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The Journal of Craniofacial Surgery
Topics: Face; Humans; Mexiletine; Skin Aging
PubMed: 34608011
DOI: 10.1097/SCS.0000000000008262 -
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 -
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 -
European Journal of Pharmacology Aug 2020Transient outward K current, I, contributes to cardiac action potential generation and is primarily carried by K4.3 (KCND3) channels. Two K4.3 isoforms are expressed in...
Transient outward K current, I, contributes to cardiac action potential generation and is primarily carried by K4.3 (KCND3) channels. Two K4.3 isoforms are expressed in human ventricle and show differential remodeling in heart failure (HF). Lidocaine and mexiletine may be applied in selected patients to suppress ventricular arrhythmias, without effects on sudden cardiac death or mortality. Isoform-dependent effects of antiarrhythmic drugs on K4.3 channels and potential implications for remodeling-based antiarrhythmic management have not been assessed to date. We sought to test the hypotheses that K4.3 channels are targeted by lidocaine and mexiletine, and that drug sensitivity is determined in isoform-specific manner. Expression of KCND3 isoforms was quantified using qRT-PCR in left ventricular samples of patients with HF due to either ischemic or dilated cardiomyopathies (ICM or DCM). Long (K4.3-L) and short (K4.3-S) isoforms were heterologously expressed in Xenopus laevis oocytes to study drug sensitivity and effects on biophysical characteristics activation, deactivation, inactivation, and recovery from inactivation. In the present HF patient cohort KCND3 isoform expression did not differ between ICM and DCM. In vitro, lidocaine (IC-K4.3-L: 0.8 mM; IC-K4.3-S: 1.2 mM) and mexiletine (IC-K4.3-L: 146 μM; IC-K4.3-S: 160 μM) inhibited K4.3 with different sensitivity. Biophysical analyses identified accelerated and enhanced inactivation combined with delayed recovery from inactivation as primary biophysical mechanisms underlying K4.3 current reduction. In conclusion, differential effects on K4.3 isoforms extend the electropharmacological profile of lidocaine and mexiletine. Patient-specific remodeling of K4.3 isoforms may determine individual drug responses and requires consideration during clinical application of compounds targeting K4.3.
Topics: Animals; Anti-Arrhythmia Agents; Female; Heart Ventricles; Humans; Lidocaine; Male; Mexiletine; Oocytes; Potassium Channel Blockers; Protein Isoforms; Shal Potassium Channels; Xenopus laevis
PubMed: 32360350
DOI: 10.1016/j.ejphar.2020.173159 -
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 -
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 -
Clinical and Translational Science May 2021The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID-19), but the reported...
The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID-19), but the reported number of life-threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 μM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L-type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch-clamp system. Using the concentration-inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life-threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 μM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. WHAT QUESTION DID THIS STUDY ADDRESS? Our objective was to assess the arrhythmogenicity of CQ and HCQ/AZ over a wide range of drug concentrations using a multiscale heart simulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study showed that CQ and HCQ/AZ do not induce fatal arrhythmias even at concentrations much higher than in vitro antiviral half-maximal effective concentration (EC ) values at which QT prolongation exceeds 150 ms. We also found that estimated free plasma concentrations of CQ and HCQ/AZ achieved by currently used dosing protocols are lower than the antiviral EC for these drugs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chloroquine; Computer Simulation; Electrocardiography; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33404133
DOI: 10.1111/cts.12976 -
Journal of Molecular and Cellular... Jul 2020Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na channel blockers can vary. We...
BACKGROUND
Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na channel blockers can vary. We previously reported a case of an infant with malignant LQT3 and a missense Q1475P SCN5A variant, who was effectively treated with phenytoin, but only partially with mexiletine. Here, we functionally characterized this variant and investigated possible mechanisms for the differential drug actions.
METHODS
Wild-type or mutant Na1.5 cDNAs were examined in transfected HEK293 cells with patch clamping and biochemical assays. We used computational modeling to provide insights into altered channel kinetics and to predict effects on the action potential.
RESULTS
The Q1475P variant in Na1.5 reduced the current density and channel surface expression, characteristic of a trafficking defect. The variant also led to positive shifts in the voltage dependence of steady-state activation and inactivation, faster inactivation and recovery from inactivation, and increased the "late" Na current. Simulations of Na1.5 gating with a 9-state Markov model suggested that transitions from inactivated to closed states were accelerated in Q1475P channels, leading to accumulation of channels in non-inactivated closed states. Simulations with a human ventricular myocyte model predicted action potential prolongation with Q1475P, compared with wild type, channels. Patch clamp data showed that mexiletine and phenytoin similarly rescued some of the gating defects. Chronic incubation with mexiletine, but not phenytoin, rescued the Na1.5-Q1475P trafficking defect, thus increasing mutant channel expression.
CONCLUSIONS
The gain-of-function effects of Na1.5-Q1475P predominate to cause a malignant long QT phenotype. Phenytoin partially corrects the gating defect without restoring surface expression of the mutant channel, whereas mexiletine restores surface expression of the mutant channel, which may explain the lack of efficacy of mexiletine when compared to phenytoin. Our data makes a case for experimental studies before embarking on a one-for-all therapy of arrhythmias.
Topics: Action Potentials; Amino Acid Substitution; Anti-Arrhythmia Agents; Cardiac Conduction System Disease; Cells, Cultured; Disease Management; Disease Susceptibility; Gain of Function Mutation; HEK293 Cells; Humans; Ion Channel Gating; Long QT Syndrome; Models, Biological; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phenytoin; Voltage-Gated Sodium Channel Blockers
PubMed: 32339567
DOI: 10.1016/j.yjmcc.2020.04.027