Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

Efficiency and safety of desloratadine in combination with compound glycyrrhizin in the treatment of chronic urticaria: a meta-analysis and systematic review of randomised controlled trials.

CONTEXT: Desloratadine, an H1 receptor antagonist, is suggested as an effective first-line drug for chronic urticarial (CU). However, the efficacy of desloratadine alone is limited, and the recurrence rate of CU is relatively high. OBJECTIVE: We sought to evaluate the efficacy and clinical feasibility of desloratadine in combination with compound glycyrrhizin in the treatment of CU. MATERIALS AND METHODS: A systematic literature search was conducted in the databases of the China National Knowledge Infrastructure Database, VIP, WanFang, PubMed, and Web of Science using subject terms: "Chronic urticaria", "Loratadine", and "Compound glycyrrhizin". Randomised controlled trials (RCTs) that compared the efficiency and safety of the combination treatment with desloratadine alone starting from January 1, 2014 until February 10, 2021 were selected by two co-first authors independently, and the extracted data were analysed using Rev Man 5.3 software. RESULTS: Fourteen RCTs were included in our meta-analysis with a total of 1501 patients. The results showed that the combination treatment yielded a better treatment effect (total response rate: RR = 1.23, 95% CI: 1.17 to 1.29, p < 0.00001; cure rate: RR = 1.50, 95% CI: 1.30 to 1.73, p < 0.00001), lower recurrence rate as well as superior immune improvement than the treatment with desloratadine alone. In addition, there was no significant difference in the safety of the two treatments. DISCUSSION AND CONCLUSION: The combination of desloratadine and compound glycyrrhizin is a promising treatment for CU and is associated with decreased serum IgE level and improved proportions of CD4+ T and CD8+ T cells.

Molecular Origin of the Distinct Tabletability of Loratadine and Desloratadine: Role of the Bonding Area - Bonding Strength Interplay.

PURPOSE: To explain the different tabletability of two structurally similar H1-receptor antihistamine drugs, loratadine (LOR) and desloratadine (DES), based on the molecular basis of bonding area and bonding strength. METHODS: LOR and DES were characterized by powder X-ray diffractometry, thermal analysis, and dynamic water sorption. The compressibility, tabletability, compactibility, and Heckel analysis of their bulk powders and formulations were evaluated. A combined energy framework and topological analysis was used to characterize the crystal structure - mechanical property relationship. Surface energy of bulk powder was assessed by contact angle measurement using the Owens/Wendt theory. RESULTS: Both LOR and DES bulk powders are phase pure and stable under compaction. The superior tabletability of LOR is attributed to both larger bonding area (BA) and higher interparticle bonding strength (BS). The larger BA of LOR results from its experimentally established higher plasticity, which is explained by the presence of more densely packed molecular layers with smooth surface topology. The higher BS of LOR corresponded to its significantly higher dispersive component of the surface energy. CONCLUSIONS: This work provides new insights into the molecular origins of BA and BS, which can be applied to improve mechanical properties and tableting performance of drugs through appropriate crystal engineering.

Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

Desloratadine and loratadine stand out among common H1-antihistamines for association with improved breast cancer survival.

BACKGROUND: As tumors maintain an inflammatory microenvironment, anti-inflammatory medication can be useful in cancer therapy. We have previously shown an association with improved survival in melanoma for use of the H1-antihistamines desloratadine and loratadine, and here we examine use of H1-antihistamines and breast cancer mortality. MATERIAL AND METHODS: We investigated use of the six major H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) and breast cancer-specific and overall mortality in a nation-wide register-based study of all 61,627 Swedish women diagnosed with breast cancer 2006-2013. Both peri- and post-diagnostic antihistamine use was analyzed using Cox regression models. Analyses were stratified for age and subgroup analyses based on estrogen receptor status and menopausal status were performed. RESULTS: We found a consistently improved survival of desloratadine users (HR = 0.67; 95% CI 0.55-0.81, p < .001), as well as of loratadine users (HR = 0.80; 95% CI 0.67-0.95, p = .012), relative to nonusers, regardless of patient age, menopause, estrogen receptor status or stage of the tumor, or whether breast cancer-specific or overall survival was analyzed. The survival of users of other antihistamines varied relative to non-users. CONCLUSION: Based on their safety and current use within the patient population, together with our observations, we suggest the initiation of trials of desloratadine and loratadine as treatment of breast cancer as well as studies of the mechanism behind their possible effect. Further studies on any effects of other H1-antihistamines may also be merited, as well as of H1-antihistamine use and survival in other malignancies.

Levocetirizine for the treatment of itch in psoriasis patients: An open-label pilot study in a real-world setting.

Itch is the most bothersome symptom in psoriasis, often leading to impaired quality of life. Treatment of psoriasis-induced itch is frequently unsatisfactory as the various therapies employed have a delayed onset of effect. Histamine-1 receptor (H1) antihistamines are not recommended in treatment guidelines as histamine is not considered a key mediator in psoriasis. However, patients using H1 antihistamines frequently report benefits in questionnaire-based studies. To address these contradictions, we examined the short-term effects of levocetirizine, a nonsedating H1 antihistamine, on psoriasis-related itch and itch-related quality of life. In this pilot study, patients with psoriasis-related itch received levocetirizine 5-10 mg daily as a concomitant treatment for 5 days. Change of itch intensity as measured by hourly itch ratings and the change of itch-related quality of life were measured at different time points. A total of 29 of 30 patients (96%) reported a decline in itch within 5 days. Mean itch reduction was 23% after Day 1 (p = .005), 40% after Day 3 (p < .001), and 41% after Day 5 (p < .001). Furthermore, itch-related quality of life also significantly improved after 5 days (p < .001). Only 2 of 30 patients (6.7%) reported mild sleepiness. Levocetirizine 5-10 mg daily as an add-on therapy seems to be an effective treatment to improve itch and itch-related quality of life within only a few days.

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria.

Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and Cmax values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC0-24 and Cmax were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo.Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar.What is Known:• Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day).• An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years.What is New:• As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years.• Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo.

Development of medicated chewing gum of taste masked levocetirizine dihydrochloride using different gum bases: in vitro and in vivo evaluation.

Objective: The aim of this study was to develop medicated chewing gum (MCG) formulation for taste-masked levocetirizine dihydrochloride (LCZ) that can provide fast drug release into the salivary fluid.Methods: Taste-masked LCZ was first prepared by two methods: cyclodextrin complexation using Kleptose or Captisol and formation of drug resin complex using Kyron T-154 or Kyron T-314 to overcome poor LCZ palatability. MCGs were then prepared using the taste-masked drug, gum base (Artica-T, Chicle, or Health In Gum (HIG), plasticizer (glycerol or soy lecithin at 6 or 8% of the final gum weight). The developed MCGs were evaluated for physical properties, content uniformity, and drug release. Best release MCGs were evaluated thermally to investigate the plasticizer effectiveness and for ex vivo chew out study to confirm adequate drug release. Drug bioavailability was determined for selected formula compared to commercial tablets.Results: Based on taste-masking efficiency, drug/Kleptose complex (1:3 molar ratio) was chosen for incorporation into chewing gums. Physical properties and drug release showed that gum base type, plasticizer type, and level affected not only physical properties but also drug release from MCGs. Thermal study showed decreased glass transition temperature (Tg) with increased plasticizer level. Chew out study confirmed almost complete drug release after a few minutes of chewing. Pharmacokinetic results showed shorter tmax (0.585 vs. 1.375 h) and higher Cmax (0.113 vs. 0.0765 µg/mL) for MCGs than conventional tablets.Conclusion: Results provided evidence that MCGs could be a better alternative to conventional tablet formulations with improved bioavailability and enhanced palatability.

Development of nanoemulsion gel drug delivery systems of cetirizine; factorial optimisation of composition, in vitro evaluation and clinical study.

Aim: This work aimed to develop topical nanoemulsion gels of cetirizine, a second-generation antihistamine, to avoid its oral intake drawbacks and enhance skin permeation.Methods: Cetirizine nanoemulsions were formulated and characterised for their particle size, polydispersity index, zeta potential, drug release and drug permeation through rat skin. The optimised formulation, obtained using 23 full factorial design, was incorporated in carbopol and chitosan gels and evaluated clinically for urticaria treatment.Results: The optimised formulation had particle size of 32.015 ± 1.87 nm, polydispersity index of 0.29 ± 0.04, zeta potential of -19.31 ± 0.43 mV, cetirizine percent released of 98.50 ± 1.23% and permeability coefficient of 7.65 cm.h-1. Cetirizine nanoemulsion gels were more effective than their control gels in urticaria treatment with significant decrease in the degree of wheals and itching and higher recovery percent.Conclusion: Cetirizine nanoemulsion topical gels are expected to be a rational and effective tool for avoiding cetirizine oral side effects and targeting the affected skin.

