piperidines and levocabastine

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

We performed a systematic review of randomized, controlled trials to determine whether intranasal corticosteroids offered an advantage over topical antihistamines in the treatment of allergic rhinitis.. We searched for studies using MEDLINE, Embase, Cinahi, and Cochrane databases, pharmaceutical companies, and references of included trials.. Criteria for considering trials included: 1) published randomized controlled trials; 2) single- or double-blind studies; and 3) presence of one of the following clinical outcomes: nasal symptoms, eye symptoms, global symptoms evaluation of quality of life and side effects.. Nine studies including 648 subjects (mean age 30.4 years, range 13 to 73) with allergic rhinitis were selected. Intranasal corticosteroids produced significantly greater reduction of total nasal symptoms (standardized mean difference -0.36, 95% confidence interval -0.57 to -0.14), sneezing (-0.41, -0.57 to -0.24), rhinorrhea (-0.47, -0.64 to -0.29), itching (-0.38, -0.56 to -0.19), and nasal blockage (-0.86, -1.07 to -0.64) than did topical antihistamines. There was no significant difference between treatments for ocular symptoms (-0.07, -0.27 to 0.12). The effects on sneezing, rhinorrhea, itching, and ocular symptoms were significantly heterogeneous between studies. Other outcomes (total nasal symptom score and nasal blockage) were homogeneous between studies. Subgroup and sensitivity analysis suggested that most of the heterogeneity of outcomes could be explained on the basis of the methodologic quality of studies.. Intranasal corticosteroids produced greater relief of nasal symptoms than did topical antihistamines (topical H1 receptor antagonists). However, there was no difference in the relief of the ocular symptoms.

Topics: Administration, Intranasal; Administration, Topical; Adolescent; Adult; Aged; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Budesonide; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Histamine H1 Antagonists; Humans; Middle Aged; Phthalazines; Piperidines; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Seasonal; Treatment Outcome

The paper presents the main ocular injuries due to allergic mechanism and it point out the actual data about etiopathogenesis of type 1 hypersensitivity and immunologic mechanism involved in allergic keratoconjunctivitis. Then are exposed the classification of ocular allergy, the main signs and symptoms, the paraclinical methods of diagnosis and the actual agents of therapy.

Topics: Anti-Inflammatory Agents; Conjunctivitis, Allergic; Cyclosporine; Drug Therapy, Combination; Histamine H1 Antagonists; Humans; Immunoglobulin E; Immunosuppressive Agents; Ophthalmic Solutions; Piperidines; Prednisone

Levocabastine is a selective histamine H1-receptor antagonist exerting inhibitory effects on the release of chemical mediators from mast cells and on the chemotaxis of polymorphonuclear leukocytes and eosinophils. Both histamine and antigens induced conjunctivitis was inhibited by levocabastine in several allergy models. Levocabastine moderately inhibited histamine-release from guinea pig conjunctive induced by antigen-antibody reactions and prevented an increase in the vascular permeability of the conjunctive elicited by both histamine and antigen instillation. Symptoms of allergic rhinitis, which were induced by histamine, substance P and antigen, were also reduced by levocabastine. Levocabastine prevented an increase in the vascular permeability of nasal mucosa elicited by instillation of these three inducers. Furthermore, levocabastine has shown a large difference between the antiallergic dose and other non-specific pharmacological effective dose than that with other antiallergic drugs. The non-specific pharmacological effect of levocabastine reveals only blepharoptosis. With these pharmacological effects and topical usage, levocabastine was shown to be useful for allergic conjunctive and rhinitis in both seasonal and perennial clinical use.

Topics: Animals; Chemotaxis, Leukocyte; Clinical Trials as Topic; Conjunctivitis, Allergic; Depression, Chemical; Disease Models, Animal; Eosinophils; Histamine H1 Antagonists; Histamine Release; Humans; Mast Cells; Neutrophils; Piperidines; Rhinitis, Allergic, Perennial

The article presents two topical antihistaminics: levocabastine and azelastine. Most attention is paid to discussing the pharmacokinetics and antihistamine, antiallergic and antiinflammatory activities of these drugs. Their clinical usefulness in allergic rhinitis and conjunctivitis is also presented. Finally the authors describe the adverse reaction observed after administrating of topical antihistaminics.

Topics: Administration, Topical; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Conjunctivitis, Allergic; Cytochrome P-450 Enzyme System; Histamine H1 Antagonists; Humans; Nasal Mucosa; Phthalazines; Piperidines; Rhinitis, Allergic, Perennial

Allergic eye conditions, particularly seasonal allergic conjunctivitis (SAC), are common. Itching, oedema and hyperaemia are relieved with topical H1-antagonists or sodium cromoglycate. The newer mast-cell stabilizing agent nedocromil sodium has a similar safety profile to sodium cromoglycate, but is more potent and has a more convenient twice-daily dosing regimen. When several placebo-controlled studies of its use in the treatment of SAC were analysed, it was found that 80% of patients reported symptom relief. In a further study, nedocromil sodium eyedrops (twice-daily dosing) had similar overall efficacy to sodium cromoglycate eyedrops (four-times-daily dosing) in subjects with SAC during the birch season, but during the period of highest pollen challenge, only the former agent was significantly more effective than placebo. Another study found that nedocromil sodium had efficacy equivalent to levocabastine over 7 days, but tended to have a more rapid onset of action. In patients with perennial allergic conjunctivitis (PAC) unresponsive to sodium cromoglycate, both clinicians and patients reported significantly better control of symptoms with nedocromil sodium eyedrops than with placebo. Recently, in a long-term study of treatment for vernal keratoconjunctivitis (VKC), it was found that nedocromil sodium 2% eyedrops produced a more rapid and marked improvement in symptoms than sodium cromoglycate 2% eyedrops and enabled lower use of steroid rescue medication. Both drugs were well tolerated and without serious side-effects.

Topics: Anti-Allergic Agents; Conjunctivitis, Allergic; Controlled Clinical Trials as Topic; Cromolyn Sodium; Histamine H1 Antagonists; Humans; Nedocromil; Patient Satisfaction; Piperidines

Topical ocular allergy drugs are indicated for the treatment of allergic conjunctivitis after more conservative measures have been employed. Antihistamines, vasoconstrictors, nonsteroidal anti-inflammatory drugs, mast cell stabilizers and corticosteroids are available. Levocabastine and ketorolac tromethamine are new drugs for the treatment of allergic conjunctivitis. Lodoxamide is currently indicated only for the treatment of vernal keratoconjunctivitis, although treatment efficacy has been demonstrated in patients with giant papillary conjunctivitis and atopic keratoconjunctivitis. As a general rule, topical ocular allergy drugs are well tolerated by most patients except for transient stinging and burning on instillation. Ocular steroids should be reserved for severe cases and should be prescribed by an ophthalmologist, who can monitor the patient for possible ocular side effects.

Topics: Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Ketorolac Tromethamine; Oxamic Acid; Piperidines; Tolmetin; Tromethamine

Topics: Administration, Oral; Administration, Topical; Clinical Trials as Topic; Conjunctivitis, Allergic; Double-Blind Method; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Seasonal; Terfenadine

The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.

Topics: Administration, Topical; Animals; Histamine H1 Antagonists; Humans; Piperidines; Skin Absorption

Levocabastine is a potent and selective histamine H1-receptor antagonist which has been evaluated as a topical treatment (nasal spray and/or eyedrops) for allergic rhinitis and/or conjunctivitis. Data available at the time of the previous review in Drugs, together with more recent results, have clearly demonstrated that levocabastine nasal spray and eyedrops are clinically effective, have a rapid onset of action and are well tolerated in patients with nasal and/or ocular allergic conditions. Previous evidence indicating that topical levocabastine has efficacy similar to or better than that of topical sodium cromoglycate (cromolyn sodium) has been confirmed in more recent studies. Furthermore, results from a number of controlled clinical trials have also shown that topical levocabastine is at least as effective as oral terfenadine for the treatment of allergic rhinoconjunctivitis. Notably, topical levocabastine appears to be more effective than oral terfenadine in improving the severity of selected symptoms. Limited data indicating efficacy equivalent to that of oral loratadine, oral cetirizine or azelastine nasal spray will need to be confirmed. Data from several studies have shown that topical levocabastine has a tolerability profile similar to that of placebo, topical sodium cromoglycate or oral terfenadine. The main adverse events seen in patients treated with topical levocabastine are ocular irritation after application of eyedrops, and headache, nasal irritation, somnolence and fatigue after administration of the nasal spray. Administered doses of topical levocabastine, and subsequent plasma concentrations, are low, and the risk of systemic adverse events is therefore expected to be minimal. Thus, topical administration of levocabastine rapid and effective symptom relief with no apparent serious adverse events in patients with allergic rhinitis and/or conjunctivitis. Topical levocabastine is a useful alternative to topical sodium cromoglycate or oral terfenadine. Additional data supporting current evidence that topical levocabastine can provide more effective symptom relief than oral terfenadine, together with clarification of the relative efficacies of these agents in relation to varying pollen exposure, would help to further confirm its clinical potential. However, the results available to date suggest that the topical formulations of levocabastine are a valuable treatment option in patients with allergic rhinitis and/or conjunctivitis.

Topics: Aerosols; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal

Topics: Amino Acid Sequence; Animals; Brain; Cholic Acids; Chromatography; Mice; Molecular Sequence Data; Piperidines; Receptors, Neurotensin; Receptors, Neurotransmitter; Transduction, Genetic

Levocabastine is a novel H1-receptor antagonist for topical use, which is being investigated in allergic rhinitis (nasal spray) and conjunctivitis (eye drops). Its anti-allergic effects have been demonstrated in nasal and ocular provocation tests. Clinical studies have been performed in 1,363 patients with allergic rhinitis and 1,218 patients with allergic conjunctivitis, comparing levocabastine mainly to placebo and cromoglycate. Levocabastine was effective when used at a dose of 2 sprays per nostril or 1 drop per eye twice daily, which if necessary can be increased up to four times daily. Levocabastine was superior to placebo in alleviating symptoms such as sneezing, itchy nose, runny nose, itchy eyes, red eyes and lacrimation. In global evaluations some 60% of patients had good to excellent results with the nasal spray and some 75% with the eye drops. Levocabastine was shown to be as good or even slightly better than cromoglycate. Onset of action was fast, with 73% of patients reporting symptom relief within 30 min after administration of levocabastine nasal spray. Adverse experiences were similar in type and incidence with levocabastine, cromoglycate and placebo, for nasal spray as well as eye drops. The most frequent complaints were nasal and ocular irritation, respectively, with a similar incidence for the three drugs. Limited data are available in children so far, but they indicate response rate and adverse-experience profile to be similar to what was observed in adults. Levocabastine, thus, is an interesting new antihistamine available for topical use in allergic rhinoconjunctivitis. It has been extensively evaluated in adults, and preliminary data indicate that it can also be useful in allergic children.

Topics: Administration, Intranasal; Animals; Child; Clinical Trials as Topic; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Nasal Provocation Tests; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Levocabastine is a new topical histamine H1 antagonist. The antihistaminic and antiallergic effects of levocabastine eye drops have been evaluated in eight conjuctival provocation studies (n = 238). Two studies used a histamine challenge; five studies used allergen challenge; one study used both and in one study allergic provocation was with compound 48/80. In all but one study, only one single dose of levocabastine (one or two drops) was given. Six studies were against placebo only; one was against cromoglycate and one study used both placebo and cromoglycate as reference drugs. Single instillation of levocabastine eye drops protected against histamine and allergen-induced ocular symptoms within a period of 10 minutes. Levocabastine eye drops significantly alleviated conjunctival itching, redness, chemosis, eyelid swelling and tearing induced by histamine or allergen challenge (p < or = 0.05). Four hours after administration levocabastine was still active. With levocabastine, but not with cromoglycate, a significant increase was observed in the allergen threshold. Even when compared to cromoglycate given as a pre-treatment four times daily for two weeks before the allergen challenge, a single dose of levocabastine was significantly more effective in inhibiting hyperaemia, eyelid swelling, chemosis and tearing (all p < 0.05). In conclusion, conjunctival provocation studies have established that levocabastine has a rapid and long-lasting effect in protecting against histamine or allergen-induced conjunctival symptoms.

Topics: Conjunctivitis, Allergic; Evaluation Studies as Topic; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Premedication

Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H1 antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistamine compound available, being 15,000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action. In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.

Topics: Animals; Antazoline; Conjunctivitis, Allergic; Cromolyn Sodium; Histamine H1 Antagonists; Humans; Naphazoline; Ophthalmic Solutions; Piperidines; Placebos; Terfenadine

The new H1-receptor antagonist levocabastine is the most potent antihistamine available, as shown in classical animal tests for antihistamine activity. Its effects also are very specific, with doses as high as 40,000 times the effective antihistamine dose not displaying other pharmacological effects. In nasal and ocular provocation tests, levocabastine nasal spray and eye drops protected against allergen-induced nasal and ocular symptoms. Twenty-three clinical trials have been performed with levocabastine nasal spray in 1363 patients with allergic rhinitis. At a dose of two sprays per nostril twice daily (if necessary to be increased up to four times daily), levocabastine was significantly better than placebo and as good as or slightly better than cromoglycate in alleviating nasal symptoms. Good to excellent results were reported in about 60% of patients on levocabastine, compared with 37% with placebo and 47% with cromoglycate. Levocabastine eye drops were studied in 21 clinical trials including 1218 patients with allergic conjunctivitis. One drop per eye twice daily (up to four times daily) provided significantly better symptom control than placebo and similar effects as those observed with cromoglycate. Response rates were 71-80% with levocabastine, 55% with placebo and 76% with cromoglycate. Levocabastine has a fast onset of action, with 94% of patients experiencing symptom relief within 15 min after the first instillation of levocabastine eye drops. Three long-term studies (10-16 weeks' duration) showed absence of tachyphylaxis during prolonged treatment with levocabastine. The incidence of adverse experiences was similar for levocabastine, cromoglycate and placebo, for nasal spray as well as eye drops.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Topical; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Levocabastine is a long acting, highly potent and selective histamine H1-receptor antagonist, which has been developed for nasal and ocular administration. In controlled trials performed to date levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Comparative studies have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate (cromolyn sodium) in alleviating symptoms associated with seasonal allergic conditions. Although levocabastine appears to be less effective than the topical corticosteroid beclomethasone with regard to relieving runny and blocked nose, further comparative trials between these 2 agents would be desirable. Similar to other antihistamines, levocabastine provides minimal relief of nasal blockage, but this symptom is believed to be mediated by receptors other than histamine H1. The prompt onset of antiallergic activity after application differentiates levocabastine from the reference topical antiallergic, sodium cromoglycate, which has an onset of efficacy characterised by a lag period, thereby necessitating maintenance treatment. The incidence of adverse effects associated with levocabastine therapy is low and is similar to that observed with placebo and sodium cromoglycate. Levocabastine provides prophylactic protection as well as acute relief from nasal and ocular symptoms in patients with seasonal allergic disorders. With the ever increasing trend towards topical therapy for the treatment of allergic rhinitis and allergic conjunctivitis, levocabastine is a useful addition to the range of drugs currently available. Possible avenues for additional research should include determining whether the antiallergic efficacy of topical levocabastine is superior to that of oral agents such as astemizole and terfenadine, and whether topical therapy is indeed preferred, considering the relative ease of administration of effective oral antiallergic agents.

Topics: Administration, Topical; Animals; Conjunctivitis, Allergic; Cromolyn Sodium; Drug Evaluation; Drug Tolerance; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Perennial

The clinical manifestations of allergic rhinitis are the result of an immune-mediated process after exposure of a sensitized individual to airborne allergens. The primary symptomatology includes nasal congestion, rhinorrhea, nasal and conjunctival pruritus, and sneezing. Principles of management include allergen avoidance, palliative therapy, immunotherapy, and pharmacotherapy. Oral decongestants stimulate alpha-adrenergic receptors in the nasal cavity, resulting in vasoconstriction and decreased edema. Oral antihistamines block histamine1 (H1) receptors, and may relieve rhinorrhea, sneezing, and nasal and conjunctival pruritus. Topical decongestants have a local effect on adrenergic receptors in the nasal mucosa, resulting in rapid, marked vasoconstriction. Intranasal corticosteroids inhibit mediator release from mast cells and basophils, and reduce edema of the nasal mucosa. Dexamethasone sodium phosphate, beclomethasone dipropionate, and flunisolide are currently available for intranasal administration. Cromolyn sodium inhibits allergen-induced degranulation and mediator release from sensitized cells, and is useful primarily as a prophylactic agent. Several agents, including the corticosteroids budesonide and flucortin butylester, the mast cell-stabilizing agent nedocromil sodium, the anticholinergic agent ipratropium bromide, and the H1 receptor antagonist levocabastine are being investigated for intranasal use in the management of allergic rhinitis.

Topics: Administration, Intranasal; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Glucocorticoids; Histamine H1 Antagonists; Humans; Ipratropium; Nedocromil; Piperidines; Pregnenediones; Quinolones; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump.. This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 μg) as a fixed-dose combination (FDC), FF (110 μg), or LEVO (200 μg) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration.. Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups.. These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.

Topics: Administration, Intranasal; Adult; Androstadienes; Biological Availability; Cross-Over Studies; Drug Combinations; Female; Glucocorticoids; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Piperidines; Young Adult

Allergic rhinitis (AR) is a common chronic disease, which has significant detrimental effect on well-being and quality of life as well as substantial socio-economic impact. Combination pharmacotherapy is utilized by 40-50% of patients to treat their symptoms.. To compare the effects of intranasal fluticasone furoate (FF)/levocabastine (LEVO) fixed-dose combination (FDC) with each component alone on allergen-induced nasal and ocular symptoms.. A randomized, double-blind, placebo-controlled, three-way, incomplete block, cross-over, proof-of-concept study in 71 patients with AR, evaluated FF 100 μg, LEVO 200 μg and FDC (FF 100/LEVO 200 μg), once daily via intranasal spray for 8 days. On days 1 and 8, total nasal symptom score (TNSS) and total ocular symptom score (TOSS) were assessed every 15 min during a 4-h allergen exposure in the Vienna Challenge Chamber. The primary endpoint was Day 8 weighted mean TNSS.. After 8 days, FDC resulted in both statistically and clinically significant reductions in mean TNSS compared with FF and LEVO alone [adjusted mean differences (95% CI): FDC vs. FF: -2.26 (-2.90, -1.62); FDC vs. LEVO: -2.57 (-3.21, -1.93)]. All active treatments were significantly superior to placebo [adjusted mean difference (95% CI) from placebo: FDC: -4.1 (-4.86, -3.34); FF: -1.84 (-2.66, -1.03); LEVO: -1.53 (-2.34, -0.72)]. Onset of action was rapid following FDC and LEVO treatment with an approximate two unit reduction in mean TNSS from pre-dose levels by 30 min and 1 h. Mean TOSS was also reduced following all active treatments relative to placebo (range 0.6-0.8 unit reduction). All treatments were equally well tolerated.. These results suggest that once daily FF/LEVO FDC could provide a clinical therapeutic advantage to existing standard monotherapies in the treatment of moderate-to-severe AR, and support progression to evaluation in larger phase III clinical studies.

Topics: Adolescent; Adult; Aged; Androstadienes; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic

To test the hypothesis that intranasal levocabastine (LEVO) may provide benefits as a oncedaily treatment in allergic rhinitis (AR), this non-inferiority study compared the effect at steady state of once- and twice-daily dosing with LEVO on allergen-induced nasal symptoms in AR patients.. This was a randomized, double-blind, three-way cross over study evaluating the effects of repeat doses of LEVO 200 µg once-daily, LEVO 200 µg twice-daily (total dose 400 µg) and placebo, all via intranasal spray, in 78 AR patients. The primary endpoint was weighted mean total nasal symptom score (TNSS) during a 4-hour allergen exposure in the Environmental Exposure Chamber measured at trough pharmacokinetic levels either 12 (LEVO twice-daily) or 24 (LEVO once-daily) hours post-dose.. After 7 days dosing, the difference in weighted mean TNSS (0-4 hours) following LEVO once-daily versus twice-daily was 0.23 units (95% CI -0.36, 0.82), demonstrating noninferiority between the two LEVO dosing regimens by meeting the pre-specified criterion of an upper limit of 95% CI<1.0. Both dosing regimens of LEVO resulted in a statistically significant reduction in mean TNSS compared with placebo (adjusted mean difference from placebo: LEVO once-daily: -1.12 (95% CI -1.71, -0.53); LEVO twice-daily: -1.35 (-1.94, -0.76)), meeting the pre-specified criterion for superiority (upper limit of 95% CI<0). All treatments were well-tolerated.. The results of this study support the hypothesis that at steady state LEVO 200 µg taken once-daily provides similar benefit to LEVO 200 µg dosed twice-daily.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic; Young Adult

To evaluate the safety and efficacy of preservative-free levocabastine 0.05 % ophthalmic solution compared to placebo (vehicle) and to preserved levocabastine 0.05 % ophthalmic suspension in the prevention of allergic conjunctivitis induced by a conjunctival provocation test.. Ninety-two subjects (18-50 years) with a previous history of allergic conjunctivitis to pollen were randomised to receive either preservative-free levocabastine solution in one eye and preserved levocabastine suspension in the fellow eye (n=69), or preservative-free levocabastine in one eye and placebo in the fellow eye (n=23). One drop of each product was administered 10 minutes (visit 3) and 4 hours (visit 4) prior to the provocation test. The primary efficacy criterion was the sum of the itching and conjunctival hyperemia scores assessed at 3, 5 and 10 minutes after the provocation test. The safety evaluation included adverse events, visual acuity, intra-ocular pressure and study drug drop sensation.. The efficacy of the preservative-free solution was significantly higher than that of placebo at all time points (P≤0.01) with one exception at visit 4 (3 minutes after the provocation test). It was significantly higher than that of the preserved suspension at visit 3, and equivalent at visit 4. The incidence of adverse events was lower with the preservative-free solution than with the preserved suspension. 94.2 % and 95.7 % subjects rated preservative-free levocabastine drop sensation as "good" or "very good" at visits 3 and 4 respectively, whereas these rates were 68.1 % and 63.8 % with preserved levocabastine. This difference between the two formulations was highly statistically significant (P<0.001).. The efficacy of preservative-free levocabastine was superior to that of the placebo and of the preserved suspension at visit 3, at least as effective as the preserved suspension at visit 4, and better tolerated at each visit.

Topics: Administration, Ophthalmic; Adolescent; Adult; Allergens; Chemistry, Pharmaceutical; Conjunctiva; Conjunctivitis, Allergic; Diagnostic Techniques, Ophthalmological; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Preservatives, Pharmaceutical; Treatment Outcome; Young Adult

To compare the onset of action, efficacy, and safety of azelastine and levocabastine in the treatment of allergic rhinitis.. In a multicenter, randomized, double-blind, parallel-group trial, 244 patients with moderate-to-severe allergic rhinitis were randomized to receive either azelastine hydrochloride nasal spray (ANS) 0.1% or levocabastine hydrochloride nasal spray (LNS) 0.05% for 14 consecutive days. A visual analog scale was used to record total nasal symptom score (TNSS) changes. Indexes for further assessment included onset of action, total effective rate, and evaluation of therapeutic effect.. Statistically significant changes from baseline in TNSS were seen in both the LNS group and the ANS group. No significant differences were seen between the two groups in terms of evaluation of therapeutic effect, total effective rate, and onset of action, except for a higher symptom relief rate in the LNS group than in the ANS group within 30 min of administering the first dose. Adverse reactions were mild to moderate, with an incidence of 0.9% for LNS and 2.5% for ANS.. Both ANS and LNS were effective and safe in the treatment of moderate-to-severe persistent allergic rhinitis. Moreover, LNS reached a higher symptom relief rate within 30 min of administering the first dose.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Nasal Sprays; Phthalazines; Piperidines; Retrospective Studies; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Treatment Outcome; Young Adult

Allergic conjunctivitis is the most common form of conjunctivitis encountered in daily ophthalmological practice. Its therapy can be problematic: it must be simple, free of complications, and adaptable to everyday life.. We conducted a randomized prospective single-center survey on 102 patients between 4 and 80 years of age who presented moderate allergic conjunctivitis. Patients were divided into two groups, one treated in monotherapy with N-acetyl-aspartyl glutamic acid (NAAGA) over 4 weeks and the other treated with bi-therapy (NAAGA and Levocabastine during the first week and NAAGA only for the next 3 weeks), with evaluation of the sum of the scores of the cardinal signs of allergic conjunctivitis at D0, D7 and D28.. The two populations were homogeneous at inclusion: the majority of the patients had a history of allergies, with a nonspecific disrupted allergy workup (IgE and eosinophils) and a higher initial score for the children included in the study. The scores decreased sharply at D7 (50% reduction) and at D28 (bordering 1) with no significant difference between the two groups. Tolerance to the treatment judged by unusual sensations upon instillation was better for the NAAGA treatment (80.8% of the cases). Clinical and functional signs disappeared without recourse to corticoids.. In the moderate forms of seasonal and intra-annual allergic conjunctivitis, NAAGA treatment alone is sufficient. The association with Levocabastine is necessary only in cases of highly bothersome functional signs. The use of corticoids should be reserved for the serious forms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Allergic Agents; Child; Child, Preschool; Clinical Protocols; Conjunctivitis, Allergic; Dipeptides; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Seasons; Young Adult

To evaluate the efficacy of a combined therapy with levocabastine hydrochloride ophthalmic suspension and pemirolast potassium ophthalmic solution compared to single therapy with levocabastine hydrochloride ophthalmic suspension alone.. Thirty-two allergic conjunctivitis patients were randomized to combined-treatment (n = 15) or single-treatment groups (n = 17). The improvement of subjective symptoms as well as objective findings were evaluated.. The degree of improvement was significantly higher in the combined-treatment group for lacrimation (p = 0.008) among the subjective symptoms, for conjunctival edema (p = 0.030), eyelid edema (p = 0.032) and conjunctival papilla formation(p = 0.040) among the objective findings.. Both objective assessments and subjective symptoms of allergic conjunctivitis showed the greatest improvements when patients were treated with combined therapy as compared to single-agent therapy. The enhanced benefits of combined therapy may result from these agents having different mechanisms of action.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Conjunctivitis, Allergic; Drug Therapy, Combination; Eosinophils; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Leukocyte Count; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Pyridines; Pyrimidinones; Treatment Outcome

This comparative and randomised pilot study assessed the clinical and biological efficacy of Naaxia Sine(R) eye-drops versus levocabastine eye-drops in the treatment of vernal keratoconjunctivitis (VKC).. Twenty-three VKC patients were randomised and treated bilaterally for 28 days with N-acetyl-aspartyl-glutamate (NAAGA) or levocabastine (LEVO) eye-drops. The primary efficacy variable, overall evolution of eosinophil cationic protein (ECP) tear concentrations, was assessed in a masked fashion on D0, D7 and D28. Clinical symptoms and signs were reported at the same time points. Biological parameters were analysed with a non-parametric rank-based approach. Global tolerance was assessed by the investigator and patient.. At all time points, ECP tear levels were significantly reduced in the NAAGA compared with the LEVO group (p = 0.023). Reduction of eosinophil leucocytes and tear lymphocytes was higher not significant in the NAAGA group. The same trend was observed for the evolution of total ocular symptom score. There were no significant differences between treatment groups in the occurrence of adverse effects, except for burning which was more frequent in the LEVO group (p = 0.002).. The anti-eosinophilic actions of NAAGA were shown by a significant reduction of ECP tear concentrations. A decreased lymphocyte count and an overall improvement of the symptomatology were also noted. Moreover, the tolerability of NAAGA appeared to be better.

