Thromboelastographic assessment of the impact of mexiletine on coagulation abnormalities induced by air or normal saline intravenous injections in conscious rats.

BACKGROUND: Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic. METHODS: Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8). Blood samples were collected at baseline, one hour (h) and 24 h in all groups and analyzed by TEG to record the R, K, angle α and MA parameters. RESULTS: In Group 1, VAE decreased significantly R at 1 h (31%), K at 1 h (59%) and 24 h (34%); α increased significantly at 1 h (30%) and 24 h (22%). While R returned to baseline values within 24 h, K, MA and α did not. In group-2 (Mexiletine + VAE), K and R decreased at 1 h (48% and 29%, respectively) and at 24 h the changes were non-significant. Angle α increased at 1 h (28%) and remained increased for 24 h (25%). In group 3 (NS), only R was temporarily affected. MA increased significantly at 24 h only in the VAE alone group. CONCLUSION: As expected, VAE produced a consistent and significant hypercoagulable response diagnosed/confirmed by TEG. Mexiletine prevented the MA elevation seen with VAE and corrected R and K time at 24 h, whereas angle α remained unchanged. Mexiletine seemed to attenuate the hypercoagulability associated with VAE in this experiment. These results may have potential clinical applications and deserve further investigation.

Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.

BACKGROUND: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. METHODS: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose. RESULTS: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E(max) 13% and 20% respectively, P<0.01-0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7 ± 0.5 ms (quinidine, NS), +1.8 ± 0.8 ms (mexiletine, P<0.05) and +2.8 ± 0.8 ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR). CONCLUSION: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.

Design and assessment of a potent sodium channel blocking derivative of mexiletine for minimizing experimental neuropathic pain in several rat models.

Physical or chemical damage to peripheral nerves can result in neuropathic pain which is not easily alleviated by conventional analgesic drugs. Substantial evidence has demonstrated that voltage-gated Na+ channels in the membrane of damaged nerves play a key role in the establishment and maintenance of pathological neuronal excitability not only of these peripheral nerves but also in the second- and third-order neurons in the pain pathway to the cerebral cortex. Na+ channel blocking drugs have been used in treating neuropathic pain with limited success mainly because of a preponderance of side-effects. We have developed an analogue of mexiletine which is approximately 80 times more potent than mexiletine in competing with the radioligand, 3H-batrachotoxinin for binding to Na+ channels in rat brain membranes and also it is much more lipophilic than mexiletine which should enhance its uptake into the brain to block the increased expression of Na+ channels on second- and third-order neurons of the pain pathway. This analogue, HFI-1, has been tested in three different rat models of neuropathic pain (formalin paw model, ligated spinal nerve model and contusive spinal cord injury model) and found to be more effective in reducing pain behaviours than mexiletine.

Valoración electrofisiológica clínica de la mexiletina / Electrophysiological evaluation of mexiletine

Dieciseis pacientes con taquiarritmias sostenidas fueron sometidos a estudio electrofisiológico para valoración diagnóstica y prueba farmacológica aguda con mexiletina (3 mg/Kg). Fueron siete hombres (43%) y 9 mujeres (57%), con una edad promedio de 35 años. Las arritmias identificadas fueron: ocho pacientes con taquicardia ventricular (TV) y ocho mas con taquicardia supraventricular (TSV), debida a haz de Kent oculto izquierdo (50%), haz de Kent derecho (25%), haz de James funcional (12.5%) (en total, siete pacientes ó 43% del total con fascículos accesorios) y un paciente con reentrada nodal. Veinte minutos después de la administración intravenosa de la mexiletina, el ciclo sinusal se redujo el 12.7% (p < 0.05), y se observó un acortamiento del 6.1% del intervalo H-V (p < 0.05). Hubo una prolongación no significativa del tiempo de conducción nodal (A-H) del 2.3%. No se observó incremento significativo de los períodos refractarios tanto atriales como ventriculares. El período refractario retrógrado de los fascículos accesorios se acortó el 27% (p < 0.05), mientras que el anterógrado no se modificó. En los pacientes con TSV, fue posible la reinducción de la taquicardia en el 66% de ellos, con un incremento significativo del ciclo. Las ocho taquiarritmias ventriculares se observaron en siete pacientes: seis taquicardias ventriculares sostenidas (un paciente tuvo dos de ellas), y dos enfermos con extrasistolia ventricular. Tres de las taquicardias (37.5%) no fueron sostenidas posteriormente a la administración del antiarrítmico, además de tener una frecuencia menor. Dos taquicardias (en el mismo paciente) fueron reinducibles después de la administración de la mexiletina y una mas, la taquicardia degeneró rápidamente en fibrilación ventricular, por lo que fue chocada; posteriormente no se repitió