Pharmacological treatment promoting remyelination enhances motor function after internal capsule demyelination in mice.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by remyelination failure, axonal degeneration, and progressive worsening of motor functions. Animal models of demyelination are frequently used to develop and evaluate therapies for MS. We recently reported that focal internal capsule (IC) demyelination in mice with lysophosphatidylcholine injection induced acute motor deficits followed by recovery through remyelination. However, it remains unknown whether the IC demyelination mouse model can be used to evaluate changes in motor functions caused by pharmacological treatments that promote remyelination using behavioral testing and histological analysis. In this study, we examined the effect of clemastine, an anti-muscarinic drug that promotes remyelination, in the mouse IC demyelination model. Clemastine administration improved motor function and changed forepaw preference in the IC demyelinated mice. Moreover, clemastine-treated mice showed increased mature oligodendrocyte density, reduced axonal injury, an increased number of myelinated axons and thicker myelin in the IC lesions compared with control (PBS-treated) mice. These results suggest that the lysophosphatidylcholine-induced IC demyelination model is useful for evaluating changes in motor functions following pharmacological treatments that promote remyelination.

Effect of Clemastine Fumarate on Perioperative Hemodynamic Instability Mediated by Anaphylaxis During Cardiopulmonary Bypass Surgery.

BACKGROUND Perioperative hemodynamic instability mediated by anaphylaxis is a life-threatening complication in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to evaluate the effect of clemastine fumarate in this specific patient population. MATERIAL AND METHODS We enrolled 100 participants who met the inclusion criteria and randomly allocated them to the treatment group and the placebo group. Participants in the treatment group and the placebo group were treated separately with an injection of clemastine fumarate and saline, respectively. Plasma histamine concentration and blood pressure were quantified at 5 timepoints during the perioperative period, and differences between the 2 groups were assessed by repeated-measures ANOVA. The postoperative complications and in-hospital mortality also were evaluated. All participants were followed up for 7 days after cardiac surgery. RESULTS Plasma histamine concentrations increased in both groups but were statistically significantly lower in the treatment group during the perioperative period (P=0.007). Diastolic blood pressure (P=0.014) and mean arterial pressure (P=0.024) in the treatment group were significantly higher than in the placebo group during the perioperative period. The coefficients of variation for systolic (13.9±4.2% vs 17.2±4.4%, P<0.01) and diastolic (12.9±4.9% vs 15.3±5.2%, P=0.02) blood pressure were significantly lower in the treatment group compared with the placebo group. CONCLUSIONS Pretreatment with clemastine fumarate restrains the increase in histamine concentration and provides safer hemodynamics in patients undergoing cardiac surgery with CPB.

Torsadogenic potential of a novel remyelinating drug clemastine for multiple sclerosis assessed in the rabbit proarrhythmia model.

We assessed the torsadogenic effects of a novel remyelinating drug clemastine for multiple sclerosis using an in vivo proarrhythmia model of acute atrioventricular block rabbit, since the drug has been demonstrated to suppress the human ether-á-go-go related gene (hERG) K+ channels. Bradycardia was induced by atrioventricular node ablation in isoflurane-anesthetized New Zealand White rabbits (n = 5), and the ventricle was electrically driven at 60 beats/min throughout the experiment, except when extrasystoles appeared. Intravenous administration of clinically relevant dose of 0.03 mg/kg of clemastine and 10-times higher dose of 0.3 mg/kg hardly affected the QT interval or duration of the monophasic action potential (MAP) of the ventricle. Additional administration of clemastine at 3 mg/kg significantly increased the QT interval, MAP duration and the short-term variability of repolarization. Meanwhile, the premature ventricular contractions with R on T phenomenon were observed in 3 out of 5 animals, and torsades de pointes arrhythmias were detected in 1 out of 5 animals. These results suggest that the torsadogenic potential of clemastine is obviously observed in the acute atrioventricular block rabbit, which will not appear within the prescribed dose for multiple sclerosis.

Randomized control trial of evaluation of Clemastine effects on visual evoked potential, nerve fiber layer and ganglion cell layer complex in patients with optic neuritis.

OBJECTIVES: Optic neuritis (ON) is the most common cause of optic neuropathy; typically presenting with a unilateral visual loss in young adults, with incidence of 1-5 in 100,000 per year. We evaluated the effect of Clemastine, a first-generation and CNS (central nervous system)-penetrant H1 receptor antagonist on visual evoked potential (VEP), retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) complex in patients with optic neuritis. PATIENTS AND METHODS: This is a prospective comparative interventional case series in 25 patients with acute optic neuritis. Patients were randomly assigned to group 1 (treated with Clemastine 1 mg orally twice a day for 90 days; 16 patients) or group 2 (received placebo for 90 days; 9 patients) and both groups received standard treatment of optic neuritis. We recorded VEP and peripapillary OCT (optical coherence tomography) of patients before and after three months of treatment. RESULTS: In contrast to patients treated with Clemastine, RNFL thickness loss between base line phase and after three months follow up in control group were statistically significant in temporal, supra temporal, Infrotemporal and almost global sections of RNFL map. The reduction in GCL thickness between base line phase and after three months follow up in control group were significant, while it did not reach significance in treatment group except in inferior region. CONCLUSION: In contrast to treatment group, RNFL and GCL thickness of most quadrants are decreased significantly after three months in patients with ON in control group. In contrast to control group, p100 wave's amplitude recovered in a significant manner in treatment group.

Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia.

OBJECTIVE: This study investigated the relevance of the cytochrome P450 (CYP) 2D6 genotype to the adverse drug reactions (ADRs) of H1-antihistamines and the level of sedation. METHODS: Japanese participants in a health screening program were asked to describe any past history of ADRs. Any subjects reporting ADRs induced by H1-antihistamines were then individually interviewed and defined as cases. Excessive daytime sleepiness, which had occurred in the cases as an H1-antihistamine-induced ADR, was assessed by the Epworth sleepiness scale (ESS), and an ESS score >or=12 was considered hypersomnia. CYP2D6*4, *5, *14, and *10 were genotyped by a panel of polymerase chain reaction techniques. RESULTS: Out of 2,074 participants, 100 cases (M:F = 37:63, mean age 51.9 +/- 9.2 years) were eligible for analysis. The most common etiological drug was chlorpheniramine, which is the most frequently used H1-antihistamine in Japan. CYP2D6*10 allele and genotypes were more frequently found in the cases than in the healthy Japanese population in a large study (P < 0.005 and P = 0.039, respectively), but no difference was observed in the null alleles and genotypes. The ESS scores in 75 cases (M:F=25:50) who had experienced excessive daytime sleepiness were 9.5 +/- 5.5 in men and 12.9 +/- 6.1 in women (P < 0.001, cases vs. 34 subjects without symptoms; P = 0.001 men vs. women). The occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased (P = 0.045). CONCLUSION: The results suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H1-antihistamine-induced ADRs in Japanese.

Anaphylactic reaction and unrelated, subsequent, known side effects during therapy with thiethylperazine.

We report the first case presenting with successive anaphylactic reaction and extra-pyramidal syndrome after treatment with thiethylperazine maleate (thiethylperazine). Both reactions were caused due to this anti-emetic drug, but an additive effect of clemastine fumarate, prescribed to treat the anaphylactic reaction, is suggested by the sequence of events. We discuss the importance of knowing the pharmacological similitudes of common prescribed drugs in order to avoid the occurrence of side effects.

Toxic pustuloderma associated with clemastine therapy.

Toxic pustuloderma is an acute pustular eruption of the skin occurring a few days after the initiation of treatment with the responsible drug. A case of toxic pustuloderma following treatment with the antihistamine clemastine is now reported.

Neuropsychologic and cardiovascular effects of clemastine fumarate under pressure.

Allergic rhinitis and mild respiratory infections have been widely accepted as temporary contraindications for fitness to dive. Nonetheless, several sport and professional divers use antihistamines to ease ear, nose, and throat (ENT) problems, especially for opening tubal ostium. Some divers know they are unfit to dive, but for a variety of reasons (e.g., money or short holiday) they try to clear their ears. Thus, the use of antihistaminic drugs (like clemastine fumarate) is common during diving. This double-blind, crossover study indicates that this special antihistamine does not increase the sedative effects of nitrogen narcosis, nor does it increase the level of cardiac arrhythmias. Liberal use of antihistamines while diving cannot be recommended because of possible complications connected with different preparations and the temporary limitations they impose on the diver.

Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989-94.

The review summarizes the major results of eight double-blind, placebo-controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of "sedating" and "nonsedating" antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine, loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular "weaving" (i.e., standard deviation of lateral position (SDLP)). Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4-5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1-2x the currently recommended levels. One or possibly two of the newer drugs possessed both performance-enhancing and -impairing properties, depending on dose, suggesting two mechanisms of action.

Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine.

An observational, historical cohort evaluation was performed to examine the hypothesis that terfenadine (Seldane) exposure increases the risk of developing life-threatening ventricular arrhythmias. The study population consisted of Medicaid recipients from 4 states that were included in the Computerized On-Line Medical Pharmaceutical Analysis and Surveillance System (COMPASS). The drug exposure period was defined prospectively as 30 days in all treatment cohorts. The primary end point was the development of life-threatening ventricular arrhythmias (ventricular tachycardia, fibrillation and flutter, and cardiac arrest and sudden death). The comparison cohorts included terfenadine (n = 181,672), over-the-counter antihistamines (n = 150,689), ibuprofen (n = 181,672) and clemastine (Tavist; n = 83,156). Over the exposure period, a total of 317 life-threatening ventricular arrhythmic events occurred, 244 of which were cardiac arrests. The incidence of total life-threatening ventricular arrhythmic events and cardiac arrests were more frequent in patients receiving over-the-counter antihistamines (relative risk 0.36) than in those receiving terfenadine, a finding that was consistent across all subgroups. There was no increased risk of life-threatening ventricular arrhythmias in the terfenadine cohort as compared with the ibuprofen cohort (relative risk 0.62), and in some analyses, the ibuprofen cohort had a significantly higher arrhythmic event rate. In all comparisons with the clemastine cohort, the terfenadine cohort had a statistically indistinguishable relative risk (1.08). Age, race, sex and cardiovascular risk were all considered in the adjusted relative-risk analyses. No baseline historical characteristic or imbalance of baseline medications explained the differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of mizolastine and clemastine on actual driving and psychomotor performance in healthy volunteers.