Topics: Anti-Inflammatory Agents; Child; Conjunctivitis, Allergic; Dipeptides; Eosinophil Cationic Protein; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Lymphocyte Count; Male; Ophthalmic Solutions; Osmolar Concentration; Pilot Projects; Piperidines; Preservatives, Pharmaceutical; Tears; Treatment Outcome

Patients with allergic rhinitis demonstrate hyperreactive response in distilled water nasal provocation, shown by significant increase in nasal airway resistance (NAR). Antihistamines, including topical antihistamine, levocabastine, reduce response in non-specific nasal provocation tests. Furosemide is a diuretic which reduces hyperreactivity in lower airways, but the mode of its action is not yet fully understood. In this study, we hypothesized that either levocabastine or furosemide pre-treatment in allergic rhinitis patients reduced response to nasal challenge with non-isotonic aerosol. To test the hypothesis, we measured the effect of pre-treatment with levocabastine and furosemide in topical application on suppression of hyperreactive response to distilled water nasal inhalation. Nasal resistance was measured, prior to and after the provocation, by active anterior rhinomanometry in two randomized groups of patients, according to pre-treatment, either by levocabastine or furosemide, 20 patients in each group, respectively. Nasal airflow resistance and level of hyperreactive response considering nasal eosinophilia were tested. Significant increase in nasal resistance following provocation was found at baseline conditions (without pre-medication); pre-treatment with levocabastine and furosemide has suppressed such response. Patients with positive nasal eosinophilia showed a significantly higher increase in nasal resistance compared to those with negative smears. Furosemide has shown significantly better protective effect on nasal resistance increase in patients with positive eosinophils nasal smears. Levocabastine and furosemide pre-treatment suppress hyperreactive response to distilled water nasal provocation. Comparison of resistances (pre-treatment vs. without) showed more protective effect of furosemide, measured on both better and worse patent side of nose, in contrast to levocabastine group for which it was shown only on better patent side prior to provocation. Protection of furosemide was significantly more pronounced in patients with significant nasal eosinophilia.

Topics: Administration, Intranasal; Adolescent; Adult; Diuretics; Female; Furosemide; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Nasal Obstruction; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Perennial; Rhinomanometry; Saline Solution, Hypertonic; Time Factors; Young Adult

This study was conducted to investigate the efficacy and safety of 0.025% levocabastine hydrochloride in Japanese subjects with seasonal allergic conjunctivitis and its duration of action using the conjunctival allergen challenge (CAC) test.. Twenty-four asymptomatic subjects were randomized to instill 0.025% levocabastine ophthalmic suspension in one eye and vehicle in the other eye 10 minutes before the CAC test. Signs and symptoms of allergic conjunctivitis were scored 10, 15, and 25 minutes after the CAC test. The duration of drug effects was also evaluated by allergen rechallenge 4 hours after levocabastine administration. The itching score for each eye as the primary efficacy endpoint was assessed 15 minutes after the CAC test using a 5-point scale.. The mean itching score in the levocabastine-treated group was 0.08 +/- 0.06, which was significantly lower than the mean score of 1.98 +/- 0.16 in the vehicle group (P < 0.0001). The redness and chemosis of the conjunctiva were also improved significantly compared with the vehicle group. Levocabastine showed prolonged efficacy in inhibiting itching (0.42 +/- 0.12 vs 0.94 +/- 0.17, P < 0.0002) and redness (1.04 +/- 0.18 vs 1.42 +/- 0.22, P < 0.01) of the conjunctiva upon the rechallenge test. No significant topical or systemic adverse safety findings were observed in the levocabastine group.. The results indicate that 0.025% levocabastine ophthalmic suspension is effective and safe in the treatment of allergic conjunctivitis with a duration of action of at least 4 h.

Topics: Adult; Allergens; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Japan; Male; Ophthalmic Solutions; Piperidines; Seasons; Suspensions; Treatment Outcome

Approximately 16.2% of the Japanese population suffer from cedar pollinosis, with various manifestations such as ophthalmic, laryngo-pharyngeal and skin symptoms in addition to nasal symptoms. Thus, the annual pollen season is an agonizing period for patients. No study has reported symptoms and their clinical courses after conjunctival provocation with purified cedar pollen allergen Cry j1 as well as suppression of these allergen-induced ocular symptoms by antihistamine eye drops.. Nine patients with Japanese cedar pollinosis who had no nasal or ocular symptoms were included in the present study, after obtaining informed consent in writing. 1) Purified cedar pollen allergen Cry j1 was instilled in the left eye and phosphate-buffered saline (PBS) in the right eye as a control. 2) Levocabastine hydrochloride ophthalmic suspension and ketotifen fumarate ophthalmic solution were respectively instilled in the left and right eyes, which were then challenged with the allergen. Ocular symptoms after provocation with the allergen were recorded through the clinical course.. Pollen allergen-induced ocular symptoms were itching and hyperemia of the palpebral conjunctiva, and itching lasted for more than 5 hours. Moreover, preadministration of antihistamine eye drops suppressed the increases in the ocular symptom scores, eliminating itching within 1 hour. Allergen provoked not only ocular symptoms but also nasal symptoms in 77.8% of patients.. Preadministration of antihistamine eye drops suppressed the symptoms induced by the allergen, which suggests that this is an effective early therapy for Japanese cedar pollinosis, if it is started before the pollen season. However, self-protection by patients using a mask may not be effective enough to suppress nasal symptoms during the pollen season, requiring them to additionally wear glasses to avoid exposure to the allergen.

Topics: Adult; Allergens; Antigens, Plant; Conjunctivitis, Allergic; Cryptomeria; Dose-Response Relationship, Immunologic; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Hyperemia; Japan; Ketotifen; Ophthalmic Solutions; Piperidines; Plant Proteins; Pollen; Premedication; Pruritus; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Treatment Outcome

Drug treatment and specific immunotherapy (SIT) are both effective in seasonal rhinoconjunctivitis, but the former acts only on allergic symptoms while the latter modifies the natural history of the disease. Only a few studies compared the clinical efficacy of the two treatments with contrasting results. We planned a study to compare the efficacy of SIT (15 patients) and drug treatment (15 patients) in moderate to severe seasonal rhinoconjunctivitis caused by sensitization to grass pollen. SIT was performed by a 5-grass extract standardized in IR and absorbed onto calcium phosphate (Phostal, Stallergénes, Antony, France) using the conventional build-up phase in 12 weeks and a maintenance treatment with monthly injection for three years. Drug treatment was done with cetirizine as antihistamine, mometasone furoate as nasal topical steroid, and levocabastine eyedrops. All patients registered during the pollen season their symptoms and drug consumption. After one year 12 of 15 patients treated with SIT had less symptoms and drug consumption in respect to baseline compared to none in drug treated group (p = 0.021) and after three years 15 of 15 were improved in group A compared to one of 15 in group B (p = 0.008). These findings indicate an higher efficacy of SIT in patients with seasonal rhinitis not only in the long term but also in the first year of treatment.

Topics: Administration, Intranasal; Adolescent; Adult; Allergens; Anti-Allergic Agents; Anti-Inflammatory Agents; Cetirizine; Conjunctivitis, Allergic; Desensitization, Immunologic; Drug Therapy, Combination; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Mometasone Furoate; Ophthalmic Solutions; Piperidines; Poaceae; Pollen; Pregnadienediols; Rhinitis, Allergic, Seasonal; Treatment Outcome

In order to assess the efficacy of an antihistaminic eye drop containing 0.05% mequitazine in the prevention of allergy induced by a conjunctival provocation test, a double-masked, randomized, intraindividual study compared this eye drop to 0.05% levocabastine and 0.1% dexamethasone eye drops in 24 subjects allergic to grass pollen.. During the first phase of treatment, randomized subjects received one drop of dexamethasone in one eye and one drop of either mequitazine or levocabastine in the fellow eye. During the second phase of treatment, they were given one drop of dexamethasone in the same eye as previously, and one drop of the treatment that had not been given during the first phase (levocabastine or mequitazine) in the fellow eye. Fifteen minutes after each instillation phase, a conjunctival provocation test was performed. Hyperemia, itching, tearing, chemosis and palpebral edema were the five signs or symptoms taken into account to assess the treatment efficacy. Their intensity was evaluated 3, 5 and 10 min after the conjunctival provocation test. The primary efficacy criterion was the global score obtained by measuring hyperemia and itching intensity.. The score was reduced significantly more (p < 0.0001) for the eyes treated with mequitazine or levocabastine than for those treated with dexamethasone at all evaluation times. The difference was also significant for hyperemia (p < 0.001), itching (p < 0.001), and tearing (p < 0.05). The tolerability of the three eyedrops was satisfactory.. Mequitazine and levocabastine were safe and significantly more effective than dexamethasone in preventing the allergic response induced by a conjunctival provocation test when they were instilled 15 min before contact with the allergen.

Topics: Adult; Allergens; Anti-Allergic Agents; Anti-Inflammatory Agents; Conjunctiva; Conjunctivitis, Allergic; Data Interpretation, Statistical; Dexamethasone; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Phenothiazines; Piperidines; Time Factors

Current guidelines recommend intranasal glucocorticosteroids as first-line therapy for seasonal allergic rhinitis.. To compare the efficacy, cost-effectiveness, and tolerability of the topical glucocorticosteroid mometasone furoate, the topical antihistamine levocabastine hydrochloride, and the cromone disodium cromoglycate in seasonal allergic rhinitis.. This study was performed during the 2003 grass pollen season as an open, randomized, parallel-group, single-center study of 123 patients assigned to receive mometasone furoate (200 microg once daily), levocabastine hydrochloride (200 microg twice daily), or disodium cromoglycate (5.6 mg 4 times daily). Symptom scores and nasal inspiratory peak flow measurements were recorded in a patient diary. The global efficacy of the study medication was evaluated by patients after treatment. Eosinophil cationic protein concentrations were measured in nasal secretions before and after treatment. Cost-effectiveness was evaluated as medication cost per treatment success.. Mometasone furoate therapy was significantly superior to the use of levocabastine or disodium cromoglycate with respect to all nasal symptoms, the global evaluation of efficacy, and eosinophil cationic protein concentration. Furthermore, mometasone furoate therapy was significantly superior to disodium cromoglycate therapy with respect to nasal inspiratory peak flow. Medication cost per treatment success was lowest with mometasone furoate use and highest with levocabastine use.. This is the first study to compare mometasone furoate nasal spray with nonsteroidal topical treatments for seasonal allergic rhinitis. Mometasone furoate nasal spray was confirmed as a first-choice topical treatment option for seasonal allergic rhinitis.

Topics: Administration, Intranasal; Adolescent; Adult; Anti-Allergic Agents; Cromolyn Sodium; Eosinophil Cationic Protein; Female; Humans; Male; Middle Aged; Mometasone Furoate; Piperidines; Pregnadienediols; Respiratory Function Tests; Rhinitis, Allergic, Seasonal; Treatment Outcome

A double masked randomised trial comparing 0.05% mequitazine eye drops with 0.05% levocabastine and placebo was carried out in otherwise healthy volunteers allergic to house dust mites (Dermatophagoides pteronyssinus).. Double masked, randomised, single centre study, comparing three parallel treatment groups. 60 healthy adults with a confirmed history of allergic conjunctivitis to house dust mites for at least 2 years were included and completed the trial. Conjunctival provocation tests (CPT) were done at screening, at visit 2 (V2) (1 week later), and at visit 3 (V3) (2 weeks after V2). Treatment was instilled in the same eye, 5 minutes after the CPT at V2, and twice daily until V3. CPT were scored 5, 10, 15, and 60 minutes after instillation of the dose of Dermatophagoides pteronyssinus antigen determined at inclusion (V2, curative test) or resulting in positivity (V3, preventive test). In the V2 (curative) test the difference between the active treatments and placebo on the redness+itching scores was not significant. At the V3 (preventive) CPT there was a lower number of reactions at the threshold dose with mequitazine (20%) compared to placebo (60%, p = 0.01) or levocabastine (45%, p = 0.10).. This trial failed to clearly demonstrate curative superiority of topical antihistamines with placebo, when a single dose of treatment was instilled following CPT. However mequitazine 0.05% eye drops were superior to placebo in preventing a reaction to CPT, after 2 weeks of treatment.

Topics: Adolescent; Adult; Chi-Square Distribution; Conjunctivitis, Allergic; Dermatophagoides pteronyssinus; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Phenothiazines; Piperidines; Statistics, Nonparametric

Epinastine hydrochloride is an antihistamine with mast cell-stabilizing and anti-inflammatory activity.. The aim of this study was to assess the efficacy and tolerability of ophthalmic epinastine in patients with seasonal allergic conjunctivitis (SAC) exposed to environmental allergens.. This randomized (age-stratified), double-masked, parallel-group, active- and vehicle-controlled, environmental, Phase III clinical trial was conducted at 6 ophthalmology clinics in the United States. Patients aged >or=9 years diagnosed with SAC and who had a positive reaction in a conjunctival allergen challenge were enrolled. Patients were randomly assigned in a 2:2:1 ratio to receive 1 drop/eye BID of epinastine hydrochloride 0.05% ophthalmic solution, levocabastine hydrochloride 0.05% ophthalmic suspension, or vehicle of epinastine, respectively, for 8 weeks. The primary end point was ocular itching, and secondary end points included ocular hyperemia, chemosis, ocular mucous discharge (all assessed on a 5-point scale), eyelid swelling (assessed on a 4-point scale), and tearing (present or absent). Efficacy analyses used assessments from the two 1-week periods with the highest pollen counts. For tolerability assessment slit-lamp biomicroscopy and visual acuity examinations were conducted at each study visit (weeks 0, 2, 4, 6, and 8).. Two-hundred ninety-eight patients (159 females, 139 males; mean [SD] age, 32.7 [14.6] years [range, 9-71 years]) entered the study; 118 received epinastine, 118 received levocabastine, and 62 received vehicle. Epinastine-treated patients reported significantly less ocular itching than those receiving vehicle (P=0.045); scores for hyperemia were similar between these 2 groups. Ocular itching and hyperemia scores were similar between the epinastine and levocabastine groups. No clinically or statistically significant between-group differences were seen in slit-lamp biomicroscopy findings, changes in visual acuity from baseline, or the incidence of treatment-related adverse effects.. In this study of patients with SAC, ophthalmic epinastine instilled twice daily was more effective than vehicle for the control of ocular itching and was similar in efficacy to levocabastine for control of ocular itching and hyperemia. Epinastine was well tolerated.

Topics: Adolescent; Adult; Aged; Child; Conjunctivitis, Allergic; Dibenzazepines; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Imidazoles; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal

To compare the efficacy of olopatadine and levocabastine in reducing ocular allergic itching and vascular hyperemia (redness) induced by conjunctival allergen challenge.. The study was a randomized, double-masked, contralateral study using the conjunctival allergen challenge (CAC) model. At Visit 1, subjects with a positive allergen skin test and a history of allergic conjunctivitis were administered increasing concentrations of allergen until at least a moderate grade 2 ocular itching and conjunctival redness response was obtained in both eyes. Allergic signs were graded on standardized 0-4 scales. Subjects who reacted positively were re-challenged at Visit 2 with the pre-determined concentration of allergen. Subjects who again responded with at least a grade 2 bilateral ocular itching and conjunctival redness score at Visit 2 were eligible for drug evaluation. At Visit 3, subjects received olopatadine in one eye and levocabastine in the contralateral eye according to a computer-generated randomization scheme generated prior to commencement of the study. Ocular discomfort was then graded in both eyes. Subjects were bilaterally challenged with the predetermined concentration of allergen 27 min after topical drug administration, such that the first post-challenge assessment was made 30 min post-drug instillation. Allergic signs and symptoms were evaluated at 3 min, 10 min, and 20 min postchallenge and safety and efficacy analyses were performed.. Sixty-eight subjects received study drug and were included in the safety and efficacy analyses. Ocular itching scores for olopatadine were significantly lower than levocabastine at 3 min and 10 min post-challenge (p < 0.001). Ocular redness scores for olopatadine were significantly lower than levocabastine at all time points post-challenge (p < 0.0001). Of all subjects, 4.41% reported ocular discomfort in the olopatadine eye and 26.5% in the levocabastine treated eye.. Olopatadine treated eyes had significantly less itching and redness than levocabastine treated eyes after conjunctival allergen challenge. Olopatadine was also associated with less discomfort upon instillation than levocabastine.

Topics: Adolescent; Adult; Aged; Conjunctivitis, Allergic; Dibenzoxepins; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Olopatadine Hydrochloride; Ophthalmic Solutions; Piperidines; Severity of Illness Index; Treatment Outcome

Azelastine is a selective H(1)-receptor antagonist that inhibits histamine release and interferes with activation of several other mediators of allergic inflammation. Together with demonstrated efficacy in seasonal allergic conjunctivitis, azelastine indicated a therapeutic potential for perennial allergic conjunctivitis (PAC). The present study aimed to evaluate azelastine eye drops in patients with PAC compared to placebo.. A multinational trial in 22 centres randomised 139 patients to twice-daily treatment for 6 weeks with masked 0.05% azelastine eye drops, matching masked placebo, or open-label levocabastine. Randomisation required a sum itching and conjunctival redness score of at least 3 (0-6 scale) after 1 week of placebo. The change in sum score was evaluated during treatment.. Azelastine significantly improved itching and conjunctival redness compared to placebo (p < 0.001) with global tolerability that was not substantially different from placebo. On day 7, the mean symptoms sum score improved with azelastine by 1.9 +/- 1.1 and with levocabastine by 1.5 +/- 1.2 compared to placebo (0.6 +/- 1.1) from baseline values of 3.7-3.8. The sum scores continued to improve up to day 42. Daily patient logs confirmed the clinically assessed scores. Most frequent adverse events following azelastine were bitter taste and application site reaction.. Topical azelastine progressively improved itching and conjunctival redness in PAC patients compared to placebo and was at least as effective as levocabastine. Rapid relief is consistent with H(1)-receptor antagonist action, while continued improvement up to 6 weeks may be consistent with mechanisms involving other mediators of allergic inflammation.

Topics: Administration, Topical; Adolescent; Adult; Aged; Analysis of Variance; Anti-Allergic Agents; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Phthalazines; Piperidines; Rhinitis, Allergic, Perennial

Ketotifen blocks histamine H(1) receptors, stabilises mast cells, and prevents eosinophil accumulation. These multiple, pharmacological mechanisms provided the rationale for assessing the efficacy and safety of ketotifen 0.025% eye drops in subjects with seasonal allergic conjunctivitis (SAC) in an environmental setting.. This was a double masked, randomised, multicentre trial conducted in Australia. Subjects were randomly assigned to ketotifen fumarate 0.025% ophthalmic solution, placebo (as vehicle), or levocabastine hydrochloride 0.05% ophthalmic suspension, twice daily in each eye for a 4 week period. Subjects were assessed at follow up (days 5-8) and termination (days 25-31) visits. The primary efficacy variable was the responder rate, based on the subjects' assessment of global efficacy at the follow up visit.. 519 subjects were randomised to treatment. At the follow up visit, the responder rate, based on subjects' assessment of global efficacy, was significantly greater in the ketotifen group (49.5%) than in the placebo group (33.0%) for subjects with a positive diagnostic test for pollen allergy (p = 0.02). The investigators' assessment of responder rates also showed that ketotifen was superior to placebo (p = 0.001). Ketotifen produced a significantly better outcome than levocabastine (p<0.05) for relief of signs and symptoms of SAC, at both the follow up and the termination visit. The type and frequency of adverse events were similar across treatment groups.. In an environmental setting, ketotifen fumarate 0.025% ophthalmic solution was well tolerated and effective in reducing the signs and symptoms of SAC, and in preventing their recurrence. Ketotifen consistently showed the best efficacy in comparison with both placebo and levocabastine. These results indicate that ketotifen eye drops are a valuable treatment option for this condition.

Topics: Anti-Allergic Agents; Conjunctivitis, Allergic; Double-Blind Method; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Ketotifen; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Seasons; Secondary Prevention; Treatment Outcome

To assess the cost effectiveness of emedastine, a new antihistamine, versus levocabastine in the treatment of acute allergic conjunctivitis (AAC) in Belgium, France, Germany, The Netherlands, Norway, Portugal and Sweden.. Randomised double-blind multicountry clinical trial followed by economic modelling from the treatment provider perspective.. A total of 221 patients (109 emedastine, 112 levocabastine) with AAC were included.. The clinical trial compared the efficacy and safety of emedastine 0.05% and levocabastine 0.05%, both twice daily, for 42 days, using ocular redness, itching, days without symptoms and clinical failure as outcome measures. The cost of first-line treatment failure, including visits, drugs and laboratory examinations, was established in each country from a panel of ophthalmologists and general practitioners. Full sensitivity analyses were conducted.. From day 7 to 42, patients treated with emedastine had less itching (p < 0.001) and less redness (p < 0.001). The failure rate was 10% less (p < 0.02) with emedastine and patients treated with emedastine had an incremental 8.5 days (p < 0.01) without symptoms. Emedastine and levocabastine were equally well tolerated. In all European countries, the cost of failure was lower with emedastine. Emedastine was found to be economically dominant relative to levocabastine, i.e. more effective and less expensive, in Belgium, Germany, Portugal and Sweden; in France, The Netherlands and Norway the incremental cost was low (less than 1 euro per additional symptom-free day).. Through a model based on a randomised clinical trial and cost estimates of treatment failure derived from practitioner interviews, emedastine is a cost-effective treatment of AAC.

Topics: Benzimidazoles; Conjunctivitis, Allergic; Cost-Benefit Analysis; Double-Blind Method; Health Care Costs; Histamine H1 Antagonists; Humans; Piperidines

The efficacy and safety of emedastine 0.05% eye drops (Emadine; Alcon Laboratories, Inc, Fort Worth, Texas), a new H(1) antagonist, were studied in comparison to levocabastine 0.05% eye drops (Livostin; Janssen-Cilag N V, Berchem, Belgium) during a twice-daily treatment schedule for 6 weeks in adult and pediatric patients with seasonal allergic conjunctivitis.. In a prospective, multicenter, randomized, double-masked, parallel group study, 222 patients with allergic conjunctivitis were randomized (221 received treatment) to either emedastine or levocabastine, instilled twice daily for 6 weeks. Patient diaries were completed four times daily (before the morning and evening instillations, at noon, and in the afternoon), and clinical examinations were conducted at regular intervals. Primary efficacy variables of ocular redness and itching and secondary efficacy variables of chemosis, eyelid swelling, patient diary data, and physician's global assessment were analyzed.. Both emedastine and levocabastine produced a statistically significant (P =.0001) reduction in itching and redness within 5 minutes of the first instillation. All signs and symptoms improved progressively over the 6-week treatment period. After 7 days of use, and throughout the remainder of the study, emedastine was statistically superior to levocabastine (P <.006) in preventing and alleviating the signs and symptoms (itching, redness, chemosis, and eyelid swelling) of allergic conjunctivitis.. Emedastine 0.05% eye drops administered twice daily are more efficacious than levocabastine 0.05% eye drops in the prevention and treatment of the signs and symptoms of allergic conjunctivitis in adults and children of 4 years and above. Both emedastine 0.05% eye drops and levocabastine 0.05% eye drops were well tolerated.

Topics: Adolescent; Adult; Aged; Benzimidazoles; Child; Child, Preschool; Conjunctivitis, Allergic; Double-Blind Method; Drug Administration Schedule; Female; Histamine H1 Antagonists; Humans; Middle Aged; Ophthalmic Solutions; Piperidines; Prospective Studies; Pruritus

The aim of the present investigation was to compare the efficacy and tolerability of azelastine (CAS 58581-89-8) (1.12 mg/day) and levocabastine (CAS 79547-78-7) (0.4 mg/day) nasal spray administered twice daily to patients with seasonal allergic rhinitis. A total of 180 patients participated in a 4-week, double-blind, parallel group (n = 90 each) study. Symptom severity of nasal, ocular and other symptoms were recorded, out of which a total symptom score (TSS) was calculated. Physicians assessed symptoms at baseline and at days 7, 14, and 28, patients and physicians evaluated the efficacy and tolerability. After 4 weeks of treatment with azelastine the mean overall TSS was reduced from a baseline score of 18.7 to 4.2, after levocabastine from 17.8 to 5.9. Patients morning scores for treatment days 1 to 28 gave a mean total score of 212.4 for the azelastine group and 230.6 for the levocabastine group; the equivalent evening scores yielded a mean total score of 115.5 and 175.6 respectively. Global efficacy was judged by physicians as either 'very good' or 'good' for 90% of azelastine patients and for 74% of the levocabastine group; 92% of azelastine patients and 76% of levocabastine patients judged treatment to be either 'very good' or 'good'. No serious adverse events were reported, all adverse events were related to nasal symptoms. Both azelastine and levocabastine administered twice daily as a nasal spray provide effective and well tolerated symptomatic treatment of seasonal allergic rhinitis. Azelastine, however, was statistically superior in efficacy as well as in safety (PWei-Lachin < 0.0001, combined results).

Topics: Administration, Intranasal; Adult; Aerosols; Aged; Anti-Allergic Agents; Double-Blind Method; Endpoint Determination; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Phthalazines; Piperidines; Rhinitis, Allergic, Seasonal; Risk Assessment

Nedocromil sodium and levocabastine are widely used for the treatment of ocular allergy, but their mechanisms of action are unclear.. We sought to compare the efficacy and mechanisms of action of nedocromil sodium and levocabastine in reducing conjunctival symptoms after ocular allergen challenge.. We performed a double-blind, placebo-controlled study in which 48 subjects were randomized to 3 groups to receive nedocromil sodium (2%), levocabastine (0.05%), or placebo eye drops twice daily for 2 weeks before ocular challenge with 10 microL of ryegrass extract. Symptoms and tear histamine and PGD(2) concentrations were determined before challenge and at 10, 20, 30, 60, 180, and 360 minutes after challenge. Bulbar biopsy specimens were taken at 6 and 24 hours after challenge to assess conjunctival inflammatory cell numbers, adhesion molecule expression, and mast cell-associated IL-4, IL-5, IL-6, IL-13, and TNF-alpha levels.. Both drugs significantly reduced total symptom scores (P <.05) at all times after challenge compared with placebo. Itching, hyperemia, and lacrimation were most affected. Nedocromil sodium treatment reduced tear concentrations of histamine (by 77%) and PGD(2) (by 70%) at 30 minutes after challenge (both P <.05). In biopsy specimens nedocromil sodium reduced the number of 3H4-positive mast cells (purportedly the secreted form of IL-4) by 49% at 6 hours and 59% at 24 hours (both P <.05). Levocabastine reduced intercellular adhesion molecule 1 expression by 52% at 6 hours and 45% at 24 hours (both P <.05).. Nedocromil sodium and levocabastine both reduced the conjunctival symptoms after ocular allergen challenge but appeared to work by different mechanisms. Nedocromil sodium reduced mast cell function, whereas levocabastine appeared to have primarily antihistaminic actions, although it also reduced the expression of intercellular adhesion molecule 1.

Topics: Adult; Anti-Allergic Agents; Conjunctiva; Conjunctivitis, Allergic; E-Selectin; Female; Histamine; Histamine H1 Antagonists; Humans; Intercellular Adhesion Molecule-1; Lolium; Male; Middle Aged; Nedocromil; Piperidines; Prostaglandin D2; Tears; Vascular Cell Adhesion Molecule-1

To determine the efficacy and tolerance of emedastine 0.05% ophthalmic solution compared to levocabastine 0.05% ophthalmic suspension in pediatric subjects.. In a randomized, double-masked, parallel controlled study, emedastine 0.05% ophthalmic solution BID was compared to levocabastine 0.05% ophthalmic suspension BID, for control of the signs and symptoms of allergic conjunctivitis in pediatric subjects ages 3-16. Subjects who met all inclusion and exclusion criteria received masked study medication with instructions to instill drops twice daily, in the morning and evening. A diary was completed by the parents four times daily for the first two and last two weeks of the study. Treatment lasted 42 days. Drug efficacy was assessed at the initial administration in the office at Day 0 and after 3, 7, 14, 30 and 42 days.. Overall results showed both drugs have an effect and that emedastine was significantly superior (p < 0.05) to levocabastine for the relief of chemosis on Days 14, 30 and 42; of itching on follow-up Days 30 and 42 (p < 0.05); of redness on Days 30 and 42; for eyelid swelling on Days 14 and 30; and for physician's impression score on Days 7, 14, 30 and 42.. These results confirm previous preclinical and clinical data on the potent and long acting efficacy of this promising new ophthalmic anti-allergic drug, emedastine in pediatric subjects.

Topics: Adolescent; Benzimidazoles; Child; Child, Preschool; Conjunctivitis, Allergic; Double-Blind Method; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Safety; Suspensions

To compare emedastine ophthalmic solution 0.05% BID to levocabastine ophthalmic suspension 0.05% BID in reducing chemosis, eyelid swelling and other signs and symptoms in subjects with seasonal allergic conjunctivitis.. In a randomized, double-masked, parallel controlled study, emedastine ophthalmic solution 0.05% BID was compared to levocabastine ophthalmic suspension 0.05% BID for control of chemosis, eyelid swelling and other parameters in the environmental allergy study model.. At Days 7, 14, 30 and 42, emedastine was significantly better than levocabastine at controlling chemosis and eyelid swelling (p < 0.05). A statistical trend was seen at Day 3 (0.05 < p < 0.10). Results were clinically relevant at Days 30 and 42. Emedastine was also significantly better at reducing redness and itching at Days 7, 14, 30 and 42 (p < 0.05).. Emedastine is more efficacious than levocabastine in reducing chemosis, eyelid swelling and other efficacy variables associated with seasonal allergic conjunctivitis.

