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Medicine Jul 2022This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze...
BACKGROUND
This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze the relationship between genotype and clinical phenotype.
METHODS
CLCN1 and SCN4A genes in patients with clinical features and muscle pathology indicative of NDM were sequenced. Furthermore, KCNE3 and CACNA1S genes were assessed in patients with wild-type CLCN1 and SCN4A.
RESULTS
Patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia, and joint contracture as determined by needle electromyography. All the study participants were administered mexiletine in combination with carbamazepine and showed significant improvements in myotonia symptoms in response to this therapy. CLCN1 gene mutation was detected in 8 cases diagnosed with myotonia congenital using gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion, and 2 insertions. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita.
CONCLUSIONS
Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in associated with clinical features.
Topics: Chloride Channels; Humans; Mutation; Myotonia; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel
PubMed: 35866763
DOI: 10.1097/MD.0000000000029591 -
Perioperative Medicine (London, England) Jun 2023The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and...
BACKGROUND
The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and duration of mexiletine in rats.
METHODS
Nociceptive blockage was evaluated by the inhibition of response to skin pinpricks in rats via the cutaneous trunci muscle reflex (CTMR). After subcutaneous injection, the analgesic activities of mexiletine in the absence and presence of either dopamine or phenylephrine were assessed. Each injection was standardized into 0.6 ml with a mixture of drugs and saline.
RESULTS
Subcutaneous injections of mexiletine successfully induced dose-dependent cutaneous analgesia in rats. The results revealed that rats injected with 1.8 μmol mexiletine exhibited 43.75% blockage (%MPE), while rats injected with 6.0 μmol mexiletine showed 100% blockage. Co-application of mexiletine (1.8 or 6.0 μmol) with dopamine (0.06, 0.60, or 6.00 μmol) elicited full sensory block (%MPE). Sensory blockage ranged from 81.25% to 95.83% in rats injected with mexiletine (1.8 μmol) and phenylephrine (0.0059 or 0.0295 μmol), and complete subcutaneous analgesia was observed in rats injected with mexiletine (1.8 μmol) and a higher concentration of phenylephrine (0.1473 μmol). Furthermore, mexiletine at 6.0 μmol completely blocked nociception when combined with any concentration of phenylephrine, while 0.1473 μmol phenylephrine alone exhibited 35.417% subcutaneous analgesia. The combined application of dopamine (0.06/0.6/6 μmol) and mexiletine (1.8/6 μmol) resulted in increased %MPE, complete block time, full recovery time, and AUCs compared to the combined application of phenylephrine (0.0059 and 0.1473 μmol) and mexiletine (1.8/6 μmol) (p < 0.001).
CONCLUSION
Dopamine is superior to phenylephrine in improving sensory blockage and enhancing the duration of nociceptive blockage by mexiletine.
PubMed: 37312135
DOI: 10.1186/s13741-023-00314-2 -
Frontiers in Pharmacology 2017Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (Na1.4)....
Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (Na1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives , suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native Na1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (I) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (I), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with Na1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect CC-cells from HO-cytotoxicity in the concentration range effective on Na1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of HO, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of Na1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.
PubMed: 29379434
DOI: 10.3389/fphar.2017.00907 -
Circulation Research Feb 2019Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3).... (Clinical Trial)
Clinical Trial
RATIONALE
Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3). Mexiletine, which is structurally related to the Na channel-blocking anesthetic lidocaine, is used to treat LQT3 patients. However, the patient response is variable, depending on the genetic mutation in SCN5A.
OBJECTIVE
The goal of this study is to understand the molecular basis of patients' variable responses and build a predictive statistical model that can be used to personalize mexiletine treatment based on patient's genetic variant.
METHODS AND RESULTS
We monitored the cardiac Na channel voltage-sensing domain (VSD) conformational dynamics simultaneously with other gating properties for the LQT3 variants. To systematically identify the relationship between mexiletine block and channel biophysical properties, we used a system-based statistical modeling approach to connect the multivariate properties to patient phenotype. We found that mexiletine altered the conformation of the Domain III VSD, which is the same VSD that many tested LQT3 mutations affect. Analysis of 15 LQT3 variants showed a strong correlation between the activation of the Domain III-VSD and the strength of the inhibition of the channel by mexiletine. Based on this improved molecular-level understanding, we generated a systems-based model based on a dataset of 32 LQT3 patients, which then successfully predicted the response of 7 out of 8 patients to mexiletine in a blinded, retrospective trial.
