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Jean Bousquet - One of the best experts on this subject based on the ideXlab platform.
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double blind placebo controlled study comparing the efficacy and safety of Fexofenadine hydrochloride 120 and 180 mg once daily and cetirizine in seasonal allergic rhinitis
The Journal of Allergy and Clinical Immunology, 1999Co-Authors: Peter H Howarth, Martin A Stern, Larry Roi, Robert Reynolds, Jean BousquetAbstract:Abstract Background: Fexofenadine hydrochloride (HCl) is a new H 1 antihistamine used twice daily in some countries. Objective: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of Fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis. Methods: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, Fexofenadine HCl 120 mg once daily, Fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded. Results: Both doses of Fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of Fexofenadine HCl or between either dose of Fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) ( P = .07) or Fexofenadine (4%) ( P = .02). Conclusions: Once-daily Fexofenadine is thus a valuable addition to the nonsedating group of H 1 receptor antagonists currently available for the treatment of seasonal allergic rhinitis. (J Allergy Clin Immunol 1999;104:927-33.)
Toshitaka Nabeshima - One of the best experts on this subject based on the ideXlab platform.
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Effects of single therapeutic doses of promethazine, Fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers
Archives of Dermatological Research, 2012Co-Authors: Hiroyuki Kamei, Koji Senzaki, Kazuhiro Ishikawa, Yukihiro Noda, Ami Isaji, Kiyofumi Yamada, Kazumitsu Sugiura, Yasushi Tomita, Toshitaka NabeshimaAbstract:Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients’ quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and Fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of Fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with Fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, Fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and Fexofenadine did not cause cognitive or psychomotor impairment.
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comparative study of acute effects of single doses of Fexofenadine olopatadine d chlorpheniramine and placebo on psychomotor function in healthy volunteers
Human Psychopharmacology-clinical and Experimental, 2003Co-Authors: Hiroyuki Kamei, Koji Senzaki, Isao Muraoka, Kazuhiro Ishikawa, Ian Hindmarch, Yoshinori Hasegawa, Yukihiro Noda, Toshitaka NabeshimaAbstract:Since most classical (first-generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second-generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second-generation antihistamines are not fully elucidated. In this randomized, double-blind, crossover study, the acute effects of single doses of second-generation antihistamines, Fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d-chlorpheniramine (4 mg), a first-generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d-chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d-chlorpheniramine, reduced the behavioural activity, while Fexofenadine had no effect in any of the tests. No significant changes in the subjects' self-ratings of drowsiness were found with the three antihistamines. These results suggest that d-chlorpheniramine and olopatadine, but not Fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of Fexofenadine is different from that of olopatadine. Copyright © 2003 John Wiley & Sons, Ltd.
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comparative study of acute effects of single doses of Fexofenadine olopatadine d chlorpheniramine and placebo on psychomotor function in healthy volunteers
Human Psychopharmacology-clinical and Experimental, 2003Co-Authors: Hiroyuki Kamei, Koji Senzaki, Isao Muraoka, Kazuhiro Ishikawa, Yoshinori Hasegawa, Yukihiro Noda, Toshitaka NabeshimaAbstract:Since most classical (first-generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second-generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second-generation antihistamines are not fully elucidated. In this randomized, double-blind, crossover study, the acute effects of single doses of second-generation antihistamines, Fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d-chlorpheniramine (4 mg), a first-generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d-chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d-chlorpheniramine, reduced the behavioural activity, while Fexofenadine had no effect in any of the tests. No significant changes in the subjects' self-ratings of drowsiness were found with the three antihistamines. These results suggest that d-chlorpheniramine and olopatadine, but not Fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of Fexofenadine is different from that of olopatadine.
David G. Bailey - One of the best experts on this subject based on the ideXlab platform.
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Fruit juice inhibition of uptake transport: a new type of food-drug interaction
British journal of clinical pharmacology, 2010Co-Authors: David G. BaileyAbstract:A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral Fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral Fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume–effect relationship study using a normal juice amount halved average Fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of Fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, Fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, Fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.
