The added value of H2 antagonists in premedication regimens during paclitaxel treatment.

BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the two-sided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine. CLINICAL TRIAL REGISTRATION: www.trialregister.nl ; NL8173.

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.

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug.

Williams syndrome (WS), caused by a heterozygous microdeletion on chromosome 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor IIi (Gtf2i) has been linked to hypersociability in WS, although the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in the excitatory neurons of the forebrain caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased messenger RNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioral deficits. The frontal cortex from patients with WS similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.

Clemastine effects in rat models of a myelination disorder.

BackgroundPelizaeus Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system caused by impaired differentiation of oligodendrocytes. This study was prompted by findings that antimuscarinic compounds enhance oligodendrocyte differentiation and remyelination in vitro. One of these compounds, clemastine fumarate, is licensed for treatment of allergic conditions. We tested whether clemastine fumarate can promote myelination in two rodent PMD models, the myelin-deficient and the PLP transgenic rat.MethodsPups were treated with daily injections of clemastine (10-30 mg/kg/day) on postnatal days 1-21. Neurologic phenotypes and myelination patterns in the brain, optic nerves, and spinal cords were assessed using histological techniques.ResultsNo changes in neurological phenotype or survival were observed even at the highest dose of clemastine. Postmortem staining with Luxol fast blue and myelin basic protein immunohistochemistry revealed no evidence for improved myelination in the CNS of treated rats compared to vehicle-treated littermates. Populations of mature oligodendrocytes were unaffected by the treatment.ConclusionThese results demonstrate lack of therapeutic effect of clemastine in two rat PMD models. Both models have rapid disease progression consistent with the connatal form of the disease. Further studies are necessary to determine whether clemastine bears a therapeutic potential in milder forms of PMD.

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination.

Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

Treatment of angiotensin receptor blocker-induced angioedema: A case series.

BACKGROUND: Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist. METHODS: We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n = 3) or prednisolone-21-hydrogen succinate/clemastine (n = 5). Both patient groups were compared with an untreated patient cohort (n = 3). All patients were previously diagnosed with essential hypertonia. RESULTS: Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema. CONCLUSIONS: Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker-induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway.

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.

Identification of some new clemastine metabolites in dog, horse, and human urine with liquid chromatography/tandem mass spectrometry.

The metabolism of clemastine was studied in dogs, horses, and humans after a single dose of Tavegyl. The urine collected was extracted by solid-phase extraction or hydrolyzed with beta-glucuronidase and then extracted by liquid-liquid extraction, prior to analysis for unchanged drug and phase I and II metabolites by liquid chromatography/tandem mass spectrometry. The metabolites were identified by their molecular mass and interpretation of the product ion spectra, since no standard substances were available. Unchanged drug was recovered in urine samples from dogs and humans, but not from horses. In dogs and humans, the phase I metabolite, norclemastine, was identified, and clemastine metabolites with one and two additional oxygens were found in all three species. In horses and dogs monohydroxylation on one of the aromatic rings or the adjacent methyl group was favored while, in humans, the additional oxygen was positioned on either the aromatic or the aliphatic part of the structure, and the aliphatic reaction seemed to result in at least three isomers. In the metabolites with two additional oxygens, both the oxygens were found on the aliphatic fragment in humans and dogs, whereas they were situated on the aromatic part of the structure in horses. In human patients, glucuronidated monohydroxyclemastine was recovered, and in urine from horses both mono- and dihydroxyclemastine glucuronides were identified, while phase II metabolites could not be recovered from the dog urine. Clemastine metabolism in dogs and horses has, to our knowledge, not been studied before, and new metabolites from humans are presented in this article. Thus, the metabolites described in the present work have not been previously reported in the literature.

Clinical pharmacology of clemastine in healthy dogs.

The pharmacokinetic properties of clemastine were investigated in six healthy dogs and compared with the effect of the drug recorded as inhibition of wheal formation induced by intradermal injections of histamine. Clemastine clearance was high (median: 2.1 L h(-1) kg(-1)) and the volume of distribution large (13.4 L kg(-1)). The half-life after intravenous administration was 3.8 h and the plasma protein binding level in vitro was 98%. After oral administration, the bioavailability was only 3%. Given intravenously, clemastine (0.1 mg kg(-1)) inhibited wheal formation completely for 7 h, whereas the effect after oral administration (0.5 mg kg(-1)) was minor. The data show that most dosage regimens suggested in the literature for the oral administration of clemastine to dogs are likely to give too low a systemic exposure of the drug to allow effective therapy.

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens.

Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone.

Pharmacokinetics and pharmacodynamics of clemastine in healthy horses.

Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 microg/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 microg/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations.

Dose reduction of steroid premedication for paclitaxel: no increase of hypersensitivity reactions.