CONCLUSIONS
Our results imply that the modulated receptor theory of local anesthetic action, which confines local anesthetic binding effects to the channel pore, should be revised to include drug interaction with the Domain III-VSD. Using an algorithm that incorporates this mode of action, we can predict patient-specific responses to mexiletine, improving therapeutic decision making.
Topics: Adolescent; Adult; Animals; Anti-Arrhythmia Agents; Female; HEK293 Cells; Humans; Ion Channel Gating; Long QT Syndrome; Male; Mexiletine; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Pharmacogenomic Variants; Sodium Channel Blockers; Xenopus
PubMed: 30566038
DOI: 10.1161/CIRCRESAHA.118.314050 -
Dermatology Practical & Conceptual Jul 2023Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent erythema, burning pain and warmth of the extremities. The symptoms greatly compromise...
INTRODUCTION
Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent erythema, burning pain and warmth of the extremities. The symptoms greatly compromise the patients' quality of life leading to severe disability. SCN9A mutations can be the cause of the disease. Dermatologists are often the specialists these patients turn to for assistance.
OBJECTIVES
To describe the demographic and clinical characteristics of patients with primary EM, to assess the presence and mutation types in the SCN9A gene, to evaluate the effectiveness of several therapeutic approaches, and to propose a diagnostic algorithm with therapeutic implications.
METHODS
A monocentric retrospective study using the database of patients with a discharge diagnosis of primary EM of our Center. Demographic, clinical, instrumental and laboratory data of patients were reviewed.
RESULTS
Eleven female patients (age range 16 to 57) were selected. All patients were affected in both the lower and upper extremities. Follow-up ranged from 2 to 9 years. Four patients had four different heterozygous variants of the SCN9A gene. Two patients, although genetically negative, had a suggestive family history. A variety of medications were tried in all our patients to alleviate symptoms, but their efficacy was variable, partial and/or transitory. The most effective therapies were antihistamines, venlafaxine, and mexiletine.
CONCLUSIONS
The diagnosis and treatment of EM remain challenging. Patients with this condition display a wide spectrum of clinical manifestations and severity, as well as a paucity of resources and structures to support them. Mutations in the SCN9A gene are not always detected.
PubMed: 37557164
DOI: 10.5826/dpc.1303a191 -
Journal of Pharmaceutical Policy and... 2020Drug repositioning is the scientific strategy of investigating existing drugs for additional clinical indications. The advantages of drug repositioning are that it... (Review)
Review
Drug repositioning is the scientific strategy of investigating existing drugs for additional clinical indications. The advantages of drug repositioning are that it benefits patients and that it adds new indications to existing drugs for lower costs compared to de novo drug development. Clinical research groups recognizing efficacy of these "old" drugs for a new indications often face an uphill struggle due to a lack of funding and support because of poor structural and regulatory support for clinical drug development. The current framework for drug repositioning allows "venture capital" companies to abuse loopholes in the legislation to gain long-term market authorization among with excessive high pricing. A new regulatory framework is needed to prevent abuse of the legislation and promote clinical investigator-driven drug repositioning. The COVID-19 pandemic has boosted funding and regulatory support for drug repositioning. The lessons learned from the COVID-19 pandemic should be implemented in a new clear blueprint for drug repositioning. This blueprint should guide clinicians through legislation for drug repositioning in the EU. This review summarizes the routes for registration and discusses the current state of drug repositioning in Europe.
PubMed: 32695427
DOI: 10.1186/s40545-020-00249-9 -
CMAJ : Canadian Medical Association... Oct 2016
Topics: Age of Onset; Anticipation, Genetic; Arrhythmias, Cardiac; Cause of Death; Humans; Mexiletine; Myotonic Dystrophy; Voltage-Gated Sodium Channel Blockers
PubMed: 27270116
DOI: 10.1503/cmaj.151384 -
Frontiers in Pharmacology 2021The European Commission highlights in its Pharmaceutical Strategy the role of academic researchers in drug repurposing, especially in the development of orphan...
