QT interval monitoring during clinical studies with mizolastine, a new H1 antihistamine.

BACKGROUND: Some H1 antihistamines are at risk for rare but severe dysrhythmias due to an effect on the ventricular repolarization. OBJECTIVE: To present an overview of the QT interval monitoring performed during the clinical development of mizolastine, a new selective second-generation H1 antihistamine. METHODS: The ECGs database analysis of clinical studies conducted in volunteers and patients is summarized and focused on the results of reported studies and studies specifically designed for the assessment of the effect of mizolastine on cardiac repolarization, through the QT interval measurements. Mizolastine was orally administered up to 75 mg single dose and 40 mg repeated dose in healthy volunteers (i.e. 7. 5 and 4 times the recommended dose, respectively) and at a dose of 10 or 15 mg in patients. RESULTS: In healthy volunteers, no increased incidence of QTc values >440 msec or DeltaQTc >/=40 msec were recorded compared to placebo. No dose-related increase in QTc interval was observed. The ECG parameters were not modified by the co-administration of mizolastine with digoxin, diltiazem and erythromycin, when compared to the effect of each co-administered drug alone. In patients, the mean QTc interval changes from baseline did not significantly differ from placebo. In comparative studies vs. loratadine a similar incidence of out of range values was observed with mizolastine and loratadine. CONCLUSION: ECG monitoring of volunteers and patients included in clinical studies conducted with mizolastine showed no significant effect of mizolastine on cardiac repolarization.

Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1-receptor antagonist.

AIMS: The occurrence of serious dysrhythmias, such as torsades de pointes, with terfenadine and astemizole had led to a reexamination of the potential effect of H1 antihistamines on cardiac repolarization. Mizolastine is a potent, selective, nonsedating peripherally acting H1-receptor antagonist which is registered for rhinitis and urticaria at a recommended dose of 10 mg once daily. The present study was carried out to investigate the effects of therapeutic and supratherapeutic doses of mizolastine, on ventricular repolarization in healthy volunteers. METHODS: Twenty-four healthy young volunteers participated in a double-blind, placebo-controlled, randomised study with three parallel groups. Each group consisted of 2 way cross-over 7 day treatment periods where mizolastine (10, 20 or 40 mg) and placebo were randomly administered. On day 1 and day 7, 12-lead ECG recordings were performed prior and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 20 h after dosing and from day 2 to day 6, before dosing and 1, 2, 3, and 4 h after. RESULTS: Whatever the analysis used (raw data, changes from baseline, incidence of individual out-of-range values) no significant differences were observed at any dose level vs placebo, on any of ECG parameters (HR, PR, QRS, QT, and QTc). In particular, no effect of mizolastine vs placebo was shown on QT and QTc although 95% CIs were wide. The only subject who exhibited a QTc>/=450 ms received placebo for 7 days. CONCLUSIONS: This study found no evidence of an effect of mizolastine up to 40 mg (four times the therapeutic dose) on ventricular repolarization in healthy volunteers.

Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery.

The protective activity of small stress proteins (sHsp) against H2O2-mediated cell death in the highly sensitive murine L929 fibroblast has been analyzed. We report here that the human Hsp27- and murine Hsp25-mediated rise in glutathione (GSH) levels as well as the maintenance of this redox modulator in its reduced form was directly responsible for the protection observed at the level of cell morphology and mitochondrial membrane potential. sHsp expression also buffered the increase in protein oxidation following H2O2 treatment and protected several key enzymes against inactivation. In this case, however, the protection necessitated both an increase in GSH and the presence of sHsp per se since the pattern of protection against protein oxidation mediated by a simple GSH increase was different from that induced by sHsp expression. Among the enzymes analyzed, we noticed that sHsp significantly increased glucose-6-phosphate dehydrogenase (G6PD) activity and to a lesser extent glutathione reductase and glutathione transferase activities. Moreover, an increased GSH level was observed in G6PD-overexpressing L929 cell clones. Taken together our results suggest that sHsp protect against oxidative stress through a G6PD-dependent ability to increase and uphold GSH in its reduced form and by using this redox modulator as an essential parameter of their in vivo chaperone activity against oxidized proteins.

Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers.

