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Medical research on patanol
Allergol Int. 2008 Jul 1; 57(3):
Izumi N, Mizuguchi H, Umehara H, Ogino S, Fukui H
Background: H(1) antihistamines are widely used as therapeutics for allergic diseases. Sedation is a well-known side effect of H(1) antihistamines and sometimes it is life-threatening for patients. Thus it is important to evaluate the sedative properties of H(1) antihistamines to avoid side effects. For this purpose, histamine H(1) receptor (H1R) occupancy and proportional impairment ratios (PIR) are now being used. However, it is not easy to obtain these parameters. Here, we sought to evaluate the sedative properties of H(1) antihistamines by means of a large-scale surveillance at health insurance pharmacies. Methods: The survey was conducted at 37 health insurance pharmacies. The therapeutic efficacy and the degree of sleepiness were quantified through a questionnaire using the visual analog scale (VAS) directly from 1742 patients who received H(1) antihistamines. Results: The degree of sleepiness caused by the first-generation antihistamines was significantly higher than that of the second-generation antihistamines. The high VAS score in case of efficacy was found in d-chlorpheniramine, olopatadine, and ebastine. Among the mean values of efficacy, all second-generation antihistamines except for loratadine, bepotastine, and mequitazine were significantly higher than that of clemastine. Regarding the degree of sleepiness, clemastine scored the highest VAS score, and significantly lower scores were obtained in all second-generation antihistamines. Conclusions: The sedative properties of the H(1) antihistamines obtained from VAS analysis were very similar to those of H1R occupancy from positron emission tomography (PET) studies and PIR from meta-analysis. Our results indicate that large-scale surveillance using VAS might be useful to evaluate the profiles of H(1) antihistamines.
Enhancement of basophil apoptosis by olopatadine and theophylline.
Allergy Asthma Proc. 2008 May-Jun; 29(3): 322-8
Kawakami A, Suzukawa M, Koketsu R, Komiya A, Ohta K, Yamamoto K, Yamaguchi M
Regulation of basophil survival is an important aspect in the pathogenesis of allergic inflammation associated with local accumulation of basophils. However, pharmacologic modulation of basophil survival is largely unknown except for the apoptosis-enhancing effect of glucocorticoids. We tested the effects of two anti-allergic and anti-asthmatic drugs, olopatadine and theophylline, on basophil survival. Basophils were highly purified from normal human peripheral blood. Apoptosis was analyzed by flow cytometry using annexin V staining or another staining method that detected alterations in the mitochondrial transmembrane potential. In addition to the conventional method using annexin V, basophil apoptosis was successfully established by analysis of the mitochondrial transmembrane potential. Olopatadine decreased the number of live basophils, and they induced apoptosis of basophils during culture. The decline in live basophils was induced by olopatadine even when low doses of IL-3 were included in the culture medium. Theophylline also affected basophil apoptosis and induced a decrease in the number of live basophils. Basophil apoptosis was enhanced by both olopatadine and theophylline. This effect may partly explain the pharmacologic basis of why these drugs are effective on allergic diseases.
J Pharmacol Sci. 2008 May; 107(1): 66-79
Hishinuma S, Sato Y, Kobayashi Y, Komazaki H, Saito M
We evaluated changes in the binding properties of sedative and non-sedative histamine H1-receptor antagonists induced by internalization of H1 receptors in intact human U373 MG astrocytoma cells. Internalization of H1 receptors was induced without their degradation by treatment with 0.1 mM histamine for 30 min at 37 degrees C, and then the intact cell binding assay was performed at 4 degrees C. The binding properties of [3H]mepyramine, a cell-penetrating radioligand for H1 receptors, were not changed by histamine pretreatment. Displacement curves for sedative H1-receptor antagonists (diphenhydramine, chlorpheniramine, promethazine, ketotifen, azelastine and oxatomide) against [3H]mepyramine binding were not changed by histamine pretreatment. In contrast, the displacement curves for non-sedative H1-receptor antagonists (mequitazine, bepotastine, olopatadine, epinastine, carebastine, desloratadine and fexofenadine) were changed by histamine pretreatment: two types of changes, i.e. a rightward shift in the monophasic curve or an increase in the proportion of the low affinity component of the biphasic curve, were prevented under hypertonic conditions, in which clathrin-mediated receptor internalization is known to be inhibited. Thus, internalization-mediated changes in the binding properties of H1-receptor antagonists were well correlated with their sedative and non-sedative behaviors, which might confirm their permeability through the biomembrane and possibly the blood brain barrier.