BACKGROUND: Premedication with dexamethasone, ranitidine and clemastine is mandatory for patients receiving paclitaxel to avoid hypersensitivity reactions. The proposed dexamethasone dose is 20 mg orally 12 and 6 h prior to paclitaxel infusion. With this premedication severe hypersensitivity reactions are reduced to 1-2% of the treated patients. Besides this oral schedule a single dose of dexamethasone, 40 mg given i.v., just prior to paclitaxel has been shown to be equally effective. In an attempt to reduce steroid-induced side effects, especially for patients receiving weekly paclitaxel protocols, we reduced the dexamethasone dose. PATIENTS AND METHODS: A total of 132 patients were treated on an outpatient basis with paclitaxel-containing protocols. Paclitaxel was given in doses of 135-175 mg/m(2) once every 3 weeks in 76 patients and/or with 100 mg/m(2) weekly in 70 patients. Dexamethasone premedication was given in a single dose (40, 20, 10 mg) as an infusion directly before paclitaxel. RESULTS: 0/46 patients receiving 40 mg dexamethasone premedication in 235 cycles and 0/48 patients receiving 20 mg dexamethasone premedication in 186 cycles experienced a severe hypersensitivity reaction. 1/52 patients receiving 10 mg dexamethasone in 480 applications developed a severe hypersensitivity reaction with bronchospasm, hypotension and supraventricular tachycardia shortly after her first paclitaxel infusion started. CONCLUSION: No increase of severe hypersensitivity reactions is seen when dexamethasone premedication is reduced to doses of 20 or even 10 mg prior to paclitaxel infusion.

Administration of clemastine--H1 histamine receptor blocker in the prevention of haemodynamic disorders after protamine sulfate administration in patients subjected to coronary artery bypass grafting in extracorporeal circulation.

INTRODUCTION: Adverse effects of protamine administration after CPB: fall in arterial blood pressure and pulmonary hypertension are still a source of problems. CPB and protamine administration are both accompanied by increased histamine levels in blood. The aim of this study was to examine if clemastine can accelerate the normalisation of arterial blood pressure during the protamine administration after CPB during CABG operations. MATERIAL AND METHODS: Fifty three patients subjected to CABG operations were studied. Control group (n = 27) did not receive clemastine, Clemastine group (n = 26) received 2 mg i.v. clemastine, before CPB. After CPB were completed, patients were given protamine (heparin to protamine ratio--1:1.5) within 7 minutes, through peripheral vein. Changes in arterial blood pressure from the beginning of protamine administration to 2.5, 5, 7.5, 10, 15, and 30 minutes thereafter, as well as heart rate, CVP, doses of inotropic drugs and vasodilators were compared between the groups. RESULTS: No difference in heart rate, CVP, doses of inotropic drugs and vasodilators between the group was noted. An increase in arterial blood pressure 5, 7.5, 10, and 15 minutes after the beginning of the protamine administration were greater in clemastine group than in control group. Groups were comparable with regard to surgical procedures and doses of anaesthetic drugs. It is now known that protamine exerts a negative effect on cardiac contractility either through a decrease in coronary perfusion pressure (vasodilatation), or through a direct toxic effect on cardiac muscle. The administration of clemastine before CPB can reduce peripheral vasodilatation and capillary leak related to histamine release during CPB. In the clemastine group, faster increase in arterial blood pressure toward a physiologic range was observed. We conclude that administration of clemastine is connected with the normalization of ABP during and after protamine reversal of heparin coagulation during CABG operations.

Fexofenadine's effects, alone and with alcohol, on actual driving and psychomotor performance.

BACKGROUND: Fexofenadine is the hydrochloride salt of terfenadine's active metabolite. OBJECTIVE: Fexofenadine's effects on performance were assessed in this study for the purpose of determining its safety of use by patients who engage in potentially dangerous activities, especially car driving. METHODS: Fexofenadine was administered in daily doses of 120 or 240 mg, each in single and divided units given over 5 days. Two milligrams of clemastine given twice daily and placebo were given in similar series. Twenty-four healthy volunteers (12 men, 12 women; age range, 21 to 45 years) participated in a double-blind six-way crossover study. Psychomotor tests (critical tracking, choice reaction time, and sustained attention) and a standardized actual driving test were undertaken between 1.5 to 4 hours after administration of the morning dose on days 1, 4, and 5 of each series. On day 5, subjects were challenged with a moderate alcohol dose before testing. RESULTS: Fexofenadine did not impair driving performance. On the contrary, driving performance was consistently better during twice daily treatment with 120 mg fexofenadine than during treatment with placebo, significantly so on day 4. Both of the 240 mg/day regimens significantly attenuated alcohol's adverse effect on driving on day 5. Effects in psychomotor tests were not significant, with the exception of the critical tracking test in which the first single doses of fexofenadine, 120 and 240 mg, had significantly impairing effects. CONCLUSION: It was concluded that fexofenadine has no effect on performance after being taken in the recommended dosage of 60 mg twice daily.

Effectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold.

