Mexiletine Research Articles

Acute Effects on Signal-Averaged Electrogram Parameters and Suppressing Premature Ventricular Contractions in Single or Combined Use of Class I Antiarrhythmic Drugs

Disopyramide (DP), mexiletine (MX), and flecainide (FL) are class I antiarrhythmic drugs. However, these drugs exert different effects on the electrocardiogram (ECG) based on their unique actions on cardiac myocytes. The electrocardiographic changes during combination therapy with these drugs are not well understood. The purpose of the present study was to evaluate acute morphologic changes in the ECG based on signal-averaged high resolution ECG (SAECG) after administration of the drugs in relation to their antiarrhythmic eficacy and safety. Twenty-one patients with frequent and stable premature ventricular contractions (PVC) were studied. Changes in the filtered QRS duration (f-QRS) and the root mean square voltage of the last 40 msec of the QRS complex (RMS40) were evaluated. Suppression of PVCs was achieved soon after intravenous administration of the drugs (63% for DP, 43% for MX, 86% for FL and 100% for DP+MX). Although DP and FL significantly prolonged f-QRS, MX had little effect on f-QRS. DP+MX also prolonged f-QRS, but the degree of prolongation was moderate. RMS40 was significantly decreased by DP and FL, but not by MX. DP+MX also decreased RMS40, but the decrease was less than for DP alone. Late potentials were observed after administration in 56% of patients with DP, 0% with MX, 67% with FL and 0% with DP+MX. No adverse events were reported during the study.In summary, the class I antiarrhythmic drugs exerted different acute effects on SAECG parameters. The combination of DP and MX increased the eficacy on suppressing PVC without excess additive changes on SAECG parameters. We conclude that combination therapy with DP and MX is eficacious and safe in patients with PVC and the analysis of SAECG during antiarrhythmic therapy is clinically important.

Acute Effects on Signal-Averaged Electrogram Parameters and Suppressing Premature Ventricular Contractions in Single or Combined Use of Class I Antiarrhythmic Drugs

Disopyramide (DP), mexiletine (MX), and flecainide (FL) are class I antiarrhythmic drugs. However, these drugs exert different effects on the electrocardiogram (ECG) based on their unique actions on cardiac myocytes. The electrocardiographic changes during combination therapy with these drugs are not well understood. The purpose of the present study was to evaluate acute morphologic changes in the ECG based on signal-averaged high resolution ECG (SAECG) after administration of the drugs in relation to their antiarrhythmic eficacy and safety. Twenty-one patients with frequent and stable premature ventricular contractions (PVC) were studied. Changes in the filtered QRS duration (f-QRS) and the root mean square voltage of the last 40 msec of the QRS complex (RMS40) were evaluated. Suppression of PVCs was achieved soon after intravenous administration of the drugs (63% for DP, 43% for MX, 86% for FL and 100% for DP+MX). Although DP and FL significantly prolonged f-QRS, MX had little effect on f-QRS. DP+MX also prolonged f-QRS, but the degree of prolongation was moderate. RMS40 was significantly decreased by DP and FL, but not by MX. DP+MX also decreased RMS40, but the decrease was less than for DP alone. Late potentials were observed after administration in 56% of patients with DP, 0% with MX, 67% with FL and 0% with DP+MX. No adverse events were reported during the study. In summary, the class I antiarrhythmic drugs exerted different acute effects on SAECG parameters. The combination of DP and MX increased the eficacy on suppressing PVC without excess additive changes on SAECG parameters. We conclude that combination therapy with DP and MX is eficacious and safe in patients with PVC and the analysis of SAECG during antiarrhythmic therapy is clinically important.