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naringin is a major and selective clinical inhibitor of organic anion transporting polypeptide 1a2 oatp1a2 in grapefruit juice
Clinical Pharmacology & Therapeutics, 2007Co-Authors: George K Dresser, David G. Bailey, Brenda F Leake, Richard B KimAbstract:We showed previously that grapefruit and orange juices inhibited human enteric organic anion-transporting polypeptide (OATP)1A2 in vitro and lowered oral Fexofenadine bioavailability clinically. Inhibition of OATP1A2 transport by flavonoids in grapefruit (naringin) and orange (hesperidin) was conducted in vitro. Two randomized, crossover, pharmacokinetic studies were performed clinically. In one study, 120 mg of Fexofenadine was ingested with 300 ml grapefruit juice, an aqueous solution of naringin at the same juice concentration (1,200 microM), or water. In the other study, Fexofenadine was administered with grapefruit juice, with or 2 h before aqueous suspension of the particulate fraction of juice containing known clinical inhibitors of enteric CYP3A4, but relatively low naringin concentration (34 microM), or with water. Naringin and hesperidin's half-maximal inhibitions were 3.6 and 2.7 microM, respectively. Fexofenadine area under the plasma drug concentration-time curves (AUCs) with grapefruit juice and naringin solution were 55% (P<0.001) and 75% (P<0.05) of that with water, respectively. Fexofenadine AUCs with grapefruit juice and particulate fractions were 57% (P<0.001), 96% (not significant (NS)), and 97% (NS) of that with water, respectively. Individuals tested in both studies (n=9 of 12) had highly reproducible Fexofenadine AUC with water (r(2)=0.85, P<0.001) and extent of reduction of it with grapefruit juice (r(2)=0.72, P<0.01). Naringin most probably directly inhibited enteric OATP1A2 to decrease oral Fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved. Naringin appears to have sufficient safety, specificity, and sensitivity to be a clinical OATP1A2 inhibitor probe. Inherent OATP1A2 activity may be influenced by genetic factors. This appears to be the first report of a single dietary constituent clinically modulating drug transport.
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intestinal drug transporter expression and the impact of grapefruit juice in humans
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Hartmut Glaeser, G K Dresser, J C Gregor, U I Schwarz, J S Mcgrath, David G. Bailey, E JolicoeurAbstract:The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered Fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of Fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before Fexofenadine administration was associated with reduced oral Fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for Fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced Fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.
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effect of grapefruit juice volume on the reduction of Fexofenadine bioavailability possible role of organic anion transporting polypeptides
Clinical Pharmacology & Therapeutics, 2005Co-Authors: George K Dresser, Richard B Kim, David G. BaileyAbstract:Objectives The purpose of this study was to elucidate the potential clinical relevance and mechanism(s) of action of 2 different volumes of grapefruit juice on the reduction of bioavailability of Fexofenadine, a substrate of organic anion transporting polypeptides. Methods Grapefruit juice or water at normal (300 mL) or high (1200 mL) volume was ingested concomitantly with 120 mg Fexofenadine by 12 healthy volunteers in a randomized 4-way crossover study, and Fexofenadine pharmacokinetics were determined over a period of 8 hours. Results The 300-mL volume of grapefruit juice decreased the mean area under the plasma drug concentration-time curve (AUC) and the peak plasma drug concentration of Fexofenadine to 58% (P < .001) and 53% (P < .001), respectively, of those with the corresponding volume of water, and 1200 mL grapefruit juice reduced these parameters to 36% (P < .001) and 33% (P < .001), respectively, of those with the corresponding volume of water. The 300-mL volume of grapefruit juice diminished the AUC of Fexofenadine variably among individuals. This decline correlated with baseline AUC of Fexofenadine with water at equivalent volume (r2 = 0.97, P < .0001). The 1200-mL volume of grapefruit juice decreased the AUC of Fexofenadine more than the 300-mL volume of grapefruit juice compared with the corresponding volume of water in each subject by a constant amount. Grapefruit juice, 300 mL and 1200 mL, reduced the coefficient of variation of the AUC of Fexofenadine by 2-fold compared with that with a matching volume of water. Conclusions Grapefruit juice at a commonly consumed volume diminished the oral bioavailability of Fexofenadine sufficiently to be pertinent clinically, likely by direct inhibition of uptake by intestinal organic anion transporting polypeptide A (OATP-A; new nomenclature, OATP1A2). A much higher volume caused an additional modest effect, possibly from reduced intestinal concentration and transit time of Fexofenadine. This food-drug interaction appears to be novel and may be relevant to other fruit juices and drugs. Clinical Pharmacology & Therapeutics (2005) 77, 170–177; doi: 10.1016/j.clpt.2004.10.005
Peter H Howarth - One of the best experts on this subject based on the ideXlab platform.
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double blind placebo controlled study comparing the efficacy and safety of Fexofenadine hydrochloride 120 and 180 mg once daily and cetirizine in seasonal allergic rhinitis
The Journal of Allergy and Clinical Immunology, 1999Co-Authors: Peter H Howarth, Martin A Stern, Larry Roi, Robert Reynolds, Jean BousquetAbstract:Abstract Background: Fexofenadine hydrochloride (HCl) is a new H 1 antihistamine used twice daily in some countries. Objective: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of Fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis. Methods: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, Fexofenadine HCl 120 mg once daily, Fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded. Results: Both doses of Fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of Fexofenadine HCl or between either dose of Fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) ( P = .07) or Fexofenadine (4%) ( P = .02). Conclusions: Once-daily Fexofenadine is thus a valuable addition to the nonsedating group of H 1 receptor antagonists currently available for the treatment of seasonal allergic rhinitis. (J Allergy Clin Immunol 1999;104:927-33.)
