Neuroprotective Effects of Carbonic Anhydrase Inhibition and Cyclic Adenosine Monophosphate Activation in Mouse Model of Transient Global Cerebral Ischemia and Reperfusion.

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.

Drug repurposing in skeletal muscle ion channelopathies.

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.

Marked reduction in paralytic attacks in a patient with Andersen-Tawil syndrome switched from acetazolamide to dichlorphenamide.

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.

Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.

INTRODUCTION/AIM: Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP). METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Increased sarcolemma chloride conductance as one of the mechanisms of action of carbonic anhydrase inhibitors in muscle excitability disorders.

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.

Efficacy and Safety of Dichlorphenamide for Primary Periodic Paralysis in Adolescents Compared With Adults.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%]). CONCLUSIONS: Dichlorphenamide was comparably effective and tolerated among a small number of adolescents as well as adults, although types of adverse events differed between groups.

Open-Label, Dose-Escalation, Phase 1 Study of Safety and Single and Multiple-Dose Pharmacokinetics of Dichlorphenamide in Healthy Volunteers.

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).

Dichlorphenamide: A Review in Primary Periodic Paralyses.

Oral dichlorphenamide (Keveyis™) is a carbonic anhydrase inhibitor that is approved in the USA for the treatment of primary hyperkalaemic and hypokalaemic periodic paralyses and related variants. The efficacy and safety of dichlorphenamide in patients with primary periodic paralyses have been evaluated in four 9-week, randomized, double-blind, placebo-controlled, phase III trials [two parallel-group trials (HOP and HYP) and two crossover trials]. In two trials in patients with hypokalaemic periodic paralysis, dichlorphenamide was associated with a significantly (eightfold) lower paralytic attack rate and fewer patients with acute intolerable worsening compared with placebo. In two trials in patients with hyperkalaemic periodic paralysis, the attack rate was lower with dichlorphenamide than placebo, with this comparison reaching statistical significance in one trial (crossover) but not the other (HYP), although the attack rate was approximately fivefold lower with dichlorphenamide than placebo in the HYP trial. In 52-week, open-label extensions of the HOP and HYP trials, dichlorphenamide provided sustained efficacy in patients with hypokalaemic or hyperkalaemic periodic paralysis. Dichlorphenamide was generally well tolerated in all four phase III trials and during the extension trials; the most common adverse events were paraesthesia, cognitive disorders and dysgeusia. As the first agent to be approved in the USA for this indication, dichlorphenamide is a valuable treatment option for patients with primary hyperkalaemic or hypokalaemic periodic paralysis.

Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.

OBJECTIVE: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. METHODS: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. RESULTS: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). CONCLUSIONS: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. CLASSIFICATION OF EVIDENCE: 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.

Emerging role of calcium-activated potassium channel in the regulation of cell viability following potassium ions challenge in HEK293 cells and pharmacological modulation.

Emerging evidences suggest that Ca(2+)activated-K(+)-(BK) channel is involved in the regulation of cell viability. The changes of the cell viability observed under hyperkalemia (15 mEq/L) or hypokalemia (0.55 mEq/L) conditions were investigated in HEK293 cells expressing the hslo subunit (hslo-HEK293) in the presence or absence of BK channel modulators. The BK channel openers(10(-11)-10(-3)M) were: acetazolamide(ACTZ), Dichlorphenamide(DCP), methazolamide(MTZ), bendroflumethiazide(BFT), ethoxzolamide(ETX), hydrochlorthiazide(HCT), quercetin(QUERC), resveratrol(RESV) and NS1619; and the BK channel blockers(2 x 10(-7)M-5 x 10(-3)M) were: tetraethylammonium(TEA), iberiotoxin(IbTx) and charybdotoxin(ChTX). Experiments on cell viability and channel currents were performed using cell counting kit-8 and patch-clamp techniques, respectively. Hslo whole-cell current was potentiated by BK channel openers with different potency and efficacy in hslo-HEK293. The efficacy ranking of the openers at -60 mV(Vm) was BFT> ACTZ >DCP ≥RESV≥ ETX> NS1619> MTZ≥ QUERC; HCT was not effective. Cell viability after 24 h of incubation under hyperkalemia was enhanced by 82+6% and 33+7% in hslo-HEK293 cells and HEK293 cells, respectively. IbTx, ChTX and TEA enhanced cell viability in hslo-HEK293. BK openers prevented the enhancement of the cell viability induced by hyperkalemia or IbTx in hslo-HEK293 showing an efficacy which was comparable with that observed as BK openers. BK channel modulators failed to affect cell currents and viability under hyperkalemia conditions in the absence of hslo subunit. In contrast, under hypokalemia cell viability was reduced by -22+4% and -23+6% in hslo-HEK293 and HEK293 cells, respectively; the BK channel modulators failed to affect this parameter in these cells. In conclusion, BK channel regulates cell viability under hyperkalemia but not hypokalemia conditions. BFT and ACTZ were the most potent drugs either in activating the BK current and in preventing the cell proliferation induced by hyperkalemia. These findings may have relevance in disorders associated with abnormal K(+) ion homeostasis including periodic paralysis and myotonia.

Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy.

Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.

Biodegradable fumarate-based drug-delivery systems for ophthalmic applications.