Drug-Induced Hypersensitivity Syndrome due to Mexiletine Associated with Human Herpes Virus 6 and Cytomegalovirus Reactivation

A 66-year-old man developed a fever of 38 degrees C and generalized pruritic rash about one month after mexiletine hydrochloride administration for ventricular tachycardia. The rash appeared as edematous erythema and papules with purpura on the lower extremities. Liver dysfunction, leukocytosis, and atypical lymphocytes were also present. Elevated antibody titer against human herpes virus 6 (HHV-6) was detected during the course of the disease (1:20 -> 1:640). The patient was diagnosed as having drug-induced hypersensitivity syndrome (DIHS) due to mexiletine. Discontinuation of the mexiletine administration and systemic corticosteroid treatment led to a temporary improvement, but tapering the corticosteroid dose twice led to recrudescence. Simultaneous with the recrudescence, elevated antibody titers against HHV-6 and cytomegalovirus were detected, as well as viral DNA in the blood, suggesting that these two viruses may have been involved in the recrudescence. The patient died of myocarditis, most likely related to cytomegalovirus. Our case indicates that, in addition to HHV-6, other herpes viruses such as cytomegalovirus can be reactivated in DIHS and may modify the clinical disease activity.

Acute Painful Neuropathy Restricted to the Abdomen following Rapid Glycaemic Control in Type 2 Diabetes

A 46-year-old Japanese man with type 2 diabetes mellitus, whose only diabetic complication was simple retinopathy, developed acute painful neuropathy. This presented as paresthesia and hyperesthesia restricted to the abdomen. The patient's haemoglobin A(1c) had dropped from 12% to 7.5% within 5 months, following a rapid improvement in glycaemic control. On investigation, there were no indications of disease in the intraabdominal area. Nerve conduction studies were consistent with mild sensorimotor peripheral and autonomic neuropathy. The patient required medication (mexiletine, sulpiride and imipramine hydrochloride) to control the pain. Four months after presentation, the symptoms showed a dramatic improvement and the treatment for pain relief was discontinued without any recurrence of paresthesia or hyperesthesia in the patient's abdomen. This was a very unusual case of diabetic post-treatment painful neuropathy in which the prominent features were severe pain, paresthesia and hyperesthesia restricted to the abdomen.

Retention Behavior of Anti-Arrhythmic Drugs on the Chromolith Performance RP 18 Column. Liquid Chromatographic Determination of Mexiletine Hydrochloride

The retention behavior in liquid chromatography of a series of anti-arrhythmic drugs is described. Chromatographic analysis was performed on a Chromolith Performance ODS column with acetonitrile–phosphate buffer mixtures as mobile phases. The effects of the proportion of organic solvent (from 20 to 90%), phosphate buffer pH (from 2.73 to 7.5), flow rate (from 1 to 6 mL min−1), and isocratic or gradient elution on the retention of the compounds was studied. Mexiletine hydrochloride was determined in the pure substance and in capsules by isocratic liquid chromatography with 20:80 (v/v) acetonitrile–0.007 M phosphate buffer, pH 3.0, as mobile phase at 2 mL min−1. Methanol was found to be a suitable solvent for extraction of the active substance from capsules. The calibration plot was linear (r=0.9999) in the concentration range 1.0 to 6.0 μg mL−1. The proposed method is selective, precise (RSD=0.37%), and accurate (recovery=100.08%).

Normal-phase TLC separation of some antiarrhythmics. Densitometric determination of mexiletine hydrochloride in capsules

A normal-phase (NP) TLC method has been established for separation of the five antiarrhythmics — disopyramide, flecainide, mexiletine, tocainide, and verapamil. The analysis was performed in horizontal chambers on aluminum oxide 60 F 254 and silica gel 60 F 254 TLC plates. The best mobile phases for separation of the compounds were tetrahydrofuran-hexane-25% ammonia, 5 + 4.8 + 0.2 ( v/v ), on the alumina plates and chloroform-tetrahydrofuran-ethanol-25% ammonia, 8.1 + 1.9 + 2 + 0.1 ( v/v ), on the silica plates. The substances were identified by use of different reagents and under UV irradiation at λ = 254 nm. Quantification of mexiletine hydrochloride in Mexicord capsules was performed densitometrically at λ = 210 nm. A good correlation coefficient ( r = 0.9974) was obtained for the calibration plot constructed in the concentration range 20–45 μg per band. The active substance was extracted from the formulation with methanol (recovery 97.01 ± 2.39%, mean ± SD ). The RSD expressing the precision of the pr...

A Modified Reverse‐Phase HPLC Method for the Analysis of Mexiletine Hydrochloride

Mexiletine hydrochloride is an orally active class I antiarrythmic agent. The purpose of this work is to develop a sensitive, selective, and stability indicating reverse phase HPLC assay for the quality control analysis and stability testing of mexiletine hydrochloride dosage forms. The method was developed to quantify the drug for various formulations. Analysis was carried out on a 4 mm × 150 mm C‐18 microsorb column, using a 50:50 methanol:0.053 M sodium acetate buffer. The pH of the mobile phase was adjusted to 4.8. The flow rate was set at 1 mL/min and the analysis was carried out at 254 nm. The internal standard used in the analysis was thiamine hydrochloride. The drug eluted at about 8 min, while the internal standard eluted at about 3 min. The stability of the assay was studied by subjecting the drug to extreme pH conditions. The limit of quantification (LOQ) and limit of detection (LOD) were found to be 0.06 µg and 0.02 µg, respectively. The reproducibility of the method was tested by carrying out multiple injections on the same day, as well as, on five consecutive days. The coefficient of variation for the intra‐day and inter‐day studies was found to be 0.81% and 1.47%, respectively.

Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.

Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.

Suppression by gabapentin of pain-related mechano-responses in mice given orthotopic tumor inoculation.

In this study, we examined whether several types of non-opioid agents would inhibit the pain-related responses of melanoma-bearing mice. Orthotopic inoculation with melanoma into the hind paw induced marked tactile allodynia and mechanical hyperalgesia. A peroral injection (p.o.) of gabapentin (100-300 mg/kg) inhibited the allodynia and hyperalgesia, without effects on gross behaviors. An intraperitoneal injection (i.p.) of ketamine hydrochloride (30 mg/kg) produced partial inhibition in allodynia and hyperalgesia and prostate posture at 15 min after injection. Diclofenac sodium (10 and 30 mg/kg, i.p), mexiletine hydrochloride (20 mg/kg, i.p.), clonidine hydrochloride (0.1 mg/kg, i.p.) and suramin (100 mg/kg, i.p.) were without effects on allodynia and hyperalgesia. Subcutaneous injections of baclofen (3 mg/kg) and N(G)-nitro-L-arginine methyl ester (100 mg/kg) were also without effects. Repeated administration of gabapentin (150 mg/kg, p.o.) produced constant inhibitions, suggesting no analgesic tolerance. Gabapentin may be useful for the management of cancer pain.

Moricizine, an Antiarrhythmic Agent, as a Potent Inhibitor of Hepatic Microsomal CYP1A

We examined the inhibitory effect of moricizine (MOR) on hepatic cytochrome P-450 (CYP) in mice. Spectrophotometric analysis revealed that MOR had a relatively high affinity for CYP molecules. MOR most potently inhibited the CYP1A1-dependent ethoxyresorufin O-deethylation and the CYP1A2-dependent methoxyresorufin O-demethylation, among the metabolic reactions mediated by CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A subfamilies expressed in untreated and CYP-inducer-treated hepatic microsomes. The inhibition constants (K_i) for ethoxyresorufin and methoxyresorufin O-dealkylations were 0.43 and 0.98 µmol/l, respectively. These K_i values were one to three orders of magnitude lower than those of cimetidine (CIM) and mexiletine (MEX) that have been accepted as the clinical inhibitors of CYP1A2 and were below the therapeutic serum concentration of MOR. Theophylline 3-demethylation and 8-hydroxylation in untreated hepatic microsomes, clinical probes for CYP1A2 activities, were subjected to marked and competitive inhibition by MOR with K_i values similar to that of methoxyresorufin O-demethylation, and the inhibitory potency of MOR was much higher than those of CIM and MEX. In addition, the zoxazolamine paralysis time, an in vivo measure of the hepatic CYP1A2 capacity, was markedly prolonged by pretreatment of mice with MOR rather than CIM and MEX, while the prolonging effect of MOR on the pentobarbital sleeping time, an indicator of the metabolic function of phenobarbital-inducible CYP species, was not so pronounced as compared with the zoxazolamine paralysis time. These results indicate that MOR acts as a potent and preferential inhibitor of hepatic CYP1A enzymes in vitro and in vivo.

A New Sensitive Fluorirnetric Method for the Determination of Heptaminol and Mexiletine in Pharmaceuticals

An accurate and very sensitive spectrofluorimetric method is proposed for the estimation of heptaminol (HP) and mexiletine (MX) in their pure forms and in pharlnaceutical formulations. The method is based on the reaction of these drugs with the strong fluorigenic reagent [9,1O-Dimethoxy-2-anthracenesulfonic acid sodium salt (DAS)] at pH (2.5). The formed complexes are extracted into chloroform and measured spectrofluori~netrically. The maximum wavelengths of excitation and emission spectra of heptaminol complex are 381 and 441 m, respectively. While those of mexiletine complex are 385 and 450 nrn, respectively. Heptaminol can be determined in the concentration range of 0.016-0.144 µg ml−1 and that of mexiletine in the range of 0.024-0.176 µg ml−1, when extracted from the solutions into chloroform. Different parameters affecting the reaction conditions were thoroughly studied. No interference was observed in the presence of common pharmaceutical excipients. The proposed method has been successfully applied to the analysis of commercial pharmaceutical fonnulations and the results have been statistically compared with those obtained by the reference methods.

Enantioselective analysis of N-hydroxymexiletine glucuronide in human plasma for pharmacokinetic studies.

Enzymatic hydrolysis with beta-glucuronidase/sulfatase was used for the enantioselective determination of N-hydroxymexiletine glucuronide in plasma for pharmacokinetic studies. N-Hydroxymexiletine glucuronide was determined as the quantity of mexiletine released by hydrolysis (difference between the enantiomeric concentrations of mexiletine obtained with and without hydrolysis). Plasma samples (100 microliters) were treated at pH 5.0 with 10 mg of the enzyme (Limpet Acetone Powder type I) for 16 hr at 37 degrees C and extracted at pH 10.4 with diisopropyl ether. Chiral mexiletine discrimination was obtained by reaction with o-phthalaldehyde/N-acetyl-L-cysteine, separation of the resulting diastereomers on a C-18 reversed-phase column with a mobile phase of methanol-0.05 N acetate buffer, pH 5.5 (6.5:3.5, v/v), and fluorescence detection (lambda ex 350 nm, lambda em 455 nm). The performance characteristics for the enantioselective analysis of mexiletine preceded by enzymatic hydrolysis were recovery approximately 90%, quantification limit 1 ng/ml, and linearity up to 1000 ng/ml plasma for both enantiomers. The coefficients of variation obtained in the study of intra- and inter-day precision were respectively 5% and 7% for both enantiomers. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with the arrhythmic form of chronic Chagas' heart disease treated with 200 mg t.i.d. of racemic mexiletine hydrochloride. The high sensitivity of the method allows analysis of only 100 microliters plasma.

Chiral separation of racemic mexiletine hydrochloride using cyclodextrins as chiral additive by capillary electrophoresis

Enantiomeric separation of racemic mexiletine hydrochloride was performed using cyclodextrins (CDs) including α-CD, β-CD, heptakis-2,6-di-O-methyl-β-CD (DM-β-CD), heptakis-2,3,6-tri-O-methyl-β-CD (TM-β-CD), 2-O-(2-hydroxypropyl)-β-CD and γ-CD as chiral selectors. However, the enantiomers can be chirally separated only by methyl-β-CDs. The enantiomers could be baseline separated when TM-β-CD was used, and were only partially separated by DM-β-CD and no chiral separation was obtained using β-CD; thus, it is believed that methoxy groups of methyl-β-CDs play a key role in the chiral recognition for racemic mexiletine. Effects of CD concentration, applied voltage and the organic additive on chiral separation were studied. Under the conditions of 40 mmol/l Tris–H 3PO 4 buffer at pH 2.5 containing 20 mmol/l TM-β-CD, baseline separation ( R s =2.3) of the enantiomers can be achieved.

Long QTc and Torsades de Pointes in Human Immunodeficiency Virus Disease

Three patients with human immunodeficiency virus (HIV) infection presented with QT, prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the etiology of the long QT syndrome in these patients without previously identified causes for QT, prolongation, and determine the prevalence among patients with HIV infection. The three index patients underwent: (1) left stellate ganglion block; (2) beta-blocker challenge; and (3) electrocardiographic stress testing. QTc interval was measured before and after intervention. We undertook a retrospective analysis of prevalence of QTC prolongation among all patients with computerized ECGs over a 6-month period at one institution and compared it to the prevalence in hospitalized patients with HIV disease. Thirty-four thousand one hundred eighty-one patients with computerized ECGs were screened for QTc prolongation. Forty-two hospitalized patients with HI disease had computerized ECG during the same 6-month period. In the three index patients, the QTc failed to shorten with left stellate ganglion blockade, beta-blocker challenge, or stress testing, suggesting an acquired form of the long QT syndrome in these patients with HIV disease. None had previously recognized acquired causes of QT, prolongation. Mexiletine hydrochloride was useful in preventing recurrences of torsades de pointes. We observed a 7.0% prevalence of QT, prolongation among all patients screened. Hospitalized patients with HIV disease (n = 42) during this same period, demonstrated an increased prevalence of QT, prolongation (28.6%, P = 0.002). Patients with HIV disease have a significantly higher prevalence of QTc prolongation than a general hospital-based population, may have an unrecognized acquired form of the long QT syndrome, and are at risk for torsades de pointes.

High Performance Liquid Chromatographic Analysis of Some Antiarrhythmic Drugs in Human Serum Using Cyanopropyl Derivatized Silica Phase

Abstract A high performance liquid chromatographic determination of antiarrhythmic agents: propafenone (PPF) with its principal active metabolite 5-hydroxypropafenone (5-OHPPF), amiodarone (AD) with an active metabolite desethylamiodarone (DEAD), mexiletine (MEX) and diltiazem (DILT) in human serum is presented. The compounds are separated on Supelcosil LC-CN column at ambient temperature under isocratic conditions. For PPF, 5-OHPPF, MEX and DILT analysis the mobile phase: CH3CN: H2O: 0.5 M KH2PO4 (360:620:20 v/v) is pumped at a flow rate of 1.8 mL/min and the ultraviolet detection is performed at 210 nm. AD and DEAD are eluted with stronger mobile phase: CH3OH: CH3CN: H2O: 0.5 M KH2PO4 (480:136:360:24 v/v) at a flow rate of 1.5 mL/min and detected at 240 nm. Sample preparation is based on simple liquid-liquid extraction from acidified serum for AD and DEAD and on liquid-liquid extraction from alkalized serum followed by back extraction for PPF, 5-OHPPF, MEX and DILT analysis. Sensitivity of the assay was...

Antiarrhythmic Drug Prescription in Patients After Myocardial Infarction in the Last Decade