The acute effect of doses of mizolastine 5, 10, 20 and 40 mg, an active control (clemastine 2 mg) and placebo on actual car driving and psychomotor performance have been compared. Twenty four healthy volunteers were treated according to a double-blind, 6-way cross-over design. In the driving test, lasting about 1 h, lateral position control and speed were continuously measured; the psychomotor test battery, lasting 50 min, comprised critical flicker-fusion frequency, critical instability tracking, divided attention, memory search and choice reaction time, and vigilance studies; and mood changes and possible adverse-effects were rated on visual analogue scales. The results showed a dose-response relationship: mizolastine 40 and 20 mg impaired driving and psychomotor performance. The effect of mizolastine 40 mg on driving was strongly correlated with that of clemastine (r = 0.78) and was comparable to the effect of a blood ethanol level of 0.8 mg.ml-1. Mizolastine 5 mg and 10 mg did not have a significant effect on driving performance and psychomotor tests. It was concluded that at a 10 mg dose of mizolastine, the therapeutic dose, it could be considered a safe anti-histamine, although individual adverse reactions cannot be completely ruled out.

Safety and efficacy of terfenadine/pseudoephedrine versus clemastine/phenylpropanolamine in the treatment of seasonal allergic rhinitis.

A double-blind, randomized, placebo-controlled, parallel trial was conducted to compare the efficacy and safety of terfenadine, 60 mg (immediate-release)/pseudoephedrine hydrochloride, 120 mg (controlled-release) (T/Ps) and clemastine fumarate, 1.34 mg (immediate-release)/phenylpropanolamine, 75 mg (sustained-release) (C/Ph) in a combination tablet b.i.d. in 178 patients (12-59 years of age) with symptoms of seasonal allergic rhinitis. After seven days of treatment, the total symptom scores recorded in the diaries of 175 patients showed that both therapies had a highly significant overall treatment effect when compared with placebo (P < or = .02). The overall level of improvement, as well as improvement of individual symptoms, was similar with the two therapies. Total symptom scores assigned by physicians to 170 patients showed significant and similar levels of improvement with both therapies when compared with placebo (P < .01). The two therapies were also similar on physicians' evaluations of overall effectiveness. Both therapies relieved most histamine-mediated symptoms as well as nasal congestion, although only T/Ps showed improvement of the latter symptom in both the patients' diaries and physicians' evaluations. Among 178 patients, drowsiness and fatigue occurred more often in the C/Ph group (25% and 11.7% for the two adverse events, respectively) than in the T/Ps group (10.2% and 1.7%, respectively). The incidence of insomnia and dry mouth/nose/throat was higher with T/Ps (23.7% and 11.9%, respectively) than with C/Ph (6.7% and 3.3%, respectively). No serious or unexpected adverse events were reported. These results indicate that T/Ps and C/Ph are both superior to placebo and equally effective in the treatment of symptoms of seasonal allergic rhinitis.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicentre study of loratadine, clemastine and placebo in patients with perennial allergic rhinitis.

This multicentre, double-blind, randomized parallel-group study compared 3 weeks' treatment with either loratadine (Clarityn) 10 mg once daily, or clemastine (Tavegyl) 1 mg twice daily, and placebo in outpatients with active perennial allergic rhinitis. 155 patients were evaluated for efficacy and safety. Grading of four nasal and three non-nasal symptoms, rhinoscopy signs, and therapeutic response was performed on treatment days 6, 13, and 20. Patients recorded daily symptoms and possible adverse experiences in a diary, also indicating when symptoms of active rhinitis were relieved. Loratadine and clemastine were statistically significantly superior to placebo throughout the study (P less than 0.05), based on assessment of patients' nasal and eye symptoms, patients' diary scores, rhinoscopy signs of symptoms, and onset of relief. The loratadine group showed a statistically significantly (P less than 0.05) faster onset of relief of symptoms compared with the group treated with clemastine. Concerning nasal stuffiness, loratadine was significantly (P less than 0.05) superior to clemastine after 1 week's treatment. Reports of adverse reactions showed that significantly (P less than 0.05) more patients complained of sedation in the clemastine than in the loratadine group. Regarding other adverse experiences and laboratory tests, the three treatment groups were statistically comparable (P less than 0.05). The study showed that compared with placebo both loratadine and clemastine were effective in relieving nasal and eye symptoms in patients with perennial allergic rhinitis. Loratadine was safe and well tolerated and was significantly less sedative than clemastine; loratadine may therefore possess an advantage in clinical use in the treatment of perennial allergic rhinitis.