Patanol
Changes in tear function and the ocular surface after topical olopatadine treatment for allergic conjunctivitis: an open-label study.

Dogru M, Ozmen A, Erturk H, Sanli O, Karatas A.

Department of Ophthalmology, Faculty of Medicine, Uludag University, Bursa, Turkey. muratodooru yahoo.com

BACKGROUND: Olopatadine hydrochloride 0.1% eye drops represent a new class of anti-allergic agent with combined antihistaminic and mast cell-stabilizing properties. OBJECTIVE: The purpose of this study was to describe alterations in tear function and the ocular surface in patients with allergic conjunctivitis and to analyze the effect of topical olopatadine treatment on corneal sensitivity, tear function, and impression cytology variables. METHODS: This was a single-center, 3-visit, prospective, open-label study conducted in patients with allergic conjunctivitis. Patients received 1 drop of topical olopatadine hydrochloride 0.1% BID for 3 weeks. At each visit, patients and healthy control subjects underwent routine ophthalmic examinations and measurements of corneal sensitivity and tear function (Schirmer test of tear quantity, tear film break-up time [BUT], fluorescein staining of the cornea). All control subjects and a subgroup of patients also underwent conjunctival impression cytology for assessment of squamous metaplasia and goblet cell density. The outcomes of interest were changes in corneal sensitivity, tear function, and impression cytology variables after 3 weeks of treatment with olopatadine eye drops, both in patients with allergic conjunctivitis and between patients and controls. RESULTS: At enrollment, the study included 46 eyes of 23 patients (9 men, 14 women; age range, 20-42 years) with allergic conjunctivitis; results were calculated based on the 21 patients who completed the study. The control group consisted of 70 eyes of 35 healthy subjects (13 men, 22 women; age range, 22-39 years). Before treatment, 64.3% of the eyes of patients with allergic conjunctivitis had a fluorescein staining score of >1 point, whereas after treatment, 14.3% had a score of >1 point (P < 0.001). Patients' mean (+/- SD) corneal sensitivity improved to 55.0 +/- 2.5 mm from the pretreatment value of 42.5 +/- 2.5 mm (P < 0.001). Mean BUT values before and after treatment were 8.1 +/- 3.5 and 14.0 +/- 7.0 seconds, respectively (P < 0.001). Before treatment, patients' mean squamous metaplasia grade was 2.5 +/- 0.5; at the end of treatment, it had decreased to 1.0 +/- 0.5 (P < 0.001). The mean pretreatment goblet cell density of 545 +/- 85 cells/mm2 improved to 1,090 +/- 100 cells/mm2 after treatment (P < 0.001). CONCLUSION: In the patient population studied, the disorder of tear function, squamous metaplasia, and loss of ocular surface goblet cells associated with allergic conjunctivitis improved with topical olopatadine treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12240781&dopt=Abstract olopatadine Patanol



Patanol
Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities.

Kajita J, Inano K, Fuse E, Kuwabara T, Kobayashi H.

Pharmacokinetic Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Ltd, Shizuoka, Japan.

Olopatadine, a new histamine H(1) receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety. Some compounds containing a similar alkylamino group form a cytochrome p450 (p450) -iron (II)-nitrosoalkane metabolite complex [metabolic intermediate complex (MIC)], thereby causing quasi-irreversible inhibition of the p450. There was concern that olopatadine might also form MICs, therefore, the present investigation was undertaken to explore this possibility. We identified the enzymes catalyzing olopatadine metabolism and investigated the effect of olopatadine on human p450 activities. During incubation with human liver microsomes in the presence of a NADPH-generating system, olopatadine was metabolized to two metabolites, M1 (N-monodemethylolopatadine) and M3 (olopatadine N-oxide) at rates of 0.330 and 2.50 pmol/min/mg protein, respectively. Troleandomycin and ketoconazole, which are both selective inhibitors of CYP3A, significantly reduced M1 formation but specific inhibitors of other p450 isozymes did not decrease M1 formation. Incubation of olopatadine with cDNA-expressed human p450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4. The formation of M3 was enhanced by N-octylamine and was inhibited by thiourea. High specific activity of M3 formation was exhibited by cDNA-expressed flavin-containing monooxygenase (FMO)1 and FMO3. Olopatadine did not inhibit p450 activities when it was simultaneously incubated with substrates for different p450 isozymes. Also, p450 activities in human liver microsomes were unaffected by pretreatment with olopatadine or M1. Furthermore, spectral analysis revealed that neither olopatadine nor M1 formed an MIC. Therefore, it is unlikely that olopatadine will cause drug-drug interactions involving p450 isozymes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12433826&dopt=Abstract olopatadine Patanol



Patanol
Acute stress results in skin corticotropin-releasing hormone secretion, mast cell activation and vascular permeability, an effect mimicked by intradermal corticotropin-releasing hormone and inhibited by histamine-1 receptor antagonists.

