Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers.

Green tea (GT) alters the disposition of a number of drugs, such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of ~ 300 mg or water (control). In vitro transport assays were performed using HEK293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated fexofenadine transport. In the GTE phase, the area under the plasma concentration-time curve and the amount excreted unchanged into urine for 24 hours of fexofenadine were significantly decreased by 70% (P < 0.001) and 67% (P < 0.001), respectively, compared with control. There were no differences in time to maximum plasma concentration and the elimination half-life of fexofenadine between phases. Fexofenadine was confirmed to be a substrate of OATP1A2, and EGCG (100 and 1,000 µM) and GTE (0.1 and 1 mg/mL) inhibited OATP1A2-mediated uptake of fexofenadine. On the contrary, the concomitant administration of GTE did not influence the pharmacokinetics of pseudoephedrine. These results suggest that intake of GT may result in a markedly reduced exposure of fexofenadine, but not of pseudoephedrine, putatively by inhibiting OATP1A2-mediated intestinal absorption.

Evaluation of the Effects of Maytenus ilicifolia on the Activities of Cytochrome P450 3A and P-glycoprotein.

BACKGROUND: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown. OBJECTIVE: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities. METHODS: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI. RESULTS: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously. CONCLUSION: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF®) using an in vivo cocktail approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. AIM OF THE STUDY: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. MATERIALS AND METHODS: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. RESULTS: After exposure to EPP-AF®, it was observed decrease in the AUC0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25. CONCLUSIONS: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis.

OBJECTIVE: Tumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis. METHODS: In vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2. RESULTS: Serial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity. CONCLUSION: Collectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

A novel concept of immunological and allergy interactions in autism spectrum disorders: Molecular, anti-inflammatory effect of osthole.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by Diagnosis and Statistic Manual 5 (DSM-5) as persistent social interaction and communication deficient across multiple contexts. Various immunological findings have been reported in children with ASD, and co-existing allergic problems have been recorded in children diagnosed with ASD. Osthole, the effective component of Chinese traditional medicine, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of osthole on the histamine-induced inflammatory responses in PBMC cells. METHODS: Peripheral blood mononuclear cells (PBMC's) from children with: (1) ASD group with co-existing allergies/asthma (n = 29); (2) ASD group without allergy/asthma (n = 29); (3) Allergy group (n = 30) and from typically developing age-matched control subjects (n = 28) were stimulated with either histamine, FXF, osthole or mixture of this substances. mRNA COX-2 gene expression, COX-2 production and inhibitory effect of tested substances on COX-2 were assessed after stimulation. RESULTS: Children with ASD may show either an innate proinflammatory response or increased activity of COX-2 which could display more impaired behavioral profile than children with non-inflamed. This study indicated that COX-2 may be involved in pathogenesis of ASD and/or allergy, and osthole could be used to decrease the effects of COX-2 in inflammation and ASD development. High incidence of allergy in ASD patients may indicate immune dysregulation that could be of relevance to the pathophysiology, symptomatology or neuroimmunology of ASD. CONCLUSIONS: This study shows that fexofenadine (FXF - antihistamine drug) and osthole exhibit selective COX-2 enzyme inhibitory activity. The selective COX-2 activity of osthole may explain further the anti-inflammatory properties of osthole in relieving congestion in allergic rhinitis, and as distinctive effects between FXF and osthole were observed, individual antihistamines may have different modes of action via the COX enzyme system.

Real-life experience in the treatment of solar urticaria: retrospective cohort study.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis causing a significant impact on patients' quality of life (QoL), and treatment is often challenging. AIM: To analyse clinical experience with a tailored stepwise therapeutic approach. METHODS: A retrospective cohort design was used. Patients with suspected SU underwent laboratory investigations and photoprovocation. Those with a high minimal urticaria dose (MUD) were treated with a single antihistamine (protocol 1), and those with a lower MUD received three types of antihistamines (protocol 2); both protocols included a leucotriene receptor antagonist (LRA). In cases of failure, treatment was switched to omalizumab at doses of < 300 mg/month with incremental dosage increases as necessary (monthly dose range, 150-600 mg/month). Symptom relief and photoprovocation under treatment were evaluated. RESULTS: In total, 30 patients (10 men, 20 women) were enrolled. Most (87%) were sensitive to visible light (1-70 J/cm2 ) with or without extension to ultraviolet A. Of the 30 patients, 23 opted for our stepwise approach: 22 achieved complete remission on protocols 1 or 2 (n = 17) or after switching to omalizumab (n = 5), and another patient achieved partial remission under omalizumab. There were no treatment-related severe adverse effects. CONCLUSIONS: Symptoms of SU can be well controlled by treatment with antihistamines and an LRA tailored to the degree of photosensitivity, followed by omalizumab in refractory cases. This has important implications for patient QoL.