Real life management of chronic urticaria: Multicenter and cross sectional study on patients and dermatologists in Iran.

Recently, advances in understanding the etiology of urticaria and updates of diagnostic and therapeutic management guidelines have drawn attention to chronic urticaria (CU) morbidity. The present study aimed to evaluate Iranian dermatologists' practice and real life management of CU patients. A total of 35 dermatologists and 443 patients were included in the study. Number of female patients was 321 (72.5%). Mean (standard deviation) age of the study patients was 38 (13) years and the median (inter quartile range) of disease duration was 12 (6-48) months. Severity of patients' symptoms was mild for 32.1%, moderate for 38.7%, severe for 18.8%, and 10.4% of them had no evident signs or symptoms. The most common diagnostic methods were physical examination (96.6%), differential blood count (83.5%), erythrocyte sedimentation rate (77.4%), and C-reactive protein (62.8%). The number of dermatologists prescribed nonsedating antihistamines (nsAH) in regular dose and high dose mono therapy were 26 (74%) and 6 (17%), respectively. About 66% of dermatologists were familiar with British Association of Dermatologists (BAD) guideline. The most common first-line treatment for CU by Iranian dermatologists was nonsedating antihistamines in regular or high doses. The real-life management of patients with CU in Iran was in accordance with the available practice guidelines.

Levocetirizine and Prednisone Are Not Superior to Levocetirizine Alone for the Treatment of Acute Urticaria: A Randomized Double-Blind Clinical Trial.

STUDY OBJECTIVE: We evaluate the efficacy of a 4-day course of prednisone added to antihistamine for the management of acute urticaria in an emergency department (ED). METHODS: In this double-blind randomized clinical trial, patients were eligible for inclusion if aged 18 years or older and with acute urticaria of no more than 24 hours' duration. Patients with anaphylaxis or who had received antihistamines or glucocorticoids during the previous 5 days were not included. In addition to levocetirizine (5 mg orally for 5 days), patients were assigned to receive prednisone (40 mg orally for 4 days) or placebo. The primary endpoint of the study was itching relief 2 days after the ED visit, rated on a numeric scale of 0 to 10. Secondary endpoints were rash resolution, relapses, and adverse events. RESULTS: A total of 100 patients were included, 50 in each group. Seven patients in the prednisone group and 8 in the placebo group discontinued treatment. At 2-day follow-up, 62% of patients in the prednisone group had an itch score of 0 versus 76% of those in the placebo group (Δ 14%; 95% confidence interval -31% to 4%). Thirty percent of patients in the prednisone group and 24% in the placebo group reported relapses (Δ 6%; 95% confidence interval -23% to 11%). Mild adverse events were reported by 12% of patients in the prednisone group and 14% in the placebo group. CONCLUSION: The addition of a prednisone burst did not improve the symptomatic and clinical response of acute urticaria to levocetirizine. This study does not support the addition of corticosteroid to H1 antihistamine as first-line treatment of acute urticaria without angioedema.

Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
.

[Allergic rhinitis: the modern aspects of therapy]. / Allergicheskii rinit: sovremennye aspekty terapii.

The main objectives of the present article were to systematize the modern views of the causes and risk factors of allergic rhinitis, to clarify the manner of its development, to define the leading etiological mechanism underling the pathogenesis of this condition, to consider the methods used for the diagnostics and the treatment of this disease, and to sum up the clinical experience with the use of Levocetirizine (Allerwey) for the management of allergic rhinitis. Special attention is given to the achievement and the maintenance of control of the persistent or intermittent forms of allergic rhinitis and to approaches to its treatment based on the medications registered in the Russian Federation.

Citric Acid Suppresses the Bitter Taste of Olopatadine Hydrochloride Orally Disintegrating Tablets.