Topics: Adolescent; Adult; Aged; Benzimidazoles; Child; Child, Preschool; Conjunctiva; Conjunctivitis, Allergic; Double-Blind Method; Edema; Eyelid Diseases; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Safety; Seasons; Treatment Outcome

To compare a new ocular antihistamine, emedastine difumarate (Emadine Ophthalmic Solution 0.05%; Alcon Laboratories, Fort Worth, Texas), with the marketed ocular antihistamine, levocabastine hydrochloride (Livostin Ophthalmic Suspension 0.05%; CIBA Vision, Atlanta, Georgia), in the treatment of allergic conjunctivitis after conjunctival allergen challenge.. We performed a prospective, double-masked, randomized, contralateral eye study comparing emedastine 0.05% in one eye with levocabastine 0. 05% or emedastine vehicle (placebo) in the contralateral eye. Efficacy was determined 10 minutes and 2 hours after administration of study medications. Ocular itching and redness scores were recorded 3, 5, and 10 minutes after conjunctival allergen challenge.. A total of 97 subjects with a history of allergic conjunctivitis and a positive response to a diagnostic test were evaluable for safety analysis, and 91 subjects were evaluable for the efficacy analysis. Emadastine 0.05% was statistically significantly more effective than levocabastine 0.05% in reducing ocular itching after conjunctival allergen challenge in both the 10-minute and the 2-hour challenge (P <.05). Emedastine 0.05% and levocabastine 0.05% were statistically equivalent in reducing conjunctival redness after conjunctival allergen challenge, although emedastine tended to be more efficacious than levocabastine at every observation time point.. After conjunctival allergen challenge, emadastine 0.05% is significantly more effective than levocabastine 0.05% in reducing ocular itching associated with allergic conjunctivitis. The two compounds are equivalent in controlling the conjunctival redness associated with allergic conjunctivitis.

Topics: Adolescent; Adult; Aged; Allergens; Benzimidazoles; Conjunctiva; Conjunctivitis, Allergic; Double-Blind Method; Drug Evaluation; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Prospective Studies; Safety; Suspensions; Treatment Outcome

A randomised, multicentre parallel group study was undertaken to compare the efficacy and safety of 0.05% azelastine eye drops (101 patients) in an open manner with 0.05% levocabastine eye drops (103 patients) and in a double-blind manner with placebo (103 patients) during a 14-day treatment period involving patients with seasonal allergic conjunctivitis. The three main eye symptoms, scored on a four-point scale, were itching, lacrimation and conjunctival redness; the primary efficacy variable was the responder rate on day 3. Responders were patients whose sum score of the three main eye symptoms decreased by at least three points from a baseline score of at least six points. In addition to these main symptoms, five other symptoms were recorded on days 0, 3, 7 and 14, and patients kept daily diaries of the three main eye symptoms and swollen eyelids. The responder rate after 3 days of treatment was 69% in patients treated with azelastine, 59% in patients treated with levocabastine and 51% in the placebo group. Only the difference in responder rates between azelastine and placebo eye drops was statistically significant (p = 0.02). The improvements in other ocular symptoms and entries in the patients' diaries closely reflected the changes reported by the investigators. No serious adverse events occurred throughout the study. Nine patients (three in the azelastine, five in the levocabastine and one in the placebo group) terminated the study prematurely due to poor tolerability. Adverse drug reactions, mainly a mild, transient irritation and a bitter or unpleasant taste, were reported in 37% of patients receiving azelastine eye drops, 31% of patients receiving levocabastine and 9% of placebo patients. Overall tolerability was assessed as very good or good in 86% of azelastine- and levocabastine-treated patients, and in 95% of the patients receiving placebo. The results of this study indicate that azelastine possesses a tolerability profile at least comparable to that of levocabastine eye drops, but additionally appears to have a slightly quicker onset of effect, and confirm the therapeutic potential of azelastine eye drops in the treatment of allergic conjunctivitis.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Conjunctivitis, Allergic; Consumer Product Safety; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Medical Records; Middle Aged; Ophthalmic Solutions; Phthalazines; Piperidines; Time Factors

The single-dose effects of the cytochrome P-450 inhibitors erythromycin and ketoconazole on the steady-state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1-receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open-label, placebo-controlled, two-way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half-life was approximately 45 and 44 hours, respectively. In both studies, mean steady-state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P-450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P-450 system is minimal.

Topics: Administration, Intranasal; Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Biological Availability; Bradycardia; Cross-Over Studies; Drug Interactions; Electrocardiography; Erythromycin; Headache; Heart Block; Histamine H1 Antagonists; Humans; Ketoconazole; Male; Middle Aged; Piperidines; Rhinitis; Time Factors; Virus Diseases

Although prior studies have documented the rapid onset of action of topical intranasal levocabastine (LEV), little is known about its duration of action under nasal challenge conditions.. We sought to assess the onset and duration of action of escalating doses of LEV nasal spray by using a nasal allergen challenge (NAC) model.. Eighteen asymptomatic subjects with histories of seasonal allergic rhinitis were enrolled into a randomized, single-blind, placebo-controlled, dose-ranging crossover study. Each patient was randomly assigned to receive single doses of placebo and intranasal LEV 0.1, 0.2, and 0.4 mg during 2 parts of the study. In part 1 (onset of action), NAC consisted of a single dose of allergen administered 5 minutes after study drug treatment. In part 2 (duration of action), NAC consisted of increasing doses of allergen administered 0.5, 6, 12, and 24 hours on separate days after study drug treatment. Nasal symptom scores (NSSs) and nasal peak expiratory flow rates were measured after NAC in both phases of the study. Blood samples for plasma LEV concentrations were drawn after each NAC.. In part 1, NSSs were significantly lower after the administration of LEV 0.1, 0.2, and 0.4 mg compared with placebo (P <.05). In part 2, NSSs were significantly lower after LEV doses of 0.2 and 0.4 mg compared with placebo at 0.5, 6, 12, and 24 hours after treatment (P <.05). The mean provocative dose of allergen required to elicit a positive nasal reaction was increased after LEV doses of 0.2 and 0.4 mg at 0.5, 6, and 12 hours after treatment. Nasal peak expiratory flow rates demonstrated no significant differences between LEV and placebo for any doses at any time points. Mean plasma LEV concentrations were low (range, 0 to 3. 7 ng/mL) after all doses and did not correlate with drug efficacy.. Single intranasal LEV doses of 0.1, 0.2, and 0.4 mg significantly reduced the severity of the immediate nasal response to allergen when administered 5 minutes before NAC. This protective effect against NAC continued to be present 24 hours after administration of LEV doses of 0.2 and 0.4 mg. Efficacy in blocking the reaction to NAC did not correlate with plasma LEV levels, suggesting that the inhibitory effect was due largely to topical rather than systemic effects.

Topics: Administration, Intranasal; Adult; Allergens; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Nasal Provocation Tests; Piperidines; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Single-Blind Method; Trees

Treatment options for allergic rhinitis include antihistamines, decongestants, anticholinergics, cromolyn sodium and corticosteroids. As the nose is a small organ, comprising less than 1% of total body mass and surface area, it seems logical to confine treatment of rhinitis to the diseased organ.. To evaluate the effects of therapy with intranasal fluticasone propionate (FP), both on subjective symptoms and pathophysiological mechanisms, in rhinitis patients during pollen season when the patients were symptomatic.. We used a double-blind, placebo (PLA)-controlled, randomized, double dummy, parallel group study of the effect of 6 weeks treatment. The double-blind comparison was made between the following three treatments: FP aqueous nasal spray, 200 microg taken once daily, levocabastine (LEV) nasal spray, 200 microg taken twice daily and PLA nasal spray. Clinical evaluation and the levels of cells and mediators in nasal washing were performed before and after treatments. Twenty-four patients (11 men and 13 women, aged 17-50 years, mean age 30.1 +/- 8.5) with strictly seasonal allergic rhinitis to Parietaria entered the study. Clinical evaluation and the levels of inflammatory cells (eosinophils and activated eosinophils, i.e. EG2+) and their mediators (tryptase, eosinophil cationic protein, eosinophil protein X and neutrophil myeloperoxidase) in nasal-lavage were performed before and after treatments.. Treatment with FP significantly increased, with respect to placebo, the percentage of days without sneezing (P < 0. 001), nasal blockage (P < 0.001), rhinorrhea (P < 0.001), nasal itching (P < 0.001). Furthermore, treatment with FP showed additional benefits with respect to LEV. The percentage of days without nasal blockage was significantly higher in the FP group that in the placebo group (P = 0.018). The same applied to rhinorrhea (P = 0.009). The percentages of days without sneezing and itching were instead not significantly different between the two groups. As expected, no significant differences were observed in baseline medians of the rhinitis symptom scores as well as in mean values of all mediators and eosinophils in nasal lavages of the various groups under study. After treatment the mean of subjective symptoms as well as all values in nasal lavage level fell significantly only in the FP group, whereas no significant changes were observed either in LEV or PLA groups. Accordingly, significant differences were observed at the end of the treatments between the values of fluticasone group vs LEV and PLA group values. Significant correlations between these values and symptom scores were found, according with literature data suggesting a pathogenetic role for these mediators and eosinophils in rhinitis.. FP (200 microg once daily) affords a significant degree of improvement in rhinitis control during pollen season, as measured by subjective and objective parameters, compared with LEV (200 microg twice daily) and PLA. The therapeutic benefits of intranasal FP are reflected in, and may be caused by, the decrease in nasal inflammatory cells.

Topics: Administration, Topical; Adolescent; Adult; Androstadienes; Anti-Inflammatory Agents; Double-Blind Method; Eosinophils; Female; Fluticasone; Glucocorticoids; Histamine H1 Antagonists; Humans; Leukocyte Count; Male; Middle Aged; Nasal Lavage Fluid; Piperidines; Pollen; Rhinitis, Allergic, Seasonal

Fluticasone propionate aqueous nasal spray (FPANS) is a topically active glucocorticoid which has been successfully used for the treatment of seasonal allergic rhinitis (SAR). Topical levocabastine is a highly selective H1 antagonist which has been proposed as an alternative treatment of SAR. The purpose of this study was to compare the clinical efficacy of two topical nasal treatments, FPANS and levocabastine, in the treatment of SAR. Additionally, the effect of treatments on nasal inflammation was examined during natural pollen exposure. A group of 288 adolescent and adult patients with at least a 2-year history of SAR to seasonal pollens participated in a multicenter, doubleblind, double-dummy, and placebo-controlled study. Patients were treated with either FPANS 200 microg, once daily (n = 97), or topical levocabastine, 200 microg, given twice daily (n = 96), or matched placebo (n = 95) for a period of 6 weeks, starting from the expected beginning of the pollen season. Clinically relevant pollens included Parietaria, olive, and grass. Assessment of efficacy was based on scores of daily nasal symptoms and on nasal cytology of nasal lavage. Nasal lavage was performed immediately before, during, and at the end of treatment in 39 patients. FPANS significantly increased the percentage of symptom-free days for nasal obstruction on waking and during the day, rhinorrhea, sneezing, and itching. FPANS provided a better control for night and day nasal obstruction (P<0.02 and P<0.01) and rhinorrhea (P<0.01) than levocabas tine. In addition, fewer patients treated with FPANS used rescue medication (P<0.025). The percentage of eosinophils in nasal lavage was reduced only during treatment with FPANS. The results of this study indicate that FPANS 200 microg, once daily, provides a better clinical effect than levocabastine 200 microg, twice daily, in patients with SAR. Unlike levocabastine, FPANS significantly attenuates nasal eosinophilia during pollen exposure, a feature which may explain its therapeutic efficacy.

Topics: Adult; Androstadienes; Anti-Allergic Agents; Double-Blind Method; Eosinophilia; Female; Fluticasone; Histamine H1 Antagonists; Humans; Hydrocortisone; Male; Piperidines; Rhinitis, Allergic, Seasonal

This study compares the effects of two topical nasal treatments for allergic rhinitis, budesonide and levocabastine, on symptom development during seasonal pollen exposure. Additionally, the protective effects of drug treatments on allergen-challenge-induced responses (symptoms and microvascular exudation of plasma) are examined late into the pollen season. Forty-four patients with seasonal allergic rhinitis to birch pollen participated in this single-blind, randomized, and placebo-controlled study. Topical nasal treatment with either levocabastine (200 microg b.i.d.; n = 16), budesonide (200 microg b.i.d.; n = 16), or placebo (n = 12) was instituted before the start of the pollen season and continued for 5 weeks until the end of the birch pollen season. The participants kept diaries for scores of nasal and ocular symptoms. Nasal allergen challenges with increasing doses of a birch pollen extract (10[2], 10[3], and 10[4] SQ-U) were carried out both before, when patients were asymptomatic and without treatment, and late into the pollen season. A nasal lavage followed each challenge, and the lavage fluid levels of albumin were measured as an index of the acute inflammatory response of the allergic mucosa. The birch pollen season was rather mild, producing only small increases in nasal symptoms. Budesonide treatment reduced the total nasal symptoms compared to placebo (P<0.01) and to levocabastine (P<0.05), while levocabastine treatment did not differ significantly from placebo. Ocular symptoms and use of rescue medication did not differ between placebo and the active treatments. At the end of the pollen season, both treatments reduced allergen-challenge-induced nasal symptoms compared to placebo (P<0.01). Only budesonide reduced allergen-challenge-induced increments of albumin levels in postchallenge nasal lavage fluids (P<0.05, in comparison with placebo). The results suggest that budesonide reduces both seasonal and allergen-challenge-induced nasal symptoms, while levocabastine is effective against allergen-challenge-induced symptoms also during the season. In addition, the topical steroid treatment, but not the antihistamine, inhibits the inflammatory exudation evoked by allergen challenge in patients with active seasonal disease.

Topics: Administration, Intranasal; Adult; Anti-Inflammatory Agents; Budesonide; Capillary Permeability; Female; Glucocorticoids; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; Single-Blind Method

It has been hypothesized that concentrations of exhaled nitric oxide (NO) may be related to the extent of cytokine-mediated airway inflammation. Recent findings indicate the nasal airways as an important site of NO production. Our objective was to evaluate whether children with allergic rhinitis show different nasal NO levels when compared with normal healthy subjects and the effect of topical steroids and anti-histamine therapy. We have measured the concentration of NO drawn from the nose of 21 children (5-17 years old) affected by perennial allergic rhinitis (house dust mite) out of therapy for at least 3 weeks. Thirteen children were then treated with nasal beclomethasone dipropionate (BDP) (400 micrograms daily) and eight subjects with nasal anti-histamine levocabastine (200 micrograms daily). Measurements were performed before and after 10 days of treatment. As a control group we evaluated 21 healthy children aged 5-15 years. To measure NO we used a chemiluminescence analyser. Before treatment the whole group of children with allergic rhinitis showed a mean (+/- SEM) nasal NO concentration of 267 +/- 18 ppb, significantly higher (P < 0.01) than the control group (186 +/- 15 ppb). The group of children treated with BDP showed, after 10 days of therapy, a significant (P < 0.05) decrease of nasal NO concentration (271 +/- 21 ppb vs. 212 +/- 20 ppb). Indeed, in the group treated with levocabastine, nasal NO concentrations did not present a significant difference (P not significant) compared with baseline (261 +/- 33 ppb and 252 +/- 31 ppb, respectively). These data suggest that (1) children with allergic rhinitis have higher levels of nasal NO than non-atopic controls and (2) intranasal steroid therapy significantly reduces nasal NO production in children with allergic rhinitis. We speculate that the allergic inflammatory response may influence the nasal NO levels and that NO measurements may be a useful marker of nasal inflammation.

Topics: Adolescent; Anti-Inflammatory Agents; Beclomethasone; Child; Child, Preschool; Female; Histamine H1 Antagonists; Humans; Male; Nitric Oxide; Pilot Projects; Piperidines; Rhinitis, Allergic, Perennial; Treatment Outcome

In a randomised, multicentre study, the effect of azelastine eye drops (n = 51 patients) was compared in a double-blind manner with placebo eye drops (n = 30 patients) and in an open manner with levocabastine eye drops (n = 32 patients) during a 14-day treatment period involving 113 children (aged 4 to 12 years) suffering from seasonal allergic conjunctivitis/rhinoconjunctivitis. The primary variable was the response rate defined as the number of patients showing an improvement after three days of treatment of at least three score points, from a minimum baseline score of six, in the main ocular symptoms of itching, conjunctival redness and lacrimation (each assessed on a four-point scale). Patients discontinuing due to inefficacy were regarded as non-responders. The mean response rate in the azelastine eye drops group (74%) was significantly higher (p < 0.01) than that in the placebo group (39%) and comparable with that in the levocabastine group. The response rates assessed by the patients in their diaries were very similar. Significant differences (p < 0.01) for azelastine compared with placebo were observed on days 3 and 14 in the mean sum scores for the three main symptoms and for a total of eight eye symptoms. The overall assessment of efficacy confirmed the superiority of both active treatments compared with placebo. Adverse drug reactions were reported in 23% of placebo-, 35% of azelastine- and 38% of levocabastine-treated patients. These were mainly local irritant effects. Overall tolerability was assessed as very good or good in 80%, 84% and 91% of placebo-, azelastine- and levocabastine-treated patients, respectively. Azelastine eye drops are effective and well-tolerated in children with seasonal allergic conjunctivitis.

Topics: Child; Child, Preschool; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Phthalazines; Piperidines; Rhinitis, Allergic, Seasonal; Severity of Illness Index

Mast cells are known to accumulate in tissue during allergic inflammation. However, the chemotaxins responsible are undefined. Using a modified Boyden chamber and the human mast-cell line HMC-1, we first identified mast-cell chemotactic activity in nasal lavage fluid collected before the pollen season after allergen provocation of allergic patients (n=29) (mean migratory response compared to medium control was 121%, range 85-198%). Mast-cell chemotactic activity was also detected in lavage fluid collected after allergen provocation at the end of a Swedish birch-pollen season from three different treatment groups: topical steroid treatment with budesonide; the topical antihistamine, levocabastine; and placebo. There was no significant difference in mast-cell chemotactic activity between nasal lavage fluid collected from the placebo group (mean=102%), the budesonide-treated group (mean=114%), or the levocabastine group (mean=125%). Stem cell factor (SCF), a known mast-cell chemotaxin, was present in the nasal lavage fluids from all three groups, and correlated with the mast-cell chemotactic activity (r=0.67, P<0.01). The mast-cell chemotactic activity was inhibited (range 5-100%) in some, but not all, nasal lavage fluids by a polyclonal antibody directed against SCF. This report describes the presence of mast-cell chemotactic activity in nasal lavage fluid during an allergic reaction. These findings show that SCF may play a pivotal role in the recruitment of mast cells in allergic rhinitis.

Topics: Allergens; Budesonide; Cell Line; Chemotactic Factors; Chemotaxis, Leukocyte; Enzyme-Linked Immunosorbent Assay; Humans; Mast Cells; Nasal Lavage Fluid; Nasal Provocation Tests; Piperidines; Pollen; Rhinitis, Allergic, Perennial; Single-Blind Method; Stem Cell Factor

This study evaluated the effectiviness and the onset of action of levocabastine (CAS 79547-78-7) nasal spray and eyedrops as well as of nedocromil (CAS 69049-74-7) nasal spray and eyedrops in practical relevant circumstances. The study was designed as an open observational study with parallel groups in 10 centres and comprised 102 patients. All patients presented with seasonal allergic rhinitis and evidenced conjunctival symptoms requiring therapy. The patients as well as the investigators were required to rate the symptoms using symptom scores in order to evaluate the effectiveness of the used drugs. The effectiveness according to symptom scores did not differ significantly between investigator's and patient's judgment. Onset of action was within the first hour in 81.6% of the patients treated with levocabastine and in 82.9% of the patients treated with nedocromil. Symptoms were evaluated on a visual analogue scale ranging from 0 to 100. The use of both substances reduced the severity of the reported symptoms by 50% within the first hour. Thus, no significant difference in the onset of action could be observed even though a later onset of action was expected of the stabiliser of mast cell membranes. Both drugs were tolerated well.

Topics: Administration, Intranasal; Adolescent; Adult; Aerosols; Anti-Allergic Agents; Child; Child, Preschool; Conjunctivitis, Allergic; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Nedocromil; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal; Time Factors

Levocabastine is an antihistaminic agent for topical application. It is without not advisable general side-effects and since many years is widely used for the treatment of pollinosis in adults and children more than 12 years of age. The group of 32 children aged from 5 to 11 years suffering from seasonal allergic rhinitis and conjunctivitis were treated by means of levocabastine applied topically by 20 days during the period of natural exposition to grass pollen. The clinical efficacy and tolerability including potential side-effects, were evaluated on the basis of clinical-laryngological investigations, visual analogs scales and diary cards filed in by parents of examined children. Levocabastine has been demonstrated to have rapid onset of action in children with SAR and the topical application of the drug does not irritate the mucosa of conjunctivas and nasal cavities.

Topics: Child; Child, Preschool; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal

In allergic rhinitis, a nasal H1-antihistamine spray seems to be well suited for usage on an as-needed basis, because it has a quick onset of action, and many patients prefer to take medicine only when they have symptoms. It is a prerequisite, however, that nasal hypersecretion during a rhinitis episode does not significantly reduce the efficacy of intranasal treatment by washing away the drug before it reaches the H1-histamine receptors. In order to investigate this problem, we have induced nasal hypersecretion with a methacholine challenge in one experiment and in four experiments we have washed the nasal cavities 0.5 min. before, 5 min. before, 0.5 min. after and 5 min. after intranasal use of the H1-antagonist, levocabastine. The symptom response to a subsequent histamine challenge was used as the effect parameter. Levocabastine reduced the number of histamine-induced sneezes with 81% (p < 0.0001) and the secretion weight with 62% (p < 0.001) compared with placebo. Neither methacholine-induced hypersecretion nor washing the nose with saline reduced the efficacy of the antihistamine spray. We conclude that experimentally induced nasal hypersecretion does not reduce the efficacy of the antihistamine spray, and probably the same applies to rhinorrhea during an acute episode of allergic rhinitis.

Topics: Administration, Intranasal; Adult; Analysis of Variance; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Methacholine Chloride; Nasal Lavage Fluid; Nasal Mucosa; Nasal Provocation Tests; Piperidines; Rhinitis; Sneezing; Statistics, Nonparametric

The authors present the result of an open controlled trial of the effectiveness of a new antiallergic ophthalmological preparation, Livostin, for local use, a product of Janssen-CILAG. They evaluate the results obtained in 86 patients with symptoms of allergic conjunctivitis. The preparation was followed up for four weeks, in particular the rate of onset of effect and its duration. Evidence was provided that this preparation is a highly effective local antiallergic drug with a long-term effect.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines

Allergic conjunctivitis is one of the most frequent allergic diseases of the anterior eye segment.. This multicentre, clinical trial was an investigation to compare the antiallergic efficacy, local tolerance and safety of Antazolin/Tetryzolin eye drops and Levocabastine eye drops. 69 patients were treated over a 2 weeks course of therapy. The subjective and objective ocular symptoms were documented over the treatment period.. Both eye drops reduced subjective and objective ocular symptoms effective. The difference between the treatments (p = 0.0395) was the faster onset of action of Antazolin/Tetryzolin 30 minutes after administration of the first drop of trial medication.. A fast and effective onset of action is of high clinical relevance. Therefore the benefits of using Antazolin/Tetryzolin eye drops was clearly outweigh.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antazoline; Anti-Allergic Agents; Conjunctivitis, Allergic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Histamine H1 Antagonists; Humans; Imidazoles; Male; Middle Aged; Nasal Decongestants; Ophthalmic Solutions; Piperidines

The ultrastructure of the nasal mucosa following the use of intranasal levocabastine was studied in 20 patients suffering from perennial allergic rhinitis. The patients received twice daily 0.05 per cent levocabastine spray with a treatment duration of four weeks. At the end of the treatment period regression of the allergic process was evidenced by progressive reappearance of normal cilia and microvilli on the columnar cells, decrease of intercellular oedema and cytoplasmic vacuoles, increased number of mucous acinar cells, gradual decrease of vascular congestion, as well as diminished oedema fluid formation. The drug, however, had no effect on mast cell degranulation nor on eosinophilic infiltration. Normalization of the ultrastructural features correlated well with clinical improvement. Considering the results of the present study, levocabastine nasal spray appears to be an effective treatment for perennial allergic rhinitis and can be used with, or as an alternative to, other anti-allergic medications.

Topics: Administration, Intranasal; Adult; Chronic Disease; Female; Histamine H1 Antagonists; Humans; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Nasal Mucosa; Piperidines; Rhinitis, Allergic, Perennial; Treatment Outcome

Levocabastine is a selective topical H1 antagonist, effective in the treatment of seasonal allergic rhinitis and conjunctivitis.. We evaluated the possible effects of levocabastine eye drops on early (EPR) and late phase (LPR) inflammatory changes induced by allergen-specific conjunctival challenge (ASCC). We focused our attention on the possible effect of levocabastine on expression of the intracellular adhesion molecule-1 (ICAM-1) on epithelial cells. Such a phenomenon is likely to play an important role in allergic inflammation.. The study was a double-blind, placebo-controlled, randomized trial, performed in cross-over, outside the pollen season. Ten out-patients suffering from allergic rhinoconjunctivitis due to parietaria judaica (wall parietary) were enrolled. Patients randomly received levocabastine eye drops (0.5 mg/mL) or placebo eyedrops, one drop in the left eye (right eye as control), 30 min before ASCC. Clinical evaluation (hyperaemia, burning-itching, lacrimation and eyelid swelling) and cytological assessment (number of neutrophils, eosinophils and lymphocytes, and ICAM-1 expression on conjunctival epithelium) were evaluated at baseline, 30 min and 6 h after ASCC. In parallel, we evaluated the in vitro effect of levocabastine at concentrations ranging from 2 x 10(-9) M to 2 x 10(-5) M on ICAM-1 expression and shedding by a continuously cultured differentiated epithelial cell line (WK).. Levocabastine reduced symptom scores during EPR (15 min and 30 min, P < 0.002), inflammatory cell infiltration during EPR (P < 0.002 for neutrophils, eosinophils and lymphocytes) and ICAM-1 expression on epithelium both during EPR (P < 0.002) and LPR (P < 0.02). LPR symptom scores and inflammatory cell infiltration were only slightly modified by levocabastine treatment. In vitro levocabastine at 2 x 10(-5) M concentration was able to down-regulate basal ICAM-1 expression, although it exerted no effect on ICAM-1 release by epithelium.. Levocabastine exerts anti-allergic activity, in that it reduces in vivo inflammatory cell infiltration due to ASCC, and also adhesion molecule expression on conjunctival epithelium. The latter phenomenon may be due, at least in part, to a direct effect of levocabastine on epithelial cells.

Topics: Acute-Phase Reaction; Administration, Topical; Adolescent; Adult; Cells, Cultured; Cross-Over Studies; Double-Blind Method; Drug Administration Routes; Epithelium; Eye; Female; Humans; Hypersensitivity, Delayed; Intercellular Adhesion Molecule-1; Male; Middle Aged; Piperidines

We have evaluated the efficacy of topical levocabastine in 42 patients (20 males and 22 females; mean age 37.5 yrs.) affected by perennial allergic rhinoconjunctivitis due to Dermatophagoides pteronyssinus. Diagnosis was performed on the basis of clinical history, Skin Prick test and RAST. The study lasted for 90 days and nasal spray levocabastine was administered at the dose of 2 puff in each nostril twice a day. Patients had to record the severity of the symptoms considered (sneezing, nasal pruritus, nasal obstruction and rhinorrhea) on a diary card according to an arbitrary score from 0 to 3. At the end of the treatment patients experienced a significant improvement of their symptoms and no side effects were recorded. On the basis of our results levocabastine can be considered a useful drug in the treatment of allergic rhinitis due to Dermatophagoides pteronyssinus.

Topics: Administration, Intranasal; Adult; Aerosols; Analysis of Variance; Conjunctivitis; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial

A total of 22 asymptomatic patients with a documented history of allergic rhinitis participated in this single-centre, double-blind, randomized, placebo-controlled, cross-over trial undertaken to assess the efficacy and tolerability of levocabastine nasal spray (0.5 mg/ml) in the prevention of allergen-induced nasal symptoms. Objective assessment of nasal symptoms revealed that the severity of sneezing was significantly lower following treatment with levocabastine (p < 0.001), with rhinorrhoea also tending to be less severe in the levocabastine-treated group (0.05 < p < 0.1). Rhinomanometry and acoustic rhinometry failed to reveal any significant intergroup differences, and there were no differences in nasal albumin concentrations between the two treatment groups. Patients' VAS ratings revealed significant differences in favour of levocabastine for sneezing (p < 0.001) and itching (p < 0.05), with the severity of rhinorrhoea also tending to be lower during treatment with this topical antihistamine (0.05 < p < 0.1). The mean total symptom score was also significantly lower in levocabastine-treated patients (p < 0.05). Levocabastine was well tolerated. Only two adverse events were reported: fatigue in one patient, and vesicular rash with facial oedema and urticaria in another. In conclusion, intranasal levocabastine provided effective protection from nasal allergen challenge and would appear to be a valuable therapeutic approach in patients with allergic rhinitis.

Topics: Administration, Intranasal; Adult; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Seasonal; Severity of Illness Index

Multiple ocular challenges or seasonal trials have demonstrated the efficacy of levocabastine and nedocromil sodium in the treatment of allergic conjunctivitis.. This study was designed to compare the protective effect of levocabastine eye drops with that of nedocromil in a conjunctival provocation test with allergen.. Twenty-four patients with allergic conjunctivitis to grass pollen were recruited. After a preliminary provocation to determine conjunctival reaction threshold (erythema of at least 50% of the conjunctiva with ocular itching), patients were randomized to receive either topical levocabastine (0.05%) or nedocromil (2%) 15 minutes before provocation. Erythema and pruritus intensity were recorded at each concentration of allergen up to the reaction threshold.. The allergen concentration level necessary to reach reaction threshold was increased (p < 0.001) after treatment with both drugs. Comparison between screening and each treatment indicated that the shift in allergen concentration was significantly greater after levocabastine treatment than after nedocromil treatment (p = 0.019). Conjunctival itching (symptom score) and erythema (percent conjunctival surface) were also better controlled by levocabastine than by nedocromil during provocation (p < 0.05).. In a provocation test with allergen, levocabastine and nedocromil were both effective in increasing the conjunctival tolerance to allergen, with better protection provided by levocabastine.

Topics: Administration, Topical; Adolescent; Adult; Allergens; Conjunctiva; Conjunctivitis, Allergic; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Immune Tolerance; Male; Middle Aged; Nedocromil; Piperidines; Pollen

It has been demonstrated that some oral antihistamines reduce nasal nonspecific reactivity and that topical levocabastine reduces cellular influx after nasal allergen challenge. This suggests that antihistamines possess other properties besides classical H1-receptor antagonism.. To evaluate the effect of 1 week's treatment with topical levocabastine on the nasal clinical response, inflammatory mediators, and nasal hyperreactivity.. In a double-blind, placebo-controlled, 2-period, 2-treatment, crossover study, 21 rhinitic patients allergic to house dust mite participated. After each treatment period patients were challenged with house dust mite extract. Symptom scores and nasal lavages were collected for nine and one-half hours after challenge. Allergen-induced nasal hyperreactivity was determined by nasal methacholine challenge 24 hours after allergen challenge. A nasal histamine challenge was performed as well.. Patients showed only an immediate nasal response. Levocabastine significantly reduced the symptom score after 100 (P = .0063), 1000 (P = .0035), and 10,000 biological units (BU)/mL (P = .0013) of house dust mite extract. Albumin influx and tryptase release were not significantly reduced by levocabastine. No release of histamine and eosinophil cationic protein was seen. Levocabastine did not reduce nasal response to methacholine. Active treatment significantly reduced histamine-induced nasal secretion (P = .0009) and the number of sneezes (P = .0001).. A significant effect of levocabastine was shown on the immediate clinical response to house dust mite and to histamine challenge only. Our findings suggest that levocabastine is an effective H1-receptor antagonist without anti-inflammatory properties.

Topics: Administration, Topical; Adult; Albumins; Allergens; Animals; Antigens, Dermatophagoides; Chymases; Cross-Over Studies; Double-Blind Method; Female; Glycoproteins; Histamine; Histamine H1 Antagonists; Humans; Male; Methacholine Chloride; Middle Aged; Mites; Nasal Lavage Fluid; Nasal Mucosa; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Perennial; Serine Endopeptidases; Tryptases

This study was conducted to evaluate the efficacy of 0.05% levocabastine compared with 4% cromolyn for treating allergic conjunctivitis induced by ocular allergen challenge.. Subjects who met all entry criteria and reacted positively to ocular allergen challenge at two previous visits (n = 50) received placebo in one eye and cromolyn in the fellow eye, four times daily for 2 weeks. On day 18, subjects received the final dose of cromolyn in the pretreated eye and one drop of levocabastine in the fellow eye. Subjects were challenged and evaluated after 3, 5, and 10 minutes. Four hours after drug administration, subjects were rechallenged and evaluated after 3, 5, and 10 minutes.. Levocabastine was significantly more effective than cromolyn in inhibiting itching, hyperemia, eyelid swelling, chemosis, and tearing after the initial challenge and 4-hour rechallenge (P < 0.05).. These results suggest that levocabastine is superior to cromolyn for treating allergen-induced conjunctivitis and has a duration of action of at least 4 hours.

Topics: Allergens; Conjunctivitis, Allergic; Cromolyn Sodium; Histamine H1 Antagonists; Humans; Models, Biological; Ophthalmic Solutions; Piperidines

In this international, multicentre, randomized, double-blind, parallel-group, placebo-controlled trial 262 patients participated to assess the efficacy and tolerability of levocabastine nasal spray in the treatment of seasonal allergic rhinitis. Patients were randomized to receive either twice daily 0.05% levocabastine or matching placebo nasal spray with a treatment duration of four weeks. Assessments of global therapeutic efficacy favoured levocabastine. At the end of the trial, 55% of levocabastine-treated patients considered therapeutic efficacy to be excellent or good compared to 36% of those who received placebo (p < 0.001). The corresponding values for the investigator assessments were 54% and 37% (p < 0.001), respectively. Analysis of patients' diary data showed significantly lower AUCs for all parameters in the levocabastine group (p < 0.05). Investigator assessments revealed a trend towards a greater reduction in individual symptom severity from baseline in levocabastine-treated patients compared to placebo-treated controls. Adverse experiences were reported by 21% of levocabastine-treated patients and by 19% of those who received placebo, with no statistically significant differences in incidence or type. Headache and local reactions following application were the most frequently reported adverse events. Levocabastine nasal spray appears to be effective and well-tolerated for the treatment of seasonal allergic rhinitis and is an alternative to oral antihistamines.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal

This multicenter, double-blind, double-dummy, parallel-group trial was initiated to compare the efficacy and tolerability of two antihistamines, topical levocabastine (eye-drops and nasal spray) and oral loratadine, for the treatment of seasonal allergic rhinoconjunctivitis in the primary care setting. A total of 95 adult patients participated in the study with a treatment duration of 5 weeks. Forty-seven patients were randomized to receive twice daily levocabastine eye-drops and nasal spray plus an oral placebo, and 48 to receive once daily oral loratadine with placebo eye-drops and nasal spray. Naphazoline eye-drops and xylometazoline nasal spray were permitted as rescue medication. No statistically significant intergroup differences in therapeutic efficacy were observed. Symptom severity was comparable in the two treatment groups throughout the trial period. At the end of the study, 86% of levocabastine-treated patients considered global therapeutic efficacy to be excellent or good, as compared with 77% of those who received loratadine. This difference was not statistically significant. There were no significant differences in the use of rescue medication or in the incidence or severity of adverse events in the two treatment groups. In conclusion, levocabastine eye-drops and nasal spray appear to be as effective and well tolerated as oral loratadine for the treatment of seasonal allergic rhinoconjunctivitis.

Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Aerosols; Aged; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Loratadine; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal

The efficacy and tolerability of levocabastine eye drops in vernal conjunctivitis (VC) were evaluated in a double-blind, placebo-controlled trial involving 46 patients over a period of 4 weeks. After 1 week of treatment, therapeutic efficacy was considered to be excellent or good for 70% of the levocabastine-treated patients compared with only 33% of patients in the placebo group (p < 0.009). Levocabastine patients experienced significantly greater relief of their individually severest symptom than placebo-treated patients both after 1 week and at the end of the trial (p < 0.04). The reduction in symptom severity was significantly greater in the levocabastine group than in the control group for photophobia (p < 0.003) after 1 week, and for photophobia (p < 0.008), irritation (p = 0.05) and itchy eyes (p = 0.05) at the end of the trial. The percentage of days on which patients were completely symptom-free was significantly higher in the levocabastine group than in the placebo group (28% versus 4%; p < 0.02). Eight placebo-treated patients withdrew from the trial due to treatment inefficacy compared with only four levocabastine-treated patients (p = 0.013). Two of the three levocabastine, and all five placebo patients who elected to continue on open-label levocabastine had an excellent or good overall response after 1 to 3 weeks of treatment. All reported adverse reactions were mild and their incidence was equal in the two treatment groups. Levocabastine eye drops are effective and well tolerated in the treatment of VC.

Topics: Adolescent; Adult; Child; Child, Preschool; Conjunctivitis, Allergic; Double-Blind Method; Drug Tolerance; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Prognosis

Children (n = 110) with seasonal allergic rhinoconjunctivitis were randomized to receive either twice daily 0.05% levocabastine eye drops and nasal spray plus twice daily topical placebos or 2% sodium cromoglycate eye drops and nasal spray four times daily for a period of 4 weeks. Patients were required to use the nasal sprays as directed and the eye drops only when required. The results obtained suggest that topical levocabastine is at least as effective as sodium cromoglycate for the treatment of this condition. After 2 weeks treatment the effect of therapy on nasal symptoms was considered to be excellent or good in 72% of levocabastine-treated patients and 54% of patients on sodium cromoglycate (p = 0.009), with corresponding values for ocular symptoms of 81% and 57% in the two groups, respectively (p < 0.05). Investigator assessments also revealed that the severity of sneezing and lacrimation were significantly lower in the levocabastine group at this time (p < 0.05). After 4 weeks of treatment, patient diary data revealed that levocabastine was at least as effective as sodium cromoglycate with intergroup differences attaining statistical significance in favor of the topical antihistamine for nasal congestion (p < 0.05). Both agents were well-tolerated with no significant differences in the incidence or type of adverse reactions in the two treatment groups.

Topics: Administration, Intranasal; Adolescent; Child; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal

Topics: Administration, Topical; Adult; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Seasonal

This double-blind, parallel-group study compared topical levocabastine (eye drops and nasal spray) and oral terfenadine in 27 patients with seasonal allergic rhinoconjunctivitis over a period of 8 weeks. The main aim of this trial was to assess the ocular tolerability of levocabastine eye drops. Comparison of therapeutic efficacy was a secondary study objective. Use of oral and ocular medication was mandatory, however the nasal spray was only to be used when required. The use of nasal spray was 46% in the levocabastine group and 56% in the terfenadine group. Ophthalmologic examinations indicated that levocabastine eye drops were well tolerated. The incidence of adverse reactions was 31% in the levocabastine group and 43% in the terfenadine group. At the end of the trial, a total of 88% of levocabastine-treated patients rated the effect of therapy on ocular symptoms to be excellent or good compared with 75% of those who received terfenadine, while 75% of patients in each group were satisfied with the effect of therapy on nasal symptoms. The investigator's evaluation of symptom severity revealed consistently better results with levocabastine. Levocabastine was significantly more effective than terfenadine in relieving ocular itching (p = .02). The patients' visual analogue scale ratings also showed significantly better results for levocabastine, particularly with respect to nasal symptoms. Levocabastine was significantly better than terfenadine for a number of symptoms on days when the pollen count was high. In conclusion, topical levocabastine appears to be a well-tolerated and effective alternative to oral terfenadine for the treatment of seasonal allergic rhinoconjunctivitis.

Topics: Administration, Oral; Administration, Topical; Adult; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal; Terfenadine

The objective of this study was to evaluate the efficacy of 0.05% levocabastine, a new antihistamine formulated for ophthalmic use, compared with the placebo vehicle for the treatment of allergic conjunctivitis induced by ocular allergen challenge. Subjects who reacted. positively in both eyes on two separate occasions to ocular allergen challenge with grass, ragweed, or cat dander (N = 47) received one dose of 1 to 2 drops of 0.05% levocabastine in one eye and its vehicle in the other eye. After 10 minutes, the predetermined dose of allergen was instilled in both eyes. Signs and symptoms of allergic conjunctivitis were evaluated with biomicroscopy and subjective evaluation of itching after 3, 5, and 10 minutes. Four hours after drug administration, subjects were rechallenged and reevaluated to determine levocabastine's duration of action. Results showed that levocabastine was significantly more effective than placebo in inhibiting itching, hyperemia, eyelid swelling, chemosis, and tearing after the initial challenge and in inhibiting all parameters except eyelid swelling after the rechallenge 4 hours later (p < 0.05). These results demonstrate that levocabastine, currently the only ophthalmic antihistamine available that is not combined with a vasoconstrictor, is efficacious in the inhibition of itching, as well as all of the allergic signs of a vascular origin, with a duration of action of at least 4 hours. Because of its strong effects on itching and hyperemia, chemosis, lid swelling, and tearing, levocabastine would be a valuable therapeutic agent to add to the heterogeneous family of antiallergic compounds presently available for the treatment of seasonal allergic conjunctivitis.

Topics: Adolescent; Adult; Allergens; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Models, Biological; Ophthalmic Solutions; Piperidines

The efficacy, tolerability, and adverse-effect profile of the recently developed, topical antihistamine levocabastine were compared with those of sodium cromoglycate in a 4-week double-blind, placebo-controlled trial in 95 patients with seasonal allergic conjunctivitis. At the end of the trial, global therapeutic efficacy was considered to be excellent or good in 87% of levocabastine-treated patients, as compared with 68% of sodium cromoglycate-treated patients (P = 0.006) and 63% of those who received placebo (P = 0.05). After 4 weeks of treatment, levocabastine patients had experienced significantly greater relief from their most severe ocular symptom than patients in the sodium cromoglycate group (P < 0.05). Furthermore, 37% of levocabastine-treated patients were virtually symptom-free for at least 75% of the treatment period, as compared with only 6% of patients in the sodium cromoglycate group (P < 0.01) and 4% of those who received placebo (P < 0.01). Moreover, this trend was maintained on days when the pollen count was high, when the corresponding figures were 33%, 6% (P = 0.02), and 4% (P = 0.02), respectively. Levocabastine was well tolerated. Indeed, the incidence of adverse reactions was no greater in the levocabastine group than in the placebo group. Topical levocabastine is an effective and well-tolerated drug for the prophylaxis and treatment of seasonal allergic conjunctivitis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Histamine H1 Antagonists; Humans; Middle Aged; Piperidines

This study was undertaken to compare the efficacy of twice-daily levocabastine, a new topical H1-blocking antihistamine, with that of twice-daily oral terfenadine in the treatment of allergic rhinoconjunctivitis. A total of 128 adult patients with a history of birch-pollen-provoked allergic rhinoconjunctivitis participated in this double-blind, parallel-group study. Ocular and nasal symptoms, assessed by a 100-mm visual analog scale, were recorded daily on diary cards for a period of 8 weeks. Global assessments of treatment efficacy were also performed. Conventional statistical analysis detected no significant differences between the two treatment regimens. Similarly, there was no difference in the number or type of adverse reactions in each treatment group. Statistical analysis according to Hauck & Anderson confirmed equivalence between the two treatment regimens. Topical levocabastine appears to be as effective and well-tolerated as oral terfenadine in the treatment of allergic rhinoconjunctivitis.

Topics: Administration, Intranasal; Administration, Oral; Adult; Conjunctivitis, Allergic; Double-Blind Method; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal; Terfenadine

Levocabastine is a very potent histamine H1 antagonist, available for ocular use as eye drops containing 0.5 mg/ml of levocabastine with benzalkonium chloride as a preservative. Local tolerability of the eye drops was evaluated by objective measurements including slit lamp, tonometry, fluorescein and rose Bengal staining, ophthalmoscopy, visual acuity and visual field determinations, as well as subjectively by questioning for adverse experiences. Seven ocular tolerability studies were performed in a total of 71 volunteers and 103 patients with allergic conjunctivitis. Levocabasine was given from twice to four times daily for 1-8 weeks. Two studies were open, three were placebo controlled and in two, levocabastine was compared with terfenadine. No changes of either clinical or statistical significance were observed in the ocular or peri-ocular tissues. Subjectively, local irritation, pain and tearing were virtually absent. Detailed ophthalmological tolerance studies therefore showed levocabastine eye drops to be very well tolerated.

Topics: Adolescent; Adult; Conjunctivitis, Allergic; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Piperidines; Terfenadine; Visual Acuity

For evaluation of the effect of levocabastine pretreatment on allergen-induced rhinitis symptoms, changes in nasal washings, and nasal responsiveness to histamine, 12 asymptomatic patients with documented allergic rhinitis participated in a single-blind, placebo-controlled study. Eight-day treatment with levocabastine (twice in each nostril, four times a day) caused significant reduction in nasal symptoms and inflammatory cell influx after allergen challenge, as compared with placebo administration. Levocabastine inhibited increased nasal reactivity to histamine induced by allergen provocation, as controlled by rhinitis symptoms and albumin level in nasal washings. These data reveal a high effectiveness of levocabastine in the prevention of allergen-induced rhinitis symptoms. Moreover, its inhibitory effect on inflammatory cell influx and hyperresponsiveness to histamine suggest that levocabastine is more than a simple H1-receptor antagonist.

Topics: Adult; Albumins; Allergens; Animals; Cell Count; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Mites; Nasal Lavage Fluid; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Perennial

A total of 71 patients with documented birch and grass pollen allergy participated in this randomized, double-blind, parallel-group study initiated to compare the long-term therapeutic efficacy of twice daily levocabastine, a new topical H1-receptor blocker, with that of sodium cromoglycate four times daily in the treatment of pollen-provoked conjunctivitis. There was no statistically significant difference in therapeutic efficacy between the two treatment groups, although a positive trend in favour of levocabastine was observed. Global evaluations of therapeutic efficacy were similar in both treatment groups. A total of 94% of levocabastine-treated patients rated treatment to be excellent or good compared with 86% of patients in the sodium cromoglycate group. Moreover, there were no significant differences in the severity of allergic symptoms reported on the patient diary cards. Patients were permitted to use rescue medication (oral terfenadine and betamethasone nasal spray) if symptoms became severe. The use of rescue medication was lower in the levocabastine group than in the sodium cromoglycate group. The mean number of days on which rescue medication was used was 12.8 and 26.9 in the two groups, respectively. The incidence, and type, of adverse reactions was similar in both patient groups. Levocabastine is well-tolerated and at least as effective as sodium cromoglycate in the treatment of pollen-provoked conjunctivitis.

Topics: Administration, Topical; Adult; Allergens; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Histamine H1 Antagonists; Humans; Longitudinal Studies; Middle Aged; Ophthalmic Solutions; Piperidines; Pollen

This study was designed to compare the efficacy and tolerability of a new topical (nasal spray and eye drops) H1-receptor antagonist, levocabastine, with that of orally administered terfenadine for the prophylaxis and treatment of seasonal allergic rhinoconjunctivitis.. A total of 115 patients with documented birch pollen allergy were enrolled in this randomized, double-blind, double-dummy, parallel-group trial. Treatment was initiated immediately before the birch pollen season started and continued for a total of 8 weeks. Xylometrazoline (Otrivin) nasal spray was permitted as rescue medication.. The investigator's evaluation of symptoms showed similar effects for levocabastine and terfenadine. Both the patients' and the investigator's global evaluations of ocular and nasal symptoms disclosed a somewhat higher percentage of good or excellent results for levocabastine, but the differences were not statistically significant. Visual analog scale ratings from the patients' diaries showed better results for levocabastine. Levocabastine was significantly more effective than terfenadine in relieving sneezing, rhinorrhea, lacrimation, itch, and burning sensation (p < 0.05). For some symptoms, levocabastine was significantly more effective than terfenadine on days when the pollen count was high. There were no statistically significant differences in the use of rescue medication or in the incidence of adverse reactions reported in each treatment group.. In the present study topical levocabastine was frequently more effective than orally administered terfenadine for the treatment of seasonal allergic rhinoconjunctivitis. Both drugs were well-tolerated.

Topics: Administration, Oral; Adult; Aerosols; Conjunctivitis, Allergic; Double-Blind Method; Drug Tolerance; Female; Histamine H1 Antagonists; Humans; Male; Norway; Ophthalmic Solutions; Piperidines; Remission Induction; Rhinitis, Allergic, Seasonal; Terfenadine

Levocabastine is a recently developed, potent H1-receptor blocker intended for topical application. Seventeen healthy non-atopic volunteers participated in this randomized, double-blind, placebo-controlled study undertaken to investigate the speed of onset of action, efficacy and tolerability of levocabastine eye-drops after a histamine challenge. The degree of histamine-induced ocular inflammation was found to be significantly less after administration of levocabastine compared with placebo. Furthermore, levocabastine was shown to be rapidly effective with an onset of action within 10 min. Levocabastine eye-drops were well-tolerated and no adverse reactions to the study drug were reported. Levocabastine eye-drops appear to be a valuable therapeutic approach for the treatment of histamine-mediated ocular allergies.

Topics: Adult; Animals; Chick Embryo; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Severity of Illness Index; Time Factors; Treatment Outcome

The aim of this prospective, open study was to evaluate the efficacy and tolerance of the Levocabastine eye drops in daily practice. 273 patients with allergic (rhino)conjunctivitis were treated during 2 weeks. Objective findings and subjective assessments made by the patients were analyzed. The global efficacy was evaluated by the investigator as good or excellent in 73.8% (eye) and 53.6% (nose) of the patients. The results were not age-dependent. The tolerance was scored as good or excellent in 89% of the patients. Less than 6% of the patients stopped the treatment due to intolerance.

Topics: Adult; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Piperidines

Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H1 antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistamine compound available, being 15,000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action. In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.

Topics: Animals; Antazoline; Conjunctivitis, Allergic; Cromolyn Sodium; Histamine H1 Antagonists; Humans; Naphazoline; Ophthalmic Solutions; Piperidines; Placebos; Terfenadine

The efficacy and safety of the nasal administration (twice in each nostril, four times a day) of levocabastine (0.5 mg/ml) were compared with those of sodium cromoglycate (20 mg/ml) and placebo in a 2-week, parallel, double-blind trial in patients with seasonal allergic rhinitis. At the end of treatment, 89% of patients in the levocabastine-treated group rated their treatment as globally good or excellent as compared with 32% (p = 0.003) of sodium cromoglycate-treated and 35% (p = 0.002) of placebo-treated patients. According to the investigators' ratings, the severest nasal symptom and ocular complaints responded better to levocabastine than to cromoglycate (p = 0.05 and p = 0.03) or placebo treatment (p = 0.03 and p = 0.001). Visual analogue scale ratings in patients' diaries indicated that at the end of therapy, nasal symptoms were less severe in the levocabastine-treated group than in the sodium cromoglycate-treated (p = 0.03) or placebo-treated group (p = 0.001). Total symptom severity as a percentage of the theoretical maximum symptom severity during the treatment period was lower for levocabastine than for sodium cromoglycate (p = 0.06) or placebo (p = 0.004) for the severest nasal symptom (35% versus 47% and 76%), sneezing (the most frequent symptom) (27% versus 42% and 67%), and itchy nose (18% versus 37% and 67%). The percentage of days at which nasal symptoms were entirely absent was markedly higher in the levocabastine-treated (33%) than in the sodium cromoglycate-treated (9%; p = 0.006) or placebo-treated (3%; p = 0.001) group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Administration, Topical; Adolescent; Adult; Cromolyn Sodium; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Placebos; Rhinitis, Allergic, Seasonal

The possible central nervous system effects of topical administration of levocabastine, a new H1-antagonist, were investigated in a double-blind, placebo-controlled, crossover study using a battery of objective and subjective tests. These were carried out in 12 volunteers up to five hours postapplication. Neither the recommended (0.5 mg/mL) nor the four times higher (2.0 mg/mL) concentration level was found to be distinguishable from placebo, while the verum (triprolidine 10 mg) was significantly worse, on both objective and subjective measures.

Topics: Administration, Topical; Adolescent; Adult; Cognition; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Middle Aged; Piperidines; Psychomotor Performance

Topics: Adolescent; Adult; Cohort Studies; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines

Nasal levocabastine (0.5 mg/mL) was evaluated for efficacy and tolerance against sodium cromoglycate (20 mg/mL) in a 2-week double-blind trial in 27 and 29 patients with seasonal allergic rhinitis. Globally at 2 weeks, the investigators found a 74% response rate in the levocabastine patients versus a 50% response rate in the cromoglycate patients (P less than .10). Sneezing responded better to levocabastine than to cromoglycate according to three efficacy indicators derived from patient diary ratings of symptom severity: sum of severity scores over the total treatment period as a percentage of the theoretical maximum sum of severity scores (median: 19% versus 41%, P = .01); percentage of symptom-free days (median: 46% versus 22%, P less than .07); percentage of days with moderate or severe symptoms (median: 0% versus 29%, P = .004). Further, the percentage of days with moderate or severe runny nose was lower than in cromoglycate patients (median: 0% versus 25%, P = .09). Although no significant differences were found for itchy nose, blocked nose, and ocular symptoms, severities tended to be generally less under levocabastine than under sodium cromoglycate. Adverse experiences were low level and of similar incidence in the two groups. It is concluded that in a q.i.d. schedule, levocabastine nasal spray is more efficacious than sodium cromoglycate in relieving sneezing and that it is equally well tolerated.

Topics: Administration, Intranasal; Adolescent; Adult; Child; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Rhinitis, Allergic, Seasonal; Severity of Illness Index

The efficacy and tolerance of topical administration (one drop in each eye q.i.d.) of levocabastine (0.5 mg/ml) was compared with that of sodium cromoglycate (20 mg/ml) and placebo in a 4-week double-blind trial in patients with seasonal allergic conjunctivitis. The investigator rated the treatment as globally good or excellent in significantly more patients treated with levocabastine (89%) than with cromoglycate (67%, P = 0.03) or placebo (48%, P = 0.007). The patients felt that the treatment was more efficacious in 95% (levocabastine), 35% (cromoglycate) and 36% (placebo) of the cases in which they had taken previous antiallergic medication. Total symptom severity according to the patients' diary data was consistently lower with levocabastine than with cromoglycate or placebo for all ocular symptoms. The difference was mainly apparent at the beginning of treatment. The percentage of symptom-free days was higher in the levocabastine group (53%) than in the cromoglycate (31%, P = 0.02) and the placebo group (34%, P = 0.08). Particularly at high-pollen days, levocabastine was superior to cromoglycate in eliminating moderate or severe symptoms. Adverse effects did not occur more frequently with levocabastine or cromoglycate than with placebo. It is concluded that levocabastine is an efficacious, fast-acting and well-tolerated drug in the management of seasonal allergic conjunctivitis.

Topics: Adolescent; Adult; Child; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Histamine H1 Antagonists; Humans; Middle Aged; Ophthalmic Solutions; Piperidines

Levocabastine is a new H1 receptor blocking antihistamine which is intended for topical use in the treatment of allergic conjunctivitis. The protective effect of the drug in conjunctival provocation test (CPT) was evaluated in a double blind study of 25 children aged 9-17 years with confirmed pollen allergy. One drop of levocabastine, cromoglycate or placebo was instilled into the conjunctival sac of both eyes. After 15 min CPT was performed, starting with 320 BU of pollen extract. The allergen dose was increased every 10 min in half 10-log steps in the right eye until a positive reaction occurred, or the top dose 320,000 BU was reached. The lowest dose resulting in a positive CPT reaction, i.e. at least 50% of the conjunctiva with erythema, was defined as the allergenic threshold dose (ATD). Pretreatment with levocabastine resulted in a median ATD of 32,000 BU, compared with 10,000 after cromoglycate (P less than 0.001) or placebo (P less than 0.01). Levocabastine was also superior in reducing subjective itch in the eyes. Determination of the ATD can be used as a relatively quick assessment of drugs intended for the treatment of allergic conjunctivitis.