OBJECTIVE: Amisulpride is a substituted benzamide neuroleptic, which binds selectively to dopamine D2 and D3 receptors, mainly in the limbic structures. States of delusion and agitation occur frequently in the population aged more than 65 years, especially in demented patients and this sometimes requires the use of neuroleptics. The objectives of this study were to determine the safety and the pharmacokinetic profile of 50 mg of amisulpride administered orally as a single dose to elderly volunteers. METHODS: Twenty healthy volunteers (10 men and 10 women) aged 65 79 years were included in this open trial. Frequent measurements of blood pressure and heart rate were made and ECG and blood samples were performed up to 72 h after drug intake. RESULTS: The overall clinical and cardiovascular safety was satisfactory. The mean Cmax of the racemate amisulpride in elderly people was 64.1+/-6.7 ng ml(-1), and was not different from the value of 56+/-4.1 ng ml(-1) in young subjects. As with the Cmax, the mean values of t1/2 and AUC in elderly people (15.6+/-1.3 h and 667+/-51 ng. ml(-1).h, respectively) were not different to values observed in young subject (respectively 11.7+/-0.5 h and 603+/-25 ng m1(-1) h). CONCLUSION: A single oral dose of amisulpride was well tolerated and showed a similar pharmacokinetic profile in healthy elderly and young subjects. However, these findings should be confirmed after multiple dosing in a larger population in order to establish the lack of need of dosage adjustment in this elderly population.

Lack of effect of mizolastine on the safety and pharmacokinetics of digoxin administered orally in repeated doses to healthy volunteers.

The effects of mizolatine, a new H1 receptor antagonist, on safety and pharmacokinetics of digoxin were studied in a double-blind placebo-controlled crossover study. After administration of digoxine alone (0.25 mg o.d. for 7 days), 12 healthy young male volunteers (23+/-2 years) received either placebo and digoxin (0.25 mg o.d.) or mizolastine (10 mg o.d.) and digoxin (0.25 mg o.d.) during 7 days. The assessment criteria consisted in hemodynamic and ECG parameters recordings and the pharmacokinetics of digoxin during the last day of coadministration (day 14). No difference between the 2 treatment groups was evidenced on ECG, hemodynamic, and clinical and laboratory safety parameters. No change in AUC and tmax was recorded. No clinically relevant effect of mizolastine on the digoxin pharmacokinetics was found. However, a statistically significant increase in digoxin Cmax (3.03+/-0.18 nmolxl(-1) vs 2.52+/-0.19 nmolxl(-1), p < 0.05) and Cmin (0.99+/-0.08 nmolxl(-1) vs 0.87+/-0.07 nmolxl(-1), p=0.05) occurred after the coadministration vs digoxin alone. It can be concluded that mizolastine and digoxin at therapeutic dosages can be safely coadministered.

Transient accumulation, phosphorylation and changes in the oligomerization of Hsp27 during retinoic acid-induced differentiation of HL-60 cells: possible role in the control of cellular growth and differentiation.

Expression of the mammalian small stress protein Hsp27 has been increasingly linked to cell growth regulation and differentiation. Hsp27 is a phosphoprotein which forms oligomers with native sizes ranging between 100 and 800 kDa. We have examined the fate of Hsp27 transiently expressed during the retinoic acid (tRA)-induced granulocytic differentiation of human leukemic HL-60 cells. We show that tRA, in addition to its effects on Hsp27 accumulation and phosphorylation, transiently increased the oligomerization state of this protein. While Hsp27 phosphorylation by tRA is an early phenomenon that takes place before cellular growth is altered, the redistribution of Hsp27 oligomers occurred later and concomitantly with the maximal accumulation of this protein. Hence, complex regulations of Hsp27 are induced by tRA which suggest that this protein plays a role in the pathway through which retinoids exert their effects. To approach Hsp27 function during HL-60 cell differentiation, experiments aimed at reducing the cellular content of this protein were performed by transiently inhibiting Hsp27 mRNA translation by a specific anti-sense oligonucleotide. This process, which decreased the basal level of Hsp27 by about 40%, did not interfere with the growth of undifferentiated HL-60 cells. In contrast, a decreased level of Hsp27 diminished the differentiation-mediated down-regulation of cell growth and altered some morphological changes induced by this retinoid. These results suggest that Hsp27 is a mediator of granulocytic differentiation.

Comparative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and placebo in healthy volunteers.

1. Mizolastine, a new benzimidazole derivative with potent selective, non-sedative H1-histamine antagonist activity was compared with terfenadine, cetirizine and loratadine using the histamine-induced wheal and flare model in healthy volunteers. 2. Study design was a five way double-blind crossover design using a single dose of mizolastine 10 mg, terfenadine 120 mg, cetirizine 10 mg, loratadine 10 mg and placebo. 3. Histamine tests were performed on 10 occasions up to +24 h after dosing using an intradermal injection of histamine 2 micrograms with concommittant contralateral injection of a saline control. 4. Mizolastine, terfenadine, cetirizine and loratadine significantly (P < 0.001 vs placebo) inhibited the wheal and flare formation starting 1 to 2 h after dosing up to 24 h after dosing. 5. Mizolastine was significantly more active than loratadine on the wheal (P < 0.01) and flare (P < 0.05) inhibition from 3 up to 6 and 8 h respectively, as active as terfenadine on both parameters and as active as cetirizine on wheal inhibition while less active (P < 0.01) than cetirizine on flare inhibition at 2 and 12 h post-dosing.