Orally disintegrating tablets (ODTs) are formulated to disintegrate upon contact with saliva, allowing administration without water. Olopatadine hydrochloride, a second-generation antihistamine, is widely used for treating allergic rhinitis. However, it has a bitter taste; therefore, the development of taste-masked olopatadine ODTs is essential. Some studies have suggested that citric acid could suppress the bitterness of drugs. However, these experiments were performed using solutions, and the taste-masking effect of citric acid on ODTs has not been evaluated using human gustatory sensation tests. Thus, this study evaluated citric acid's taste-masking effect on olopatadine ODTs. Six types of olopatadine ODTs containing 0-10% citric acid were prepared and subjected to gustatory sensation tests that were scored using the visual analog scale. The bitterness and overall palatability of olopatadine ODTs during disintegration in the mouth and after spitting out were evaluated in 11 healthy volunteers (age: 22.8±2.2 years). The hardness of the ODTs was >50 N. Disintegration time and dissolution did not differ among the different ODTs. The results of the gustatory sensation tests suggest that citric acid could suppress the bitterness of olopatadine ODTs in a dose-dependent manner. Olopatadine ODTs with a high content of citric acid (5-10%) showed poorer overall palatability than that of those without citric acid despite the bitterness suppression. ODTs containing 2.5% citric acid, yogurt flavoring, and aspartame were the most suitable formulations since they showed low bitterness and good overall palatability. Thus, citric acid is an effective bitterness-masking option for ODTs.

Efficacy and safety of bilastine in Japanese patients with chronic spontaneous urticaria: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II/III study.

BACKGROUND: Bilastine, a novel non-sedating second-generation H1-antihistamine, has been widely used in the treatment of allergic rhinoconjunctivitis and urticaria with a recommended dose of 20 mg once daily in most European countries since 2010. We evaluated its efficacy and safety in Japanese patients with chronic spontaneous urticaria (CSU). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled phase II/III study (trial registration No. JapicCTI-142574). Patients (age, 18-74 years) were randomly assigned to receive bilastine 20 mg, 10 mg or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline (Day -3 to 0) in total symptom score (TSS) at 2 weeks (Day 8-14), consisting of the itch and rash scores. RESULTS: A total of 304 patients were randomly allocated to bilastine 20 mg (101 patients), bilastine 10 mg (100 patients), and placebo (103 patients). The changes in TSS at 2 weeks were significantly decreased by bilastine 20 mg than did placebo (p < 0.001), demonstrating the superiority of bilastine 20 mg. Bilastine 10 mg also showed a significant difference from placebo (p < 0.001). The TSS changes for the bilastine showed significant improvement from Day 1, and were maintained during the treatment period. The Dermatology Life Quality Index scores were also improved in bilastine than in placebo. The bilastine treatments were safe and well tolerated. CONCLUSIONS: Two-week treatment with bilastine (20 or 10 mg) once daily was effective and tolerable in Japanese patients with CSU, demonstrating an early onset of action.

Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis.

There is a lack of large, randomized, double-blind studies that address antihistamine updosing for chronic spontaneous urticaria (CSU). The objective of this systematic review is to explore and analyse available data to provide clinical evidence for the efficacy of antihistamine updosing. We searched the literature in Medline, Scopus, Google Scholar, Embase, Web of Science and Cochrane databases using the keywords 'chronic, urticaria, antihistamines' to identify studies published between January 1990 and November 2014. We assessed quality using the Jadad score that evaluates quality of randomization, double-blinding and losses to follow-up. We identified 1042 articles and 15 articles were included in the final evaluation. We performed two meta-analyses, one that included studies that analysed treatment response among groups receiving different antihistamine dosages vs. placebo, and another that analysed antihistamine updosing in those patients who did not respond to standard dosages. Only five articles obtained a high quality level score. We did not find significant differences in response rates or number of weals in those patients who received a standard dosage vs. a high dosage. We found a significant improvement only in the pruritus variable of the Urticaria Activity Score scale. The estimated relative risk for improvement by increasing the antihistamine dosage was 2·27 [95% confidence interval (CI) 1·68-3·06]; however, there was significant heterogeneity. The proportion of nonrespondent patients with CSU who responded to antihistamine updosing was 63·2% (95% CI 57-69·6). We found that updosing antihistamines significantly improved control of pruritus but not weal number. However, the relative weakness of the studies and the significant heterogeneity among them made it difficult to reach a final conclusion.

Rupatadine 20 mg and 40 mg are Effective in Reducing the Symptoms of Chronic Cold Urticaria.