Effects of a Novel Barley-Based Formulation on Allergic Rhinitis: A Randomized Controlled Trial.

OBJECTIVE: Current treatment options for Allergic Rhinitis (AR) may have their own limitations and side effects. This study aimed to investigate the effects of Ma-al-Shaeer (MS), a novel natural formulation based on Hordeum vulgare, in the treatment of AR compared with Fexofenadine (FX). METHODS: A total of 77 patients with AR were divided into two groups: MS group (n=38) and FX group (n=39). The first group received 15 g of dried MS powder, and the second group received 60 mg of FX twice daily for 14 days. At baseline (week zero) and after the 14-day treatment period (week two), both groups were evaluated for sneezing, rhinorrhea, nasal congestion, nasal itching, post nasal drip, eye, throat, or ear symptoms, headache, cough, mental function, quality of life scores, blood eosinophil count and total IgE levels. Rhinitis control assessment tests were conducted at week zero and again at one week after cessation of treatment (week three) in both groups. RESULTS: All symptoms of AR except cough were significantly reduced in both groups; for nasal congestion, post nasal drip, and headache, the MS treatment was found to be superior. Rhinitis control was significantly increased after treatment in both groups (p value < 0.001). Both drugs significantly reduced total IgE levels. There was no significant change in eosinophil count in either group. CONCLUSION: MS formulation based on H. vulgare may be an effective treatment for AR. Further studies are needed to confirm the effect of MS as an alternative treatment in AR.

Effect of Garlic, Gingko, and St. John's Wort Extracts on the Pharmacokinetics of Fexofenadine: A Mechanistic Study.

The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/organic anion-transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John's wort (SJW; 1000 mg/kg; positive control), or Milli-Q water for 14 days. On day 15, rats either were administered fexofenadine (orally or i.v.), had their livers isolated and perfused with fexofenadine, or had their small intestines divided into four segments (SI-SIV) and analyzed for P-gp and Oatp1a5. In vivo, SJW increased the clearance of i.v. administered fexofenadine by 28%. Garlic increased the area under the curve0-∞ and maximum plasma concentration of orally administered fexofenadine by 47% and 85%, respectively. Ginkgo and SJW had no effect on the oral absorption of fexofenadine. In the perfused liver, garlic, ginkgo, and SJW increased the biliary clearance of fexofenadine with respect to perfusate by 71%, 121%, and 234%, respectively. SJW increased the biliary clearance relative to the liver concentration by 64%. The ratio of liver to perfusate concentrations significantly increased in all treated groups. The expression of Oatp1a5 in SI was increased by garlic (88%) and SJW (63%). There were no significant changes in the expression of P-gp. Induction of intestinal Oatp1a5 by garlic may explain the increased absorption of orally administered fexofenadine. Ginkgo had no effect on the expression of intestinal P-gp or Oatp1a5. A dual inductive effect by SJW on opposing intestinal epithelial transport by Oatp1a5 and P-gp remains a possibility.

Effect of fermented red ginseng on cytochrome P450 and P-glycoprotein activity in healthy subjects, as evaluated using the cocktail approach.

AIMS: We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P-glycoprotein (P-gp), in healthy volunteers. METHODS: This study was an open-label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). RESULTS: Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least-square mean metabolic ratio (90% CI) was 0.901 (0.830-0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720-0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925-1.197) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.150 (0.860-1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673-0.990) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast ) for fexofenadine (P-gp) was 1.322 (1.112-1.571). CONCLUSION: No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two-week administration of concentrated fermented red ginseng. However, the inhibition of P-gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P-gp substrate drugs.

Recommended Daily Dose of Sesame Lignans Has No Influence on Oral Absorption of P-Glycoprotein Substrates in Rats.

Sesamin (SM) and episesamin (ESM) are constituents of sesame seeds, which are used in health foods and considered to have various beneficial effects in the prevention of lifestyle-related diseases. P-Glycoprotein (P-gp) is an ATP-binding cassette transporter involved in drug absorption in the human gastrointestinal tract. A recent report indicated that SM influences P-gp-mediated drug transport. In the present study, we investigated whether SM and ESM inhibit P-gp in vitro, using Caco-2 cells and the typical P-gp substrates rhodamine123 (Rho123) and fexofenadine. SM and ESM showed no effect on accumulation of these compounds, indicating that SM and ESM do not influence P-gp function. In addition, an in vivo study using Rho123 indicated that SM and ESM do not affect absorption of P-gp substrates. Overall, these results suggest that health foods containing SM and ESM are unlikely to interact with P-gp substrates.

