leukotriene-b4 and Conjunctivitis--Allergic

To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial.. Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33.. Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall clinical score of 53%, composed of an improvement in symptoms of 65% [63.64-66.67%] and signs of 40% [40-40.12%] by day 56.. In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway.

Topics: Complement C5; Conjunctivitis, Allergic; Cyclosporine; Humans; Leukotriene B4; Ophthalmic Solutions; Treatment Outcome

To evaluate the effects on signs and symptoms of a coexisting vernal keratoconjunctivitis in patients treated with oral montelukast sodium for asthma.. Twelve patients with vernal keratoconjunctivitis and asthma were enrolled in this pilot study. Topical eyedrops or any systemic treatment was discontinued for at least 7 days before montelukast treatment. Patients were asked to grade their ocular discomfort daily. The following signs and symptoms were also recorded and graded through medical examination at baseline,after 15 days of treatment, and 15 days after treatment discontinuation: physician-evaluated tarsal and bulbar papillae, hyperemia, secretion, and chemosis; and patient-evaluated itching, burning, tearing, photophobia, foreign body sensation, secretion, and redness. Peak expiratory flow rate at 8 AM was also recorded. Samples were collected at the same time points for enzyme-linked immunosorbent assay measurement of leukotriene B4 in tears and leukotriene E4 in urine.. Eight of the 10 patients evaluated reported a reduction in symptoms at the end of treatment. Montelukast treatment significantly decreased physician-rated hyperemia, secretion, and chemosis as well as patient-rated burning, tearing, photophobia, secretion, and redness. Effects persisted 15 days after discontinuation of treatment. Clinical changes were associated with a significant increase in leukotriene B4 in tears and a significant decrease in leukotriene E4 in urine after 15 days of treatment.. The significant and persistent reduction of ocular signs and symptoms in asthmatic patients with vernal keratoconjunctivitis treated for 15 days with montelukast strongly suggests the need for double-masked placebo-controlled trials to confirm the potential of this new treatment in vernal keratoconjunctivitis.

Topics: Acetates; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Conjunctivitis, Allergic; Cyclopropanes; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukotriene Antagonists; Leukotriene B4; Leukotriene E4; Male; Ophthalmic Solutions; Peak Expiratory Flow Rate; Pilot Projects; Quinolines; Sulfides; Tears

We compared tear leukotriene B4 (LTB4) and leukotriene C4 (LTC4) levels of vernal keratoconjunctivitis (VKC) patients with those of age-matched controls and evaluated the effects of disodium cromoglycate (DCG) 2%, lodoxamide 0.1% and fluorometholone 0.1% on the tear LTB4 and LTC4 levels of the VKC patients.. Thirty VKC patients were divided into three groups and their tear LTB4 and LTC4 levels measured with an enzyme-linked immunoassay technique before and after treatment with either lodoxamide 0.1%, DCG 2% or fluorometholone 0.1%. The results were compared with the tear LTB4 and LTC4 levels of 10 healthy control subjects. During this trial period, clinical scores for signs and symptoms of VKC were also evaluated.. In the VKC patients median tear LTB4 and LTC4 levels were 349.0 pg/ml (range 213.3-707.7 pg/ml) and 225.2 pg/ml (range 196.1-241.1 pg/ml) respectively--significantly higher than the control group (p = 0.0065 for LTB4 and p = 0.0003 for LTC4). After treatment, LTB4 levels decreased significantly in all treatment groups when compared with baseline (for the lodoxamide group, p = 0.01; for the DCG group, p = 0.008; for the fluorometholone group, p = 0.045). LTC4 levels were also significantly reduced after treatment in all three treatment groups (for the lodoxamide group, p = 0.0209; for the DCG group, p = 0.0284; for the fluorometholone group, p = 0.0109).. Tear LTB4 and LTC4 levels are significantly higher in VKC patients than controls, which points to a possible role of lipoxygenase pathway products in the pathophysiology of ocular allergic disorders. Lodoxamide 0.1%, DCG 2% and fluorometholone 0.1% were all effective in reducing LTB4 and LTC4 levels in VKC.

Topics: Adolescent; Adult; Anti-Allergic Agents; Anti-Inflammatory Agents; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Fluorometholone; Glucocorticoids; Humans; Leukotriene B4; Leukotriene C4; Male; Oxamic Acid; Tears

A therapeutic trial of 1% indomethacin (Indoptic) eye drops was carried out in 21 children. Looking for possible mediators of inflammation in vernal conjunctivitis, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4 levels in the tears of 9 patients were measured and the effect of the treatment on them examined. A control group of 10 unaffected children was added. Out of 42 eyes in which indomethacin treatment was instilled, only 17 remained in treatment through a 6-week follow-up period. In a few of them a moderate improvement was obtained. The mean level of PGE2 in the patients before treatment was found to be slightly lower than that in the control group, and it dropped even lower during treatment. The average LTB4 level found in patients before treatment was significantly higher than the control group; it decreased somewhat following treatment, but not significantly. This is the first report of elevated LTB4 levels in vernal conjunctivitis, previously not recorded in the literature, it points to the possible role of LTB4 in the pathogenesis of the disease. A constant relationship was observed between low PGE2 levels and high LTB4 content in the patients' tears during highly inflamed states of the eye. We conclude that: (a) indomethacin did not prove to be a highly effective topical treatment for vernal conjunctivitis; (b) PGE2 does not seem to be a dominant mediator of inflammation in this disease; and (c) LTB4, on the other hand, apparently has a role in the mechanism of inflammation of the disease, thus raising hopes for future addition to therapy.