The function of a photocrosslinked poly(propylene fumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix for the sustained release of three ophthalmic model drugs, acetazolamide (AZ), dichlorphenamide (DP), and timolol maleate (TM), was investigated. The drugs differ in molecular weight and degree of dissociation in aqueous environments; both are parameters that significantly influence drug diffusivity. AZ, DP, and TM-loaded cylindrical rods (10 mm length, 0.6 mm diameter) were fabricated by photoinduced cross-copolymerization of PPF and N-vinyl pyrrolidone (NVP) in molds. The released amounts of AZ, DP, TM, and NVP were determined by high-performance liquid chromatography (HPLC). The effects of drug properties and loading on the release kinetics were investigated. The in vitro release of AZ, DP, and TM was well sustained from the polymer matrices over a period of approximately 210, 270, and 250 days, respectively. The release kinetics correlated with the HPLC retention profiles of the different drugs. Following a small initial burst release (<10%), a dual modality release controlled by diffusion and bulk erosion was found for all drugs. Drug release rates of up to 4 microg/day were reached. Matrix drug loading generally affected the extent of the burst release, release kinetics, as well as the matrix water content and matrix degradation that were determined gravimetrically. Microcomputed tomography was used to image structural and dimensional changes of the devices. A preliminary rabbit implantation study revealed promising ocular biocompatibility of drug-free PPF/PVP matrices. All results indicate the potential of photocrosslinked PPF-based matrices as polymeric carriers for long-term ophthalmic drug delivery.

Acetazolamide prevents vacuolar myopathy in skeletal muscle of K(+) -depleted rats.

BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). Whether these drugs prevent vacuolar myopathy, which is a pathogenic factor in hypoPP, is unknown. The effects of these drugs on the efflux of lactate from skeletal muscle were also investigated. EXPERIMENTAL APPROACH: For 10 days, K(+)-depleted rats, a model of hypoPP, were administered 5.6 mg kg(-1) day(-1) of acetazolamide, dichlorphenamide or bendroflumethiazide (the last is not an inhibitor of CA). Histological analysis of vacuolar myopathy and in vitro lactate efflux measurements were performed in skeletal muscles from treated and untreated K(+)-depleted rats, and also from normokalemic rats. KEY RESULTS: About three times as many vacuoles were found in the type II fibres of tibialis anterioris muscle sections from K(+)-depleted rats as were found in the same muscle from normokalemic rats. In ex vivo experiments, a higher efflux of lactate on in vitro incubation was found in muscles of K(+)-depleted rats compared with that found in muscles from normokalemic rats. After treatment of K(+)-depleted rats with acetazolamide, the numbers of vacuoles in tibialis anterioris muscle decreased to near normal values. Incubation with acetazolamide in vitro inhibited efflux of lactate from muscles of K(+)-depleted rats. In contrast, bendroflumethiazide and dichlorphenamide failed to prevent vacuolar myopathy after treatment in vivo and failed to inhibit lactate efflux in vitro. CONCLUSIONS AND IMPLICATIONS: Acetazolamide prevents vacuolar myopathy in K(+)-depleted rats. This effect was associated with inhibition of lactate transport, rather than inhibition of CA.

Treatment for periodic paralysis.

BACKGROUND: Primary periodic paralyses are rare inherited muscle diseases characterised by episodes of flaccid weakness affecting one or more limbs, lasting several hours to several days, caused by mutations in skeletal muscle channel genes. OBJECTIVES: The objective of this review was to systematically review treatment of periodic paralyses. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to July 2007), and EMBASE (from January 1980 to July 2007) and any other available international medical library sources from the University of Milan for randomised trials. SELECTION CRITERIA: We included randomised (including cross-over studies) and quasi-randomised trials in participants with primary periodic paralyses, in which any form of treatment, including physical therapy and alternative therapies, was compared to placebo or another treatment. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was the change in attack severity or frequency by eight weeks from the start of treatment. Our secondary outcome measures were: change in muscle strength and mass; change in Quality of Life, using Short Form 36 (SF36) or similar; preference of treatment strategy; adverse effects at eight weeks. MAIN RESULTS: Three studies met our inclusion criteria. In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. Fifteen preferred DCP, three placebo and six their baseline medication. Twenty-four of 31 participants with hyperkalemic periodic paralysis completed both treatment phases: for the 16 participants who had attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.006) and in severity-weighted attack rate (P = 0.02) on DCP relative to placebo were significant. Fifteen preferred DCP, one placebo and five their baseline medication. Acetazolamide proved to improve muscle strength in eight participants with HypoPP in one other study and pinacidil, a potassium channel opener, also improved muscle strength in 2/4 participants with HypoPP in a third study. AUTHORS' CONCLUSIONS: The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses. The other two studies provide some evidence that either acetazolamide or pinacidil may improve muscle strength. However we still lack sufficient evidence to provide full guidelines for the treatment of people with periodic paralysis.

Long-term management of a glaucomatous eye in a dog treated with medical therapy alone.

An acute open angle glaucoma of the right eye was diagnosed in an 8-year-old male Yorkshire terrier which was presented with anorexia, depression, and trembling. Abnormal findings of the right eye on admission included elevated intraocular pressure (IOP; 40 mmHg), the presence of fibrin and flare in the anterior chamber, and immature cataract. Morphological abnormalities of the iridocorneal angle were not detected, and an open angle was seen in the eye. Although an elevated IOP was observed at one year after admission, lowering IOP (< or = 24 mmHg) was maintained with medical therapy using dichlorphenamide (DCPA) and timolol maleate, DCPA alone, or no-treatment for 1973 days. This case suggests that lower IOP can be maintained with medical therapy alone for a long period in a patient with open angle glaucoma.

Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis.

Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double-blind, placebo-controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double-blind, placebo-controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium-sensitive periodic paralysis (PSPP). In each trial, two 8-week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP.