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 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of studies of mexiletine, a class I antiarrhythmic drug, supports its use in patients with ventricular arrhythmias or in sinus rhythm. Studies include patients likely to receive the drug in clinical use--patients with and without coronary disease and patients who have suffered acute myocardial infarction. Some studies are open and others are controlled to compare mexiletine to placebo or to lidocaine. Mexiletine in therapeutic ranges was shown not to affect arterial pressure; to prolong aortic ball travel time, indicating depression of myocardial contractility; and not to adversely affect cardiac function. Adverse effects occurred as often in patients taking placebo as in mexiletine-treated patients, even in those with impaired cardiac function. Studies bear out early reports of mexiletine as an effective antiarrhythmic drug nearly devoid of adverse hemodynamic effects when administered intravenously or orally in a dosage to maintain a therapeutic plasma concentration.
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PMID:Hemodynamic effects of mexiletine. 637 22

Lidocaine, Mexiletine, Procainamide, and Phenytoin were administered intravenously to anaesthesized rabbits. BERA alterations showed two different patterns. If the intoxication dose was exceeded, amplitude depression, threshold elevation, desynchronization, and severe cumulative prolongation of all latencies and interpeak latencies appeared. Below this dose Lidocaine and Mexiletine induced a single, reversible, dose related, cumulative prolongation of all latencies and interpeak latencies. Procainamide induced counterrelated shiftings of interpeak latencies I-III and III-V, whereas Phenytoin showed no influence. One should, therefore, take into account these effects when BERA is used clinically, since otherwise serious errors can occur. On the other hand, there are diagnostic and therapeutic aspects for the tinnitus patient.
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PMID:[Effect of membrane-effective drugs (anti-arrhythmia agents) on acoustically evoked brain-stem potentials]. 670 Mar 43

1 The antidysrhythmic and haemodynamic effects of the aminosteroid, Org 6001, were studied in the rat anaesthetized with pentobarbitone. Mexiletine was used for comparison. 2 Both Org 6001 (2--10 mg/kg) and mexiletine (1 mg/kg) given intravenously antagonized the development of dysrhythmias evoked by acute coronary artery ligation in rats. 3 In antidysrhythmic doses, Org 6001 and mexiletine exerted only moderate and transient hypotension and depression of cardiac contractility (assessed from LV dP/dtmax). Org 6001 did, however, induce a more sustained bradycardia. 4 Effective oral doses of Org 6001 (20--100 mg/kg) were similar to those of mexiletine, disopyramide and propafenone. 5 Oral Org 6001 (100 mg/kg) was effective for 18 h whereas mexiletine (100 mg/kg) failed to protect against evoked dysrhythmias 3 h after dosing. 6 Org 6001 and mexiletine differed in their actions on ventricular fibrillation threshold (VFT). Org 6001 (100 mg/kg orally 12 h before ligation) prevented the decrease in VFT produced by coronary ligation whereas mexiletine (100 mg/kg orally) had no effect. When administered intravenously, mexiletine (but not ORg 6001) increased VFT in normal ventricular muscle.
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PMID:Comparative antidysrhythmic and haemodynamic effects of orally or intravenously administered mexiletine and ORG 6001 in the anaesthetized rat. 731 87

A case is presented of a 26-year-old white male with a history of depression and previous suicide attempts. No anatomic cause of death was determined at the autopsy. Comprehensive toxicological analysis of the blood and urine specimens identified mexiletine, a class 1B antiarrhythmic drug. Mexiletine was detected by gas chromatography and confirmed by gas chromatography-mass spectrometry. Quantitations were as follows: heart blood, 38 mg/L; subclavian blood, 14 mg/L; urine, 370 mg/L; liver, 190 mg/kg; kidney, 170 mg/kg; vitreous humor, 17 mg/L; and bile, 440 mg/L. The medical examiner ruled that the cause of death was mexiletine intoxication and the manner of death was suicide.
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PMID:A mexiletine intoxication. 782 42