Recent clinical trials have shown increased, rather than decreased, mortality in patients treated with antiarrhythmic drugs after acute myocardial infarction. To determine whether these findings had an impact on prescription of antiarrhythmic drugs after acute myocardial infarction. We retrospectively analyzed the class I and III antiarrhythmic prescription data of 38,072 patients with acute myocardial infarction enrolled in three large randomized clinical trials endorsed by a highly representative sample (about 75%) of Italian coronary care units during the last 10 years. The first study was conducted in 1984 to 1985; the second, in 1988 to 1989; the pilot for the third, in 1991; and the third, in 1991 to 1994. Total class I and III antiarrhythmic prescriptions after acute myocardial infarction was halved during the last decade, from 11.9% at discharge and 14.4% at follow-up in 1984 to 1985 to 5.8% and 5.8%, respectively, in 1991 to 1994. The trend was independent of the different distributions in the three studies of the patients' characteristics associated with antiarrhythmic use (ie, age > or = 70 years, anterior acute myocardial infarction, ventricular fibrillation during hospitalization, and Killip class > or = 2 at randomization). The same decreasing trend was observed for each antiarrhythmic drug. The drug most widely used was amiodarone, accounting for about half of the antiarrhythmic prescriptions, followed by mexiletine hydrochloride and propafenone hydrochloride; flecainide acetate was dropped from the prescription list after the publication of the Cardiac Arrhythmia Suppression Trial results. The negative results of the recent clinical trials on class I antiarrhythmic drug use after acute myocardial infarction have been rapidly transferred into routine clinical practice in Italy, since the proportion of patients who received class I and III antiarrhythmic drugs after acute myocardial infarction was halved from the early 1980s to the early 1990s.

Prevention of bronchoconstriction by an orally active local anesthetic.

Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.

Inhibition Kinetics of Theophylline Metabolism by Mexiletine and Its Metabolites.

To further characterize the mode of drug interaction between theophylline (TP) and mexiletine (ME), in vitro kinetic studies were carried out using rat liver microsomes and 9000 x g supernatant. The kinetic study revealed that the Km value and Vmax/Km ratio for the metabolic conversion of TP to 1,3-dimethyluric acid (1,3-DMU) were the second lowest and the highest, respectively, of four metabolic pathways. Thus, the rank of efficiency of the oxidative metabolism by microsomal cytochrome P-450 (P-450) isozymes was TP to 1,3-DMU > TP to 1-methylxanthine (1-MX) > TP to 3-MX > 1,3-DMU to 1-methyluric acid, suggesting that the isozyme metabolizing TP would have a higher affinity for the oxidation at the 8-position in TP molecules than at the 1- and 3-positions. Lineweaver-Burk plots showed that the conversion of TP to 3-MX and to 1,3-DMU was inhibited competitively by ME and its metabolites, and that the pathway of TP to 1-MX was inhibited noncompetitively. In consideration of the Ki values calculated, it seems probable that deamino-p-hydroxy ME (DApHME) might be the most potent inhibitor of the metabolic pathways of TP, and that the rank order of inhibition is approximately DApHME > p-hydroxy ME > deamino-hydroxymethyl ME > ME > hydroxymethyl ME, with some exceptions. The mechanism of the interaction between TP and ME is probably due to the metabolic antagonism in the liver, and TP, ME and their metabolites share some of the same metabolic pathways, mediated by P-450 isozymes.

High-performance liquid chromatographic analysis using a highly sensitive fluorogenic reagent, 2-anthroyl chloride, and stereoselective determination of the enantiomers of mexiletine in human serum

A stereoselective and highly sensitive HPLC assay was developed for mexiletine enantiomers using a new fluorogenic derivatization reagent, 2-anthroyl chloride. The reagent was synthesized and utilized for the fluorescent detection (excitation at 270 nm, emission at 400 nm) of mexiletine enantiomers as their N-anthroyl derivatives on a Pirkle phenylglycine ionic HPLC column. The assay had a lower limit of quantitation at 2.5 ng/ml with a limit of detection measured at 0.5 ng/ml for each enantiomer in serum with a signal-to-noise ratio of 5:1. In a preliminary pharmacokinetic study, 200 mg of racemic mexiletine hydrochloride were administered orally to two healthy volunteers. Serum samples were collected at timed intervals over 48 h. The terminal elimination half-lives determined for total R(−)- and S(+)-mexiletine were 10.9 and 11.5 h, respectively. The serum free fractions for R(−)- and S(+)-mexiletine were found to be 0.56 and 0.53, respectively.

Contact urticaria induced by mexiletine hydrochloride in a patient receiving iontophoresis

Contact urticaria induced by mexiletine hydrochloride in a patient receiving iontophoresis