-
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 -
Journal of Neurology Aug 2015Muscle cramps are sustained, painful contractions of muscle and are prevalent in patients with and without medical conditions. The objective of this review is to present... (Review)
Review
Muscle cramps are sustained, painful contractions of muscle and are prevalent in patients with and without medical conditions. The objective of this review is to present updates on the mechanism, investigation and treatment of neurogenic muscle cramps. PubMed and Embase databases were queried between January 1980 and July 2014 for English-language human studies. The American Academy of Neurology classification of studies (classes I-IV) was used to assess levels of evidence. Mechanical disruption, ephaptic transmission, disruption of sensory afferents and persistent inward currents have been implicated in the pathogenesis of neurogenic cramps. Investigations are directed toward identifying physiological triggers or medical conditions predisposing to cramps. Although cramps can be self-limiting, disabling or sustained muscle cramps should prompt investigation for underlying medical conditions. Lifestyle modifications, treatment of underlying conditions, stretching, B-complex vitamins, diltiezam, mexiletine, carbamazepine, tetrahydrocannabinoid, leveteracitam and quinine sulfate have shown evidence for treatment.
Topics: Humans; Muscle Cramp; Muscle, Skeletal
PubMed: 25673127
DOI: 10.1007/s00415-015-7659-x -
Pacing and Clinical Electrophysiology :... Nov 2023Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na currents in myocardial tissues that are... (Review)
Review
Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na currents in myocardial tissues that are dependent on the opening of Na channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.
Topics: Humans; Anti-Arrhythmia Agents; Mexiletine; Arrhythmias, Cardiac; Long QT Syndrome; Myocardium
PubMed: 37846818
DOI: 10.1111/pace.14846