1 Standard microelectrode methods were used to record intracellular action potentials from strips of guinea-pig right ventricular myocardium superfused with either standard physiological saline ([K+] = 5.6 mM) or the same solution modified to contain [K+] = 11.2 mM. 2 The effects on action potential parameters of three therapeutic concentrations of mexiletine, quinidine and disopyramide were studied under both conditions at four different drive rates (interstimulus intervals = 2400, 1200, 600 and 300 ms). 3 Hyperkalaemia in the absence of drugs produced reductions in resting potential (-86.7 +/- 2.5 mV to -71.8 +/- 3.7 mV; n = 30; P < 0.001), maximum rate of depolarization (300 +/- 46.5 V s-1 to 205.6 +/- 37.6 V s-1; P < 0.0001), and action potential duration (205 +/- 26 ms to 188 +/- 32 ms; P < 0.05). 4 All three drugs produced increased depression of maximum rate of depolarization in hyperkalaemia compared to control conditions, but at all three concentrations this enhancement of effect was greater for mexiletine than for quinidine, with disopyramide exhibiting intermediate behaviour. 5 Mexiletine behaved very similarly to therapeutic concentrations of lignocaine as described in previous reports from this laboratory. 6 Quinidine behaved very similarly to Class Ic agents. 7 It is concluded that mexiletine demonstrated significantly greater selectivity for depolarized myocardium than quinidine and that this may have implications in terms of proarrhythmic potential. 8 Disopyramide exhibited intermediate selectivity for depolarized myocardium between mexiletine and quinidine.
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PMID:Effects of hyperkalaemia on the depression of maximum rate of depolarization by class I antiarrhythmic agents in guinea-pig myocardium. 842 9

Neuropathic orofacial pain can be difficult to diagnose because of the lack of clinical and radiographic abnormalities. Further difficulties arise if the patient exhibits significant distress and is a poor historian regarding previous diagnostic tests and treatments, such as somatosensory local anaesthetic blockade. Valuable information can be obtained by utilising the McGill Pain Questionnaire that allows the patient to choose words that describe the qualities of his/her pain in a number of important dimensions (sensory and effective). Basal pain intensity should be measured with the visual analogue scale, a simple instrument that can evaluate the efficacy of subsequent treatments. The dentist or endodontist can employ sequential analgesic blockade with topical anaesthetics and perineural administration of plain local anaesthetic to ascertain sites of neuropathology in the PNS. These can be performed in the dental chair and in a patient blinded manner. Other, more specific, tests necessitate referral to a specialist anaesthetist at a multidisciplinary pain clinic. These tests include placebo controlled lignocaine infusions for assessing neuropathic pain, and placebo controlled phentolamine infusions for sympathetically maintained pain. The treatment/management of neuropathic pain is multidisciplinary. Medication rationalisation utilises first-line antineuropathic drugs including tricyclic antidepressants such as amitriptyline and nortriptyline, and possibly an anticonvulsant such as carbamazepine, sodium valproate, or gabapentin if there are sharp, shooting qualities to the pain. Mexiletine, an antiarrhythmic agent and lignocaine analogue, may be considered following a positive patient response to a lignocaine infusion. All drugs need to be titrated to achieve maximum therapeutic effect and minimum side effects. Topical applications of capsaicin to the gingivae and oral mucosa are a simple and effective treatment in two out of three patients suffering from neuropathic orofacial pain. Temporomandibular disorder is present in two thirds of patients and should be assessed and treated with physiotherapy and where appropriate, occlusal splint therapy. Attention to the patient's psychological status is crucial and requires the skill of a clinical psychologist and/or psychiatrist with pain clinic experience. Psychological variables include distress, depression, expectations of treatment, motivation to improve, and background environmental factors. Unnecessary dental treatment to "remove the pain" with dental extractions is contraindicated and aggravates neuropathic orofacial pain.
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PMID:Neuropathic orofacial pain. Part 2-Diagnostic procedures, treatment guidelines and case reports. 1135 83