Chronic cold urticaria (ColdU) is a rare disease characterized by mast cell-mediated wheals and angioedema following cold exposure. Second-generation H1-antihistamines, such as rupatadine, are the recommended first-line therapy. As of yet, the effects of rupatadine up-dosing on development of ColdU symptom have only been partially characterized. Two-centre, randomized, double-blind, 3-way crossover, placebo-controlled study in patients with a confirmed ColdU was designed to assess the effects of up-dosing of rupatadine. A total of 23 patients were randomized to receive placebo, rupatadine 20 mg/day, and rupatadine 40 mg/day for 1 week. The primary outcome was change in critical temperature thresholds and critical stimulation time thresholds after treatment. Secondary endpoints included assessment of safety and tolerability of rupatadine. Both 20 and 40 mg rupatadine were highly effective in reducing critical temperature thresholds (p < 0.001) and critical stimulation time thresholds (p < 0.001). In conclusion, rupatadine 20 and 40 mg significantly reduced the development of chronic cold urticaria symptom without an increase in adverse effects.

A simulated car-driving study on the effects of acute administration of levocetirizine, fexofenadine, and diphenhydramine in healthy Japanese volunteers.

OBJECTIVE: Antihistamines are often used for treating allergic rhinitis. However, many older antihistamines cause sedative side effects. The sedative effects of antihistamines on car-driving have been investigated. This has not been investigated for levocetirizine, a new-generation antihistamine, in Asian populations, and so we evaluated its sedative effects in healthy Japanese subjects. METHODS: In this double-blind, placebo-controlled, four-way crossover study, healthy volunteers received single doses of levocetirizine 5 mg, fexofenadine 60 mg, diphenhydramine 50 mg, and placebo at intervals of at least 6 days. Simple brake reaction time and choice brake reaction time task (CBRT), a lateral tracking (LT) task, and a multiple task, a mixture of CBRT and LT task, were used to compare driving performance between the four drugs. Subjective sedation was also assessed. RESULTS: The simple brake reaction time and CBRT, and the CBRT component of the multiple task, did not show any significant differences between the drugs. In contrast, the LT, both as a single parameter and as a component of the multiple task, showed significant differences between diphenhydramine and the newer-generation antihistamines in a manner that corresponds with subjective sedation. CONCLUSIONS: Levocetirizine and fexofenadine did not impair psychomotor performance in subjects performing simulated car-driving tasks, while diphenhydramine did impair psychomotor performance in the subjects. Copyright © 2016 John Wiley & Sons, Ltd.

Psychological stress and its relationship with persistent allergic rhinitis.

UNLABELLED: Allergic rhinitis is considered to be a major health problem that impairs quality of life. A possible relationship with psychological stress may exist. The aim of this study is to verify the relationship between persistent allergic rhinitis (PAR) and psychological stress aiming to improve treatment and thereby quality of life (QOL) of patients. Patients with PAR (166) were diagnosed then analyzed using the Kessler Psychological Distress Scale. Patients with allergic rhinitis and who were positive on the Kessler scale (122) were randomly divided equally into a control group which received levocetirizine and a study group which received levocetirizine and imipramine. Nasal symptom assessment and QOL assessment were performed in all patients after treatment. Of the 166 patients with PAR, 122 (73.5 %) were positive on the Kessler Psychological Distress Scale. There was a marked improvement in the study group compared with the control group as regards nasal symptoms with better QOL in the study group (6.93) compared with the control group (2.13). Psychological stress has a strong impact on persistent allergic rhinitis. When stress is controlled by a combined treatment of imipramine and levocetirizine, allergic rhinitis symptoms improved and a better QOL was obtained. LEVEL OF EVIDENCE: 3b.

PREPARATION AND CHARACTERIZATION OF ORALLY DISINTEGRATING LORATADINE TABLETS MANUFACTURED WITH CO-PROCESSED MIXTURES.

The aim of this study was to develop orally disintegrated tablets (ODT) with loratadine using Parteck ODT and Ludiflash--new commercially available tableting excipients based on co-processed mannitol. ODT containing loratadine were prepared with 3% addition of various superdisintegrants (AcDiSol, Kollidon CL-F and Kollidon CL-SF) by direct compression method. Obtained tablets were characterized for friability, pore structure, and wetting and disintegration time measured by four independents methods. In order to identify possible interactions between loratadine and the excipients, differential scanning calorimetry was used. The results showed that all formulated ODT were characterized by appropriate mechanical properties (friability < 1%), the uniform content of the drug substance and pleasant mouth feeling. Disintegration time below 30 s was observed in formulations with crospovidones as disintegrant.