Lytinas M, Kempuraj D, Huang M, Boucher W, Esposito P, Theoharides TC.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

BACKGROUND: Mast cells play an important role in allergic inflammation by releasing vasoactive molecules, proteases and cytokines. Corticotropin-releasing hormone (CRH) and its structural analogue urocortin (Ucn) were shown to trigger skin mast cell activation and vascular permeability. We investigated the effect of acute stress on rat skin vascular permeability and CRH secretion, as well as the effect of intradermal CRH, and that of two histamine-1 receptor antagonists, azelastine and olopatadine, on vascular permeability. METHODS: Rats were stressed by restraint and vascular permeability was assessed by extravasation of (99)Tc-gluceptate, while mast cell activation was determined by skin rat mast cell protease-1 (RMCP-1) content. Skin CRH content was evaluated by ELISA. The effect of intradermal injection of CRH and Ucn, as well as that of two histamine-1 receptor antagonists, azelastine and olopatadine, was assessed by Evan's blue extravasation. Purified rat peritoneal mast cells (RPMCs) were also pretreated with azelastine (24 microM) or olopatadine (133 microM) for 5 min before challenge with compound 48/80 (0.5 microg/ml) for 30 min. Histamine secretion was measured fluorometrically. Intracellular Ca(2+) ions were evaluated in RPMCs loaded with calcium crimson and stimulated with compound 48/80. RESULTS: Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1. Intradermal injection of CRH or Ucn induced substantial Evan's blue extravasation that was inhibited by pretreatment with azelastine (24 microM) and olopatadine (133 microM). Both antihistamines also inhibited histamine release and intracellular increase of Ca(2+) ions from RPMCs stimulated by compound 48/80. CONCLUSIONS: These results indicate that acute stress increases skin CRH that can trigger mast cell-dependent vascular permeability, effects inhibited by certain histamine-1 receptor antagonists, possibly acting to reduce intracellular Ca(2+) ion levels. Copyright 2003 S. Karger AG, Basel

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Patanol
[In vitro effects of antiallergic eyedrops on complement activation induced by particulate matter]

[Article in French]

Blondin C, Cholley B, Haeffner-Cavaillon N, Goldschmidt P.

INSERM U430, Hopital Broussais.

BACKGROUND: Recent decades have been marked by an increasing number of patients suffering from ocular allergic-like symptoms without being associated with an increase in IgE levels. These symptoms include heaviness of the lid, foreign body sensation, burning, stinging and photophobia. Both epidemiological studies and controlled human exposure clinical studies have shown cause-effect relationships between allergic-like symptoms and environmental factors such as outdoor air pollutants or poor indoor air quality. An ocular surface subclinical inflammation is thought to be responsible for pseudoallergic, pollution-related conjunctivitis. The complement system is considered as one of the major effector mechanisms involved in initiation of the subclinical inflammation that leads to IgE-independent eye irritation. PURPOSE: To study the capability of nine antiallergic eyedrops commonly used in the treatment of allergic conjunctivitis to inhibit complement activation induced in vitro by pollutants. METHODS: Normal human serum obtained from healthy individuals was used as a source of complement. Activation of complement was assessed using the complement hemolytic 50% (CH50) assay, in the absence or the presence of antiallergic eyedrops and in the absence or the presence of various stimuli, including sand, common house dust, eye mascara, and Dactylis glomerata pollen extract. Zymosan was used as a standardized complement activator. The following eyedrops were studied: Naabak (4.9% N-acetyl aspartic acid-glutamic acid, NAAGA, sodium salt), Almide (lodoxamide 0.1%), Levophta (0.05% levocabastine), Emadine (0.05% emedastine), Tilavist (2% nedocromil), Allergodil (0.05% azelastine), Patanol (olopatadine), and Zaditen (0.025% ketotifen). Effects of preservative-free lodoxamide and ketotifen were also assessed and compared to those of the preserved formulations. A solution of 0.01% benzalkonium chloride (BAC), the most widely used preservative in topical eyedrops, was also tested. RESULTS: Zymosan-induced activation of complement (30+/-6%) was significantly lowered by preincubation of serum with unpreserved NAAGA (16.6+/-4%, p=0.0026) or benzalkonium-preserved nedocromil (20+/-2%, p=0.022). Preserved levocabastine, emedastine, olopatadine and ketotifen did not interfere with zymosan-induced complement activation, whereas preserved azelastine, lodoxamide and benzalkonium chloride significantly aggravated complement activation induced by zymosan. Similar results were obtained when complement activation was triggered by sand, common house dust, mascara, or by an allergenic extract of Dactylis glomerata pollen. In the absence of complement activator, none of the antiallergic eyedrops induced a significant change in CH50 titer, indicating that the deleterious pro-inflammatory effect of preserved azelastine and lodoxamide may occur only once complement activation has been initiated, i.e., on an inflamed ocular surface. CONCLUSION: Among the antiallergic eyedrops tested in this study, only Naabak and Tilavist were found to significantly inhibit complement activation triggered by particulate matters or pollen allergenic extract. Such an anticomplement activity confers these two molecules a potential in the therapeutic management of pollution-related pseudoallergic conjunctivitis.

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Patanol
Determination of olopatadine, a new antiallergic agent, and its metabolites in human plasma by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry.

Fujita K, Magara H, Kobayashi H.

Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.

A rapid, sensitive and specific assay method has been developed to determine plasma concentrations of olopatadine hydrochloride (A) and its metabolites, M1 (B), M2 (C) and M3 (D), using high-performance liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS). Olopatadine, its metabolites, and internal standard, KF11796 (E), were separated from plasma using solid-phase extraction (Bond Elut C18 cartridge). The eluate was dried, reconstituted and injected into the LC-ESI-MS-MS system. The calibration curves showed good linearity over the ranges 1-200 ng/ml for olopatadine and M3, and 2-100 ng/ml for M1 and M2, and the method was thoroughly validated and applied to the determination of olopatadine and its metabolites in plasma collected during Phase I clinical trials. Furthermore, the assay values were compared with those determined by the radioimmunoassay method, which has been routinely used to determine olopatadine in plasma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10510789&dopt=Abstract olopatadine Patanol