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Current Drug Metabolism 2021Human cytochrome P450 enzyme 1A2 (CYP1A2) is one of the most important cytochrome P450 (CYP) enzymes in the liver, accounting for 13% to 15% of hepatic CYP enzymes.... (Review)
Review
Human cytochrome P450 enzyme 1A2 (CYP1A2) is one of the most important cytochrome P450 (CYP) enzymes in the liver, accounting for 13% to 15% of hepatic CYP enzymes. CYP1A2 metabolises many clinical drugs, such as phenacetin, caffeine, clozapine, tacrine, propranolol, and mexiletine. CYP1A2 also metabolises certain precarcinogens such as aflatoxins, mycotoxins, nitrosamines, and endogenous substances such as steroids. The regulation of CYP1A2 is influenced by many factors. The transcription of CYP1A2 involves not only the aromatic hydrocarbon receptor pathway but also many additional transcription factors, and CYP1A2 expression may be affected by transcription coactivators and compression factors. Degradation of CYP1A2 mRNA and protein, alternative splicing, RNA stability, regulatory microRNAs, and DNA methylation are also known to affect the regulation of CYP1A2. Many factors can lead to changes in the activity of CYP1A2. Smoking, polycyclic aromatic hydrocarbon ingestion, and certain drugs (e.g., omeprazole) increase its activity, while many clinical drugs such as theophylline, fluvoxamine, quinolone antibiotics, verapamil, cimetidine, and oral contraceptives can inhibit CYP1A2 activity. Here, we review the drugs metabolised by CYP1A2, the metabolic mechanism of CYP1A2, and various factors that influence CYP1A2 metabolism. The metabolic mechanism of CYP1A2 is of great significance in the development of personalised medicine and CYP1A2 target-based drugs.
Topics: Animals; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Enzyme Inhibitors; Humans
PubMed: 33397254
DOI: 10.2174/1389200221999210101233135 -
Muscle & Nerve Oct 2020The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1... (Review)
Review
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
Topics: Acetazolamide; Age of Onset; Carbonic Anhydrase Inhibitors; Chloride Channels; Electrodiagnosis; Electromyography; Fatigue; Genetic Testing; Humans; Lamotrigine; Mexiletine; Muscle Weakness; Muscle, Skeletal; Myalgia; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Practice Guidelines as Topic; Ranolazine; Sodium Channel Blockers; Voltage-Gated Sodium Channel Blockers
PubMed: 32270509
DOI: 10.1002/mus.26887 -
Clinical and Experimental Dermatology Jul 2019Erythromelalgia is a condition characterized by episodic pain, erythema and temperature of the extremities, which is relieved by cooling and aggravated by warming. It is... (Review)
Review
Erythromelalgia is a condition characterized by episodic pain, erythema and temperature of the extremities, which is relieved by cooling and aggravated by warming. It is useful to review this topic in light of recent discoveries of the genetic mutations that now define primary erythromelalgia, as opposed to secondary erythromelalgia, which is often associated with underlying medical disorders.
Topics: Capsaicin; Erythromelalgia; Humans; Mass Screening; Mexiletine; Myeloproliferative Disorders; NAV1.7 Voltage-Gated Sodium Channel; Ranolazine; Sensory System Agents; Sodium Channel Blockers; Sympathectomy
PubMed: 30609105
DOI: 10.1111/ced.13891 -
Drug Discovery Today Mar 2023The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs... (Review)
Review
The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1.
Topics: Humans; Myotonic Dystrophy; Drug Development
PubMed: 36634841
DOI: 10.1016/j.drudis.2023.103489 -
Neurology Jan 2021To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1).
METHODS
We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months.
RESULTS
Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants.
CONCLUSIONS
There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.
Topics: Adult; Cohort Studies; Double-Blind Method; Electrocardiography; Female; Hand Strength; Humans; Male; Mexiletine; Middle Aged; Myotonic Dystrophy; Voltage-Gated Sodium Channel Blockers; Walk Test
PubMed: 33046619
DOI: 10.1212/WNL.0000000000011002 -
Current Opinion in Pharmacology Feb 2023Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we... (Review)
Review
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.
Topics: Humans; Drug Repositioning; Channelopathies; Mexiletine; Dichlorphenamide; Muscle, Skeletal; Paralyses, Familial Periodic; Myotonic Disorders; Mutation
PubMed: 36512979
DOI: 10.1016/j.coph.2022.102329