Topics: Adolescent; Child; Child, Preschool; Conjunctivitis, Allergic; Dinoprostone; Female; Humans; Indomethacin; Leukotriene B4; Male; Ophthalmic Solutions; Prospective Studies; Retrospective Studies; Tears

Itching of ocular allergy is alleviated but not completely relieved by H(1) histamine receptor antagonists, suggesting that histamine is not the sole itch mediator in ocular allergy. We investigated whether leukotriene B(4) (LTB(4)), a mediator of cutaneous itch, is involved in the itch of ocular allergy in mice. Mice were immunized by the repeated subcutaneous injections of ragweed pollen and alum into the caudal back, and given a subconjunctival injection of ragweed pollen extract into the palpebra for allergic challenge. Challenge with ragweed pollen extract markedly elicited ocular scratching in sensitized mice. The scratching was almost abolished by mast cell deficiency. The H(1) antagonist terfenadine partially inhibited scratching at a dose that almost completely suppressed plasma extravasation. Scratching was inhibited by the glucocorticoid betamethasone and the 5-lipoxygenase inhibitor zileuton at doses that inhibited the challenge-induced production of LTB(4). A subconjunctival injection of LTB(4) at doses 1/10,000 or less than that required for histamine elicited ocular scratching in naïve mice. The LTB(4) receptor antagonist ONO-4057 inhibited the ragweed pollen challenge-induced ocular scratching at doses that suppressed LTB(4)-induced ocular scratching. In addition to histamine, LTB(4) is involved in the ocular itching of pollen allergy. H(1) receptor antagonists with an inhibitory effect on the action and/or production of LTB(4) may have more potent anti-pruritic activity than selective H(1) antagonists.

Topics: Allergens; Ambrosia; Animals; Conjunctivitis, Allergic; Disease Models, Animal; Glucocorticoids; Histamine; Histamine H1 Antagonists, Non-Sedating; Hydroxyurea; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Injections, Intraocular; Injections, Subcutaneous; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mast Cells; Mice; Mice, Inbred ICR; Phenylpropionates; Pollen; Terfenadine

To elucidate the ocular pharmacological properties of bepotastine besilate, a selective histamine H(1) receptor antagonist, when compared with other histamine H(1) receptor antagonists, using guinea pig allergic conjunctivitis models and in vitro models of eosinophil recruitment and mast cell membrane stabilization. Conjunctival vascular hyperpermeability was studied in guinea pigs passively sensitized with anti-ovalbumin antiserum or following subconjunctival injection of histamine. Modulation of eosinophil recruitment was evaluated for both platelet-activating factor (PAF)-induced eosinophil infiltration in guinea pigs and leukotriene B(4)-induced in vitro chemotaxis of guinea pig peritoneal eosinophils. Membrane-stabilizing effects of bepotastine also were studied with rat peritoneal mast cells stimulated with the ionophore A23187. Histamine H(1) receptor antagonists including bepotastine besilate were topically administered before ovalbumin, histamine or PAF challenges for in vivo experiments or were added directly to mast cell and eosinophil medium in vitro. Bepotastine besilate significantly inhibited conjunctival vascular hyperpermeability in a dose-dependent manner with maximal effect for bepotastine besilate 1.5%. In separate in vivo experiments, bepotastine besilate 1.0% was significantly more effective than levocabastine 0.025% in the passive sensitization model or olopatadine 0.1% in the histamine-induced hyperpermeability model. Bepotastine besilate 1.0% further suppressed PAF-induced eosinophil infiltration into conjunctival tissue more effectively than ketotifen 0.05%. Chemotaxis of guinea pig peritoneal eosinophils and histamine release from rat peritoneal mast cells in vitro were also inhibited by addition of bepotastine. Olopatadine had a weak effect as compared to that of bepotastine on eosinophil chemotaxis and no effect on mast cell histamine release in our study conditions. Bepotastine besilate was more potent than olopatadine, ketotifen, or levocabastine in reducing vascular hyperpermeability in various animal models of allergic conjunctivitis. Mast cell function and eosinophil chemotaxis were also inhibited in vitro with bepotastine, suggesting bepotastine acts as an inhibitor of allergic response through multiple mechanisms: histamine H(1) receptor antagonism, mast cell stabilization, and inhibition of eosinophil migration to ocular inflammatory sites.