Topics: Adolescent; Child; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Ophthalmic Solutions; Piperidines; Pollen; Random Allocation

Thirty patients with allergic conjunctivitis, caused by Parietaria or grass pollens, participated in a double-blind parallel study comparing levocabastine to cromolyn sodium, both given as eye drops. Symptom and sign scores were recorded during a 4-week period. The patients received only these drugs during the time of observation. The evaluation of the clinical signs and symptoms by the clinicians and by the patients revealed a significant improvement of conjunctivitis in all patients. The intergroup comparison was equal in the two groups treated respectively with levocabastine and cromolyn. Therefore, levocabastine and cromolyn are effective in the treatment of pollen-induced allergic conjunctivitis.

Topics: Administration, Topical; Adolescent; Adult; Clinical Trials as Topic; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pollen

Twelve healthy volunteers were randomly allocated to receiving in a double-blind cross-over fashion levocabastine eye drops (0.5 mg/ml solution) and placebo. They were advised to instill 2 drops per eye, four times daily. Each treatment was administered for a period of 1 week. Before and after each treatment period psychomotor function was assessed using Critical Flicker Fusion Test and the Choice Reaction Time Test. At the same time intervals a subjective evaluation of sedation was given using a Visual Analogue of Sedation. Both objective and subjective measurements showed that no significant treatment effects could be detected. It is concluded that repeated instillations of levocabastine eye drops are devoid of any sedative side effects.

Topics: Adult; Central Nervous System; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Psychomotor Performance

Fifteen asymptomatic subjects with allergic rhinitis participated in a double-blind, randomized, crossover, placebo-controlled study. The subjects were pretreated intranasally with a single dose of a selective H1 receptor antagonist, levocabastine, and/or selective H2 receptor antagonist, ranitidine, prior to a nasal allergen challenge. The nasal symptoms obtained at the challenge were assessed using a scoring technique 15 min after the allergen exposure. The nasal airway resistance was determined twice prior to and once after the allergen challenge using anterior rhinomanometry. The nasal mucosal blood flow was determined before and 15 min after allergen challenge using the 133Xe wash-out technique. After pretreatment with the H1 antagonist there was a statistically significant reduction in the number of sneezes and rhinorrhea compared to pretreatment with placebo. Pretreatment with the H2 receptor significantly decreased the rhinorrhea but not the sneeze. The nasal blockage was unaffected by both the H1 and the H2 antagonists. Pretreatment with the H1 and/or the H2 antagonists inhibited the reduction in the nasal mucosal blood flow induced by the allergen challenge to a significant degree. The present findings suggest that topical treatment with the highly selective histamine antagonist, levocabastine, inhibits allergen-induced reflex-mediated symptoms. H1 and H2 receptors do not appear to be involved in the regulation of the tone of the capacitance vessels. This indicates that a more complex mechanism participates in the induction of nasal blockage than the direct effect of histamine on H1 and H2 receptors on the capacitance vessels of the nasal mucosa alone. Both H1 and H2 receptors are of importance for the regulation of nasal mucosal blood flow during the allergic reaction.

Topics: Administration, Topical; Adult; Airway Resistance; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Male; Nasal Provocation Tests; Nose; Piperidines; Random Allocation; Ranitidine; Rhinitis, Allergic, Seasonal

The aim of this study was to evaluate the effect of levocabastine, a new H1-blocking antihistamine for topical use, in comparison with sodium cromoglycate on conjunctival symptoms of birch pollinosis. The two drugs were compared in a randomized double-blind comparative study over 5 weeks in 37 children and adolescents (6-19 years of age) with birch pollen conjunctivitis. Nasal symptoms occurred in 31 of the children and were treated with beclomethasone dipropionate nasal spray. An oral antihistamine was offered as rescue medication for eye symptoms. Initially, the patients received placebo four times a day for a 7-day run-in period. Conjunctival symptoms were recorded daily on diary cards on a 100 mm visual analogue scale. The pollen counts indicated a short but intensive birch pollen season. There was no statistically significant difference between the two treatment groups with regard to eye symptom scores before and during active treatment. However, the patients' evaluation of the efficacy of the therapy was in favour of levocabastine (P less than 0.01). Topical levocabastine, an H1-blocker, applied twice daily, seems to protect from symptoms of allergic conjunctivities as favourably as sodium cromoglycate applied four times a day. There was no difference in number or character of reported adverse reactions between the two treatment groups.

Topics: Adolescent; Child; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Pollen; Randomized Controlled Trials as Topic

The effect of levocabastine, a new specific H1 antagonist, has been investigated against a placebo in nasal provocation tests on 42 allergic patients divided into two parallel groups. The results obtained show that it significantly inhibited the nasal reaction to the allergen and seems to have a long-lasting effect in allergic patients.

Topics: Administration, Intranasal; Adolescent; Adult; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Nasal Provocation Tests; Piperidines; Rhinitis

Levocabastine is a new, highly potent, and specific H1 antagonist. The effects of this drug, administered topically, were evaluated in a conjunctival provocation test (CPT) with allergens. CPT was performed by the instillation of one drop of allergen at increasing concentrations in the inferior conjunctival sac of each eye, alternatively, and stopped when both itching and redness of the conjunctiva were present. The concentration of allergen at this step was considered as the reaction threshold. Eleven patients, allergic to grass pollen, underwent, in winter, a first CPT without pretreatment (screening test); the CPT was then repeated twice after a 24-hour treatment, once, with a placebo, and once, with levocabastine (one drop twice a day, 0.5 mg/ml), administered in a double-blind fashion and in random order. The minimal interval between the two tests was 1 week. There was no significant difference between the thresholds determined in the two CPTs performed without medication (screening test and placebo), whereas the threshold was significantly increased (p less than 0.001) after pretreatment with levocabastine. Individually, the threshold increased in 10/11 patients (p less than 0.01). Levocabastine prevented both redness and itching. A late allergic reaction was observed by the patient in 6/11 CPTs performed after placebo treatment and 8/11 after levocabastine treatment. We conclude that, in this model of allergic conjunctivitis, levocabastine increased the conjunctival tolerance to an allergen. Further studies should help to determine the true place of this H1 antagonist in the treatment of allergic conjunctivitis.

Topics: Allergens; Conjunctiva; Conjunctivitis, Allergic; Dose-Response Relationship, Immunologic; Female; Histamine H1 Antagonists; Humans; Male; Piperidines

1. The rate of onset and magnitude of the effect of levocabastine, a potent H1-receptor antagonist, in reversing histamine-induced bronchoconstriction were determined in a double-blind cross-over trial against saline placebo. Histamine was administered by nebuliser so that forced expiratory volume in 1 second (FEV1) was reduced to 80-75% of baseline FEV1 in 10 men with mildly or moderately responsive airways and the effects of intravenous injection of saline or saline + 200 micrograms levocabastine were studied. 2. The maximum rate of recovery of FEV1 was 7[2-10]% min-1 (median [range]) in the first 5 min after levocabastine injection, but only 4[1-7]% min-1 after saline alone (P less than 0.05). 3. The median area under the recovery curve of FEV1 from 0 to 30 min after injection was 405 [228-498]% basal FEV1 X min after levocabastine and 301[98-502]% basal FEV1 X min after saline alone (P less than 0.002). 4. FEV1 returned to 90% of baseline within 30 min in all subjects after levocabastine, but not after saline alone (P less than 0.002). 5. Histamine-induced bronchoconstriction was relieved more quickly by levocabastine than saline alone. This model may have application to the study of drugs used in the treatment of anaphylaxis.

Topics: Adult; Anaphylaxis; Bronchial Spasm; Double-Blind Method; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Kinetics; Male; Middle Aged; Piperidines; Random Allocation

Forty-four patients, with symptoms of nasal obstruction, sneezing, itching and/or rhinorrhea, were entered into a placebo-controlled, double-blind study to evaluate the clinical efficacy of a topical antihistamine drug, levocabastine, applied 4 times a day for 14 days. At the end of the treatment the placebo patients were treated with levocabastine and the levocabastine patients were treated with beclomethasone dipropionate in a single-blind design for another 14 days. This study showed that levocabastine is significantly more active than placebo with reference to nasal discharge and sneezing. Placebo application improved the symptom score. Levocabastine could not be proved to be more effective against nasal obstruction than placebo in the double-blind trial. In the single-blind set-up, levocabastine resulted in an additional improvement in the score for obstruction, after the placebo period. Although the allergic group tended to respond better, no statistically significant difference could be detected between allergic and non-allergic patients. After treatment with levocabastine, beclomethasone dipropionate administration could not improve the results for nasal discharge and sneezing. For nasal congestion, beclomethasone dipropionate proved to be superior to levocabastine.

Topics: Administration, Intranasal; Beclomethasone; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Levocabastine is a new selective H1 receptor antagonist. The effect of the drug administered locally was compared to placebo in a quantified nasal and conjunctival provocation test with allergens performed in patients allergic to grass pollen. In the nasal provocation test, levocabastine was able to increase the 'reaction threshold' (dose of allergen necessary to trigger allergic symptoms) in 9 out of 12 patients; the drug inhibited rhinorrhea and sneezing, but not nasal obstruction. In the conjunctival provocation test, the 'reaction threshold' clearly increased in 10 out of 11 patients. The local administration of levocabastine might be useful in allergic rhinitis and conjunctivitis.

Topics: Administration, Topical; Adolescent; Adult; Child; Conjunctivitis, Allergic; Drug Evaluation; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Seasonal

Sixty-six patients with seasonal allergic rhinitis due to birch pollens, participated in an efficacy evaluation of topically applied, nasal and ocular, levocabastine, a highly selective H1 antagonist. A single blind comparison was performed between nasal levocabastine and flunisolide, a topical glucocorticoid preparation. Ocular levocabastine was compared with topical naphazoline/antazoline eye drops. Nasal and ocular symptom scores were recorded during a 31-day period. Pollen counts of birch pollens were done simultaneously. A global assessment of treatment efficacy was also made. In the comparison between the ocular treatments a significantly higher number of patients cited levocabastine excellent--it also had the advantage of fewer daily administrations. For nasal symptom scores the topical glucocorticosteroid therapy was in favour by number of sneezes. As for side effects, 44% of the patients complained of local irritation from naphazoline/antazoline eye drops or flunisolide nasal spray, but none with the levocabastine preparations. Topical levocabastine may provide an interesting alternative in the treatment of allergic rhinoconjunctivitis.

Topics: Administration, Intranasal; Adolescent; Adult; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Random Allocation; Rhinitis, Allergic, Seasonal

The effect of intranasal administration of levocabastine, a new selective H1-receptor antagonist, was investigated in a nasal provocation test (NPT) performed with allergens. The NPT allowed a quantitative estimation of the nasal allergic threshold (concentration of allergen necessary to trigger the reaction). In addition, the intensity of the three major rhinitis symptoms (obstruction, rhinorrhea and sneezing) was determined. Twelve adult patients, allergic to grass pollen, underwent a first NPT without pretreatment ('initial NPT'); the NPT was then repeated after the single intranasal administration of either placebo, 8 mg disodium cromoglycate (DSCG) or 0.2 mg levocabastine in a double-blind random order. The NPTs gave reproducible results since both the threshold and symptom intensities were similar in the initial NPT and in the NPT performed after placebo. The reaction threshold increased in 8/12 patients after DSCG (0.05 less than P less than 0.1) and in 9/12 patients after levocabastine (P less than 0.05). Levocabastine clearly inhibited rhinorrhea (P less than 0.001) and sneezing (P less than 0.02) but did not influence the nasal obstruction. DSCG inhibited rhinorrhea only (P less than 0.01). The intranasal administration of levocabastine might be useful in the treatment of allergic rhinitis.

Topics: Administration, Inhalation; Adolescent; Adult; Allergens; Child; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Nasal Mucosa; Nasal Provocation Tests; Piperidines; Sneezing

Forty patients suffering from allergic conjunctivitis, due to birch pollen, participated in a double-blind parallel group comparison between levocabastine (a potent new specific histamine (H1) antagonist) and placebo, both given as eye drops. Symptom scores were recorded during a 4-week period. A 1-week run-in period was followed by a 3-week treatment period. To enable a fair evaluation of the treatment effect on the ocular symptoms only, all patients were treated with topical nasal glucocorticoids for possible rhinitis symptoms during the whole study period. Plasma levels of levocabastine were determined in all subjects at the end of the 3 weeks' treatment period. Pollen counts for birch pollen were followed simultaneously. The evaluation of the symptom score cards revealed a significant reduction of ocular symptoms following use of the active compound. The resorption of the active substance through the conjunctiva was low. In accordance with the present trend of more topical treatment for allergic rhinitis, levocabastine may constitute a valuable compound for the topical treatment of allergic conjunctivitis.

Topics: Adolescent; Adult; Clinical Trials as Topic; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines

Interaction of levocabastine with human serum albumin (HSA) is investigated by applying fluorescence spectroscopy, circular dichroism spectroscopy and molecular docking methods. Levocabastine is an important drug in treatment of allergy and currently a target drug for drug repurposing to treat other diseases like vernal keratoconjuctivitis. Fluorescence quenching data revealed that levocabastine bind weakly to protein with binding constant in the order of 10

Topics: Binding Sites; Circular Dichroism; Humans; Molecular Docking Simulation; Piperidines; Protein Binding; Serum Albumin, Human; Spectrometry, Fluorescence; Thermodynamics

Nitric oxide generation is related to the activity of certain proteins located at synaptic sites. Previous findings show that NOS activity, nNOS protein expression, respiratory parameters and mitochondrial complex activities are altered in rat cerebral cortex by administration of levocabastine, an antagonist of histamine H1 and neurotensin NTS2 receptors. ATP provision by mitochondria may play an important role in the functional interaction between synaptic proteins NMDA receptor and PSD-95 with NO synthesis. In this context, our purpose was to evaluate the effect of levocabastine administration on protein expression of PSD-95, GluN2B and iNOS, as well as on mitochondrial ATP production. Male Wistar rats received a single (i.p.) dose of levocabastine (50 μg/kg) or saline solution (controls) and were decapitated 18 h later. Mitochondrial and synaptosomal membrane fractions were isolated from cerebral cortex by differential and sucrose gradient centrifugation. Expression of synaptic proteins was evaluated by Western blot assays in synaptosomal membrane fractions. Oxygen consumption, mitochondrial membrane potential and ATP production rate were determined in fresh crude mitochondrial fractions. After levocabastine treatment, protein expression of PSD-95, GluN2B and β-actin decreased 97, 45 and 55%, respectively, whereas that of iNOS enhanced 3.5-fold versus controls. In crude mitochondrial fractions levocabastine administration reduced roughly 15% respiratory control rate as assayed with malate-glutamate or succinate as substrates, decreased mitochondrial membrane potential (21%), and ATP production rates (57%). Results suggested that levocabastine administration induces alterations in synaptic proteins of the protein complex PSD-95/NMDA receptor/nNOS and in neuron cytoskeleton. Mitochondrial bioenergetics impairment may play a role in the functional link between synaptic proteins and NO synthesis.

Topics: Adenosine Triphosphate; Animals; Disks Large Homolog 4 Protein; Histamine H1 Antagonists; Male; Membrane Potential, Mitochondrial; Mitochondrial Membranes; Nitric Oxide Synthase Type II; Oxygen Consumption; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptosomes

Topics: Animals; Brain; Histamine H1 Antagonists, Non-Sedating; Male; Mitochondria; Nitric Oxide; Nitric Oxide Synthase; Piperidines; Rats; Rats, Wistar; Receptors, Neurotensin

A practical and sustainable method for the synthesis of levocabastine hydrochloride (

Topics: Histamine H1 Antagonists; Molecular Structure; Piperidines

Neurotensin behaves as a neuromodulator or as a neurotransmitter interacting with NTS1 and NTS2 receptors. Neurotensin in vitro inhibits synaptosomal membrane Na(+), K(+)-ATPase activity. This effect is prevented by administration of SR 48692 (antagonist for NTS1 receptor). The administration of levocabastine (antagonist for NTS2 receptor) does not prevent Na(+), K(+)-ATPase inhibition by neurotensin when the enzyme is assayed with ATP as substrate. Herein levocabastine effect on Na(+), K(+)-ATPase K(+) site was explored. For this purpose, levocabastine was administered to rats and K(+)-p-nitrophenylphosphatase (K(+)-p-NPPase) activity in synaptosomal membranes and [(3)H]-ouabain binding to cerebral cortex membranes were assayed in the absence (basal) and in the presence of neurotensin. Male Wistar rats were administered with levocabastine (50 μg/kg, i.p., 30 min) or the vehicle (saline solution). Synaptosomal membranes were obtained from cerebral cortex by differential and gradient centrifugation. The activity of K(+)-p-NPPase was determined in media laking or containing ATP plus NaCl. In such phosphorylating condition enzyme behaviour resembles that observed when ATP hydrolyses is recorded. In the absence of ATP plus NaCl, K(+)-p-NPPase activity was similar for levocabastine or vehicle injected (roughly 11 μmole hydrolyzed substrate per mg protein per hour). Such value remained unaltered by the presence of 3.5 × 10(-6) M neurotensin. In the phosphorylating medium, neurotensin decreased (32 %) the enzyme activity in membranes obtained from rats injected with the vehicle but failed to alter those obtained from rats injected with levocabastine. Levocabastine administration enhanced (50 %) basal [(3)H]-ouabain binding to cerebral cortex membranes but failed to modify neurotensin inhibitory effect on this ligand binding. It is concluded that NTS2 receptor blockade modifies the properties of neuronal Na(+), K(+)-ATPase and that neurotensin effect on Na(+), K(+)-ATPase involves NTS1 receptor and -at least partially- NTS2 receptor.

Topics: Animals; Cerebral Cortex; Male; Ouabain; Piperidines; Protein Binding; Rats; Rats, Wistar; Receptors, Neurotensin; Sodium-Potassium-Exchanging ATPase

Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour. We use cell-type-specific optogenetics and chemogenetics (DREADDs) to modulate activity in this population during behaviour to block or enhance fear extinction. Dissociated Thy1-eYFP neurons are isolated using FACS. RNA sequencing identifies genes strongly upregulated in RNA of this population, including Ntsr2, Dkk3, Rspo2 and Wnt7a. Pharmacological manipulation of neurotensin receptor 2 confirms behavioural effects observed in optogenetic and chemogenetic experiments. These experiments identify and validate Ntsr2-expressing neurons within the BLA, as a putative 'Fear-Off' population.

Topics: Adaptor Proteins, Signal Transducing; Animals; Bacterial Proteins; Basolateral Nuclear Complex; Clozapine; Extinction, Psychological; Fear; Gene Expression Regulation; Genes, Reporter; Injections, Intraventricular; Integrases; Intercellular Signaling Peptides and Proteins; Luminescent Proteins; Memory; Mice; Oligopeptides; Optogenetics; Piperidines; Prefrontal Cortex; Receptors, Neurotensin; Sensory Receptor Cells; Sequence Analysis, RNA; Stereotaxic Techniques; Thrombospondins; Thy-1 Antigens; Wnt Proteins

To evaluate ocular surface temperature in assessing the efficacy of anti-allergic eye drops.. Thirteen asymptomatic patients (24.7 ± 2.8 years) with proven seasonal allergic conjunctivitis due to cedar pollen were studied. A 0.025% levocabastine ophthalmic suspension was instilled in one eye (levocabastine eye) and artificial tears in the other eye (artificial tear eye) in a masked fashion 10 min prior to a conjunctival allergen challenge (CAC). Then, a drop of cedar pollen solution was dropped into the conjunctival sac to induce the allergic reaction. The surface temperature of the inferior bulbar conjunctiva was measured before and 30 min after the CAC with a newly developed non-contact ocular surface thermographer (OST). The degree of conjunctival injection and chemosis was also determined by slit-lamp biomicroscopy. The changes in the symptoms were evaluated by a questionnaire.. After the CAC, the temperature increased by 0.67 ± 0.10°C in the artificial tear eyes but by only 0.21 ± 0.06°C in the levocabastine eyes (p < 0.05). The score for conjunctival injection was 1.38 ± 0.24 and the chemosis score was 0.85 ± 0.25 for the artificial tear eyes and 0.62 ± 0.27 and 0.08 ± 0.08 in the levocabastine eyes (p < 0.01). The temperature increase was significantly correlated with the conjunctival injection scores (r = 0.63; p < 0.001).. The significant correlation of the conjunctival surface temperature with the severity of the conjunctival allergic reaction indicates that the temperature measured by the OST can be used to objectively evaluate the efficacy of topical anti-allergic agents.

Topics: Adult; Allergens; Body Temperature; Conjunctiva; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Ophthalmic Solutions; Piperidines; Thermography; Young Adult

Treatment with topical eye drops for long-standing ocular diseases like allergy can induce detrimental side effects. The purpose of this study was to investigate in vitro cytotoxicity of commercially preserved and unpreserved anti-allergic eye drops on the viability and barrier function of monolayer and stratified human corneal-limbal epithelial cells.. Cells were treated with unpreserved ketotifen solution, benzalkonium chloride (BAC)-containing anti-allergic drugs (ketotifen, olopatadine, levocabastine) as well as BAC alone. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine cell viability. Effects of compounds on barrier function were analyzed measuring transepithelial electrical resistance (TEER) to determine paracellular permeability and rose bengal assays to evaluate transcellular barrier formation.. The BAC-preserved anti-allergic formulations and BAC alone significantly reduced cell viability, monolayer cultures being more sensitive to damage by these solutions. Unpreserved ketotifen induced the least diminution in cell viability. The extent of decrease of cell viability was clearly dependent of BAC presence, but it was also affected by the different types of drugs when the concentration of BAC was low and the short time of exposure. Treatment with BAC-containing anti-allergic drugs and BAC alone resulted in increased paracellular permeability and loss of transcellular barrier function as indicated by TEER measurement and rose bengal assays.. The presence of the preservative BAC in anti-allergic eye drop formulations contributes importantly to the cytotoxic effects induced by these compounds. Stratified cell cultures seem to be a more relevant model for toxicity evaluation induced on the ocular surface epithelia than monolayer cultures.

Topics: Anti-Allergic Agents; Benzalkonium Compounds; Cell Survival; Cells, Cultured; Dibenzoxepins; Electric Impedance; Epithelial Cells; Epithelium, Corneal; Humans; In Vitro Techniques; Ketotifen; Olopatadine Hydrochloride; Ophthalmic Solutions; Piperidines; Preservatives, Pharmaceutical

Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

Topics: Analgesics; Animals; Blotting, Western; Ganglia, Spinal; Male; Microscopy, Electron, Transmission; Neuralgia; Oligopeptides; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Cord

Neurotensin (NT) analogs, NT69L, NT72, and NT79, differentially bind the two major neurotensin receptors, NTS1 and NTS2, to elicit effects similar to those of endogenous NT, including analgesia. Previous data strongly suggest NTS2 as the main receptor involved in NT- and NT analog-mediated visceral analgesia. However, this idea has yet to be confirmed with the use of mice lacking the NTS2 receptor. Here we use the writhing assay, a model of visceral pain, to investigate the analgesic effects of NT69L (binds NTS1 and NTS2 equally), NT79 (NTS2-selective), NT72 (NTS1 selective) and levocabastine (NTS2-selective) in WT, NTS1 knock-out, and NTS2 knock-out mice. Additionally, we investigate the role of NTS2 in the development of tolerance to NT69L-mediated visceral analgesia. All three NT analogs reduced writhing in the WT mice. NT79 and levocabsatine reduced writhing in the NTS1(-/-) mice while NT69L and NT72 showed significant analgesic effect in the NTS2(-/-) mice. In conclusion, the data shows that (1) both NTS1 and NTS2 are involved in mediating visceral analgesia and their respective roles appear to be NT analog-dependent; (2) NTS1 may inhibit NTS2-mediated analgesia; and (3) NTS2 is necessary for the development of tolerance to NT69L-mediated analgesia.

Topics: Acetic Acid; Analgesia; Analysis of Variance; Animals; Behavior, Animal; Histamine H1 Antagonists; Mice; Mice, Knockout; Neurotensin; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Neurotensin

β-Lactotensin (His-Ile-Arg-Leu) is a bioactive peptide derived from bovine milk β-lactoglobulin, acting as a natural agonist for neurotensin receptors. We found that β-lactotensin exhibited anxiolytic-like activity in an elevated plus-maze test after its intraperitoneal (i.p.) administration in mice. β-Lactotensin was also orally active. The anxiolytic-like activity of β-lactotensin after i.p. administration was blocked by levocabastine, an antagonist for the neurotensin NTS(2) receptor. β-Lactotensin had anxiolytic-like activity in wild-type but not Ntsr2-knockout mice. β-Lactotensin increased intracellular Ca(2+) flux in glial cells derived from wild-type mice but not Ntsr2 knockout mice. These results suggest that β-lactotensin acts as an NTS(2) receptor agonist having anxiolytic-like activity. The anxiolytic-like activity of β-lactotensin was also blocked by SCH23390 and SKF83566, antagonists for dopamine D(1) receptor, but not by raclopride, an antagonist for D(2) receptor. Taken together, β-lactotensin may exhibit anxiolytic-like activity via NTS(2) receptor followed by D(1) receptor.

Topics: Animals; Anti-Anxiety Agents; Astrocytes; Behavior, Animal; Calcium; Cattle; Cells, Cultured; Cerebral Cortex; Dopamine Antagonists; Drug Administration Routes; Drug Interactions; Exploratory Behavior; Glutamic Acid; Lactoglobulins; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Piperidines; Receptors, Dopamine D2; Receptors, Neurotensin; Time Factors

Previous work from this laboratory showed the ability of neurotensin to inhibit synaptosomal membrane Na(+), K(+)-ATPase activity, the effect being blocked by SR 48692, a non-peptidic antagonist for high affinity neurotensin receptor (NTS1) [López Ordieres and Rodríguez de Lores Arnaiz 2000; 2001]. To further study neurotensin interaction with Na(+), K(+)-ATPase, peptide effect on high affinity [(3)H]-ouabain binding was studied in cerebral cortex membranes. It was observed that neurotensin modified binding in a dose-dependent manner, leading to 80% decrease with 1 × 10(-4)M concentration. On the other hand, the single addition of 1 × 10(-6)M, 1 × 10(-5)M and 1 × 10(-4)M SR 48692 (Sanofi-Aventis, U.S., Inc.) decreased [(3)H]-ouabain binding (in %) to 87 ± 16; 74 ± 16 and 34 ± 17, respectively. Simultaneous addition of neurotensin and SR 48692 led to additive or synergic effects. Partial NTS2 agonist levocabastine inhibited [(3)H]-ouabain binding likewise. Saturation assays followed by Scatchard analyses showed that neurotensin increased K(d) value whereas failed to modify B(max) value, indicating a competitive type interaction of the peptide at Na(+), K(+)-ATPase ouabain site. At variance, SR 48692 decreased B(max) value whereas it did not modify K(d) value. [(3)H]-ouabain binding was also studied in cerebral cortex membranes obtained from rats injected i. p. 30 min earlier with 100 μg and 250 μg/kg SR 48692. It was observed that the 250 μg/kg SR 48692 dose led to 19% decrease in basal [(3)H]-ouabain binding. After SR 48692 treatments, addition of 1 × 10(-6)M led to additive or synergic effect. Results suggested that [(3)H]-ouabain binding inhibition by neurotensin hardly involves NTS1 receptor.

