of 54 [19%]).
Dichlorphenamide was comparably effective and tolerated among a small number of adolescents as well as adults, although types of adverse events differed between groups.

Single-and multiple-dose pharmacokinetics and safety were investigated in this phase 1 study of dichlorphenamide, a carbonic anhydrase inhibitor approved in the United States for treatment of primary periodic paralysis. Dichlorphenamide was administered to 6 cohorts (n = 6 each) of healthy adults. Cohorts A through E received single doses of 25-400 mg followed by 50-800 mg/day in divided doses for 10 total doses. Cohort F (safety analysis only) received up to 28 titrated doses from 100-800 mg/day. Plasma for pharmacokinetics sampling was obtained predose and up to 48 hours postdose. Twenty-five of 36 enrolled subjects completed. Median time to maximum plasma concentration ranged from 1.5-3 hours, and mean half-life from 32-68 hours. Mean area under the concentration-time curve from time 0 to tau (length of the dosing interval estimated using the trapezoidal method) and maximum observed plasma concentration increased dose-proportionally after multiple doses. The incidence and severity of adverse events (AEs) were dose-related, with at least one mild AE reported among 17%, 17%, and 67% of patients in cohorts A, B, and C, respectively; and at least one mild-to-moderate AE among 100% of subjects in cohorts D, E, and F. One serious AE of rash was reported in cohort F. Eleven subjects discontinued; 10 due to AEs at 400 or 800 mg/day (cohorts E and F), including 100% of cohort F. Hypokalemia contributed to 5 of 6 discontinuations in cohort F (all 800 mg/day).

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.

暂无摘要。