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A comparison of the effects of olopatadine and ketotifen on model membranes.

Brockman H, Graff G, Spellman J, Yanni J.

Hormel Institute, University of Minnesota, Austin, USA.

Olopatadine is a human conjunctival mast cell stabilizer with antihistaminic activity. Ketotifen is an older molecule that possesses antihistaminic activity and is reported to have additional pharmacological properties. The interactions of these two compounds with model membranes (i.e., monolayers of 1-stearoyl-2-oleoyl-sn-glycerophosphocholine at the argon-buffer interface), and natural (i.e., erythrocyte) membranes were compared in an effort to understand the differences in their biological activities. Drug-lipid interaction with monolayers was determined by monitoring the surface pressure as a function of the drug concentration in the aqueous phase supporting the monolayer. Drug interaction with erythrocyte membranes was determined by monitoring changes in the permeability of the membranes to hemoglobin and 6-carboxyfluorescein as a function of drug concentration in the medium. Olopatadine and ketotifen are both intrinsically surface active and both interact with phospholipid monolayers. However, in both the presence and absence of lipid monolayers, the changes in surface pressure induced by olopatadine are lower than those caused by ketotifen. The effects of these two drugs on cell membranes were dramatically different. Exposure of bovine erythrocytes to increasing concentrations of ketotifen (1-10 mM) resulted in complete hemolysis of the cells, whereas olopatadine (1-10 mM) caused only minimal hemolysis (< 8%). Consistent results were obtained in experiments measuring the leakage of 6-carboxyfluorescein from erythrocyte ghosts as a more sensitive marker of membrane perturbation. Olopatadine treatment (0.1-10 mM) minimally perturbed the cell membrane while ketotifen (1-10 mM) caused a concentration dependent release of the fluorescent marker. These data demonstrate fundamental differences between the two drugs in their effects on cell membranes. Moreover, the differences are consistent with the surface activities of the two compounds measured in monolayers and with reported differences in their pharmacological activities. These findings offer an explanation for the biphasic non-specific cytotoxic effect of ketotifen on histamine release from mast cells and may account for the nonlytic mast cell stabilizing activity of olopatadine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11057342&dopt=Abstract olopatadine Patanol



Patanol
Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases.

Sharif NA, Xu SX, Miller ST, Gamache DA, Yanni JM.

Alcon Laboratories, Inc., Fort Worth, Texas, USA.

Olopatadine (AL-4943A; KW-4679) [(Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2-acetic acid hydrochloride] is an antiallergic/antihistaminic drug under development for topical ocular use. The effects of the compound on release of proinflammatory mediators (histamine, tryptase and prostaglandin D2) from monodispersed human conjunctival mast cells were assessed. Histamine receptor subtype binding affinities and functional potencies were determined with ligand binding and phosphoinositide turnover assays, respectively. Olopatadine inhibited the release of histamine, tryptase and prostaglandin D2, in a concentration-dependent manner (IC50 = 559 microM). Evaluation of the interaction of olopatadine with histamine receptors revealed a relatively high affinity for the H1 receptor (Ki = 31.6 nM, pKi = 7.5 +/- 0.1, n = 7) but lower affinities for H2 receptors (Ki = 100 microM, pKi = 4.0 +/- 0.19, n = 7) and H3 receptors (Ki = 79.4 microM, pKi = 4.1 +/- 0.16, n = 7). The H1 selectivity of olopatadine was superior to that of other ocularly used antihistamines studied, such as ketotifen, levocabastine, antazoline and pheniramine. The profiling of olopatadine in 42 nonhistamine receptor binding assays revealed that olopatadine interacts with only two nonhistamine receptor/uptake sites to any significant degree (pIC50 < or = 5-6). Olopatadine inhibited histamine-induced phosphoinositide turnover in human conjunctival epithelial cells (IC50 = 10 nM, pIC50 = 8.0, n = 4) and in other human ocular cells (IC50 = 15.8-31.6 nM, pIC50 = 7.5-7.8) and exhibited apparent noncompetitive antagonist properties in these cells, with an estimated dissociation constant (Kb) of 19.9 nM (pKb = 7.7, n = 6). This combination of mast cell mediator release inhibition and selective H1 receptor antagonism suggests that olopatadine may be particularly useful in the treatment of ocular allergic diseases. Indeed, olopatadine has recently shown clinical efficacy in an allergic conjunctivitis model in human subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8819509&dopt=Abstract olopatadine Patanol



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Effect of the new antiallergic agent olopatadine on EEG spectral powers in conscious rats.

Kamei C, Ichiki C, Izumo T, Ohishi H, Yoshida T, Tsujimoto S.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Japan.

The central effect of olopatadine (((Z)-11-[3-dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride, CAS 140462-76-6, KW-4679) was studied in comparison with those of ketotifen and doxepin using spontaneous EEG and EEG spectral powers in conscious rats. Both ketotifen (20 mg/kg p.o.) and doxepin (20 mg/kg p.o.) caused drowsy patterns in spontaneous EEG characterized by slow waves of high amplitude at the frontal cortex, occipital cortex and amygdala, and by disappearance of the regularity in theta waves recorded from the hippocampus. In EEG spectral powers, both drugs caused a significant increase in the power densities of the delta band recorded from the frontal cortex, occipital cortex and amygdala. On the contrary, no visible changes were elicited by the treatment with olopatadine (20 mg/kg p.o.) in both spontaneous EEG and EEG spectral powers recorded from the frontal cortex, occipital cortex, hippocampus and amygdala. These results indicate that olopatadine provides no remarkable effect on the central nervous system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9125280&dopt=Abstract olopatadine Patanol



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Inhibition of histamine-induced human conjunctival epithelial cell responses by ocular allergy drugs.

