Comparison of Adrenaline and Dexmedetomidine in Improving the Cutaneous Analgesia of Mexiletine in Response to Skin Pinpricks in Rats.

BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 µmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 µmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 µmol), adding Dex or Adr to Mex (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 µmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 µmol) alone. A high dose of Adr is more effective with Mex 1.8 µmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 µmol combined with any dose of Adr is superior to that of Dex. CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

Effects of mexiletine, ginkgo biloba extract (EGb 761), and their combination on experimental head injury.

Lipid peroxidation (LP) and brain edema are important factors that produce tissue damage in head injury. The purpose of this study was to investigate the effect of mexiletine, gingko biloba extract (EGb 761), and their combination on LP and edema after moderate head trauma. Forty rats were randomly and blindly divided into four groups of ten animals each: control group (bolus injection of physiological saline), mexiletine group (50 mg/kg per injection), EGb 761 group (30 mg/kg per injection), and mexiletine plus EGb 761 group (50 mg/kg and 30 mg/kg per injection, respectively). The injections were given intraperitoneally at 1 h, 9 h, and 17 h after trauma. Twenty-four hours after injury, the rats were killed, and malondialdehyde (MDA) levels and brain water content were determined. Rats treated with mexiletine, EGb 761, and mexiletine plus EGb 761 had significantly lower MDA levels than the control group (P<0.01). The lowest MDA levels were measured in the mexiletine plus EGb 761 group. However, there was no significant difference in brain water content between treated groups and the control group (P>0.05). These findings show the usefulness of mexiletine and its combination with EGb 761 as a cerebroprotective agent in this model of experimental head injury.

Lack of stereoselectivity for the antiallodynic effect of mexiletine in spinally injured rats.

Systemically administered mexiletine, an antiarrhythmic, has been shown to also possess analgesic properties in some conditions of neuropathic pain. It has been suggested that the analgesic effect of mexiletine may be derived from the action of one of its optical isomers, (+)(S)-mexiletine. In the present study, we have compared the effects of systemic (-)-(R)- and (+)-(S)-mexiletine, on chronic mechanical allodynia-like behaviour in spinally injured rats, a model of central neuropathic pain in which racemic mexiletine has been shown to be active. I.p. racemic mexiletine as well as (-)-(R)- and (+)(S)-mexiletine at 25 mg/kg all produced significant, but brief, alleviation of mechanical allodynia in a similar fashion as assessed with von-Frey hair elicited vocalization in the spinally injured rats. A slight increase in motor impairment was observed in all three groups which reached statistical significance for the racemic mexiletine and (+)-(S)-mexiletine. Our results suggest that both isomers of mexiletine contribute to the antiallodynic effect in this model of central pain.

Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy.

This article reviews the data which support the use of selected drug combinations to enhance anti-arrhythmic activity. Specifically, we have focused on the mexiletine-quinidine interaction and the relation between anti-arrhythmic efficacy and electrophysiologic effects. In an initial clinical study, we found that combination therapy with mexiletine-quinidine produced enhanced efficacy in suppressing spontaneous ventricular tachycardia with fewer side-effects than high dose monotherapy. This enhanced efficacy has been confirmed in other laboratories. Combination therapy also enhanced suppression of inducible ventricular tachycardia in patients and in animal models. Animal models were used to assess the relation between electrophysiologic effects and anti-arrhythmic efficacy. In the animal studies, combination therapy produced selective prolongation of refractoriness and conduction in the infarct and peri-infarct zones without significant changes in the normal zone. Subsequent studies focused on the relative contribution of sodium channel and potassium channel blocking properties of these drugs to the enhanced activity seen with the combination. Studies using the selective sodium channel blocker tetrodotoxin confirmed that sodium channel blockade was necessary for this interaction. To assess the contribution of prolongation of action potential duration by quinidine to the combined effect we compared the anti-arrhythmic and electrophysiologic effects of the stereoisomers quinidine and quinine given alone and in combination with mexiletine. These experimental data confirm that the property of prolongation of action potential duration by quinidine is essential to the interaction. When comparing quinidine and quinine it is apparent that prolongation of refractoriness in the peri-infarct zone is essential for anti-arrhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antiarrhythmic effect and influence on myocardial contractile function of the preparation, mexitil]. / Antiarritmicheskii éffekt i vliianie na sokratitel'nuiu funktsiiu miokarda preparata meksitila.

Complex clinical instrumental examination of 30 patients with disorders of cardiac rhythm and experimental study on 49 albino rats with induced transitory coronary insufficiency of various duration which were then subjected to reperfusion showed that Mexitil is an effective anti-arrhythmic agent in the treatment of ventricular disorders of rhythm and that during long-term treatment wih it inotropic myocardial function diminishes insignificantly; treatment produced positive results in 73% of patients.

[Mexiletine, a drug with anti-arrhythmic action. Experimental research on the cardiovascular system]. / Il mexilitene, farmaco ad attività antiaritmica. Ricerche sperimentali sull'apparato cardiovascolare.

It was shown experimentally that mexilithene possesses anti-arrhythmic activity with slight depression of sino-carotid baroreceptorial and glomo-carotid and gangliar chemoreceptorial activity and catecholamine uptake. Hypotensive and bradycardizing effects were only noted when high per kg doses were used. The drug did not display vascular alpha- and beta-adrenolytic, anti-muscarinic and anti-histaminic activity.