Topics: Animals; Capillary Permeability; Cells, Cultured; Chemotaxis, Leukocyte; Conjunctiva; Conjunctivitis, Allergic; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Leukotriene B4; Male; Mast Cells; Ovalbumin; Peritoneal Cavity; Piperidines; Platelet Activating Factor; Pyridines; Rats; Rats, Wistar

Leukotrienes have been shown to play a role in the pathogenesis of ocular inflammatory and allergic reactions like vernal keratoconjunctivitis and contact lens-associated giant papillary conjunctivitis. This study was designed to determine leukotriene B4 (LTB4) and leukotriene C4 (LTC4) levels in the tears of patients with ocular prosthesis-associated giant papillary conjunctivitis (OP-GPC) and to evaluate the effects of lodoxamide 0.1% on tear LTB4 and LTC4 levels of OP-GPC patients. Tear LTB4 and LTC4 levels were determined by an ELISA technique in the tears of ten OP-GPC patients before and after treatment with lodoxamide 0.1% for one month. The results were compared with that of ten healthy control subjects. The mean tear LTB4 and LTC4 levels of the OP-GPC patients were significantly higher than those of the control group. After treatment with lodoxamide 0.1%, tear LTB4 and LTC4 levels of the OP-GPC patients decreased significantly. This is the first report of elevated LTB4 and LTC4 levels in tears of OP-GPC patients and it points to the possible role of leukotrienes in the immunopathogenesis of OP-GPC. The results also indicate that lodoxamide 0.1%, a mast cell membrane stabilizer, is effective in significantly reducing tear LTB4 and LTC4 levels in OP-GPC patients.

Topics: Adolescent; Anti-Allergic Agents; Conjunctivitis, Allergic; Enzyme-Linked Immunosorbent Assay; Eye Evisceration; Eye, Artificial; Female; Humans; Leukotriene B4; Leukotriene C4; Male; Ophthalmic Solutions; Oxamic Acid; Tears

The present studies have demonstrated the levels of N-methyl histamine in tears from normal physiological states, pathological states and contact lens wear. Histamine was significantly increased in closed eye tears compared with both open and reflex tears. Tears from other ocular conditions had low levels of histamine except for environmental hypersensitivity, which contained significantly elevated levels compared to normal tear types. Interestingly, tears from asymptomatic contact lens wearers had significant levels of histamine whereas tears from contact lens adverse events had lower levels, possibly reflecting a change in histamine metabolism.

Topics: Analysis of Variance; Conjunctivitis, Allergic; Contact Lenses; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation Mediators; Interleukin-6; Keratitis; Leukotriene B4; Methylhistamines; Tears

This study was designed to determine the presence of neutrophil chemotactic factors in the tears of patients with giant papillary conjunctivitis (BPC) secondary to contact lenses. Chemotactic activity was measured using modified Boyden chambers and the chemoattractant formylmethionyl-leucyl-phenylalanine (f-MLP) for 100 percent response. Elevated levels of chemotactic activity were found in the tears of symptomatic patients (80.8 +/- 6.4, % f-MLP) compared with control tears of asymptomatic contact lens wearers (15.7 +/- 3.3%) and non-contact lens wearers (5.6 +/- 1.2%). Using radioimmunoassay, C5a (serum-derived chemoattractant), leukotriene-B4, and interleukin-1 (immune cell-derived chemoattractants) were not detected in the tears of symptomatic patients. The authors determined whether injured conjunctival cells participate in this process by releasing neutrophil chemotactic factors. Isolated rabbit bulbar conjunctiva incubated with culture medium for 4 and 6 hr released high levels of neutrophil chemotactic factors. The release of these factors from injured conjunctiva support the premise that physical trauma of conjunctival cells induced by contact lenses may be an important component of the pathophysiology of giant papillary conjunctivitis.

Topics: Adolescent; Adult; Animals; Chemotactic Factors; Chemotaxis, Leukocyte; Complement C5a; Conjunctiva; Conjunctivitis, Allergic; Contact Lenses; Culture Techniques; Humans; Interleukin-1; Leukotriene B4; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Rabbits; Tears

Topics: Allergens; Animals; Capillary Permeability; Conjunctivitis, Allergic; Guinea Pigs; Leukotriene B4; Ovalbumin

The role of leukotrienes as mediators of microvascular permeability changes (assessed through the accumulation of [99mTc]albumin) associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva was investigated by means of two novel, structurally dissimilar 5-lipoxygenase inhibitors, L-651,392 and L-651,896. Both compounds, when applied topically in vivo to the eyes of sensitized guinea-pigs as a 0.1% suspension significantly inhibited 5-lipoxygenase in the conjunctiva as assessed by ex vivo challenge with either antigen or ionophore A23187 and measurement of the release of leukotriene B4-immunoreactive material. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs produced changes in conjunctival permeability which were blocked in part by either mepyramine (H1-receptor antagonist) or the 5-lipoxygenase inhibitors. Combinations of mepyramine and L-651,896 resulted in near complete suppression of the permeability response, suggesting that the reaction is mediated only by histamine and leukotrienes.

Topics: Animals; Arachidonate Lipoxygenases; Benzofurans; Calcimycin; Capillary Permeability; Conjunctivitis, Allergic; Guinea Pigs; Leukotriene B4; Lipoxygenase Inhibitors; Male; Phenothiazines; Pyrilamine; SRS-A