Topics: Animals; Cerebral Cortex; Male; Neurotensin; Ouabain; Piperidines; Protein Binding; Pyrazoles; Quinolines; Rats; Rats, Wistar; Receptors, Neurotensin

Neurotensin (NT) is a neuropeptide involved in the modulation of nociception. We have investigated the actions of NT on cultured postnatal rat spinal cord dorsal horn (DH) neurons. NT induced an inward current associated with a decrease in membrane conductance in 46% of the neurons and increased the frequency of glutamatergic miniature excitatory synaptic currents in 37% of the neurons. Similar effects were observed in acute slices. Both effects of NT were reproduced by the selective NTS1 agonist JMV449 and blocked by the NTS1 antagonist SR48692 and the NTS1/NTS2 antagonist SR142948A. The NTS2 agonist levocabastine had no effect. The actions of NT persisted after inactivation of G(i/o) proteins by pertussis toxin but were absent after inactivation of protein kinase C (PKC) by chelerythrine or inhibition of the MAPK (ERK1/2) pathway by PD98059. Pre- and postsynaptic effects of NT were insensitive to classical voltage- and Ca(2+) -dependent K(+) channel blockers. The K(+) conductance inhibited by NT was blocked by Ba(2+) and displayed no or little inward rectification, despite the presence of strongly rectifying Ba(2+) -sensitive K(+) conductance in these neurons. This suggested that NT blocked two-pore domain (K2P) background K(+) -channels rather than inwardly rectifying K(+) channels. Zn(2+) ions, which inhibit TRESK and TASK-3 K2P channels, decreased NT-induced current. Our results indicate that in DH neurons NT activates NTS1 receptors which, via the PKC-dependent activation of the MAPK (ERK1/2) pathway, depolarize the postsynaptic neuron and increase the synaptic release of glutamate. These actions of NT might modulate the transfer and the integration of somatosensory information in the DH.

Topics: Animals; Benzophenanthridines; Excitatory Postsynaptic Potentials; Glutamic Acid; Neurotensin; Oligopeptides; Patch-Clamp Techniques; Pertussis Toxin; Piperidines; Posterior Horn Cells; Potassium Channels; Pyrazoles; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Signal Transduction; Synapses; Synaptic Transmission

Atherosclerotic vascular disease is currently the biggest threat and the highest cause of death worldwide, approaching almost 60%.The development of atherosclerosis is affected by ecological factors associated with industry and pollution of the environment. Neurotensin (NT) is a peptide acting via 3 kinds of neurotensin receptors (NTR) localized in target tissues. In several studies, the presence of its receptors has been shown in chicken liver, and the influence of NT on the metabolism of this organ was confirmed (glycogenolysis stimulation through sympathetic nervous system, enterohepatic circulation of bile acids, metabolism of lipoproteins).. Healthy male WISTAR rats weighing 300}30 grams, were used for the experiments. The animals were divided into 4 groups: 1) control group, to which 0.9% NaCl was administrated (i.p.); 2) the second group was given levocabastine 1mg/kg i.p.; 3) the third group received SR 48692 0.4 mg/; 4) the fourth group was given NT analog [D-Trp 11]-neurotensin 15 nM/kg. Plasmatic membranes of liver, small intestine and adipose tissue were prepared according to the method of Havrankova. Analysis of results obtained in the investigation of NT receptors was performed using the Scatchard method from LIGAND-Pc, v. 3.1 software.. The investigation of antigenity of I125NT showed proper antigen-antibody reaction. No binding of the I125NT with plasmatic membranes of adipocytes or enterocytes was observed. Unspecific binding of I125NT with 10 μmol/L of free NT was observed in the plasmatic membranes of hepatocytes.. The presence of NT receptors only in the membranes of hepatocytes may suggest their role in the regulation of lipid metabolism via receptor – ligand way.

Topics: Adipocytes; Adipose Tissue; Animals; Antigen-Antibody Reactions; Cell Membrane; Enterocytes; Hepatocytes; Histamine H1 Antagonists, Non-Sedating; Intestine, Small; Iodine Radioisotopes; Isotope Labeling; Liver; Male; Neurotensin; Piperidines; Pyrazoles; Quinolines; Rats; Rats, Wistar; Receptors, Neurotensin

Neurotensin (NT) is secreted from neurons and gastrointestinal endocrine cells. We previously reported that the three NT receptors (NTSRs) are expressed in pancreatic islets and beta cell lines on which we observed a protective effect of NT against cytotoxic agents. In this study, we explored the role of NT on insulin secretion in the endocrine pancreatic beta cells. We observed that NT stimulates insulin secretion at low glucose level and has a small inhibiting effect on stimulated insulin secretion from isolated islets or INS-1E cells. We studied the mechanisms by which NT elicited calcium concentration changes using fura-2 loaded islets or INS-1E cells. NT increases calcium influx through the opening of cationic channels. Similar calcium influxes were observed after treatment with NTSR selective ligands. NT-evoked calcium regulation involves PKC and the translocation of PKCalpha and PKCepsilon to the plasma membrane. Part of NT effects appears to be also mediated by PKA but not via the Erk pathway. Taken together, these data provide evidence for an important endocrine role of NT in the regulation of the secretory function of beta cells.

Topics: Animals; Calcium Signaling; Cell Line; Cyclic AMP-Dependent Protein Kinases; Cytoprotection; Enzyme Activation; Insulin; Insulin Secretion; Insulin-Secreting Cells; Neurotensin; Piperidines; Protein Kinase C-alpha; Protein Kinase C-epsilon; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin

Six allergic conjunctivitis patients (12 eyes) and 4 healthy volunteers (8 eyes) were investigated in terms of the effect of cooling sheets on eye itching and tear histamine concentration, before and 5 min after cooling the eyelids with cooling sheets. The severity of itching was evaluated with a five-level itching score. The combination treatment of levocabastine with cooling sheets significantly reduced eye itching, while no significant change in tear histamine concentration was observed before and after cooling sheet use. The cooling sheets are useful for reducing eye itching in the therapy of allergic conjunctivitis. The tear histamine concentration did not correlate with the antiitching effect of cooling sheets in this study.

Topics: Conjunctivitis, Allergic; Cryotherapy; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine H1 Antagonists, Non-Sedating; Humans; Ophthalmic Solutions; Piperidines; Pruritus; Severity of Illness Index; Tears

To investigate the effects of levocabastine hydrochloride on the profileration, Deoxyribonucleic acid (DNA) synthesis and induction of apoptosis, in human Tenon's capsule fibroblasts.. The maximum intoxicate concentration was determined by measuring the release of lactate dehydrogenase. Proliferation of fibroblasts was analyzed with a WST-1 method. DNA synthesis was examined by quantifying the incorporation of 5-bromo-2'-deoxyuridine into dividing cells, and apoptosis was analyzed using an Annexin-V-FLUOS Staining Kit.. Levocabastine hydrochloride (10(-4) M), ketotifen fumarate (3 x 10(-5) M) and tranilast (10(-4) M) significantly inhibited proliferation of fibroblasts. Levocabastine hydrochloride (10(-4) M), ketotifen fumarate (10(-4) M) and tranilast (10(-3) M) inhibited DNA synthesis and induced apoptosis.. Levocabastine hydrochloride inhibited the proliferation of fibroblasts.

Topics: Aged; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Conjunctiva; DNA; Dose-Response Relationship, Drug; Fibroblasts; Histamine H1 Antagonists, Non-Sedating; Humans; Ketotifen; Male; ortho-Aminobenzoates; Piperidines

Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin.. We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced c-fos expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21-39 min) and late (40-60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception.. The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.

Topics: Animals; Formaldehyde; Histamine H1 Antagonists, Non-Sedating; Inflammation; Male; Neurotensin; Pain; Peptide Fragments; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Nerves; Time Factors

Neurotensin (NT) is a neuropeptide with antinociceptive effects that are mediated through NT receptors, of which there are three known subtypes (NTS1, NTS2, and NTS3). Morphine is a mu-opioid receptor agonist commonly used for pain treatment but is associated with side effects that can be serious. We hypothesize that selective NT receptor agonists may represent a novel class of analgesics and their use in conjunction with morphine will have synergistic properties which may reduce the dose of morphine administered and its side effects.. The antinociceptive activity of an NT agonist (NT69L) and morphine was studied in rats using the hot plate test to determine if there is synergism between the two drugs in reducing pain. The NTS2 receptor antagonist, levocabastine, was used to determine the receptor subtype involved in the analgesic effect of NT69L and morphine.. The administration of both NT69L and morphine resulted in a dose-dependent analgesic effect. The isobolographic analysis demonstrated that the combination of sub-analgesic doses of NT69L and morphine was synergistic in the hot plate test. Pretreatment with the NTS2 receptor antagonist, levocabastine attenuated the antinociceptive effect of NT69L and the combined effect of NT69L and morphine in the hot plate test.. The results support the hypothesis that the synergistic combination of NT69L and morphine would improve the pharmacological treatment of pain while minimizing specific adverse effects of each of the drugs at a higher dose. NTS2 is important for the antinociceptive effect of NT69L and morphine.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Male; Morphine; Neurotensin; Pain; Pain Measurement; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Time Factors

We found that beta-lactotensin (His-Ile-Arg-Leu), which has been isolated as an ileum-contracting peptide from chymotrypsin digest of bovine beta-lactoglobulin, dose-dependently suppresses food intake after intracerebroventricular (i.c.v.) or intraperitoneal administration at a dose of 40 nmol/mouse or 100mg/kg, respectively, in fasted mice. Orally administered beta-lactotensin also suppressed food intake at 500 mg/kg. We previously reported that beta-lactotensin acts as an agonist for neurotensin receptors; however, the anorexigenic activity of beta-lactotensin was not inhibited by i.c.v. co-administration with SR48692 or levocabastine, an antagonist for neurotensin NT(1) or NT(2) receptor, respectively. On the other hand, the anorexigenic effect of beta-lactotensin was blocked by i.c.v. co-administration with astressin or calcitonin gene-related peptide (CGRP)(8-37), an antagonist for corticotropin releasing factor (CRF) or CGRP, respectively. beta-Lactotensin had affinity for neither CRF nor CGRP receptor. In addition, CRF-induced anorexigenic activity after i.c.v. administration was completely blocked by CGRP(8-37), while CGRP-induced anorexigenic activity was not inhibited by astressin. These results suggest that the CGRP system is activated downstream of the CRF system in food intake regulation. Taken together, beta-lactotensin may suppress food intake by activating the CRF system followed by the CGRP system, independently of the neurotensin system.

Topics: Animals; Corticotropin-Releasing Hormone; Eating; Lactoglobulins; Male; Mice; Oligopeptides; Peptide Fragments; Piperidines; Receptors, Neurotensin

To investigate the expression and distribution of aquaporin 5 (AQP5) in allergic rhinitis (AR) treated by fluticasone propionate and levocabastine.. Forty Wistar rats were divided randomly into AR (n=30) and control groups (n=10). After AR models were established, the AR rats were divided evenly into F group, L group and AR control group. Three groups were treated respectively for 28 days, then the expression of AQP5 in nasal mucous membrane were detected by immunohistochemistry assay.. The distribution of AQP5 was consistent in all groups. The expression of AQP5 in F group was significantly different from L group and AR group (P<0.05), while there was no significant difference between that of AR group and L group (P>0.05). The expression of AQP5 in L group was significantly different from that in control group (P<0.05).. High expressions of AQP5 in rat with AR indicated the positive correlation between AQP5 and AR. AQP5 might be one of pathological factors of AR concerned with glands excessive secretion and tissue edema. Glucocorticoid can down-regulate the expression of AQP5, but H1-receptor antagonist can not reduce the expression of AQP5.

Topics: Androstadienes; Animals; Aquaporin 5; Fluticasone; Nasal Mucosa; Piperidines; Rats; Rats, Wistar; Rhinitis, Allergic, Perennial

Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin alpha(4)beta(1) is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC(50) 406 microM), but not the first-generation antihistamine chlorpheniramine, displaced (125)I-FN binding to human integrin alpha(4)beta(1) and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin alpha(4) expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the alpha(4)beta(1) integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects alpha(L)beta(2)/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC.

Topics: Animals; Anti-Allergic Agents; Cells, Cultured; Chlorpheniramine; Guinea Pigs; Histamine H1 Antagonists, Non-Sedating; Humans; Integrin alpha4beta1; Jurkat Cells; Male; Piperidines; Protein Binding

The intracerebroventricular administration of the tridecapeptide neurotensin (NT) produces strong analgesic effects in tests evaluating acute pain. We investigated whether these effects are mediated by the opioid receptors. In the hot plate test, the NT receptors agonist NT1 (N(alpha)Me-Arg-Lys-Pro-Trp-Tle-Leu), s.c. injected (0.3-3 mg/kg), increased paw licking and jump latencies. These effects were inhibited by the NTS2 antagonist levocabastine (2.5 mg/kg, i.p.) but not by the selective NTS1 antagonist SR48692 (3 mg/kg, i.p.). The opioid receptor antagonist naloxone did not modify (up to the dose of 4.5 mg/kg, s.c.) the NT1 effect on licking, but abolished the increase in the jump latency (from the dose of 1.5 mg/kg). In mice made tolerant to the analgesic effect of morphine (2 mg/kg, s.c.) by previous morphine injections (32 mg/kg, s.c., twice a day, 4 days), NT1 maintained its effect on licking, but its effect on jump latency was suppressed. Levocabastine (up to the dose of 4.5 mg/kg) failed to antagonize the effects of morphine (2 mg/kg, s.c.) on both licking and jump latencies. In mice made tolerant to the analgesic effect of NT1 (0.3 mg/kg, s.c.) by previous NT1 injections (3 mg/kg, s.c., twice a day, 4 days) morphine maintained its analgesic effects both on licking and jumping latencies. We can conclude that neurotensinergic and opioidergic transmissions are functionally independent as regards the licking response. However, in the jump response, neurotensinergic transmission seems to regulate opioidergic transmission, inducing its stimulation.

Topics: Analgesia; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Histamine H1 Antagonists, Non-Sedating; Injections, Intraventricular; Ligands; Male; Mice; Morphine; Neurotensin; Pain Threshold; Piperidines; Pyrazoles; Quinolines; Reaction Time; Receptors, Neurotensin; Receptors, Opioid

We investigated the early efficacy of topical levocabastine, an H(1) histamine-receptor antagonist, in improving the clinical symptoms of allergic conjunctivitis.. Thirty-six patients with allergic conjunctivitis were enrolled. One drop of levocabastine was instilled in one eye and one drop of artificial tears in the contralateral eye. Clinical examinations were performed before, and 15 and 30 minutes after instillation. Symptoms of itching and signs of injection were assessed at each time point.. Both levocabastine and artificial tears resulted in a statistically significant reduction in ocular itching. However, levocabastine was significantly more effective.. Although artificial tears had a positive effect in reducing symptoms of allergic conjunctivitis, by the washing out of allergens, levocabastine was more effective than artificial tears in controlling acute symptoms of allergic conjunctivitis, demonstrating that the selective H1 histamine-receptor antagonist action of levocabastine is rapidly effective in a clinical setting.

Topics: Administration, Topical; Adult; Aged; Conjunctivitis, Allergic; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Treatment Outcome

The present study demonstrated that alternative splicing of the rat nts2 receptor gene generates a 5-transmembrane domain variant isoform (vNTS2) that is co-expressed with the full-length NTS2 receptor throughout the brain and spinal cord, as evidenced by reverse transcription-PCR. The vNTS2 polypeptide is 281 amino acids in length, which is 135 amino acids shorter than the full-length isoform. Immunohistochemical and radioligand binding studies revealed that the HA-tagged recombinant vNTS2 receptor is poorly targeted to plasma membranes in transfected COS-7 cells. Binding studies also showed that the truncated receptor displayed a 5000-fold lower affinity for neurotensin (NT) than its full-length counterpart (IC(50) of 10 mum and 2 nm, respectively). Yet NT binding induced efficient internalization of receptor-ligand complexes in vNTS2-transfected cells. Furthermore, it produced a rapid (<5 min) activation of the mitogen-activated protein kinases (ERK1/2) pathway, indicating functional coupling of the variant receptor. This activation is sustained (>1 h) and is also produced by the NTS2 agonist levocabastine. Western blotting experiments suggested that vNTS2 is not expressed in monomeric form in the rat central nervous system. However, it does appear to form a variety of multimeric complexes, including homodimers and heterodimers, with the full-length NTS2. Indeed, co-immunoprecipitation studies in dually transfected cells demonstrated that the two receptor isoforms can form stable associations. Taken together, the present results indicated that the rat vNTS2 is a functional receptor that may play a role in NT signaling in mammalian central nervous system.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Binding, Competitive; Blotting, Western; Brain; Cell Line; Central Nervous System; CHO Cells; COS Cells; Cricetinae; Densitometry; Dimerization; DNA, Complementary; Dose-Response Relationship, Drug; Epitopes; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Inhibitory Concentration 50; Ligands; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Sequence Data; Neurotensin; Peptides; Piperidines; Protein Binding; Protein Isoforms; Protein Structure, Tertiary; Rats; Receptors, Neurotensin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Homology, Amino Acid; Signal Transduction; Spinal Cord; Time Factors; Tissue Distribution; Transfection

The effect of the simultaneous use of 0.025% levocabastine hydrochloride eye drops (levocabastine) and 0.1% pemirolast potassium ophthalmic solution (pemirolast) on experimental allergic conjunctivitis in rats was investigated. Levocabastine and pemirolast significantly inhibited allergic conjunctivitis compared with the control group when separately administered. In addition, the simultaneous use of both drugs inhibited allergic conjunctivitis more potently than the original activity of levocabastine or pemirolast. Furthermore, the simultaneous use of levocabastine and pemirolast also significantly inhibited increased vascular permeability induced by antigen compared with levocabastine or pemirolast alone, respectively. Levocabastine and pemirolast inhibited histamine release from the rat conjunctiva in correlation with a decrease in histamine content in tears. When levocabastine and pemirolast were simultaneously applied to the eyes, histamine release from the conjunctiva was greater than for the original activities of both drugs. Similar to histamine release from the conjunctiva, the histamine content in tears induced by the simultaneous use of both drugs was significantly decreased compared with levocabastine and pemirolast alone, respectively. A potentiating effect induced by the simultaneous use of levocabastine and pemirolast may be attributable to the antihistaminic activity of levocabastine and histamine release inhibition by levocabastine and pemirolast.

Topics: Animals; Conjunctivitis, Allergic; Drug Synergism; Drug Therapy, Combination; Histamine Release; Male; Piperidines; Pyridines; Pyrimidinones; Rats; Rats, Wistar

To study the effects of ketotifen fumarate, olopatadine, and levocabastine on ocular active anaphylaxis in guinea pigs and on ocular immediate hypersensitivity in albino rats.. Clinical grading scores and Evans blue dye leakage to eyelids and to eyeballs were assessed in five treatment groups (n = 10): ketotifen fumarate 0.025%, olopatadine 0.1%, levocabastine 0.05%, negative control, and positive control.. At 20 minutes after challenge, edema scores for ketotifen-treated guinea pigs were statistically significantly lower than those for levocabastine or olopatadine. Active treatment significantly reduced vascular leakage in both models. Ketotifen significantly reduced vascular leakage in eyelids compared with the other drugs. In guinea pigs, vascular leakage in eyeballs was significantly reduced with ketotifen fumarate compared with olopatadine and levocabastine.. In the guinea pig model, ketotifen was more effective than olopatadine and levocabastine at reducing conjunctival edema and vascular permeability in eyelids and eyeballs. In the rat model, ketotifen was more effective at reducing vascular permeability in eyelids than olopatadine and levocabastine.

Topics: Anaphylaxis; Animals; Capillary Permeability; Conjunctivitis, Allergic; Dibenzoxepins; Disease Models, Animal; Edema; Eyelids; Guinea Pigs; Histamine H1 Antagonists; Ketotifen; Male; Olopatadine Hydrochloride; Ophthalmic Solutions; Ovalbumin; Piperidines; Rats

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyrpsi(CH2NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.(3.7))-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.

Topics: Analgesics; Animals; Ganglia, Spinal; Hot Temperature; In Vitro Techniques; Injections, Spinal; Lumbar Vertebrae; Models, Animal; Neurotensin; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Cord; Tail

The role and signaling properties of the low-affinity neurotensin receptor (NTS2) are still controversial. In particular, it is unclear whether neurotensin acts as an agonist, inverse agonist, or antagonist at this site. In view of the growing evidence for a role of NTS2 in antinociception, the elucidation of the pharmacological and coupling properties of this receptor is particularly critical. In the present study, we demonstrate that in Chinese hamster ovary (CHO) cells expressing the rat NTS2 receptor, neurotensin (NT), levocabastine, neuromedin N, and the high-affinity NT receptor antagonist SR48692 [2-[[1-(-7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid] all bind to and activate the NTS2 receptor. This activation is followed by ligand-induced internalization of receptor-ligand complexes, as evidenced by confocal microscopy using a fluorescent NT analog. All compounds tested produced a rapid and sustained activation of extracellular signal-regulated kinases 1/2 (ERK1/2) but were without specific effect on Ca(2+) mobilization. The agonist-induced activation of ERK1/2 was completely abolished by preincubation of the cells with the endocytosis inhibitors phenylarsine oxide and monodansylcadaverine as well as overexpression of a dominant-negative mutant of dynamin 1 (DynK44A), indicating that receptor internalization was required for ERK1/2 activation. NTS2-induced activation of ERK1/2 was not species-specific, because the same agonistic effects of NT and analogs were observed in CHO cells transfected with the human NTS2 receptor. In conclusion, this study demonstrates that NTS2 is a bona fide NT receptor and that activation of this receptor by NT or NT analogs results in an internalization-dependent activation of the ERK1/2 signaling cascade.

Topics: Animals; Base Sequence; Calcium; CHO Cells; Cricetinae; DNA Primers; Enzyme Activation; Histamine H1 Antagonists; Kinetics; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neurotensin; Piperidines; Rats; Receptors, Neurotensin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transfection

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.. 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.. 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.. 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.. 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.

Topics: Air Pollutants; Anti-Allergic Agents; Benzalkonium Compounds; Benzimidazoles; Complement Activation; Conjunctivitis; Cosmetics; Dibenzoxepins; Dipeptides; Drug Evaluation; Dust; Humans; In Vitro Techniques; Ketotifen; Nedocromil; Olopatadine Hydrochloride; Ophthalmic Solutions; Oxamic Acid; Phthalazines; Piperidines; Pollen; Silicon Dioxide; Zymosan

Neurotensin is a neuropeptide involved in dopaminergic signalling. We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons. DARPP-32 is also phosphorylated by cyclin-dependent kinase 5 on Thr75, and the phosphorylated form of DARPP-32 at Thr75 inhibits protein kinase (PKA) activity. In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices. Neurotensin decreased the level of phospho-Thr75 DARPP-32 at 2 min of incubation, maximally to about 50% of control at a concentration of 1 micro m. Pretreatment with a combined neurotensin receptor type 1 (NTR1)/type 2 (NTR2) antagonist, SR142948, reduced the basal level of phospho-Thr75 DARPP-32 and abolished the ability of neurotensin to decrease DARPP-32 Thr75 phosphorylation. However, neither an NTR1 antagonist, SR48692, an NTR2 antagonist, levocabastine, nor the two combined affected the basal level and the neurotensin-mediated decrease in DARPP-32 Thr75 phosphorylation. The effect of neurotensin was abolished by tetrodotoxin (TTX) or MK801 plus CNQX, but not by SCH23390 or raclopride. These results indicate that neurotensin stimulates the release of glutamate by activating a hypothesized unidentified neurotensin receptor, resulting in the dephosphorylation of DARPP-32 at Thr75 by activating NMDA and AMPA receptors expressed at medium spiny neurons. Thus, neurotensin, by removing the inhibition of PKA by phospho-Thr75 DARPP-32, potentiates its signalling via the dopamine/D1 receptor/PKA/phospho-Thr34 DARPP-32/PP-1 cascade.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Anesthetics, Local; Animals; Benzazepines; Dizocilpine Maleate; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Glutamic Acid; Histamine H1 Antagonists; Immunoblotting; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Neostriatum; Nerve Tissue Proteins; Neurons; Neurotensin; Phosphoproteins; Piperidines; Pyrazoles; Quinolines; Raclopride; Receptors, Neurotensin; Signal Transduction; Tetrodotoxin; Threonine; Time Factors

Beta-lactotensin, a neurotensin NT2 agonist derived from beta-lactoglobulin, has hypocholesterolemic activity after administration for 2 days at a dose of 30 mg/kg (i.p.) or 100 mg/kg (p.o.) for 2 days in mice fed a high-cholesterol/cholic acid diet. The onset of hypocholesterolemic activity of beta-lactotensin was observed 90 min after a single i.p. or p.o. administration at the same dose as described above. Neurotensin also induced hypocholesterolemic activity 90 min after single i.p. administration at a dose of 2 microg per mouse but was ineffective after oral administration. The rapid onset of hypocholesterolemic activities of beta-lactotensin and neurotensin was blocked by levocabastine (50 microg/kg), an NT2 antagonist, and raclopride (0.5 mg/kg), a dopamine D2 antagonist.

Topics: Animals; Cholesterol; Dopamine Antagonists; Male; Mice; Mice, Inbred ICR; Neurotensin; Oligopeptides; Piperidines; Raclopride; Receptors, Neurotensin

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4-7-fold with a K(0.5) of approximately 50 nM. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.

Topics: Animals; Cobalt; Dopamine; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamine; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neostriatum; Nerve Tissue Proteins; Neurons; Neurotensin; Phosphoproteins; Phosphorylation; Piperidines; Pyrazoles; Quinolines; Receptors, Dopamine D1; Receptors, Neurotensin; Signal Transduction; Tetrodotoxin

The effects of neurotensin on focal adhesion kinase were investigated using lung cancer cells. Neurotensin bound with high affinity to large cell carcinoma cell line NCI-H1299 as did neurotensin-(8-13), but not neurotensin-(1-7) or levocabastine. Addition of 100 nM neurotensin to NCI-H1299 cells caused transient tyrosine phosphorylation of focal adhesion kinase which was maximal after 1-2.5 min. Also, neurotensin-(8-13), but not neurotensin-(1-8) or levocabastine, caused tyrosine phosphorylation of focal adhesion kinase after addition to NCI-H1299 cells. Focal adhesion kinase tyrosine phosphorylation caused by neurotensin was inhibited by the nonpeptide neurotensin receptor antagonist (2-(1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl)amino)-adamantane-2-carboxylic acid) (SR48692). SR48692 inhibited the clonal growth of NCI-H1299 cells, whereas neurotensin-stimulated proliferation and levocabastine had no effect. These results indicate that lung cancer cells have functional neurotensin receptors which regulate focal adhesion kinase tyrosine phosphorylation. It remains to be determined if neurotensin receptors and focal adhesion kinase plays a role in lung cancer cellular adhesion and migration.

Topics: Binding, Competitive; Cell Division; Cytochalasin D; Dose-Response Relationship, Drug; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Lung Neoplasms; Neurotensin; Nucleic Acid Synthesis Inhibitors; Peptide Fragments; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Quinolines; Receptors, Neurotensin; Tumor Cells, Cultured; Tyrosine

The binding and signaling properties of neuronal NTS2 neurotensin (NT) receptors were examined in cultured rat cerebellar granule cells. As shown by reverse transcription-PCR, receptor autoradiography, and confocal microscopic localization of fluorescent NT, these cells selectively express the NTS2 receptor subtype. Accordingly, a single apparent class of (125)I-NT-binding sites, with an affinity of 3.1 nm, was detected in cerebellar granule cell cultures. This binding was competed for with high affinity (IC(50) = 5.7 nm) by the NTS2 ligand levocabastine and with low affinity (IC(50) = 203 nm) by the NTS1 antagonist SR48692. Hypertonic acid stripping of surface-bound ligand and hyperosmolar sucrose treatment revealed that 64% of specifically bound (125)I-NT was internalized at equilibrium via a clathrin-dependent pathway. In cells loaded with the Ca(2+)-sensitive fluorescent dye Fluo4, SR48692, but neither NT nor levocabastine, triggered a marked increase in cytosolic [Ca(2+)](i). By contrast, both NT and levocabastine, but not SR48692, induced a sustained (>60 min) activation of the mitogen-activated protein kinases, p42/p44, indicating functional coupling of NTS2 receptors. Complementary experiments carried out on synaptosomes from adult rat cerebellum demonstrated the presence of presynaptic NTS2 receptors. However, in contrast to perikaryal NTS2 sites, these presynaptic receptors did not internalize in response to NT stimulation. Taken together, the present results demonstrate that NTS2 receptors are present both presynaptically and postsynaptically in central neurons and that NT and levocabastine act as agonists on these receptors.