Mexiletine, an anti-arrhythmic agent, is used for the control of ventricular arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is sometimes used together with psychotropic drugs in patients with depression, schizophrenia or sleep disorder. It is metabolized mainly by cytochrome P450 (CYP) 2 D 6 and, to a minor extent, by CYP1A2. To predict possible drug interactions between mexiletine and psychotropic drugs, the inhibitory effects of 14 psychotropic drugs (phenytoin, carbamazepine, fluvoxamine, paroxetine, fluoxetine, citalopram, sertraline, imipramine, desipramine, haloperidol, thioridazine, olanzapine, etizolam, and quazepam) on mexiletine metabolism in human liver microsomes were determined. Fluoxetine (Ki=0.6+/- 0.1 microM), sertraline (Ki=7.6+/- 0.8 microM) and desipramine (Ki=3.2+/- 0.5 microM) competitively inhibited the mexiletine p-hydroxylation in human liver microsomes. Thioridazine (Kis=0.5+/- 0.2 microM; Kii =3.6+/-1.6 microM) and paroxetine (Kis=1.7+/- 0.7 microM; Kii=3.6+/- 0.9 microM) exhibited a mixed-type inhibition (competitive and non-competitive) toward mexiletine p-hydroxylation in human liver microsomes. The changes of the in vivo clearance of mexiletine by the psychotropic drugs were predicted by 1+(I/Ki) using the in vitro Ki and unbound inhibitor concentrations in liver. The values were calculated as 2.4 for paroxetine, 5.5 for fluoxetine, 1.1 for sertraline, 2.8 for desipramine and 2.2 for thioridazine. In addition, paroxetine exhibited a mechanism-based inactivation with Ki=0.7 microM and Kinact=0.15 min(-1). The present study predicted the possibility of drug interactions between mexiletine and paroxetine, fluoxetine, desipramine, and thioridazine in clinical use.
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PMID:Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions. 1619 7

Chronic pain, whether arising from viscera, bone, or any other tissue or structure, is, more often than commonly thought, the result of a mixture of pain mechanisms, and therefore there is no simple formula available to manage chronic complex pain states. Box 1 summarizes a pharmacological algorithm for difficult-to-treat chronic pain, which merely introduces the medication aspect of the treatment. In effect, any comprehensive algorithm should call for an interdisciplinary approach that would include rehabilitation, as well as psychosocial, and when indicated, interventional techniques. Box 1 Analgesic algorithm for difficult-to-treat pain syndromes. Pharmacological Interventions. Moderate to severe pain/functional impairment; pain with a score of >4 on the brief pain inventory. 1. Gabapentinoid (gabapentin, pregabalin)+/-Opioid/opioid rotation or 2. Antidepressant (TCA, duloxetine, venlafaxine)+/-Opioid/opioid rotation or 3. Gabapentinoid+antidepressant+Opioid/opioid rotation; in addition, may consider trials of one or more of the following adjuvants when clinically appropriate: Topical therapies for cutaneous allodynia/hyperalgesia. Anti-inflammatory drugs (corticosteroids for acute inflammatory neuropathic pain)IV bisphosphonates for cancer bone pain or CRPS/RSDNon-gabapentinoid AEDs such as carbamazepine or oxcarbazepine or lamotrigine+/-baclofen for intermittent lancinating pain due to cranial neuralgiasNMDA antagonists Mexiletine On a compassionate basis, according to the patient's clinical condition and pain mechanism, the physician may want to consider an empirical trial of one or more of the emergent topical, oral or parenteral/intrathecal therapies as discussed in the text. If SMP, consider topical clonidine and sympatholytic interventions; if clinically feasible, trials of topical therapies, eg, lidocaine 5% patch, may be considered for a variety of pain states and features.The major rationale for introducing adjuvants is to better balance efficacy and adverse effects. The following scenarios should prompt the use of adjuvants in clinical practice: The toxic limit of a primary analgesic has been reached. The therapeutic benefit of a primary analgesic has plateaued, eg, treatment has reached its true efficacy limit or pharmachodynamic tolerance has developed. The primary analgesic is contraindicated, eg, substance abuse, aberrant behavior, organ failure, allergy, and so forth. Subjective and qualitative symptoms demand broader coverage. Patients often convey that different medications will impart distinct analgesic benefits. Presence of disabling nonpainful complaints and need to manage symptoms such as insomnia, depression, anxiety, and fatigue that all cause worsening of the patient's quality of life and function. Physicians have also been drawn to the adjuvants secondary to new realities of clinical practice. Moreover, aversion to addiction and diversion remains a potent force that shapes prescribing profiles.
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PMID:Adjuvant analgesics. 1716 7

Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100-150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10-15 mg/d, increasing to 30-90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60-120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.
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PMID:[Pharmacotherapy of cancer pain. 3. Adjuvant drugs.]. 1841 35


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