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This multicenter, randomized, double-blind, parallel-group, 2-week comparative study was conducted during the 2004 fall allergy season in patients with moderate to severe SAR. After a 1-week placebo lead-in period, patients were randomized to receive azelastine nasal spray 2 sprays per nostril twice daily plus placebo tablets or cetirizine 10-mg tablets once daily plus a placebo saline nasal spray for the 2-week double-blind treatment period. The primary efficacy variables were (1) change from baseline to day 14 in the 12-hour reflective total nasal symptom score (TNSS), which combines scores for rhinorrhea, sneezing, itchy nose, and nasal congestion, and (2) onset of action, based on the instantaneous TNSS over 4 hours after the first dose of study drug. During the double-blind treatment period, patients recorded their symptom scores on diary cards twice daily (morning and evening). Patients aged > or =18 years also completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at baseline and on day 14.
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Antiallergic effects of AL-3264 (N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(6-methyl-3- pyridyl)acrylamide, CAS 118420-47-6) were compared with those of ketotifen, oxatomide, azelastine and tranilast in experimental animals. AL-3264 inhibited passive cutaneous anaphylaxis (PCA) in rats with an ED50 value of 6.1 mg/kg p.o. In inhibiting PCA, AL-3264 was the most potent among the antiallergic drugs examined. The anti-PCA effect of AL-3264 was long-lasting. Tolerance was not produced by repeated administration of AL-3264. AL-3264 inhibited antigen-induced bronchoconstriction in actively sensitized rats and in passively sensitized guinea pigs, with ED50 values of 14.5 and 0.44 mg/kg p.o., respectively. In the in vitro experiments, AL-3264 inhibited 5-lipoxygenase activity of guinea pig leukocytes with an IC50 value of 4.9 mumol/l, being the most potent among antiallergic drugs examined, and suppressed the antigen-induced histamine release from rat peritoneal mast cells with an IC50 value of 12.2 mumol/l. AL-3264 antagonized histamine-induced contractions in isolated guinea pig trachea with an IC50 value of 0.16 mumol/l. These results suggest that AL-3264 is an orally active, potent and long-lasting antiallergic compound which inhibits 5-lipoxygenase activity, histamine release and histamine H1 receptors at the similar concentrations.
Azelastine hydrochloride (AZE) is an anti-allergic drug that inhibits the release of various chemical mediators from mast cells. We compared the immunosuppressive effects of AZE and FK-506 in vivo and in vitro. Topical application of AZE strongly inhibited the efferent phase of contact hypersensitivity, as did application of FK-506. In in vitro experiments, we found that 1) the suppression by AZE on interleukin (IL)-2 production from splenic T cells was partial and considerably large amounts of IL-2 were still produced, even in the presence of 10(-5) M of AZE, which was in sharp contrast to the observed marked inhibition of [3H]-TdR incorporation; 2) AZE significantly inhibited the phorbol myristate acetate-induced IL-2 responsiveness; 3) AZE did not inhibit the IL-2 receptor alpha expression of activated T cells; and 4) the significant inhibitory action was still observed even when AZE was added at 48 h after the initiation of culture. In regard to FK-506, we found that 1) FK-506 completely blocked the production of IL-2; 2) exogeneous IL-2 consistently restored the FK-506-induced inhibition; 3) FK-506 affected the phorbol myristate acetate-induced IL-2 responsiveness very little, if any; and 4) the significant suppression was observed only when FK-506 was added within 24 h after the initiation of culture. Thus, AZE exerts its in vitro immunosuppressive activity preferentially by interfering with the IL-2 responsiveness, with partial inhibition of IL-2 production. Conversely, FK-506 acts as a strong inhibitor of IL-2 production without a prominent effect on IL-2 responsiveness. The immunosuppressive activity of AZE shown in vitro may also be operative in vivo and may be applicable for topical use.
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Three multicenter, randomized, double-blind studies were conducted to determine whether patients with moderate-to-severe symptoms of seasonal allergic rhinitis who had responded inadequately to monotherapy with either an oral antihistamine or an intranasal corticosteroid, and who were candidates for combination therapy with both an oral antihistamine and an intranasal corticosteroid, could be effectively treated with azelastine nasal spray monotherapy.
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The results of this study indicate that the therapeutic use of azelastine eye drops in patients with seasonal allergic conjunctivitis or rhino-conjunctivitis can be recommended.
