olopatadine-hydrochloride and pemirolast

To address the current trends of therapeutic mechanisms for treatment of allergic conjunctivitis (AC), based on topical antihistamines and mast cell stabilizers (MCS).. The antihistamine drug alcaftadine has H4 receptor inverse agonism, anti-inflammatory and MCS activities. The antihistamines levocabastine and azelastine are more effective than placebo in treatment of AC symptoms in randomized controlled trials (RCTs). The topical dual-action antihistamines/MCS olopatadine, azelastine, ketotifen, and epinastine are commonly used in Europe and in the United States for mild subtypes of AC. For the main symptoms of AC, ocular itch and conjunctival hyperemia, epinastine 0.05% was superior to placebo, but equal or more effective than olopatadine 0.1%, while the later was more effective than ketotifen. High concentration olopatadine 0.77% had longer duration of action, better efficacy on ocular itch, and a similar safety profile to low-concentration olopatadine 0.2%. The new formulas of topical dual-action agents present longer duration of action, leading to a decreased frequency of use.. The topical dual-action agents are the most effective agents treating signs and symptoms of mild forms of AC. There is superiority to the high-concentration olopatadine drug over other agents on ocular itch, with prolonged effect when used once-daily.

Topics: Administration, Ophthalmic; Anti-Allergic Agents; Benzazepines; Conjunctivitis, Allergic; Cromolyn Sodium; Dibenzazepines; Histamine Antagonists; Humans; Hyperemia; Imidazoles; Ketotifen; Nedocromil; Olopatadine Hydrochloride; Phthalazines; Piperidines; Pruritus; Pyridines; Pyrimidinones

To investigate the cytotoxic effect of three kinds of topical ocular anti-allergic agent, including olopatadine 0.1% (A group), ketotifen fumarate 0.025% (B group) and pemirolast potassium 0.1% (C group), on cultured human corneal epithelial cells in vitro.. Primary human corneal epithelial cells were cultured with keratinocyte serum-free medium. The cells were exposed to three kinds of topical ocular anti-allergic agent for a period of 10 min, 30 min, 2 h, 6 h, 12 h and 24 h. Toxicity was examined in three ways. MTT assay was used to quantify cytotoxicity. Cell membrane permeability and intracellular esterase activity were analyzed with live-dead viability staining of fluorescent calcein-AM/ethidium homodimer. The morphologic analysis was performed by light and scanning electron microscopy. Statistical methods adopted one-way ANOVA (analysis of variance) and Student-Newman-Keuls q test between each group. The P-value of 0.05 was considered statistically significant.. (1) Morphologic changes: The Findings under the light microscopy were demonstrated that cells became round or edematic and detached from dishes after exposure to topical ocular anti-allergic agent. The cellular damage was more severe with longer exposure time and increasing concentration. Likewise, the electron microscopy examination showed reduced microvilli with longer exposure time and increasing concentration. The cellular changes of 20.0% olopatadine 0.1% were reduced when compared to the other agents. (2) Live/dead viability/cytotoxicity assay: Ethidium homodimeric permeates damaged cell membranes and results in red fluorescence. These results indicated that cell membrane damage caused by 20.0% olopatadine 0.1% at 6, 12, 24 h was less than those of ketotifen fumarate 0.025% and pemirolast potassium 0.1%. The data of A group were (29.7 +/- 2.6)%, (36.9 +/- 3.2)%, (51.2 +/- 4.3)%, B group were (36.5 +/- 3.1)%, (48.5 +/- 4.3)%, (75.5 +/- 3.8)% and C group were (37.1 +/- 2.2)%, (52.7 +/- 3.4)%, (71.1 +/- 5.1)%, respectively. The q values of A to B group and A to C group at 6 h were 3.27, 4.31, respectively (P < 0.05). The green fluorescent staining of calcein-AM indicated intracellular esterase activity was decreased after incubation with increasing concentration and longer exposure time. There was no significantly different result between each group (P > 0.05). The proportion of green staining cell of A, B and C group at 24 h were 100.0% with 50.0% concentration and were (23.2 +/- 4.6)%, (29.5 +/- 5.2)%, (31.1 +/- 5.5)% respectively with 20.0% concentration (F = 1.97, P = 0.377). (3) MTT assay: The results of the three groups revealed cell viability decreased significantly with increasing concentration and longer exposure time at all the concentrations except 0.8%. MTT values for A, B and C group at the concentration of 20.0%, at 6 h were 0.429 +/- 0.028, 0.367 +/- 0.038, 0.379 +/- 0.012 and 4% at 24 h were 0.457 +/- 0.025, 0.401 +/- 0.008, 0.387 +/- 0.012, respectively. The data for olopatadine 0.1% were significantly improved over those of ketotifen fumarate 0.025% and pemirolast potassium 0.1%. The q value of A to B group, A to C group were 3.01, 3.77 (P < 0.05) at the concentration of 20.0%, 6 h and were 3.63, 4.11 (P < 0.05) at the concentration, 24 h. There were no statistical significant results at other concentrations.. The topical ocular anti-allergic agent, olopatadine 0.1%, showed less toxic effects on human corneal epithelial cells compared to ketotifen fumarate 0.025% and pemirolast potassium 0.1%. Olopatadine 0.1% may offer a safer option to the corneal epithelium when used to treat allergic keratoconjunctivitis over an extended period of time.

Topics: Anti-Allergic Agents; Cell Membrane Permeability; Cell Survival; Cells, Cultured; Dibenzoxepins; Epithelial Cells; Epithelium, Corneal; Humans; Ketotifen; Olopatadine Hydrochloride; Ophthalmic Solutions; Pyridines; Pyrimidinones

The concept of mast cell heterogeneity is well established. Recent data indicate that human conjunctival tissue mast cells and human connective tissue mast cells respond to various secretagogues in similar fashion. It is now recognized that different mast cell populations respond differently to anti-allergic drugs.. The purpose of the study is to compare the effects of three new ocular anti-allergic drugs (nedocromil, olopatadine, and pemirolast) on mediator release from the target human conjunctival mast cell population with those of cromolyn sodium. The affinity of the compounds for the histamine H1 receptor was also compared.. A monodispersed suspension of partially purified human conjunctival mast cells was prepared from cadaver conjunctival tissue. Mast cells (5 x 10(3)) were challenged with anti-human IgE in the presence or absence of test drugs, and histamine content of the cell supernatants was determined using a specific radioimmunoassay. H1 receptor binding activity was assessed using a radioligand binding assay.. Cromolyn and pemirolast (100 nM to 1 mM) failed to significantly inhibit histamine release from human conjunctival mast cells using exposure times of 1 and 15 minutes prior to challenge. Using identical nedocromil concentrations and exposure times, statistically significant (P < .05) inhibition (28%) of histamine release was observed at only the 100 microM concentration and 1-minute exposure time. In contrast, olopatadine inhibited histamine release in a concentration-dependent fashion (r = 0.891, n = 59, IC50 = 653 microM). Only olopatadine exhibited significant H1 receptor binding activity at relevant concentrations (Ki = 36 nM, n = 13).. These data indicate that olopatadine possesses anti-allergic activity in the appropriate targets for topical ocular anti-allergic drug therapy, human conjunctival mast cells. Coupled with the compound's antihistaminic activity, this suggests that olopatadine will have efficacy advantages in allergic conjunctivitis patients over the other drugs tested.

Topics: Administration, Topical; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Conjunctiva; Dibenzoxepins; Histamine Release; Humans; Mast Cells; Nedocromil; Olopatadine Hydrochloride; Pyridines; Pyrimidinones; Receptors, Histamine H1