Treatment of solar urticaria using antihistamine and leukotriene receptor antagonist combinations tailored to disease severity.

BACKGROUND: Solar urticarial (SU) is characterized by erythema, whealing, and/or pruritus occurring minutes after sun exposure. Treatment is difficult and often unsatisfactory. OBJECTIVES: To determine the action spectra and minimal urticaria dose (MUD) and to tailor a treatment regimen graded according to disease severity in a series of patients with SU. PATIENTS AND METHODS: Eleven patients (seven females, four males, age range: 5-60 years) with a clinical history suggestive of SU, verified by photo-provocation tests to ultraviolet A (UVA), visible light, and/or UVB, were treated with various combinations of antihistamines and leukotriene receptor antagonist. RESULTS: All patients were sensitive to visible light (median MUD 50 J/cm(2)). Three patients were sensitive to UVA (median MUD 3.75 J/cm(2)), and one patient was sensitive to UVB (MUD of 0.03 J/cm(2)). Two patients experienced a spontaneous remission without treatment. One patient declined treatment. The remaining eight patients were managed by a combination of antihistamines (desloratidine, fexofenadine, cetirizine HCl) and a leukotriene receptor antagonist (montelukast). Seven of the 8 patients experienced a sustained remission of symptoms and signs following treatment. CONCLUSIONS: Photoprovocation for SU with determination of action spectra and MUD enables specifically tailored treatment regimens consisting of combinations of antihistamines and leukotriene receptor antagonist.

Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers.

PURPOSE: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. METHODS: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 µM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice. RESULTS: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t max) of both enantiomers (P < 0.001). Although apple juice greatly reduced the amount of (R)- and (S)-fexofenadine excretion into urine (Ae0-24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. CONCLUSIONS: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice.

Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

Investigation on modulation of human P-gp by multiple doses of Radix Astragali extract granules using fexofenadine as a phenotyping probe.

ETHNOPHARMACOLOGY: Herb-drug interactions may potentially affect drug efficacy and/or the likelihood of adverse drug reactions. Radix Astragali (RA) extract formulation is usually prescribed for long-term use for patients with immunodeficiency, diabetes, nephropathy or cardiovascular diseases. Its use in combination with P-glycoprotein (P-gp) substrates is possible in clinical practice. Currently there is little knowledge about whether concomitant use of RA extract has an influence on disposition of P-gp substrate. AIM OF THE STUDY: This study was to investigate whether continuous and multiple doses of RA extract granules had modulatory effects on human P-gp. MATERIAL AND METHODS: A randomised, placebo-controlled, two-period crossover pharmacokinetic drug interaction study was conducted in healthy Chinese volunteers. Fexofenadine was used as a P-gp phenotyping probe. Fourteen volunteers received RA extract granules or placebo (4g bid) for 7 days and then received a single oral dose of 120mg fexofenadine. Fexofenadine plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by non-compartmental method and bioequivalence evaluation was performed. RESULTS: Pharamcokinetic parameters in the placebo phase were as follows: T1/2 (3.75±1.47h), Cmax (745.11±137.41µg/L), Tmax (2.25±0.47h), AUC(0-t) (3894.27±923.45µgh/L), AUC(0-∞) (3993.84±912.97µgh/L). Pharamcokinetic parameters in the RA extract phase were as follows: T1/2 (4.00±1.24h), Cmax (709.44±170.03µg/L), Tmax (2.21±0.51h), AUC(0-t) (3832.72±1077.60µgh/L), AUC(0-∞) (3983.53±1019.83µgh/L). The influence of RA extract on fexofenadine Cmax and AUC lacks statistical significance. Fexofenadine in the two phases were bioequivalent. In the placebo phase, T1/2 of fexofenadine in ABCB1 3435T mutation allele carriers was longer compared to ABCB1 3435CC carriers (4.43±1.44h vs. 2.54±0.21h, p<0.05). However, RA extract pretreatment abolished such genotype-related difference due to the lengthened T1/2 in ABCB1 3435CC carriers. There was no association of the C3435T polymorphism with Cmax and AUC(0-t) in subjects with two pretreatments. CONCLUSION: One-week administration of RA extract granules did not have a statistically significant impact on systematic exposure to fexofenadine, suggesting that RA extract is not a potent modulator of P-gp in vivo. RA extract appears to have ABCB1 C3435T genotype-dependent inhibitory effect on elimination rather than absorption of a P-gp substrate. Further investigations are necessary in patients who receive long-term use of RA extract formulation and combined P-gp substrates, especially in those ABCB1 3435CC carriers.