Topics: Aniline Compounds; Animals; Binding Sites; Binding, Competitive; Calcium; Cerebellum; Clathrin; Cytosol; Dose-Response Relationship, Drug; Fluorescent Dyes; Histamine H1 Antagonists; Inhibitory Concentration 50; Male; Microscopy, Confocal; Piperidines; Polymerase Chain Reaction; Protein Binding; Pyrazoles; Quinolines; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Neurotensin; Receptors, Presynaptic; Reverse Transcriptase Polymerase Chain Reaction; RNA; Time Factors; Xanthenes

To observe the effect of Livostin spray on children's allergic rhinitis and to search the mechanism of treating allergic rhinitis.. 113 patients were treated with Livostin spray (Livostin group) or normal saline spray (control group).. The total efficiency of Livostin group in treating allergic rhinitis is above 95.1% and that of the control group is 25.0%. Initial time of starting effect of Livostin (72.1%) is in 1 minute, and that of the control group (mostly 23.1%) is in 3 minutes. The keeping curative effect time of Livostin spray is mostly (72.1%) above 5 hours and that of the control group is mostly (30.8%) in 3 hours. After 2 weeks, the eosinophilic granulocyte number in nose's secretion of Livostin group is obviously reduced (P < 0.05).. Livostin is better than control group in relieving symptoms, keeping curative effect and safety, so Livostin is one kind of effective drug in treating children's allergic rhinitis.

Topics: Administration, Intranasal; Adolescent; Aerosols; Child; Child, Preschool; Female; Histamine H1 Antagonists; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial

The brain localization of the neurotensin receptor NTS2 was studied with [3H]levocabastine, using an autoradiographic procedure. This study suggests that NTS2 receptors are mainly intracellular. High densities of binding sites were observed in the cingulate, insular, temporal, occipital, enthorhinal cortex, amygdaloid complex, septohippocampal nuclei, medial thalamus, mammillary bodies and superior colliculi; a moderate labelling was observed in the anterior and medial hippocampus, olfactory tubercle, hypothalamus, periaqueductal gray matter, caudate putamen, nucleus accumbens, septum, lateral thalamus, dorsal raphe nucleus and cerebellum; finally, a low labelling was apparent in the ventral tegmentum area and substantia nigra. Thus it appears that NTS2 receptors are particularly abundant in the cerebral cortex, the limbic areas and some areas involved in pain perception.

Topics: Animals; Autoradiography; Binding, Competitive; Brain; Brain Chemistry; Histamine H1 Antagonists; Male; Neurotensin; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin

The expression of the 3 currently known neurotensin receptors was studied in human cancer cells of prostatic, colonic or pancreatic origin by means of RT-PCR analysis and binding experiments. All the cells selected for this work have been shown to exhibit a growth response to neurotensin. We found that the 7 transmembrane domain, levocabastine insensitive receptor (NTR1) is expressed in most but not all of the cells studied whereas the 7 transmembrane domain, levocabastine sensitive receptor (NTR2) is present in none of these cells. The 100 kDa-type I neurotensin receptor (NTR3) is expressed in all the cells assayed. Moreover, we demonstrated that neurotensin can stimulate the growth of CHO cells stably transfected with the NTR3. Taken together, our results strongly suggest that the NTR3 subtype could be involved in the growth response of human cancer cells to neurotensin.

Topics: Animals; Cell Membrane; CHO Cells; Cholic Acids; Colonic Neoplasms; Cricetinae; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Humans; Kinetics; Male; Neurotensin; Pancreatic Neoplasms; Piperidines; Prostatic Neoplasms; Protein Binding; Protein Structure, Tertiary; Receptors, Neurotensin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transfection; Tumor Cells, Cultured

Radioiodinated neurotensin ((125)I-NT) was used to characterize and localize NT binding sites in normal human sigmoid colon. Specimens were obtained from patients (30-77 years old) undergoing resection for colon carcinoma. Specific binding of (125)I-NT to sigmoid circular muscle membranes was enhanced by o-phenanthroline (1 mM) but other peptidase inhibitors were ineffective. (125)I-NT bound to a high-affinity site of K(d) = 0.88 +/- 0.09 nM and B(max) = 4.03 +/- 0.66 fmol/mg of wet weight tissue (n = 14), although in the majority of patients another site, of low but variable affinity, could also be detected. Specific binding of 50 pM (125)I-NT was inhibited by NT(8-13) > NT > SR142948A > or = neuromedin N > or = SR48692, consistent with binding to the NT1 receptor. In autoradiographic studies, dense specific binding of (125)I-NT was seen over myenteric and submucosal ganglia, moderate binding over circular muscle, and sparse binding over longitudinal muscle and taenia coli. Levocabastine, which has affinity for the NT2 receptor, did not inhibit specific binding of (125)I-NT in membrane competition or autoradiographic studies. NT contracted sigmoid colon circular muscle strips with a pD(2) value of 6.8 +/- 0.2 nM (n = 25). The contractile responses to NT were significantly potentiated in the presence of tetrodotoxin (1 microM), indicating a neural component. Results from functional studies support actions for NT on both muscle and enteric neurons, consistent with the presence of NT receptors on circular muscle and ganglia of human sigmoid colon. The lack of inhibition by levocabastine suggests that the second binding site detected does not correspond to the NT2 receptor.

Topics: Adult; Aged; Autoradiography; Binding, Competitive; Colon, Sigmoid; Dose-Response Relationship, Drug; Enteric Nervous System; Female; Histamine H1 Antagonists; Humans; In Vitro Techniques; Iodine Radioisotopes; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Neurotensin; Peptide Fragments; Phenanthrolines; Piperidines; Protease Inhibitors; Receptors, Neurotensin; Tetrodotoxin

Two G protein-coupled neurotensin (NT) receptors, termed NTR1 and NTR2, have been identified so far. In contrast to the NTR1, which has been extensively studied, little is known about the pharmacological and biological properties of the NTR2. In the course of characterizing NT analogs that exhibited binding selectivity for the NTR2, we discovered that this receptor constitutively activated inositol phosphate (IP) production. Here, we report on the constitutive activity of the human NTR2 (hNTR2) transfected in COS cells and on compounds that exhibit agonism, inverse agonism, and neutral antagonism at this receptor. IP levels increased linearly with time, whereas they remained constant in mock-transfected cells. Furthermore, IP production was proportional to the amount of hNTR2 present at the cell membrane. SR 48692, a nonpeptide antagonist of the NTR1, stimulated IP production, whereas levocabastine, a nonpeptide histamine H1 antagonist that binds the NTR2 but not the NTR1, behaved as a weak partial inverse agonist. NT analogs modified at position 11 of the NT molecule, in particular by the introduction of bulky aromatic D amino acids, exhibited binding selectivity at the hNTR2 and also behaved as partial inverse agonists, reversing constitutive IP production up to 50%. Finally, NT barely affected constitutive IP production but antagonized the effects of both agonist and inverse agonist compounds, thus behaving as a neutral antagonist. The unique pharmacological profile of the hNTR2 is discussed in the light of its sequence similarity with the NTR1 and the known binding site topology of NT and SR 48692 in the NTR1.

Topics: Amino Acid Sequence; Animals; COS Cells; Histamine H1 Antagonists; Humans; Molecular Sequence Data; Neurotensin; Piperidines; Pyrazoles; Quinolines; Receptors, Neurotensin; Sequence Homology, Amino Acid; Transfection

Recent evidence suggests that some types of neurotensin receptors may be expressed by astrocytes. In order to explore the function of neurotensin receptors in astrocytes, the effect of a neurotensin receptor agonist, neurotensin(8-13), on intracellular Ca(2+) dynamics in mixed neuronal/glial cultures prepared from rat ventral tegmental area was examined. It was found that neurotensin(8-13) induces a long-lasting rise in intracellular Ca(2+) concentration in a subset of glial fibrilary acidic protein-positive glial cells. This response displays extensive desensitization and appears to implicate both intracellular and extracellular Ca(2+) sources. In the absence of extracellular Ca(2+), neurotensin(8-13) evokes only a short-lasting rise in intracellular Ca(2+). The neurotensin-evoked intracellular Ca(2+) accumulation is blocked by the phospholipase C inhibitor U73122 and by thapsigargin, suggesting that it is initiated by release of Ca(2+) from an inositol triphosphate-dependent store. The Ca(2+)-mobilizing action of neurotensin(8-13) in astrocytes is dependent on at least two receptors, because the response is blocked in part only by SR48692, a type 1 neurotensin receptor antagonist, and is blocked completely by SR142948A, a novel neurotensin receptor antagonist. The finding that the type 2 neurotensin receptor agonist levocabastine fails to mimic or alter the effects of neurotensin(8-13) on intracellular Ca(2+) makes it unlikely that the type 2 neurotensin receptor is involved. In summary, these results show that functional neurotensin receptors are present in cultured ventral tegmental area astrocytes and that their activation induces a highly desensitizing rise in intracellular Ca(2+). The pharmacological profile of this response suggests that a type 1 neurotensin receptor is involved but that another, possibly novel, non-type 2 neurotensin receptor is also implicated. If present in vivo, such signalling could be involved in some of the physiological actions of neurotensin.

Topics: Adamantane; Animals; Animals, Newborn; Astrocytes; Calcium; Cells, Cultured; Estrenes; Gadolinium; Imidazoles; Neurotensin; Peptide Fragments; Piperidines; Pyrrolidinones; Rats; Receptors, Neurotensin; Thapsigargin; Type C Phospholipases; Ventral Tegmental Area

Neurotensin is a peptide present in mammalian CNS and peripheral tissues, which may play a major role in neurotransmission or neuromodulation, subserving diverse physiological functions. We studied the effect of added neurotensin on ATPase activities in synaptosomal membranes isolated from rat cerebral cortex. Neurotensin at 3 x 10(-8)-3 x 10(-6) M concentration decreased 20-44% Na+,K+-ATPase activity but failed to modify Mg2+-ATPase activity; lower neurotensin concentrations (3 x 10(-14)-3 x 10(-10) M) had no effect on enzyme activities. This inhibitory effect was abolished by neurotensin heating, by enzyme preincubation with neurotensin during periods exceeding 10 min, or by adding 1 x 10(-6) M SR 48692, a high affinity neurotensin receptor antagonist. Levocabastine, which blocks low affinity neurotensin receptor, failed to alter enzyme inhibition by the peptide. It is suggested that the sodium pump may be a target for neurotensin effects at neuronal level involving the participation of high affinity neurotensin receptor.

Topics: Animals; Cerebral Cortex; Heating; In Vitro Techniques; Intracellular Membranes; Male; Neurotensin; Piperidines; Rats; Rats, Wistar; Receptors, Neurotensin; Sodium-Potassium-Exchanging ATPase; Synaptosomes

The postnatal ontogeny of the levocabastine-sensitive neurotensin receptor (NT2) mRNA was studied by in situ hybridization in the rat brain and compared with the distribution of the levocabastine-insensitive NT1 receptor. NT2 receptor mRNA was absent at birth from all brain structures except the ependymal cell layer lining the ventricles. The development of NT2 receptor mRNA followed three ontogenetic patterns. The first pattern, involving the majority of the cerebral gray matter, was characterized by a continuous increase from postnatal day 5 (P5) to P30. The second one, involving regions rich in myelinated fibers such as the corpus callosum and lacunosum moleculare layer of the hippocampus, exhibited a pronounced increase between P5 and P10, peaked at P15 and was followed by a plateau or a slight decrease. The third pattern was observed in the ependymal cell layer lining the olfactory and lateral ventricles, where the high labeling already present at birth continued to increase during development. These different developmental patterns could reflect the variety of cells expressing NT2 receptor mRNA, including neurons, protoplasmic astrocytes in gray matter, fibrous astrocytes present in myelinated fibers tracts, and ependymal cells. In contrast, NT1 receptor mRNA, which seems to be associated only with neurons, was highly and transiently expressed during the perinatal period in the cerebral cortex, hippocampus and striatal neuroepithelium. Other regions, notably the ventral tegmental area and substantia nigra compacta, exhibited a gradual increase in NT1 receptor signal, reaching adult levels by P21. Both the differential localization and ontogenetic profiles of NT1 and NT2 receptor mRNAs suggest different involvement of these two receptors in brain functions and development.

Topics: Amygdala; Animals; Brain Chemistry; Cerebellum; Cerebral Cortex; Cerebral Ventricles; Ependyma; Gene Expression Regulation, Developmental; Hippocampus; Histamine H1 Antagonists; In Situ Hybridization; Male; Mesencephalon; Nerve Fibers; Neuroglia; Neurons; Piperidines; Pons; Prosencephalon; Rats; Rats, Wistar; Receptors, Neurotensin; RNA, Messenger

The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adamantane; Animals; Autoradiography; Binding Sites; Carrier Proteins; Caudate Nucleus; Denervation; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Down-Regulation; Imidazoles; In Situ Hybridization; Macaca fascicularis; Membrane Glycoproteins; Membrane Transport Proteins; Neostriatum; Nerve Tissue Proteins; Neurotensin; Piperidines; Putamen; Receptors, Dopamine; Receptors, Neurotensin; RNA, Messenger; Substantia Nigra

Receptors for regulatory peptides, such as somatostatin or vasoactive intestinal peptide (VIP), expressed at high density by neoplastic cells, can be instrumental for tumor diagnosis and therapy. Little is known about the expression of neurotensin receptors in human tumors. In the present study, 464 human neoplasms of various types were investigated for their neurotensin receptor content by in vitro receptor autoradiography on tissue sections using 125I-[Tyr3]-neurotensin as radioligand. Neurotensin receptors were identified and localized in tumor cells of 11/17 Ewing's sarcomas, 21/40 meningiomas, 10/23 astrocytomas, 5/13 medulloblastomas, 7/24 medullary thyroid cancers and 2/8 small cell lung cancers. They were rarely found in non-small cell lung cancers and breast carcinomas; they were absent in prostate, ovarian, renal cell and hepatocellular carcinomas, neuroendocrine gut tumors, pituitary adenomas, schwannomas, neuroblastomas and lymphomas. When present, the receptors bound with nanomolar affinity neurotensin and acetyl-neurotensin-(8-13), with lower affinity neuromedin N, diethylenetriamine penta-acetic acidneurotensin-(8-13) and SR 48692, but not neurotensin-(1-11). They were all of the NT1 type, without high affinity for levocabastine. Further, in 2 receptor-positive Ewing's sarcomas, neurotensin mRNA was detected by in situ hybridization techniques. Since neurotensin is known to stimulate cell proliferation, the presence of neurotensin receptors in human neoplasia may be of biological relevance, possibly as an integrative part of an autocrine feedback mechanism of tumor growth stimulation.

Topics: Animals; Bone Neoplasms; Humans; Neoplasm Proteins; Neoplasms; Neurotensin; Organ Specificity; Peptide Fragments; Piperidines; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin; RNA, Messenger; RNA, Neoplasm; Sarcoma, Ewing

The antihistaminic drug levocabastine is a ligand for the low affinity neurotensin receptor (NTS2). Its intracerebroventricular administration to mice induced a significant analgesia in the writhing test but not in the hot plate test. In the writhing test, levocabastine decreased neurotensin-induced analgesia to a level not significantly different from the effects of levocabastine alone. In the hot plate test, levocabastine had no analgesic effect but completely reversed the neurotensin-induced analgesia. Mepyramine, another antihistaminic drug, did not share these levocabastine effects. Neither levocabastine nor mepyramine modified the colonic temperature or reversed the neurotensin-induced hypothermia. Thus, levocabastine behaves as a partial agonist at neurotensin NTS2 receptors, which are involved in visceral nociception, but not at yet unidentified neurotensin receptors involved in hypothermia.

Topics: Analgesia; Analgesics; Animals; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Male; Mice; Neurotensin; Pain; Pain Threshold; Piperidines; Pyrilamine; Receptors, Neurotensin

Identified cholinergic and a subtype of non-cholinergic, fast-firing neurons were recorded intracellularly in vitro from slices of guinea-pig brain. Recorded neurons were within the boundaries of the medial septum and vertical limb of the diagonal band of the forebrain. The effects of superfused neurotensin and neurotensin receptor antagonists were measured under single-electrode current clamp. Neurotensin consistently caused a dose-dependent, slow depolarization of cholinergic neurons that was accompanied by an increase in membrane resistance and a block of the long-duration (1-10 s) post-spike afterhyperpolarization when present. Neurotensin also blocked a shorter duration, slow afterhyperpolarization, but only in a minority of cholinergic neurons. When present, inhibition of the slow afterhyperpolarization changed the spike pattern from single spikes to short bursts. Inhibition of post-spike afterhyperpolarizations by neurotensin reversed more slowly than did other effects of neurotensin. Tetrodotoxin did not prevent the depolarizing effect of neurotensin. The non-selective neurotensin receptor antagonist, SR142948A, blocked the depolarizing effect of neurotensin but the low-affinity receptor antagonist, levocabastine, did not. A subgroup of noncholinergic, fast-firing neurons (23%) was also depolarized by neurotensin, an effect antagonized by SR142948A but not levocabastine. Neurotensin did not effect post-spike voltage transients or change the firing pattern of non-cholinergic neurons. These data suggest that neurotensin causes a slow depolarization and increased excitability of cholinergic and some noncholinergic neurons in an area of the brain that projects to the hippocampus. Neurotensin type 1 receptors appear to mediate these effects. Neurotensin may modulate hippocampal-dependent learning and memory processes through its effects on septohippocampal neurons.

Topics: Action Potentials; Adamantane; Animals; Dose-Response Relationship, Drug; Female; Guinea Pigs; Histamine H1 Antagonists; Imidazoles; In Vitro Techniques; Male; Membrane Potentials; Neurons; Neurotensin; Patch-Clamp Techniques; Piperidines; Prosencephalon; Receptors, Neurotensin; Tetrodotoxin

The effects of levocabastine, a novel histamine H1-receptor antagonist, on lipid mediator release induced by antigen-antibody reaction from actively sensitized guinea pig lung fragments were studied. Levocabastine dose-dependently inhibited the release of leukotriene C4 from guinea pig lung fragments induced by antigen. A significant effect was observed with levocabastine at a concentration of 10(-4) M. On the other hand, levocabastine produced no effect on the release of leukotriene E4 or thromoboxane B2. From these findings, it was concluded that levocabastine may be useful for relieving the nasal obstruction in allergic rhinitis caused by inhibition of leukotriene C4 release.

Topics: Animals; Antigens; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Leukotriene C4; Leukotriene E4; Lung; Male; Piperidines; Thromboxane B2

The recently cloned new subtype of G protein-coupled neurotensin receptor (NTRL) was stably expressed in the HEK 293 cell line in order to investigate its binding and internalization properties. The expressed receptor exhibited the typical binding characteristics of the low affinity, levocabastine-sensitive binding site previously described in rat and mouse brain and was detected as a protein with an apparent MW of 45 kDa by photoaffinity labeling. Although intracellular modulation of adenylate cyclase, guanylate cyclase and phospholipase C was not detected after application of neurotensin or levocabastine on NTRL-transfected cells, this receptor was able to internalize iodinated neurotensin. The internalization process was followed by recycling of receptors to the cell membrane. By contrast, no recycling was observed with the high affinity neurotensin receptor (NTRH). The differential intracellular routing of NTRH and NTRL after internalization is most probably the consequence of their divergent carboxy-terminal sequences.

Topics: Amino Acid Sequence; Animals; Binding, Competitive; Cell Line; Endocytosis; Gene Expression Regulation; Humans; Iodine Radioisotopes; Kinetics; Mice; Molecular Sequence Data; Neurotensin; Peptides; Photoaffinity Labels; Piperidines; Protein Binding; Receptors, Neurotensin; Signal Transduction; Transfection

The present study describes in vivo experiments in the rat addressing the role of levocabastine, and two other specific histamine H1 antagonists, diphenhydramine and pyrilamine, at neurotensin (NT)-mediated hypothermia and antinociception (hotplate). Levocabastine given i.p. or microinjected directly into the periaqueductal gray (PAG) did not cause antinociception or hypothermia. This indicates that despite the results with the recently-cloned levocabastine-sensitive NT receptors (NTR) in the rat (NTR-2) and mouse (NTRL), levocabastine by itself does not mediate either hypothermia or antinociception at NT receptors. However, pretreatment with 5 or 50 microg/kg of levocabastine or 5 microg/kg diphenhydramine all caused over a three-fold reduction in NT-mediated antinociception. Higher doses (500 or 5000 microg/kg) of levocabastine did not cause any antagonism of NT-mediated antinociception. All three antihistamines did not affect NT-mediated hypothermia. In addition, histamine H1 pathways are not involved in NT-mediated antinociception, as pretreatment with the much more potent histamine H1 antagonist pyrilamine did not affect antinociception mediated by NT. Therefore, these data may suggest the presence of yet unidentified NTR subtypes responsible for NT-mediated hypothermia and antinociception.

Topics: Animals; Body Temperature Regulation; Diphenhydramine; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Male; Mice; Neurotensin; Pain; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley

The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain.

Topics: Adamantane; Animals; Autoradiography; Binding Sites; Brain; Imidazoles; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Tritium

A normal ciliary beat frequency of ciliated cells is necessary for the mucociliary clearance of the nose and paranasal sinuses. An in vitro investigation was performed to evaluate the influence of topical corticosteroids and antihistamines on the ciliary beat frequency of human nasal mucosa. The nasal sprays examined contained the corticosteroids budesonide or fluticasone propionate and the topical antihistamines azelastine or levocabastine. All tests were performed on cell cultures of human nasal mucosa during constant conditions. Three of the four nasal sprays tested contained benzalkonium chloride as preservative. An irreversible cessation of ciliary movement was observed in all cells exposed to nasal sprays containing benzalkonium chloride in a 50 per cent solution. The nasal spray containing budesonide was benzalkonium chloride-free and caused minor but fully reversible decreases in ciliary beat frequency after 20 min. As benzalkonium chloride can cause complete standstill of ciliary beat frequency in vitro in human nasal mucosa, we recommend that this preservative should not be used anymore in topical nasal medications.

Topics: Administration, Topical; Androstadienes; Anti-Inflammatory Agents; Benzalkonium Compounds; Budesonide; Fluticasone; Glucocorticoids; Histamine H1 Antagonists; Humans; In Vitro Techniques; Mucociliary Clearance; Nasal Mucosa; Phthalazines; Piperidines; Preservatives, Pharmaceutical

Neurotensin has been shown to produce pharmacological effects both in brain and periphery. Several of these effects are mediated by a high-affinity neurotensin NT1 receptor. On the other hand, a low-affinity levocabastine-sensitive neurotensin NT2 receptor was molecularly cloned from rodent brain recently. In this study, in contrast to NT1 receptor, levocabastine (a histamine H1 receptor antagonist) and SR48692 (an antagonist for NT1 receptor) strongly stimulated intracellular Ca2+ mobilization in transfected Chinese hamster ovary cells expressing rat NT2 receptor, thus acting as potent NT2 receptor. Furthermore, despite of their affinities for NT2 receptor, the Ca2+ responses to potent NT1 agonists, neurotensin or JMV449 ([Lys8-(CH2NH)-Lys9]Pro-Tyr-Ile-Leu, a peptidase resistant analogue of neurotensin) were much smaller than that observed with SR48692. These findings suggest that NT1 and NT2 receptors present distinct functional characteristics and that SR48692 may act as a potent agonist for NT2 receptor.

Topics: Animals; Calcium; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Neurotensin; Oligopeptides; Piperidines; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin; Signal Transduction; Transfection

The aim of this study was to determine the regional and cellular distribution of the neurotensin type 2 receptor (NT-2R) mRNA in the rat brain. Using a radioactive in situ hybridization approach, the distribution of NT-2R transcripts was quantified from autoradiograms, and the cellular localization was examined in liquid emulsions. In rat brain, NT-2R mRNAs, are more widespread than the neurotensin type 1 receptor mRNA. NT-2R transcripts are diffusely distributed throughout the brain, with higher quantities found in the pia mater, the ventricles, the subfornical organ, the subiculum, the substantia nigra, the ventral tegmental area, the superior colliculus, the periaqueductal gray matter, the Purkinje cells and certain hypothalamic and brainstem nuclei. At the cellular level, silver grains appear to be concentrated on glia, neurons and ependymal cells, such as cell bodies of the glia-rich corpus callosum, Purkinje neurons in the cerebellum and ependymal cells lining the ventricles. In contrast, the thalamus and the amygdala contain low amounts of NT-2R mRNA. We discuss the anatomical location of NT-2R mRNA in relation to possible roles for this new receptor subtype.

Topics: Animals; Brain; Brain Stem; Cerebellum; Histamine H1 Antagonists; In Situ Hybridization; Male; Oligonucleotide Probes; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; RNA, Messenger; Tissue Distribution

SR 142948 is an original and extremely potent neurotensin receptor antagonist developed in a promising approach to novel antipsychotic drugs. The X-ray structure was elucidated and compared to SR 48692 and levocabastine, providing new informations about the possible recognition process of NT receptor subtypes.

Topics: Animals; Crystallography, X-Ray; Mice; Models, Molecular; Piperidines; Protein Conformation; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin

This work describes the molecular cloning of a variant isoform of the low-affinity levocabastine-sensitive neurotensin receptor isolated from mouse brain. Although the corresponding mRNA encodes for a 282 amino acid protein unable to bind neurotensin after transient transfection in COS-7 cells, this non-functional neurotensin receptor is expressed in cerebral neocortex, cerebellum, olfactory bulb, striatum and hypothalamus with a level similar to that of the full-length low-affinity neurotensin receptor. By contrast, this receptor form is very weakly expressed in mesencephalon and absent in the pituitary, but is the major product in the spinal cord.

Topics: Amino Acid Sequence; Animals; Base Sequence; Brain; Cloning, Molecular; COS Cells; DNA, Complementary; Gene Expression; Genetic Variation; Mice; Molecular Sequence Data; Neurotensin; Piperidines; Receptors, Neurotensin

Two G-protein-coupled receptors for the tridecapeptide neurotensin (NT) have been identified and cloned in mammalian brain: a high-affinity (Kd = 0.3 nM) receptor, sensitive to the antagonist SR 48692 but insensitive to levocabastine, and a lower-affinity (Kd = 2-4 nM) receptor, sensitive to levocabastine but with poor affinity for SR 48692. Although there is good evidence that the high-affinity site is predominantly expressed in neurons, little is known of the cellular localization of the low-affinity receptor. In the present study, we identify by confocal microscopy selective levocabastine-sensitive, SR 48692-resistant binding of a fluorescent derivative of NT (fluo-NT) to a subpopulation of glial fibrillary acidic protein-immunoreactive glial cells grown in culture from the midbrain and cerebral cortex of embryonic and neonatal rats, respectively. We also demonstrate, by combining fluo-NT detection with tyrosine hydroxylase immunofluorescence, that these glial binding sites are differentially regulated from the SR 48692-sensitive NT receptor expressed in the same cultures by mesencephalic dopamine neurons. Whereas the latter undergoes rapid ligand-induced internalization followed by centripetal mobilization of ligand-receptor complexes from processes to perikarya and from perikaryal periphery to cell center, the former induces the formation of cell-surface clusters that fail to internalize. It is concluded that NT may exert its effects on both neurons and astrocytes in the CNS. Whereas NT neural signaling is exerted through high-affinity receptors and may be partly effected through internalization of receptor-ligand complexes, glial signaling is exerted through low-affinity NT receptors and appears to be transduced exclusively at the level of the plasma membrane.

Topics: Animals; Animals, Newborn; Binding Sites; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Endocytosis; GTP-Binding Proteins; Mesencephalon; Nerve Tissue Proteins; Neuroglia; Neurons; Neurotensin; Piperidines; Protein Binding; Pyrazoles; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Signal Transduction; Tegmentum Mesencephali; Tyrosine 3-Monooxygenase

The effect of the drug SR 48692 on the Ca(2+)-activated Cl- current induced by neurotensin on Xenopus oocytes injected with cRNAs encoding rodent high and low affinity neurotensin receptors, was examined. In this receptor expression system, SR 48692 failed to antagonize electrophysiological measurement of neurotensin-evoked current via the rat high affinity neurotensin receptor, whereas its application onto oocytes expressing the mouse low affinity neurotensin receptor triggered an inward current, as well as neurotensin itself. However, no current activation was observed after application of the drug on oocytes expressing the rat high affinity neurotensin receptor. These observations in the oocyte expression system did not reflect typical antagonist properties of SR 48692 drug.

