Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to ...relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m‐hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time‐ and voltage‐dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m‐hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta‐position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds.
Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the ...2,2,5,5‐tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual‐acting drugs potentially useful in the protection of the heart against post‐ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert‐butyl‐substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.
Compounds with heart: Investigations into the antiarrhythmic and antioxidant potential of a series of pyrroline derivatives identified a potent antiarrhythmic agent (2 b), more active than the parent compound mexiletine. Because it also displays antioxidant activity, it is a good candidate for the development of dual‐acting drugs potentially useful in protecting the heart against post‐ischemic reperfusion injury.
Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison ...with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.
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•Search for new antiarrhythmic agents.•Antiarrhythmic effects evaluation of mexiletine analogues.•Identification of potent and selective antiarrhythmic agents.
Guided biopsy of hepatocellular carcinoma has been recently discussed again due to the progress of imaging techniques and the risk of malignant seeding after the procedure. Ultrasound is probably ...still the most accurate imaging modality for early detection of nodules arising on cirrhosis, even when compared with more advanced imaging techniques. It can be easily employed in the surveillance of high‐risk cirrhotic patients. Ultrasound‐guided biopsy has very high sensitivity and almost absolute specificity, which allows the appropriate treatment to start after a positive diagnosis. It also allows correct diagnosis of lymphomatous nodules, the incidence of which is increased in hepatitis C virus‐related cirrhosis. The risk of seeding appears limited according to the currently available epidemiological data; this should be considered against the risk of false‐positive diagnosis of malignancy based on imaging studies alone. Ultrasound‐guided biopsy is a valuable tool also for the diagnosis of small nodules (less than 10 mm in diameter). The best accuracy in the sampling of hepatocellular carcinoma nodules is obtained by combining smear cytology and microhistology. This can be achieved by a single biopsy with a fine cutting needle that furnishes pathologic material suitable for both examinations, reducing risks and costs. (Liver Transpl 2004;10:S26–S29.)
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