Antihistamines (H1-receptor antagonists) act by competitive antagonism of histamine at H1-receptors. In addition, high concentrations of some antihistamines inhibit allergen-induced histamine release from mast cells in vitro.
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The present study was undertaken to examine the influence of antihistamines on TARC and MDC production from CD14+ cells after antigenic stimulation in vitro.
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Azelastine rhinitis medications (nasal spray and tablets) have been shown to relieve the symptoms of allergic rhinitis. Nevertheless, many rhinitic subjects suffer from acute exacerbations of symptoms that sometimes require additional treatment.
The present data do not support the thesis that the increased plasma histamine concentration is causally related to pruritus in hemodialysis patients or that the antiallergic drug, azelastin HCL, alleviates the pruritus of dialysis patients by decreasing plasma histamine levels. The possible role of the increased tissue levels of histamine remains to be studied.
The introduction of a topically active H1-antihistamine nasal spray Azelastine, has given an extra dimension in the management of allergic rhinitis. The drug acts rapidly and avoids the systemic adverse effects of antihistimines. An objective prospective study was performed to detect the effect of Azelastine nasal spray on nasal airway resistance. Twelve healthy adult volunteers with no rhinological problems were included in the study. Nasal cavities were sprayed with 280 micrograms (two puffs) of Azelastine nasal spray and the nasal airway resistance was measured with anterior rhinomanometry at intervals of 30 minutes for up to two hours. Our study has shown a statistically significant increase in the total nasal airway resistance following the use of Azelastine nasal spray in the absence of a subjective change in nasal airway resistance. There are substances when inhaled which can cause subjective improvement in nasal airway patency without changing the measured nasal airway resistance. However this medication gives no subjective change in nasal airway patency in spite of increasing nasal airway resistance.
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Intranasal corticosteroids and intranasal antihistamines are efficacious topical therapies in the treatment of allergic rhinitis. This review addresses their relative roles in the management of this disease, focusing on their safety and tolerability profiles. The intranasal route of administration delivers drug directly to the target organ, thereby minimising the potential for the systemic adverse effects that may be evident with oral therapy. Furthermore, the topical route of delivery enables the use of lower doses of medication. Such therapies, predominantly available as aqueous formulations following the ban of chlorofluorocarbon propellants, have minimal local adverse effects. Intranasal application of therapy can induce sneezing in the hyper-reactive nose, and transient local irritation has been described with certain formulations. Intranasal administration of corticosteroids is associated with minor nose bleeding in a small proportion of recipients. This effect has been attributed to the vasoconstrictor activity of the corticosteroid molecules, and is considered to account for the very rare occurrence of nasal septal perforation. Nasal biopsy studies do not show any detrimental structural effects within the nasal mucosa with long-term administration of intranasal corticosteroids. Much attention has focused on the systemic safety of intranasal application. When administered at standard recommended therapeutic dosage, the intranasal antihistamines do not cause significant sedation or impairment of psychomotor function, effects that would be evident when these agents are administered orally at a therapeutically relevant dosage. The systemic bioavailability of intranasal corticosteroids varies from <1% to up to 40-50% and influences the risk of systemic adverse effects. Because the dose delivered topically is small, this is not a major consideration, and extensive studies have not identified significant effects on the hypothalamic-pituitary-adrenal axis with continued treatment. A small effect on growth has been reported in one study in children receiving a standard dosage over 1 year, however. This has not been found in prospective studies with the intranasal corticosteroids that have low systemic bioavailability and therefore the judicious choice of intranasal formulation, particularly if there is concurrent corticosteroid inhalation for asthma, is prudent. There is no evidence that such considerations are relevant to shorter-term use, such as in intermittent or seasonal disease. Intranasal therapy, which represents a major mode of drug delivery in allergic rhinitis, thus has a very favourable benefit/risk ratio and is the preferred route of administration for corticosteroids in the treatment of this disease, as well as an important option for antihistaminic therapy, particularly if rapid symptom relief is required.
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In all three studies a total of 1,070 patients were randomized to double-blind treatment. There were no statistically significant differences in the percentage of patients treated with azelastine nasal spray versus patients treated with a combination of loratadine tablets and beclomethasone nasal spray who did not require additional anti-rhinitis medication (32% to 45% and 39% to 46%, respectively). The patient global evaluation indicated that 77% to 84% of the patients treated with azelastine nasal spray had symptomatic improvement and 85% to 90% of the patients treated with loratadine tablets and beclomethasone nasal spray had symptomatic improvement. The most commonly reported adverse experience with azelastine nasal spray was a transient aftertaste (8%), while the most commonly reported adverse experience with loratadine tablets and beclomethasone nasal spray in combination was headache (6%).
