Mequitazine (LM-209)

[Pharmacological study of Mequitazine (LM-209). (V). Pharmacological actions of a main metabolite of LM-209, mequitazine sulfoxide (LM-209 SO) (author's transl)]

The pharmacological action of a main metabolite of Mequitazine (LM-209), Mequitazine sulfoxide (LM-209 SO), was compared with data on LM-209 to investigate whether LM-209 is metabolized in vivo to the active form and if it has pharmacological actions. In the excised ileum of guinea-pigs, the anti-histaminic and anti-cholinergic activities of LM-209 SO were about 1/8 and 1/20, respectively, of LM-209. The protective activity of LM-209 SO on sudden death induced by histamine in mice was about 1/2.5 of LM-209. Acute toxicity of LM-209 SO given orally to mice was 1/3 of LM-209. In the EEG of rabbits, LM-209 SO did not affect the spontaneous pattern or the arousal and recruiting responses. The mydriatic and local anesthetic activities of LM-209 SO were significantly less than those of LM-209. Thus, the pharmacological activities and toxicity of LM-209 SO were significantly less potent than those of LM-209.

[Pharmacological study of mequitazine (LM-209) (II). Anti-allergic action (author's transl)]

The anti-allergic effect of Mequitazine (LM-209) which was found to have an anti-histaminic activity was investigated in guinea-pigs. The inhibitory activities of LM-209 on the Schultz-Dale reaction and ileum contraction by some mediators released from the sensitized guinea-pig lung were the same as those of clemastine fumarate (CL) but with 5 times the potency. LM-209 and CL, but these activities were less potent than in the case of disodium cromoglycate. The various anaphylactic reactions mediated by IgG in guinea-pigs were inhibited by LM-209, CL and chlorpheniramine maleate (CPM). The homologous PCA mediated IgE in rats was also inhibited by LM-209, CL and CPM, but the duration of the action with LM-209 was markedly longer. In experimentally-induced asthma, the decrease of respiratory rate and volume was significantly inhibited by LM-209, but was not affected by CL. Thus, LM-209 seems to inhibit the allergic reaction mainly by an antagonistic action on allergic mediators.

[Pharmacological study of mequitazine (LM-209) (III). Action on the central nervous system (author's transl)]

The action of an anti-histaminic agent, Mequitazine (LM-209) on the central nervous system was investigated. We found that LM-209 did not affect the spontaneous and co-operative movement in mice, did not induce muscle relaxation, analgesic effects or anti-convulsant effect in micr or hypothermic effects in rats. The anti-oxotremorine effect of LM-209 in mice was about 10 times more potent than clemastine fumarate (CL) and the same as promethazine. The activity and duration of the action were also superior to diethazine and orphenadrine used as an anti-Parkinson drug. LM-209 prolonged by 50% the hypnotic time induced by hexobarbital at 50 mg/kg (p.o.) in mice, while CL prolonged 50 and 100% it at 25 and 50 mg/kg (p.o.) respectively. In the EEG of rabbits, LM-209 produced a resting pattern, inhibited the arousal responses and recruiting responses and the effect was the same as CL and less potent than promethazine. From these results, the activity of LM-209 on the central nervous system (except for the anti-oxotremorine effect) seems to be the same as or somewhat less potent than CL. Therefore LM-209 should be an effective and anti-histaminic agent for clinical application.

[Pharmacological study of mequitazine (LM-209) (I). Antagonistic actions of chemical mediators (author's transl)]

Antagonistic activities of Mequitazine (LM-209) on chemical mediators and in particular histamine were investigated in guinea-pigs, mice and rats. The antagonistic activity of LM-209 for histamine in the isolated ileum and trachea of guinea-pigs was less potent than that for clemastine fumarate (CL) and chlorpheniramine maleate (CPM) while that for acetylcholine was more potent than CL and CPM. Moreover, the antagonistic activities of these three compounds on serotonin and bradykinin were almost equipotent in the excised ileum. Using a modified Konzett-R?ssler method, the bronchodilating effect of LM-209 (p.o.) for histamine was same as CL, but that for acetylcholine was more potent than CL and CPM. The protective activity of LM-209 (p.o.) on acute death induced by histamine and metacholine in mice was the same as CL, but the duration of the anti-histaminic action was markedly longer than CL. LM-209 given orally inhibited markedly the increased vascular permeability by histamine in rats and the diarrhea by 5-HTP in mice, but did not affect on the histamine-induced ulcer in guinea-pigs. From these results, LM-209 appears to have potent and long acting antagonistic activity on various chemical mediators.

On-the-road driving performance after use of the antihistamines mequitazine and l-mequitazine, alone and with alcohol

Objective: Previous studies demonstrated that mequitazine produces mild sedation after single doses. Its enantiomer, l-mequitazine, has a stronger potency for the H1 receptor. The aim of the current study was to assess the effects of l-mequitazine and mequitazine, alone and with alcohol, on driving.
Methods: Twenty-five healthy volunteers were treated with l-mequitazine 2.5, 5.0 and 10 mg, mequitazine 10 mg and placebo, alone and in combination with alcohol in a double-blind crossover design. Driving performance was assessed using the standardized highway driving test in normal traffic. Its primary measure is the Standard Deviation of the Lateral Position (SDLP). Secondary measures consisted of an auditory word learning test during driving, and subjective measures of driving performance.
Results: L-mequitazine 2.5 and 5.0 mg showed no effect on SDLP in the highway driving test, while SDLP significantly increased after l-mequitazine 10 mg (alone +1.59 cm; with alcohol +1.41 cm) and mequitazine 10 mg (with alcohol +1.17 cm). Alcohol significantly impaired all performance measures (SDLP +2.63 cm) but did not interact with the effects of treatment. Subjective measures indicated that participants were aware of the impairing effects of alcohol, but not of l-mequitazine and mequitazine.
Conclusion: L-mequitazine can be considered safe to drive in dosages of 2.5 and 5.0 mg. L-mequitazine 10 mg led to mild driving impairment. Alcohol impaired all performance measures and added to the effects of l-mequitazine and mequitazine.