The European Commission highlights in its Pharmaceutical Strategy the role of academic researchers in drug repurposing, especially in the development of orphan medicinal products (OMPs). This study summarizes the contribution of academia over the last 5 years to registered repurposed OMPs and describes barriers to success, based upon three real world cases. OMPs granted marketing authorization between January 2016 and December 2020 were reviewed for repurposing and whether the idea originated from academia or industry. Three cases of drug repurposing were selected from different therapeutic areas and stages of development to identify obstacles to success. Thirteen of the 68 OMPs were the result of drug repurposing. In three OMPs, there were two developments such as both a new indication and a modified application. In total, twelve developments originated from academia and four from industry. The three cases showed as barriers to success: lack of outlook for sufficient return of investments (abatacept), lack of regulatory alignment and timing of interaction between healthcare professionals and regulators (etidronate), failure to register an old drug for a fair price, resulting in commercialization as a high priced orphan drug (mexiletine). While the majority of repurposed OMPs originates in academia, a gap exists between healthcare professionals, regulators and industry. Future strategies should aim to overcome these hurdles leading to more patient benefit through sustainable access of repurposed drugs. Potential solutions include improved regulatory and reimbursement knowledge by academia and the right for regulators to integrate new effectiveness data into product labels.
PubMed: 34744726
DOI: 10.3389/fphar.2021.746987 -
British Journal of Pharmacology Feb 2022Voltage-gated sodium (Na ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal...
BACKGROUND AND PURPOSE
Voltage-gated sodium (Na ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of Na 1.5 (nNa 1.5), which has several amino acid substitutions in the domain I voltage-sensor compared with its adult counterpart (aNa 1.5). This study aimed to determine whether nNa 1.5 channels could be distinguished pharmacologically from aNa 1.5 channels.
EXPERIMENTAL APPROACH
Cells expressing either nNa 1.5 or aNa 1.5 channels were exposed to low MW inhibitors, an antibody or natural toxins, and changes in electrophysiological parameters were measured. Stable expression in EBNA cells and transient expression in Xenopus laevis oocytes were used. Currents were recorded by whole-cell patch clamp and two-electrode voltage-clamp, respectively.
KEY RESULTS
Several clinically used blockers of Na channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine, and riluzole) could not distinguish between nNa 1.5 or aNa 1.5 channels. However, two tarantula toxins (HaTx and ProTx-II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNa 1.5 or aNa 1.5 channels by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNa 1.5/lysine in nNa 1.5), that is, the charge reversal in the spliced region of the channel, played a key role in the selectivity, especially in antibody binding.
CONCLUSION AND IMPLICATIONS
We conclude that the cancer-related nNa 1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNa 1.5 channels. Thus, it may be possible to design low MW compounds as antimetastatic drugs for non-toxic therapy of nNa 1.5-expressing carcinomas.
Topics: Carcinoma; Humans; NAV1.7 Voltage-Gated Sodium Channel; Spider Venoms; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels
PubMed: 34411279
DOI: 10.1111/bph.15668 -
Journal of Pharmacological and... 2022Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical...
Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control is recommended to accurately analyze the effects of drugs on cardiac contractility. Therefore, we investigated the relationship between contraction parameters and beating rates of cardiac cell sheet tissues by directly measuring the contraction force and compared the effects of ion channel drugs (mexiletine, ranolazine, and dofetilide) on contraction parameters under spontaneous beating conditions with those under pacing (1 Hz) conditions. To characterize the contraction/relaxation kinetics, we introduced a novel analysis tool, called a "C-V loop," a plot of contraction force versus force-changing rate ("velocity"). When we increased the beating rate, the contraction force, force-changing rate, and relaxation time markedly decreased. The occurrence frequencies of beating arrest and irregular beats at high concentration ranges of mexiletine and ranolazine were more suppressed in paced samples than in spontaneously beating ones. We also found that relaxation time increased by treatment with dofetilide and contraction amplitude decreased in a concentration-dependent manner by mexiletine treatment only in the samples under pacing. These drug responses were consistent with the previous reports using human samples. These results indicated that beating rate control is necessary to stably evaluate the effects of drugs on contractility and that tests under 1-Hz pacing are more relevant to clinical settings.
Topics: Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Ranolazine; Mexiletine; Cells, Cultured
PubMed: 36273536
DOI: 10.1016/j.vascn.2022.107228