P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1-receptor antagonist.
Drug Metab Pharmacokinet. 2008; 23(2): 106-14
Mimura N, Nagata Y, Kuwabara T, Kubo N, Fuse E
Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine. The uptake amount of olopatadine in human P-gp transfected LLC-PK1 cells (LLC-GA5-COL150) was lower than that in LLC-PK1. The uptake of olopatadine in LLC-GA5-COL150 was increased in the same level as that in LLC-PK1 in the presence of cyclosporine A, a P-gp inhibitor. After intravenous or oral administration of olopatadine to wild type (WT) and mdr1a/1b knockout (KO) mice at a dose of 1 mg/kg, the brain concentration in KO mice was higher than that in WT mice. On the other hand, the plasma concentration of olopatadine after either route of administration was not different between WT and KO mice. These results suggest that olopatadine is a substrate of P-gp, and that P-gp limits the brain penetration but dose not affect the plasma concentration of olopatadine.
Int Immunopharmacol. 2008 Jun; 8(6): 916-21
Tamura T, Komai M
The main symptoms of allergic rhinitis (AR) are sneezing, rhinorrhea and nasal obstruction. In patients with AR, levels of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) increase. Olopatadine hydrochloride (olopatadine) is an anti-allergic agent with histamine H1 receptor antagonistic action. To investigate whether olopatadine has an effect on inflammatory reactions, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as an animal model of nasal allergy. Nasal allergy signs (sneezing, rhinorrhea and inflammation) were induced after TDI challenge. Amounts of NGF and VEGF in the nasal lavage fluid increased. Olopatadine reduced nasal allergy signs and inhibited increases in NGF and VEGF. These findings suggest that the increases in NGF and VEGF production are involved in the mechanism responsible for nasal allergy signs in TDI-challenged rats. Other histamine H1 receptor antagonists did not inhibit and instillation of histamine did not increase TDI-induced NGF and VEGF production. Therefore, olopatadine appears to exert additional biological effects other than its blockade of the histamine H(1) receptor. These results suggest that suppression of neurogenic inflammatory reactions might be partially involved in the improvement of allergy signs after treatment with olopatadine.
Olopatadine 0.2% ophthalmic solution: the first ophthalmic antiallergy agent with once-daily dosing.
Expert Opin Drug Metab Toxicol. 2008 Apr; 4(4): 453-61
Abelson MB, Gomes PJ
BACKGROUND: Olopatadine 0.2% is the first topical ophthalmic antihistamine/mast cell stabilizer indicated for once-daily dosing. OBJECTIVE: This review provides a comprehensive description of the pharmacology of the olopatadine molecule, as well as of the clinical efficacy, tolerability, and safety of olopatadine 0.2% ophthalmic solution. METHODS: References cited in this review were obtained from the PubMed biomedical literature database. Also included were several posters presented at nationally renowned ophthalmology-related conferences. RESULTS/CONCLUSION: Olopatadine 0.2% was found to be a safe and effective medication for the reduction of itching with a duration of action of up to 24 h. The added convenience of a once-a-day dosing regimen is a major advancement in this drug class.
Exp Eye Res. 2008 May; 86(5): 791-7
Sanchis-Merino ME, Montero JA, Ruiz-Moreno JM, Rodriguez AE, Pastor S
In order to compare the relative efficacy of topical antihistamines with balanced saline solution (BSS) and benzalkonium chloride (BC) in the early phase of allergic conjunctivitis in an animal model of ocular anaphylaxis, 96 male guinea pigs were sensitized with intraperitoneal egg albumin (EA) and aluminum hydroxide. Seventy-six animals were used for determination of Evans blue (EB) extravasation and 20 for clinical evaluation of the allergic response (redness, edema, discharge and itch-scratch response). Eighteen days after sensitization the animals were topically challenged by conjunctival instillation of EA and treated 15min before and 15min after challenge with commercially available drugs (ketotifen, ketotifen single dose units [SDU], olopatadine, azelastine, spaglumic acid and emedastine) and controls (BSS and BC). The animals used for EB quantification were anesthetized and received an intravenous injection of EB simultaneously to the topical challenge. The ocular extravasation of the colorant was determined by 620nm absorbance spectrophotometry. The animals used for clinical evaluation were observed for clinical signs of the allergic reaction. EB ocular extravasation was significantly lower in the eyes treated by spaglumic acid and emedastine. The clinical scoring was consistent with EB extravasation, though the difference was not statistically significant. Spaglumic acid and emedastine seem to be the most useful drugs to reduce EB extravasation and allergic signs in an animal model of early phase allergic conjunctivitis.