Comparison of nasal steroid with antihistamine in prophylactic treatment against pollinosis using an environmental challenge chamber.

Environmental challenge chambers (ECC) have been used to expose people to pollen allergens within a stable atmosphere and to examine the efficacy of treatment. Although pollinosis is one of the typical IgE-mediated type I allergic diseases, allergic inflammation is thought to contribute to the fundamental pathogenesis and prophylactic treatment may reduce exacerbations of pollinosis. The purpose of this study was to compare the efficacy of prophylactic treatment with nasal steroid (mometasone furoate nasal spray) or an antihistamine (fexofenadine) in the control of cedar pollinosis using the ECC. In a randomized, double-blind two-way crossover study, 48 patients received nasal steroid or antihistamine for 7 consecutive days (days 1-7). On day 8, patients were exposed to cedar pollen (8000 grains/m(3)) in the ECC for 3 hours. Nasal symptoms induced by pollen exposure were assessed. Total nasal symptom scores (TNSSs) during the exposure in the ECC were not significantly different between the antihistamine and the nasal steroid groups. Nasal symptoms induced by pollen exposure using the ECC persisted for up to 3 days. TNSSs after pollen exposure on days 8-11 were significantly lower in the nasal steroid group compared with the antihistamine group. Prophylactic treatment with nasal steroid is more effective than antihistamine against pollinosis, particularly in the late phase. Clinical trial registration JAPIC CTI 101182 (www.clinicaltrials.jp/user/ctiMain_e.jsp).

Enhancement of clara cell 10-kD protein (CC10) production from nasal epithelial cells by fexofenadine hydrochloride.

BACKGROUND: Clara cell 10-kD protein (CC10) is well known to be an immuno-suppressive protein secreted from airway epithelial cells after inflammatory stimulation and is involved in the development of allergic disorders. Although histamine H1 receptor antagonists are used for the treatment of allergic disorders, the influence of the agents on CC10 production is not well understood. In the present study, we examined the influence of a histamine H1 receptor antagonist, fexofenadine hydrochloride (FEX) on CC10 production in vitro and in vivo. METHODS: Nasal epithelial cells (5 x 10(6) cells/ml) were stimulated with 20 ng/ml TNF-alpha in the presence of various concentrations of FEX for 24 hours. CC10 levels in culture supernatants were examined by ELISA. Patients with Japanese cedar pollinosis were treated orally with FEX twice a day at a single dose of 60 mg for two weeks during Japanese cedar pollen season (February 2011 to April 2011). CC10 levels in nasal secretions were also examined by ELISA. RESULTS: The addition of FEX into cell cultures caused increase in CC10 production induced by TNF-alpha stimulation, and the minimum concentration that caused significant increase was 200 ng/ml. Oral administration of FEX also increased CC10 levels in nasal secretions from pollinosis patients along with attenuation of clinical symptoms. CONCLUSION: The ability of FEX to enhance CC10 production may account, at least in part, for the clinical efficacy of the agent in allergic disorders, including allergic rhinitis.

Preseasonal prophylactic treatment with antihistamines suppresses IL-5 but not IL-33 mRNA expression in the nasal mucosa of patients with seasonal allergic rhinitis caused by Japanese cedar pollen.

CONCLUSIONS: These findings suggest that the down-regulation of interleukin (IL)-5 gene expression in collaboration with the suppression of histamine H(1) receptor (H1R) gene expression in the nasal mucosa provides the basis for better therapeutic effects of preseasonal prophylactic treatment with antihistamines in patients with seasonal allergic rhinitis caused by Japanese cedar pollen. OBJECTIVES: The effects of prophylactic administration of antihistamines on the expression of IL-5 and IL-33 mRNA in the nasal mucosa of the patients with pollinosis were investigated. METHODS: Eight patients had already visited the hospital before the peak pollen period and started preseasonal prophylactic treatment with antihistamines. Seventeen patients who first visited the hospital during the peak pollen period were designated as the no treatment group. After local anesthesia, nasal mucosa was obtained by scraping the inferior concha with a small spatula during the peak pollen period. RESULTS: During the peak pollen period, the expression of IL-5 mRNA, but not that of IL-33 mRNA, in the nasal mucosa of patients receiving preseasonal prophylactic treatment with antihistamines was significantly lower in comparison with that of patients without treatment. Moreover, there was a significant correlation between the expression of IL-5 mRNA and the nasal symptoms or the expression of H1R mRNA.

Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose.

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.