Limited data support the use of first-generation antihistamines for treatment of the common cold. The purpose of this study was to test the effectiveness of clemastine fumarate, a first-generation antihistamine, for treatment of sneezing and rhinorrhea associated with naturally occurring common colds. Four hundred three subjects (202 clemastine fumarate recipients and 201 placebo recipients) who reported new onset (< 24 hours) of cold symptoms that included rhinorrhea or sneezing were studied. At baseline (day 1), the mean symptom-severity scores +/- SEM for the clemastine fumarate and placebo groups were not significantly different. The mean rhinorrhea-severity score +/- SEM was not different on day 2; however, on day 3, the mean rhinorrhea-severity score +/- SEM was 1.02 +/- 0.07 for the clemastine fumarate group and 1.39 +/- 0.07 for the placebo group (P < .001). This treatment effect persisted on day 4. A significant effect on sneezing was noted on days 2-4. Sedation occurred in 14% of the clemastine fumarate-treated subjects and 1.5% of the placebo-treated subjects (P < .0001).

Low dose clemastine inhibits sneezing and rhinorrhea during the early nasal allergic reaction.

BACKGROUND: Clemastine (1 mg) is currently available over-the-counter for the treatment of allergic rhinitis. OBJECTIVE: To evaluate the efficacy of half the standard dose of clemastine (0.5 mg) in inhibiting the nasal response to allergen and the cutaneous response to histamine. METHODS: Double-blind, placebo-controlled, crossover study of 20 allergic subjects out of season. The subjects received placebo or clemastine administered one, four, and six hours before the challenges. Filter paper discs were used both to challenge the nasal mucosa with diluent and allergen and collect generated secretions. Sneezes, secretion weights, nasal and ocular symptoms, and albumin levels in nasal secretions were monitored for the nasal challenge. Intradermal skin testing was performed with diluent followed by histamine and the wheal and flare reactions were measured. RESULTS: There was a significant reduction in the number of sneezes after clemastine administered one, four, and six hours prior to challenge compared with placebo (P < .01). Clemastine administered four and six hours before challenge reduced sneezing significantly more than clemastine administered one hour before challenge (P < .05). Antigen-induced increases in secretion weights and symptoms of rhinorrhea were significantly reduced compared with placebo only when clemastine was administered four and six hours prior to challenge (P < .05). Pretreatment with clemastine had no significant inhibitory effects on other nasal symptoms or on albumin levels in nasal secretions, an objective index of increased vascular permeability. Pretreatment with clemastine did not inhibit the histamine-induced wheal skin reaction but showed a tendency, when administered six hours prior to the intradermal challenge, to reduce the flare reaction induced by the lowest dose of histamine (P = .05). CONCLUSIONS: The data show that clemastine, given at half the usual dose four and six hours prior to allergen challenge, provides relief for sneezing and rhinorrhea and suggests that this dose might be useful in the treatment of allergic rhinitis.

Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been studied primarily on a 3-week schedule as a 3-, 24-, or 96-hour infusion at doses ranging from 135 to 250 mg/m2. The observed toxicity profile seems to be both dose and schedule dependent. Dose densification of paclitaxel given weekly over 6 weeks on a split-dose schedule for an overall increase in dose intensity was thought to improve the therapeutic index of paclitaxel in a variety of advanced malignancies and to be suitable for outpatient administration. For this study, chemotherapy consisted of a weekly 1-hour infusion of paclitaxel at a starting dose of 40 mg/m2/wk for 6 weeks, followed by a 2- to 3-week interval. Paclitaxel dosage was escalated in 10 mg/m2/wk increments in subsequent patients, to a maximum dosage of 90 mg/m2/wk. Intravenous dexamethasone, cimetidine, clemastine, and ondansetron were administered immediately before the paclitaxel infusion. Fifty patients participated in the study. The male to female ratio was 21 to 29, the median age was 53.2 years (age range, 33 to 74), and the median performance status was 1. All patients were chemotherapeutically pretreated. Overall response included five complete responses (10%), 15 partial responses (30%), 19 no change (38%), and 11 disease progressions (22%). Median dose intensity was 410 mg/m2/6 wk (range, 200 to 540 mg/m2/6 wk). Hematologic toxicity was mild, with no grade 3 or 4 toxicity up to 90 mg/m2/wk. No hypersensitivity reactions or neurologic or cardiac toxicities were documented. Dose-densified, weekly paclitaxel is concluded to be active in a variety of pretreated tumor entities. The overall low hematologic and peripheral toxicity profile suggests that further dose intensification of weekly paclitaxel and/or combination with other cytotoxic agents (eg, cisplatin/carboplatin, ifosfamide, etoposide) may be warranted. Paclitaxel can be given safely in the outpatient setting. Paclitaxel 90 mg/m2/wk is recommended for single-agent treatment. Dose-densified paclitaxel may be considered a valuable and promising alternative to standard 3-week treatment, with further options possible in combination chemotherapy.