J Pharmacol Sci. 2008 Mar; 106(3): 325-31
Fukui H
Brown Norway allergy model rats sensitized to toluene 2,4-diisocyanate (TDI) were developed. Histamine H(1) receptor mRNA level was elevated in nasal mucosa of allergy model rats after the provocation with TDI, which was followed by H(1)-receptor up-regulation. Elevation of histamine H(1) receptor mRNA was partially suppressed by d-chlorpheniramine and olopatadine, antihistamines. Histamine induced increase in histamine H(1) receptor gene expression in vitro, and the protein kinase C-delta isoform was suggested to mediate the gene expression. On the other hand, elevation of histamine H(1) receptor mRNA was completely suppressed by dexamethasone in allergy model rats. Provocation with TDI also induced mRNA elevation of histidine decarboxylase, a sole histamine-forming enzyme, followed by the increase of both HDC activity and histamine content in nasal mucosa of allergy model rats. HDC mRNA elevation and increase in both HDC activity and histamine level were almost completely suppressed by dexamethasone. These observations suggest that histamine H(1) receptor up-regulation and increase in histamine level play an important role in allergy through the regulation of histamine signaling.
Arch Dermatol Res. 2008 Feb 28;
Takahashi H, Zhang Y, Morita E
Potency of the antihistamine effects of olopatadine, cetirizine and fexofenadine in standard-dose application were compared from 11.5 to 24 h after application. The test was designed in a double-blind, randomized, crossover, placebo-controlled study of ten healthy volunteers on histamine-induced flare and wheal response using an iontophoresis technique. The suppressive effect of olopatadine on the wheals induced by a 0.1-mA histamine iontophoresis lasted for 24 h after dosing. Fexofenadine administered using the same regimen was the least effective among three drugs tested. Suppression of the wheal response by cetirizine, taken once-daily, decreased with time. Olopatadine completely suppressed even the wheal response induced by a 0.2-mA histamine iontophoresis, although fexofenadine and cetirizine were less effective on the wheals induced by the same histamine challenge. There were no significant differences in subjective drowsiness and objective cognitive function between drug- and placebo-treated subjects. These results demonstrate that olopatadine is the most potent antihistamine among the three H(1)-blockers when administered in a standard dosage.
Pharmacology. 2008; 81(3): 266-74
Matsumoto Y, Funahashi J, Mori K, Hayashi K, Yano H
Calcium responses to various concentrations of histamine were monitored in Chinese hamster ovary cells stably expressing the human histamine H(1) receptor. The effects of various histamine H(1) receptor antagonists on the dose-response curve for histamine were evaluated. Olopatadine hydrochloride (olopatadine) inhibited the histamine-induced maximum response (pD(2)': 7.5) but had insignificant effects on histamine EC(50) values. This noncompetitive property exhibited by olopatadine, which was also observed in human umbilical vein endothelial cells, was the most striking among the antihistamines tested in this study. The geometrical isomer of olopatadine (E-isomer), which had a similar binding affinity to the histamine H(1) receptor as olopatadine, showed a mixed antagonistic profile (competitive and noncompetitive). These results indicate that the geometry around the double bond in the dimethylaminopropylidene group is critical for the potent noncompetitive property of olopatadine. Furthermore, binding mode analyses suggest that the protonated amine group in the dimethylaminopropylidene moiety of olopatadine forms an ionic bond with Glu 181 that is present in the second extracellular loop of the histamine H(1) receptor, whereas the amine group of the E-isomer does not. The second extracellular loop in aminergic G-protein-coupled receptors contributes to ligand binding and therefore the noncompetitive property of olopatadine may be explained by the interaction with Glu 181.