Jolene Mason - One of the best experts on this subject based on the ideXlab platform.
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the efficacy and safety of Fexofenadine hcl and pseudoephedrine alone and in combination in seasonal allergic rhinitis
The Journal of Allergy and Clinical Immunology, 1999Co-Authors: Gordon Sussman, Jolene Mason, Diana Compton, John Stewart, Nancy RicardAbstract:Abstract Background: Antihistamines effectively treat seasonal allergic rhinitis (SAR), although the ability of this drug class to reduce nasal congestion is limited. Nasal decongestants effectively treat nasal congestion but not the histamine-related components of SAR. Therefore antihistamine/nasal decongestant combinations are commonly used to maximize the treatment of SAR. Fexofenadine HCl is a nonsedating, long-acting H 1 receptor antagonist that provides fast and effective relief from SAR. It is well tolerated, with no sedative or cardiotoxic effects. Objective: We sought to compare the efficacy and safety of a Fexofenadine HCl/pseudoephedrine HCl combination with that of each individual component in the treatment of ragweed allergy. Methods: In this Canadian multicenter, double-blind, parallel-group study, 651 patients allergic to ragweed were randomized to receive 60 mg of Fexofenadine HCl twice daily, 120 mg of sustained-release pseudoephedrine HCl twice daily, or a combination of the 2 drugs (60 mg of Fexofenadine HCl/120 mg of sustained-release pseudoephedrine HCl) twice daily for 2 weeks. Efficacy analyses were based on symptom severity. In addition, a health economic assessment was performed. Results: Combination therapy was significantly more effective than pseudoephedrine alone in improving primarily histamine-mediated symptoms (sneezing; rhinorrhea; itchy nose, palate, and/or throat; and itchy, watery, red eyes) and significantly more effective than Fexofenadine alone in reducing nasal congestion. Combination therapy also produced greater improvements in daily activities and work productivity compared with the individual components. No serious adverse events were reported in any of the treatment groups. In addition, no clinically significant changes in 12-lead electrocardiogram parameters, vital signs, or clinical laboratory values were observed. Conclusion: Combination therapy is more effective than Fexofenadine alone or pseudoephedrine alone in relieving the full spectrum of SAR symptoms (ie, both the primarily histamine-related symptoms and nasal congestion). (J Allergy Clin Immunol 1999;104:100-6.)
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onset of action efficacy and safety of a single dose of Fexofenadine hydrochloride for ragweed allergy using an environmental exposure unit
Annals of Allergy Asthma & Immunology, 1997Co-Authors: Maureen P Briscoe, Anne K Ellis, April Welsh, Jeffrey Norman Smith, Adrian Clark, Jolene MasonAbstract:Background Fexofenadine hydrochloride is the active acid metabolite of terfenadine. Fexofenadine's antiallergic properties require confirmation in a clinical setting. Objective The purpose of this study was to characterize the time to onset of clinically important relief of symptoms of allergic rhinitis in subjects taking single doses of either 60 mg or 120 mg Fexofenadine HCl, or placebo, after exposure to ragweed pollen in a controlled environment. Other objectives were to assess the efficacy and safety of single doses of Fexofenadine HCl. Methods One hundred forty-six ragweed-sensitive subjects were primed in the off-season with ragweed pollen in the environmental exposure unit. One hundred thirty-six subjects who adequately responded to priming entered a single-dose placebo phase. Placebo-responders were disqualified from the study, leaving 99 subjects with adequate symptoms to be randomized and given a single dose of either Fexofenadine HCl 120 mg (33), 60 mg (33), or placebo (33) after 60 minutes of allergen exposure. Exposure continued over five hours and subjects recorded symptoms every 20 minutes. This study was of a randomized, placebo-controlled, double-blind, parallel design. Results Median time to onset for relaxed criteria clinically important relief was 60 minutes for both Fexofenadine treatment groups, and 100 minutes for placebo ( P = .018). The proportion with relief was 82% at 60 mg, 85% at 120 mg, and 64% for placebo. Treated groups had reductions in symptom scores double that of placebo. Conclusions Fexofenadine is safe and efficacious at single doses of 60 mg and 120 mg. Average time to onset was 60 minutes using controlled pollen exposure in an environmental exposure units.