Topics: Animals; Calcium; Chlorides; Electric Conductivity; Female; Mice; Neurotensin; Oocytes; Piperidines; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin

We evaluated the adsorption of levocabastine (LEV) eye drops onto soft contact lenses in rabbit eyes to confirm the safety of this antihistaminic and antiallergic agent.. Low- and high- water-content soft contact lenses were placed on the eyes of three rabbits for each type of soft contact lens (total: six rabbits) for 8 hours daily. LEV eye drops and physiological saline solution (used as a control) were instilled into the experimental eye and the fellow eye at a dosage of 0.1 mL per eye, at 1 hour intervals, eight times daily, for 6 consecutive days. Severity of possible eye injury was evaluated before soft contact lens insertion and after removal.. After completion of the study, the amounts of LEV and the preservative benzalkonium chloride (BAK) adsorbed onto the soft contact lenses were assayed using high-performance liquid chromatography. There were no significant differences between the experimental solution and the control solution using Draize's method scores or slit lamp evaluation.. LEV and BAK accumulated only slightly in the soft contact lenses, leading us to conclude that LEV eye drops could be used safely by soft contact lens wearers for about 1 week.

Topics: Adsorption; Animals; Benzalkonium Compounds; Chromatography, High Pressure Liquid; Contact Lenses, Hydrophilic; Cornea; Drug Evaluation; Follow-Up Studies; Histamine H1 Antagonists; Ophthalmic Solutions; Piperidines; Preservatives, Pharmaceutical; Rabbits

Leukocytes from ten allergic patients (five allergic to dust-mites and five allergic to pollen) were treated with N-acetyl aspartyl glutamic acid (NAAGA) 4.9%, disodium cromoglycate (DSCG) 2%, lodoxamide (LODO) 1%, and levocabastine (LEVO) 0.5% (concentrations representing the pharmaceutical eyedrop preparations) for 20 minutes. Degranulation was then induced with Complement (rHu5Ca). Histamine was measured in the supernatant with ELISA. LODO and LEVO were inactive in blocking histamine released from human cells, and paradoxical unexpected effects were found with these two agents. They both induced significant histamine release in almost 100% of the samples. DSCG was able to block histamine release in seven patients out of nine (ranging between 5 and 34%). NAAGA was the most active agent on human cells and was able to block basophil degranulation in nine patients out of nine (inhibition ranging between 4 and 66% of total histamine pool).

Topics: Allergens; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Basophil Degranulation Test; Basophils; Cell Degranulation; Complement C5; Cromolyn Sodium; Dipeptides; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity, Immediate; Ophthalmic Solutions; Oxamic Acid; Piperidines; Recombinant Proteins

Levocabastine is a potent histamine H1 receptor antagonist used topically in the treatment of patients with allergic rhinitis. It has been suggested that antihistamines also have anti-inflammatory properties.. The present study was performed to investigate whether levocabastine, in addition to the anti-H1 receptor activity, has anti-inflammatory properties and thus is able to modulate the release of histamine and cytokines, such as interleukin 5 from human leukocytes and isolated tissues.. Leukocytes suspensions were prepared by dextran sedimentation of peripheral venous blood drawn from allergic and healthy volunteers. Leukocytes obtained from allergic volunteers were preincubated for 30 minutes with levocabastine (doses 10(-8) M to 10(-6) M) and thereafter incubated with allergen. Leukocytes obtained from healthy volunteers were incubated for zero to three hours with levocabastine (doses 10(-14) M to 10(-3) M). Histamine release was measured by an automated fluorometric method. Interleukin-5 release was measured by enzyme linked immunoassay. Contractile responses to histamine on guinea pig trachea and lung parenchyma as well as the release of histamine and interleukin-5 by the tissues were investigated in the absence or presence of levocabastine and/or the histamine H2 receptor antagonist cimetidine.. Levocabastine did not influence allergen-induced histamine release from leukocytes obtained from allergic volunteers. High concentrations (10(-4)and 10(-3) M) of levocabastine, however, caused release of histamine from leukocytes obtained from healthy volunteers as well as guinea pig airway smooth muscle tissues. Pretreatment with levocabastine dose-dependently decreased the contractile response to histamine, showing an irreversible competitive mechanism. Interleukin 5 release from human leukocytes and by guinea pig airway smooth muscle was not detectable.. These findings indicate that the H1 receptor blocker, levocabastine, has probably no anti-inflammatory properties, measured as histamine release, and that the histamine release from both human leukocytes and guinea pig trachea and lung parenchyma is significantly increased by the drug only at high concentrations.

Topics: Adult; Animals; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; Interleukin-5; Leukocytes; Lung; Middle Aged; Muscle Contraction; Muscle, Smooth; Piperidines; Receptors, Histamine H1; Trachea

A search for sequences homologous to the neurotensin receptor cDNA in a rat hypothalamic library has identified a novel neurotensin receptor (NTR-2). The 1539 bp cDNA encodes a 416 amino acid protein and shows highest homology to the previously cloned neurotensin receptor (NTR-1) (64% homology and 43% identity). Binding and pharmacological studies demonstrate that NTR-2 expressed in COS cells recognizes neurotensin (NT) with high affinity as well as several other agonists and antagonists. However, a fundamental difference was found; unlike NTR-1, NTR-2 recognizes, with high affinity, levocabastine, a histamine H1 receptor antagonist previously shown to compete with NT for low-affinity binding sites in brain.

Topics: Amino Acid Sequence; Animals; Cell Line; Chlorocebus aethiops; Hypothalamus; Molecular Sequence Data; Piperidines; Rats; Receptors, Neurotensin; RNA, Messenger; Sequence Homology, Amino Acid; Tissue Distribution

This work describes the cloning and expression of the levocabastine-sensitive neurotensin (NT) receptor from mouse brain. The receptor protein comprises 417 amino acids and bears the characteristics of G-protein-coupled receptors. This new NT receptor (NTR) type is 39% homologous to, but pharmacologically distinct from, the only other NTR cloned to date from the rat brain and the human HT29 cell line. When the receptor is expressed in Xenopus laevis oocytes, the H1 antihistaminic drug levocabastine, like NT and neuromedin N, triggers an inward current. The pharmacological properties of this receptor correspond to those of the low-affinity, levocabastine-sensitive NT binding site described initially in membranes prepared from rat and mouse brain. It is expressed maximally in the cerebellum, hippocampus, piriform cortex, and neocortex of adult mouse brain.

Topics: Amino Acid Sequence; Animals; Base Sequence; Brain; Cloning, Molecular; Histamine H1 Antagonists; Humans; Mice; Molecular Sequence Data; Neurotensin; Peptide Fragments; Piperidines; Rats; Receptors, Neurotensin; RNA, Messenger; Structure-Activity Relationship; Tissue Distribution; Xenopus laevis

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

Topics: Anti-Allergic Agents; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Nedocromil; Piperidines; Rhinitis, Allergic, Perennial

Topical application of levocabastine hydrochloride (-)-[3S-[1(cis)-3 alpha,4 beta]]-1-[4-cyano-4-(4-fluorophenyl) cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride, inhibited the increase in dye leakage into the nasal cavity induced not only by antigen in actively sensitized rats but also by histamine in non-sensitized rats. The potency of levocabastine was stronger than that of ketotifen in inhibiting the increase of dye leakage in both cases. In addition, levocabastine as well as ketotifen exerted a more potent inhibition of the dye leakage induced by histamine than that induced by antigen. Levocabastine also exerted a significant inhibition on the dye leakage induced by substance P; again the effect of levocabastine was more potent than that of ketotifen. On the other hand, levocabastine elicited no remarkable influence on the dye leakage induced by either acetylcholine or platelet activating factor. However, ipratropium and (RS)-2-methoxy-3-(octadecylcarbamoyloxy)propyl 2-(3-thiazolio)ethyl phosphate were effective when the corresponding agonists were perfused, respectively.

Topics: Acetylcholine; Animals; Antigens, Helminth; Ascaris; Histamine; Histamine H1 Antagonists; Ketotifen; Male; Nasal Mucosa; Piperidines; Platelet Activating Factor; Rats; Rats, Wistar; Rhinitis; Substance P

Topics: Anti-Inflammatory Agents, Non-Steroidal; Conjunctivitis, Allergic; Drug Combinations; Histamine H1 Antagonists; Humans; Ketorolac Tromethamine; Ophthalmic Solutions; Oxamic Acid; Piperidines; Tolmetin; Tromethamine

Topics: Clinical Trials as Topic; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines

Topics: Anti-Inflammatory Agents, Non-Steroidal; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Oxamic Acid; Piperidines; United States; United States Food and Drug Administration

Levocabastine hydrochloride (R50 547, CAS79516-68-0) caused no inhibitory effect on the histamine release from rat peritoneal mast cells induced by compound 48/80, A23187 and concanavalin A. However, the drug inhibited histamine release from passively sensitized mast cells and passive peritoneal anaphylaxis in rats, though higher concentrations or doses were required. Moreover, levocabastine provided a relatively potent inhibitory effect on histamine release from lung pieces of actively sensitized guinea pigs exposed to antigen, and simultaneously the drug prevented a decrease in the cyclic AMP (cAMP) content. Levocabastine potently inhibited histamine-induced cutaneous reactions in rats and the drug also prevented histamine-induced contraction of isolated guinea pig ileum. Levocabastine did not induce any significant changes in platelet aggregation or in the contraction of guinea pig ileum induced by platelet activating factor (PAF). However, the drug inhibited eosinophil migration induced by PAF. The chemotaxis of neutrophils induced by N-formyl-methionyl-leucylphenylalanine (fMLP) was also inhibited by levocabastine in a dose-dependent fashion. Levocabastine has no influence on the order parameter tested with liposomes, suggesting that the drug provides no significant effect on the membrane fluidity of lipid bilayer. These results seem to indicate that the antiallergic effect of levocabastine is mainly dependent on its potent antihistaminic activity.

Topics: Anaphylaxis; Animals; Chemotaxis, Leukocyte; Complement Inactivator Proteins; Cyclic AMP; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; Immunoglobulin E; In Vitro Techniques; Lung; Male; Mast Cells; Mice; Mice, Inbred BALB C; Muscle, Smooth; Piperidines; Platelet Aggregation; Prostaglandins E; Rabbits; Rats; Rats, Wistar; Skin Tests

Previous studies have shown that long sleep (LS) and short sleep (SS) mice, which were selectively bred for differences in brain sensitivity to ethanol, differ in neurotensin (NT) receptor densities in specific brain regions. The present study was designed to determine whether these receptor differences mediate differences in the effects of NT on the phosphoinositide (PI) second messenger system in four brain regions from LS and SS mice. Baseline and NT- or carbachol-stimulated PI hydrolysis were Ca(2+)-dependent. Stimulation of PI hydrolysis by NT or carbachol was region specific; NT effect was approximately equal in ventral midbrain (VMB) and entorhinal cortex (EC) with slightly less stimulation in nucleus accumbens (NA) and no effect in the cerebellum (CE). Carbachol-enhanced PI hydrolysis was greatest in the VMB followed by EC and NA with no stimulation in the CE. There were no between line (LS vs. SS) differences in carbachol effects, but stimulation by NT was greater in EC and NA from LS than from SS mice. Ethanol enhanced NT-stimulated, but not carbachol-stimulated, PI metabolism in SS and LS NA brain slices. Results with levocabastine, an inhibitor of low-affinity NT receptor (NTL) binding, suggest that NT may stimulate PI hydrolysis via NTL, as well as high-affinity receptors.

Topics: Animals; Brain; Calcium; Carbachol; Cerebellum; Dose-Response Relationship, Drug; Hippocampus; Histamine H1 Antagonists; Hydrolysis; Inositol; Inositol Phosphates; Kinetics; Membrane Lipids; Mesencephalon; Mice; Mice, Inbred Strains; Neurotensin; Nucleus Accumbens; Organ Specificity; Phosphatidylinositols; Phospholipids; Piperidines; Receptors, Neurotensin; Second Messenger Systems; Sleep

The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administered levocabastine were studied in six nondialysis patients and in six patients undergoing regular hemodialysis. Levocabastine .5 mg, supplied as a solution, was administered orally to each patient 1 hour after breakfast. Compared with data in healthy volunteers, the oral absorption and disposition of levocabastine were impaired in patients with renal insufficiency. The time to reach peak plasma concentration was increased and the peak plasma concentration was decreased in the patients with renal insufficiency compared with healthy volunteers. Urinary excretion of the unchanged drug, which is the major elimination pathway of levocabastine, was reduced in the patients with renal insufficiency. The decreased urinary excretion most likely contributed to the prolonged half-life (from 36 hours to 95 hours) and increased area under the plasma concentration-time curve (+56%) in the patients with renal insufficiency as compared with the healthy volunteers. Although the 6-hour hemodialysis procedure starting 4 hours after dosing eliminated 10% of the oral dose, the terminal half-life and the total area under the plasma concentration-time curve did not differ significantly between the hemodialysis and the nonhemodialysis patients. In conclusion, the current study showed that the initial oral absorption of levocabastine is reduced and that levocabastine elimination is prolonged in patients with renal insufficiency.

Topics: Adult; Female; Half-Life; Histamine H1 Antagonists; Humans; Kidney Failure, Chronic; Male; Middle Aged; Piperidines; Renal Dialysis

Neurotensin (NT) has been shown to differentially alter many of the physiologic responses to ethanol administration in long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differences in hypnotic sensitivity to ethanol. These mice have been shown to differ in NT receptor densities in cortical and mesolimbic brain regions and it has been suggested that ethanol actions may be mediated, in part, by neurotensinergic processes. The present study was conducted to further examine this hypothesis by determining the effects of acute and chronic ethanol administration on NT receptor systems in these mice. Scatchard analysis of [3H]NT binding in brain membranes from mice chronically treated with ethanol yielded a one-site model, whereas binding in membranes from control mice were best described by a two-site model. Values for binding capacity (Bmax) were significantly reduced in several brain regions, and binding site density for total, levocabastine-sensitive, and levocabastine-insensitive binding sites were also reduced. The maximum effect was seen after 2 weeks of chronic ethanol consumption. Three weeks after withdrawal from ethanol, Kd and Bmax had returned to control values. Similarly, binding density in all regions for total, levocabastine-sensitive, and levocabastine-insensitive sites had returned to control values within 2 weeks. NT receptor characteristics measured 2 h post-3.0 g/kg ethanol revealed that ethanol caused a rapid downregulation of both subtypes of NT receptors. The finding that both acute and chronic ethanol significantly downregulate the neurotensin receptor systems further supports the hypothesis that ethanol's actions may be mediated in part by neurotensinergic systems.

Topics: Animals; Benzamides; Benzazepines; Down-Regulation; Ethanol; Histamine H1 Antagonists; Kinetics; Male; Membranes; Mesencephalon; Mice; Mice, Inbred Strains; Neural Pathways; Neurotensin; Piperidines; Pyrrolidines; Receptors, Dopamine D1; Receptors, Neurotensin; Receptors, Neurotransmitter; Sleep; Species Specificity

Topics: Administration, Intranasal; Conjunctivitis, Allergic; Histamine H1 Antagonists; Humans; Ophthalmic Solutions; Piperidines; Rhinitis, Allergic, Seasonal

Levocabastine, selected from a series of cyclohexylpiperidine derivatives protects rats from compound 48/80-induced anaphylactic shock for at least 16 h at the oral dose of 0.0015 mg/kg. At the same dose histamine skin reactions and at slightly higher doses passive cutaneous anaphylactic reactions are inhibited. Blockade of passive cutaneous anaphylactic reactions is obtained with levocabastine, despite absence of peripheral serotonin antagonism and any other known non-specific action that may facilitate inhibition of passive anaphylaxis. In dogs allergic reactions are inhibited at oral doses 40 times lower than ketotifen. In guinea-pigs orally and topically administered levocabastine are remarkably effective against allergic conjunctivitis.

Topics: Anaphylaxis; Animals; Ascaris; Conjunctivitis, Allergic; Dogs; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Piperidines; Rats

The effects of levocabastine, a new fast-acting, highly potent H1-antagonist, on nasal ciliary epithelial function were investigated in an in vitro and in vivo study. In the in vitro study, a suspension of levocabastine in Locke-Ringer solution was applied to 10 bioptic specimens of ciliated human adenoid tissue. Each specimen was exposed to the test solution for 60 min. Ciliary beat frequency (CBF) was recorded with a photoelectric recording device at 10-min intervals. There were small, insignificant decreases in CBF, which were minimal compared to that observed with ciliotoxic agents. In the in vivo study, 8 healthy volunteers were given, intranasally, one droplet of the levocabastine suspension. Mucociliary transit time (MTT) was measured by placing a saccharin particle drenched in indigo carmine in the nose just below the top of the concha and measuring the time until appearance of the dye in the pharyngeal cavity. No statistically significant differences were found in the MTT before and after application of the levocabastine suspension. The studies thus indicate that nasally administered levocabastine does not interfere with ciliary beat frequency and mucociliary function.

Topics: Adenoids; Adult; Cilia; Epithelium; Histamine H1 Antagonists; Humans; In Vitro Techniques; Middle Aged; Mucociliary Clearance; Nasal Mucosa; Piperidines

Neurotensin (NT) receptor subtypes were investigated in nine brain regions from long sleep (LS) and short sleep (SS) mice that were selectively bred for differences in sensitivity to ethanol. Differences in NT receptor densities may mediate, in part, genetically selected differences in ethanol sensitivity between the two lines of mice. The use of [3H] NT at concentrations from 0.02 to 20 nM yielded biphasic binding isotherms as revealed by Scatchard analysis. Membranes from LS ventral midbrain yielded dissociation constants (KD values) of 0.34 and 3.85 nM for the high (NTH) and low (NTL) affinity components, respectively. SS membranes displayed similar KD values, however the maximum number of binding sites (Bmax) for both receptor subtypes were significantly greater in SS than in LS membranes (46.7 vs. 71.5 fmol/mg protein for NTH and 170.2 vs. 208.2 fmol/mg protein for NTL). Using levocabastine, and H1 antagonist with selectivity for NTL, characterization of NTH and NTL binding in nine brain regions was performed. In general, membranes from each brain region of SS mice had higher densities than LS for both receptor subtypes. Significant differences for the total density of receptors and NTL were found in entorhinal cortex, nucleus accumbens, hippocampus, and ventral midbrain. The only region to differ in NTH was the ventral midbrain. Competition experiments using various NT fragments to compete for NTH binding showed the C-terminal amino acids to be essential for binding. The order of potency was NT1-13 = NT8-13 greater than Neuromedin N greater than NT1-8 = NT1-11.

Topics: Alcohol Drinking; Animals; Binding, Competitive; Brain; Chlorpheniramine; Haloperidol; Histamine H1 Antagonists; Male; Mice; Mice, Inbred Strains; Neurotensin; Piperidines; Receptors, Neurotensin; Receptors, Neurotransmitter; Sleep Stages; Species Specificity

The effect of levocabastine on allergic and histamine (Hi)-induced conjunctivitis in guinea pigs was compared with those of cromolyn sodium and amlexanox. Levocabastine inhibited both antigen- and Hi-induced conjunctivitis. Amlexanox had no effect on Hi-induced conjunctivitis; however, the drug elicited a significant inhibition of allergic conjunctivitis. On the other hand, the effect of cromolyn sodium was almost negligible in both cases. Levocabastine moderately inhibited Hi release from guinea pig conjunctiva induced by antigen-antibody reactions. Amlexanox also caused a significant inhibitory effect, whereas cromolyn sodium was not effective in suppressing Hi release induced by antigen challenge. Furthermore, levocabastine prevented an increase in the vascular permeability elicited by both Hi and antigen instillation.

Topics: Aminopyridines; Animals; Antigens; Capillary Permeability; Conjunctivitis, Allergic; Cromolyn Sodium; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Histidine Decarboxylase; Male; Piperidines; SRS-A

The effects of levocabastine (R 50 547; CAS 79516-68-0) on the central nervous system were studied in comparison with those of diphenhydramine, ketotifen and azelastine. At high doses, levocabastine caused a decrease in locomotor activity, prolongation of thiopental-induced sleep, depression of acetic acid-induced writhing in mice and inhibition of active avoidance response in rats, but these adverse effects were much less potent than those seen in diphenhydramine, ketotifen and azelastine. Oxotremorine-induced tremor and salivation in mice were delayed after extremely high dosage of levocabastine; however, these were much less effective than those seen after diphenhydramine and ketotifen. Levocabastine did not affect the tonic extensor seizure induced by maximal electroshock in mice which is different from that of diphenhydramine. In EEG analysis, levocabastine at a dose of 20 mg/kg caused no significant changes in the EEG recorded from the frontal cortex, occipital cortex, hippocampus and amygdala in rats with chronic electrodes.

Topics: Acetates; Animals; Avoidance Learning; Central Nervous System; Electroencephalography; Histamine H1 Antagonists; Male; Mice; Mice, Inbred Strains; Motor Activity; Oxotremorine; Pain; Piperidines; Rats; Rats, Inbred Strains; Salivation; Sleep; Thiopental; Tremor

Topics: Animals; Binding Sites; Brain; Guinea Pigs; Neurotensin; Piperidines; Rats; Receptors, Histamine H1

The binding of [3H]neurotensin (NT) to membranes from rat forebrain was complex, exhibiting 'high' affinity (Kd approximately 0.5 nM) and 'low' affinity (Kd approximately 5.0 nM) binding components. Dynorphin A(1-13) (DYN A(1-13] and L-156,903 (N-oxo-3-(10H-phenothiazine-10-yl)propyl-1- arginyl-1-prolyl-1-phenylalanine) potently inhibited [3H]NT binding to brain with shallow biphasic competition curves. Saturation binding studies conducted in the presence or absence of DYN A(1-13) or L-156,903 indicated that these compounds, like levocabastine, exhibited substantial selectivity for 'low' affinity NT site. Structure-activity studies indicated rigid structural requirements for the NT binding activity of DYN A(1-13) and L-156,903. In contrast to the results using brain tissue, DYN A(1-13), L-156,903 and levocabastine were very weak or inactive to inhibit [3H]NT binding to rat uterus. These studies further characterize the heterogeneity of [3H]NT binding in vitro and demonstrate clear tissue differences in binding within a given species.

Topics: Animals; Binding Sites; Brain; Brain Chemistry; Dynorphins; Female; In Vitro Techniques; Male; Neurotensin; Oligopeptides; Phenothiazines; Piperidines; Rats; Rats, Inbred Strains

The efficacy of a new antihistamine, levocabastine, in alleviating the ocular allergic reactions induced by both histamine and 48/80 was evaluated in humans. Levocabastine (0.5%) was instilled in one eye of 30 volunteers, and vehicle in the contralateral eye. After 15 minutes, half of the subjects received histamine (25 mg/ml) and half, 48/80 (7.5 mg/ml). The signs and symptoms of allergy were graded clinically after 30 minutes. Compared with a buffer control, levocabastine significantly alleviated itching (P = 0.01), redness (P = 0.0156), and chemosis (P = 0.005) induced by histamine, and itching (P = 0.032) and redness (P = 0.029) induced by 48/80. The results from these pharmacologic models support the clinical use of levocabastine for the treatment of allergic conjunctivitis.

Topics: Conjunctivitis, Allergic; Histamine; Humans; p-Methoxy-N-methylphenethylamine; Piperidines

In an animal model, topical application of levocabastine to the eye inhibits the inflammatory conjunctival response to topically applied histamine. This is so even at one-fourth the concentration at which levocabastine is normally dispensed. Total blocking of histamine response continues for 24 h and is then irregularly observable for an additional 72 h. Levocabastine may be absorbed through the conjunctiva to give systemically transmitted protection to the contralateral eye. Levocabastine is a potent competitor against histamine for conjunctival H1 receptors and should prove a useful, possibly long-acting drug for the reversal of inflammatory conjunctivitis and inhibition of its recurrence.

Topics: Administration, Topical; Animals; Conjunctivitis, Allergic; Drug Evaluation, Preclinical; Guinea Pigs; Histamine; Histamine H1 Antagonists; Piperidines

Monoiodo-[125I-Tyr3]neurotensin (NT) bound to a high affinity, low capacity binding component and a lower affinity, high capacity component in rat brain synaptic membranes. The antihistamine H1 agent levocabastine, which bears no structural relationship to NT, selectively and totally inhibited NT binding to its low affinity binding sites. The IC50 for levocabastine was 7 nM. Lowering the temperature of the binding assay from 25 to 4 degrees C markedly reduced the affinity of the high affinity NT binding site but did not affect the ability of levocabastine to discriminate between high and low affinity NT binding sites in rat brain membranes and tissue sections. Radioautographic studies of [125I-Tyr3]NT binding to rat brain tissue sections in the absence and presence of levocabastine revealed markedly different regional distributions of the two NT binding components. The levocabastine-sensitive NT binding site was present in membranes from rat and mouse brain but absent from rabbit brain membranes and from human brain tissue sections. It was also absent from mouse neuroblastoma N1E115 and human colonic adenocarcinoma HT29 cell membranes, two cell lines which have previously been shown to possess NT receptors functionally coupled to intracellular second messenger-generating systems. These findings are discussed in the light of the known properties of the high and low affinity NT binding sites in rat brain.

Topics: Animals; Autoradiography; Brain Chemistry; Cell Membrane; Histamine H1 Antagonists; In Vitro Techniques; Male; Piperidines; Rabbits; Rats; Receptors, Neurotensin; Receptors, Neurotransmitter; Temperature

Rats were chronically treated with setoperone, a mixed serotonin and dopamine antagonist. Alterations in serotonin-S2 and dopamine-D2 receptors in the brain and changes in behavioural responses to tryptamine and apomorphine were studied along with duration of treatment and drug withdrawal. As with neuroleptics, behavioural supersensitivity to apomorphine and increase in the number of striatal dopamine-D2 receptor sites were apparent after 2 days setoperone treatment, both effects were maximal with 14 days treatment and were maintained over more than 20 days drug withdrawal. In contrast to the changes in the dopaminergic system, the rats showed a decreased response to tryptamine and serotonin-S2 receptor sites in the frontal cortex were significantly reduced in numbers. Both effects developed in parallel over 14 days treatment and extinguished over 10 days drug withdrawal. KD-values of radioligand binding to dopamine-D2 and serotonin-S2 receptor sites were unchanged by the setoperone treatment. The concomitant development and extinction of the in vivo and in vitro effects suggests a causal relationship between them. Chronic treatment with a selective histamine-H1 antagonist (levocabastine) or the tranquilizer diazepam did not affect dopamine-D2 or serotonin-S2 receptor sites. These observations demonstrate that in contrast to the receptor regulation theory, serotonin-S2 receptors are down regulated following persistent receptor blockade. Implications for the clinical use of serotonin antagonists and possible molecular mechanisms involved in the receptor regulation have been discussed.

Topics: Animals; Apomorphine; Behavior, Animal; Corpus Striatum; Diazepam; Dopamine Antagonists; Frontal Lobe; Gene Expression Regulation; Ketanserin; Male; Models, Biological; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Serotonin; Serotonin Antagonists; Tryptamines

Levocabastine is a potent antihistamine drug, structurally unrelated to neurotensin. In rat and mouse brain but not in other animal species, it inhibited 60% of the [3H]neurotensin binding displaced by unlabelled neurotensin or neurotensin(8-13). The levocabastine-sensitive site or "site 1" displayed high affinity properties for levocabastine (IC50 = 25 nM) and was highly sterospecific (IC50-value higher than 10 microM for one of the isomers). Binding to the "site 1" in rat brain corresponded to the [3H]neurotensin binding displaceable by 1 microM levocabastine, whereas binding to the "site 2" corresponded to the binding displaced by 1 microM neurotensin when the "site 1" was occluded by 1 microM levocabastine. Both "site 1" and "site 2" appeared to be saturable. Scatchard plots obtained in rat bulbus olfactorius allowed to calculate a KD-values of 7.1 nM and a Bmax-values of 37.2 fmol/mg original tissue for "site 1", while "site 2" displayed a KD-value of 0.7 nM and a Bmax-value of 16.3 fmol/mg original tissue. The regional distributions of both sites showed marked differences. The "site 1" was homogeneously distributed throughout all rat brain areas, whereas the amount of "site 2" binding was markedly different in separate brain areas: bulbus olfactorius and substantia nigra had the highest amounts (8.9 and 7.8 fmol/mg tissue) while cerebellum had the lowest (0.4 fmol/mg tissue). In spite of its high affinity and stereospecificity, "site 1" has to be considered as an acceptor or recognition site for [3H]neurotensin because of its species-link, low saturability and homogeneous distribution in all rat brain areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Brain; Cats; Dogs; Guinea Pigs; Humans; In Vitro Techniques; Mice; Neurotensin; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Receptors, Neurotensin; Receptors, Neurotransmitter

Topics: Biometry; Humans; Multiple Sclerosis; Piperidines