Why fexofenadine is considered as a truly non-sedating antihistamine with no brain penetration: a systematic review.

OBJECTIVE: Fexofenadine is a second-generation inverse agonist of H1-receptor of histamine which is highly selective with proven efficacy in relieving symptoms associated with allergic conditions. It has an additional benefit of not penetrating the blood-brain barrier and therefore do not induce sedation and not impair the cognitive function/psychomotor performance. This review aimed at providing evidence based on available controlled studies to reinforce the non-sedative property of fexofenadine for treating patients with allergic rhinitis and urticaria. METHODS: We performed an electronic literature search using keywords such as fexofenadine, drowsiness, somnolence, sedation, fatigue, cognitive, impairment, psychomotor, driving performances, sleep, rapid eye movement, alertness, clinical study, in vitro study, in vivo study, and pharmacodynamics in the Embase search engine. The review included randomized controlled trials, review articles, systematic reviews, and meta-analyses, together with post-marketing analysis conducted in healthy subjects and patients with allergy and were focused on comparing the antihistaminic potential or safety of fexofenadine with other antihistamines or placebo. RESULTS: Positron emission tomography (PET) and proportional impairment ratio (PIR) data along with other objective tests from various studies confirmed the non-sedative property of fexofenadine. Results of brain H1-receptor occupancy (H1RO) obtained from PET showed no H1RO by fexofenadine, the receptor which is known to cause sedation of H1 antihistamines. Most studies calculating PIR value as 0 showed fexofenadine to be a non-impairing oral antihistamine regardless of dose. Clinical trials in adults and children showed fexofenadine to be well tolerated without sedative effect or impairment of cognitive/psychomotor function even at higher than recommended doses. CONCLUSION: Published literature based on various parameters and clinical trials conducted for evaluating the effect of fexofenadine on sedation and central nervous system shows fexofenadine is both clinically effective and non-sedating.

Oral isotretinoin with desloratadine compared with oral isotretinoin alone in the treatment of moderate to severe acne: a randomized, assessor-blinded study.

BACKGROUND: Our aim was to measure the effectiveness of oral isotretinoin with desloratadine compared with oral isotretinoin alone in treating moderate to severe acne at a tertiary care teaching hospital in North India. In this study, 90 patients with moderate to severe acne were enrolled to participate based on their fulfilling the inclusion criteria. METHODS: A randomized, assessor-blinded, parallel-arm study was conducted. Randomization was done using computer-generated tables to allocate treatments in a 1:1 ratio. A low-dose oral isotretinoin at a dose of 0.3 mg/kg/day with tab desloratadine at 5 mg/day was applied to the study group and compared against the same patients going without the dosage when controls were conducted. Follow-up was at 4, 8, and 12 weeks. RESULTS: The primary outcome was an improved global acne grading system (GAGS) score and decreased acne lesion count. SECONDARY OUTCOME: patient satisfaction with treatment. The 90 participants were randomized and 15 participants dropped out of the study, leaving 75 participants for intention to treat analysis (n = 41, n = 30). At week 12, the GAGS score and acne lesion count between the study and control groups were comparable (P > 0.05). Pruritus reported was 9.76% in the study versus 33.33% in the control group (P = 0.018). Also, 53.66% of participants reported "excellent" treatment satisfaction in the study group versus 36.67% in the control group. CONCLUSIONS: The addition of desloratadine to an isotretinoin regimen has a role in reducing disease and therapy-related pruritus in acne and leads to improved patient satisfaction.

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.

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.

Targeted Use of Placebo Effects Decreases Experimental Itch in Atopic Dermatitis Patients: A Randomized Controlled Trial.

Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to "hidden drug administration.​" In a randomized controlled trial, we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN-DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN-DRUG+INST+COND) or infused drug without any information or sight (i.e., hidden administration (control group 1: HIDDEN-DRUG)). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary end point: experimental itch intensity, numeric rating scale), and objective level (secondary end point: wheal size, mm2 ). Experimental-induced itch intensity decreased in all groups but at different rates (P < 0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN-DRUG group (OPEN-DRUG+INST+COND: P < 0.001; OPEN-DRUG+INST: P = 0.009; and PLAC+INST+COND: P < 0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (P = 0.001). Results on wheal size were similar (P = 0.048), however, no significant difference between the HIDDEN-DRUG group and the PLAC+INST+COND group (P = 0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice.