Yanni JM, Weimer LK, Sharif NA, Xu SX, Gamache DA, Spellman JM.

Ophthalmic Products Research, Alcon Laboratories Inc, Fort Worth, Tex 76134-2099, USA. John.Yanni AlconLabs.com

OBJECTIVE: To evaluate the effects of topical ocular drugs with histamine H1-antagonist activity on histamine-stimulated phosphatidylinositol turnover and interleukin (IL) 6 and IL-8 secretion from human conjunctival epithelial cells. METHODS: Primary human conjunctival epithelial cell cultures were stimulated with histamine in the presence or absence of test drugs. Phosphatidylinositol turnover was quantified by ion exchange chromatography and cytokine content of supernatants by enzyme-linked immunosorbent assay. RESULTS: Antazoline hydrochloride, emedastine difumarate, levocabastine hydrochloride, olopatadine hydrochloride, and pheniramine maleate attenuated histamine-stimulated phosphatidylinositol turnover and IL-6 and IL-8 secretion. Emedastine was the most potent in ligand binding, phosphatidylinositol turnover, and IL-6 secretion, with dissociation constant and 50% inhibitory concentrations of 1-3 nmol/L. Olopatadine, antazoline, and pheniramine exhibited similar H1-binding affinities (32-39 nmol/L). However, olopatadine was approximately 10-fold more potent as an inhibitor of cytokine secretion (50% inhibitory concentration, 1.7-5.5 nmol/L) than predicted from binding data, while antazoline and pheniramine were far less potent (20- to 140-fold) in functional assays. Levocabastine (dissociation constant, 52.6 nmol/L) exhibited greater functional activity (50% inhibitory concentration, 8-25 nmol/L) than either antazoline or pheniramine. CONCLUSIONS: Histamine-stimulated phosphatidylinositol turnover and cytokine secretion by human conjunctival epithelial cells are attenuated by compounds with H1-antagonist activity. However, antihistaminic potency alone does not predict anti-inflammatory potential. Olopatadine, emedastine, and levocabastine were notably more potent than pheniramine and antazoline. CLINICAL RELEVANCE: Selected topical ocular drugs with antihistaminic activity may offer therapeutic advantages to patients with allergic conjunctivitis by inhibiting proinflammatory cytokine secretion from human conjunctival epithelial cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10326962&dopt=Abstract olopatadine Patanol



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Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate.

Aguilar AJ.

OBJECTIVE: To compare the clinical efficacy and tolerance of 0.1% olopatadine hydrochloride (OHC) versus 0.05% ketotifen fumarate (KF) in the management of allergic conjunctivitis. MATERIALS AND METHODS: Eighty adult patients with a history of allergy (allergic conjunctivitis, hay fever, asthmatic bronchitis and dermatitis) that were showing allergic conjunctivitis signs and symptoms (itching, hyperemia, mucous discharge and tearing) at the time of inclusion in this study were evaluated. Patients were divided in two groups, A and B. Group A patients were treated with OHC and group B patients were treated with KF. Both groups received one drop in the affected eye every 12 hrs. The start time of this study was the first patient visit, in which the medication was instilled for the first time. Both groups of patients were evaluated 30 min, 48 hr., 7 days and 14 days later. Local tolerance of each medication was evaluated. RESULTS: Clinical improvement of the signs and symptoms of allergic conjunctivitis occurred in 42.5% to 62.5% of the patients in Group A when assessed 30 min following the first topical ocular dose of olopatadine. However, mucous discharge was not affected. Forty-eight (48) hrs. after the first instillation, improvements in 57.5% to 75% of the patients were shown in every evaluated parameter. After 7 days of treatment, positive clinical results were observed in 80% to 87.5% of the treated patients. Except for the patients that were dismissed from the study before the seventh day of treatment due to the absence of therapeutic response (4/40), all patients satisfactorily completed the therapeutic plan by the seventh day. No intolerance reactions were observed in patients of this group. In Group B patients (KF), clinical improvement of the signs and symptoms measured in the study was shown in 20.0% to 47.5% 30 min after instillation. As observed with olopatadine, no improvement in the number of patients showing mucous discharge was noted at the 30-min time point. At 48 hr. after the first instillation, 27.5% to 48% of patients showed improvement in every evaluated parameter. After 7 days of treatment, improvement was observed in 60% to 75% of patients. On Day 14, positive responses were observed in 67.5% to 75% of patients. Seventeen and one-half percent of the patients were dismissed from the study before the seventh day of treatment due to the absence of a therapeutic response. Approximately 23% of the patients had mild reactions of intolerance (stinging) which was not a cause to discontinue the treatment. CONCLUSION: Olopatadine hydrochloride controlled allergic conjunctivitis symptoms and signs more rapidly and to a greater extent than ketotifen fumarate. Fewer cases of treatment failure were noted with OHC, and no local intolerance reactions were observed, while KF triggered mild reactions (stinging) in 23% of patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11057352&dopt=Abstract olopatadine Patanol