Mizolastine, a Novel Selective Histamine H₁ Receptor Antagonist: Lack of Sedative Potential on the EEG in the Rodent

Abstract

The sedative potential of mizolastine, a new, potent and selective antagonist of histamine H₁-receptors, has been evaluated in the rodent with EEG techniques. In chronically implanted rabbits, sedation was observed in ECoG recordings after intravenous injection of terfenadine (1–10 mg/kg) and loratadine (0.3–3 mg/kg) but not after intravenous injection of astemizole or mizolastine (1–10 mg/kg). In freely moving implanted rats, mizolastine and cetirizine (10 mg/kg i.p.) did not modify the sleep-wakefulness pattern recorded during the dark period nor did mizolastine alter the sleep architecture recorded in rats during the light period. In contrast, during the dark-period recording, astemizole, loratadine and terfenadine (10 mg/kg i.p.) increased the total duration of slow-wave sleep; this sleep-facilitating effect had a late onset of action, beginning 3 h after drug injection. In conclusion, the results obtained with astemizole, cetirizine, loratadine and terfenadine demonstrate their low sedative potential in the rat, and suggest that the absence or low incidence of sedation seen in humans with these drugs may be due to their limited ability to cross the blood brain-barrier, especially at recommended therapeutic doses. Mizolastine appears to be devoid of sedative effects in our experimental models irrespective of the route of administration used. These results predict a lack of sedative action in humans with mizolastine at therapeutic doses.

Effects of second‐generation histamine H1 receptor antagonists on the active avoidance response in rats

“…also showed no significant effects on spontaneous EEG activity in rats 14 or cats, 2 respectively. In contrast with the above findings, when both loratadine (10 mg/kg) and terfenadine (10 mg/kg) were administered intravenously, they increased the total duration of slow‐wave sleep in rats 7 . In addition, in humans, not only drowsiness, but also behavioural changes (sedation, attention, memory and recognition) are produced by second‐generation histamine H 1 receptor antagonists 5,6 .…”

“…showed no remarkable effect on EEG activity in rats 14 or on sleep–wakefulness pattern in cats 15 . Depoortere et al 7 . reported that cetirizine showed no sleep facilitation effects at a dose of 10 mg/kg, i.p., in rats.…”

“…Recently, there have been reports that second‐generation histamine H 1 receptor antagonists also show side‐effects in the CNS similar to classical histamine H 1 receptor antagonists in humans 5,6 . However, in animal studies, there have been only a few reports that second‐generation histamine H 1 receptor antagonists cause side‐effects in the CNS 7,8 . Little is known about the effects of second‐generation histamine H 1 receptor antagonists on learning behaviour in rats.…”

The Prevalence, Morbidities, and Treatments of Insomnia

“…In studies in which sleep/wake staging was aided by recording electromyogram (EMG) tone, intraperitoneal administration of diphenhydramine [23,47] and pyrilamine [23] increased total sleep time in rats without reducing REM sleep. By contrast, 2 nd generation, non-brain penetrating antihistamines such as mizolastine [48], azelastine [44,49], clemastine [49], epinastine, ceterizine [46], and levocabastine [44] did not alter EEG patterns in rats. The distinction between non-sedating antihistamines such as epinastine and ceterizine, and sedating antihistamines such as ketotifen in rats appears to relate to the degree of receptor occupation of sedating antihistamines made possible by increased brain penetration [46].…”

Rapid symptom relief in rhinitis

“…H 1 blockers should not possess sedative effects. Mizolastine does not have sedative potential on the EEG in the rodent [20]. The psychomotor and cognitive effects of mizolastine was compared to terfenadine, triprolidine and placebo in healthy volunteers [21].…”