A novel nasal co-loaded loratadine and sulpiride nanoemulsion with improved downregulation of TNF-α, TGF-ß and IL-1 in rabbit models of ovalbumin-induced allergic rhinitis.

PURPOSE: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management. METHODS: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-ß and IL-1. RESULTS: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2 ± 0.2 nm), low PDI (0.35 ± 0.0) and appropriate Zeta Potential (-23.3 ± 0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-ß significantly decreased from 9.59 ± 1.06, 4.15 ± 0.02 and 4.15 ± 0.02 to 1.28 ± 0.02, 1.93 ± 0.06 and 1.56 ± 0.02 respectively after treatment with the selected nanoemulsion formulation. CONCLUSION: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Efficacy of Alcaftadine 0.25% (AGN-229666) for Once-daily Prevention of Cedar-Pollen Allergic Conjunctivitis: A Phase 3 Randomized Study.

Purpose: This study evaluated the efficacy and safety of once-daily Alcaftadine 0.25% (AGN-229666) for prevention of signs and symptoms of Japanese cedar-pollen allergic conjunctivitis.Methods: This was a single-center, placebo-, and comparator-controlled study using the Ora-CAC® model of allergic conjunctivitis. The primary endpoint was ocular itching 16 hours after Alcaftadine 0.25% instillation; efficacy at 16 hours was compared with 0.1% Olopatadine, 4 hours after instillation. Secondary endpoints included conjunctival hyperemia.Results: 263 Japanese subjects were enrolled; 224 completed the trial. Alcaftadine 0.25% was statistically superior to vehicle for relief of ocular itching at 16 hours (p < .0001). Alcaftadine 0.25% at 16 hours was non-inferior to Olopatadine at 4 hours. Alcaftadine 0.25% was significantly better than vehicle for relief of conjunctival hyperemia. All treatments showed a low frequency of ocular adverse events.Conclusion: Once-daily Alcaftadine 0.25% is safe and effective in preventing signs and symptoms of Japanese cedar-pollen allergic conjunctivitis.

Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels.

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 ± 0.11 µmol L-1) compared to Kir2.1 channels (IC50 = 27.8 ± 4.8 µmol L-1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 ± 2.9 µmol L-1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.

A Randomized Study on the Bioequivalence of Desloratadine in Healthy Chinese Subjects and the Association of Different Metabolic Phenotypes With UGT2B10 and CYP2C8 Genotypes.

BACKGROUND: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. OBJECTIVE: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. METHODS: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. RESULTS: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. CONCLUSION: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.

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.

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.

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.

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.

The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine.

The macrolide antibiotic erythromycin has been associated with QT interval prolongation and inhibition of the hERG-encoded channels responsible for the rapid delayed rectifier K+ current I(Kr ). It has been suggested that low concentrations of erythromycin may have a protective effect against hERG block and associated drug-induced arrhythmia by reducing the affinity of the pore-binding site for high potency hERG inhibitors. This study aimed to explore further the notion of a potentially protective effect of erythromycin. Whole-cell patch-clamp experiments were performed in which hERG-expressing mammalian (Human Embryonic Kidney; HEK) cells were preincubated with low to moderate concentrations of erythromycin (3 or 30 µM) prior to whole-cell patch clamp recordings of hERG current (IhERG ) at 37°C. In contrast to a previous report, exposure to low concentrations of erythromycin did not reduce pharmacological sensitivity of hERG to the antipsychotic thioridazine and antihistamine terfenadine. The IC50 value for IhERG tail inhibition by terfenadine was decreased by ~32-fold in the presence of 3 µM erythromycin (p < .05 vs. no preincubation). Sensitivity to thioridazine remained unchanged (p > .05 vs. no preincubation). The effects of low concentrations of erythromycin were investigated for a series of pore blocking drugs, and the results obtained were consistent with additive and/or synergistic effects. Experiments with the externally acting blocker BeKm-1 on WT hERG and a pore mutant (F656V) were used to explore the location of the binding site for erythromycin. Our data are inconsistent with the use of erythromycin for the management of drug-induced QT prolongation.

Levocetirizine Oral Disintegrating Tablet: A Randomized Open-Label Crossover Bioequivalence Study in Healthy Japanese Volunteers.

Levocetirizine is classified as a second-generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate-release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study.

Corticosteroid reduction by addition of cetirizine and montelukast in biopsy-proven minimal-change nephrotic syndrome concomitant with allergic disorders.

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score-matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.