Nociceptin, the endogenous peptide ligand for opioid receptor like-1 (ORL1) receptor, has been implicated in the inflammation and pain in the skin. We examined whether nociceptin is a pruritogen in mice. Intradermal injections of nociceptin (1-100 nmol per site) concentration dependently increased scratching in ICR mice; the effect started within 1 min, peaked at 10-20 min, and almost subsided by 30 min. The nociceptin action was absent in ORL1 receptor-deficient (ORL1(-/-)) mice. Systemic, but not local, treatment with naloxone significantly inhibited scratching induced by nociceptin. The action of nociceptin was inhibited by the leukotriene B(4) receptor antagonist ONO-4057 and azelastine, which inhibits the action and production of leukotriene B(4) in the skin. Prepronociceptin and ORL1 receptor mRNAs were substantially expressed in the skin, whereas their expression levels were very low in the dorsal root ganglia. In the skin, nociceptin- and ORL1 receptor-like immunoreactivities were localized in the epidermis. Administration of nociceptin to primary cultures of keratinocytes from ICR and C57BL/6 (ORL1(+/+)) mice, but not ORL1(-/-) mice, produced leukotriene B(4). The results suggest that nociceptin acts on ORL1 receptor on the keratinocytes to produce leukotriene B(4), which induces itch-associated responses in mice.
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In this 2-week study in patients with moderate to severe SAR, azelastine nasal spray was well tolerated and produced significantly greater improvements in TNSS and total RQLQ score compared with cetirizine.
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A liquid chromatography coupled to tandem mass spectrometry (LC-ESI/MS/MS) was validated to determine azelastine in human plasma. Azelastine and internal standard (IS, clomipramine) were separated using a mobile phase of acetonitrile:(5 mM)-ammonium acetate solution (70:30, v/v, pH=6.4) with flow rate of 0.25 mL/min over YMC C8 column. One mL of plasma was extracted by n-hexane: 2-propanol (97:3, v/v) and then injected into HPLC system after reconstitution by acetonitrile: (5 mM)-ammonium acetate (1:1, v/v) solution. Detection was carried out on API5000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI (+) and selectivity was achieved at m/z 382.2→112.2 for azelastine and m/z 315.3→228.0 for IS. Total run-time (<2.0 min) and linearity (10 (LLOQ) ~5000 pg/mL) were good. No endogenous compounds were found around the retention time. The inter- and intra-day precision and accuracy were 4.13~17.91% and 87.57~109.70%, respectively. This validated method was successfully applied to a bioequivalence study in 23 healthy Korean male volunteers from the blood samples taken up to 96 h after orally administered 2 tablets of 1 mg of reference and test formulations of azelastine in a double-blind, randomized, cross-over design. The mean peak plasma concentrations (Cmax ± SD) of 1.02 ± 0.37 and 1.10 ± 0.43 ng/mL were reached at 5.9 and 5.6 h for reference and test azelastine, respectively. The mean total area under the curve (AUC0-infinity) were 25.96 ± 10.84 and 28.24 ± 11.09 ng·h/mL for reference and test formulations, respectively. The reference and test azelastine formulations can be considered bioequivalent from the obtained pharmacokinetics by LC-ESI/MS/MS.
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To evaluate the efficacy of olopatadine in suppressing symptoms and biomarkers of the immediate reaction induced by nasal allergen provocation and to compare olopatadine with azelastine in the same model.
H1-type antihistamines have recently been reported to inhibit cytokine secretion from human and murine mast cells and basophils. In order to confirm and expand these studies, we have compared several H1-blockers and the H2-blocker ranitidine for their effect on TNF-alpha, IL-3, 6, 8 and GM-CSF release from human leukemic mast (HMC-1) and basophilic (KU812) cells, compared to dexamethasone. Cells were stimulated for 24 h with phorbol myristate acetate (25 ng/ml) and calcium ionophore A 23187 (2.5x10(-7) M) alone or with the drugs added at 10(-4) to 10(-15) M, and production of cytokines was measured by ELISA. All antihistamines caused a dose-dependent inhibition of TNF-alpha release from HMC-1 cells, with maximal effects at 10(-12) M for azelastine, 10(-9) M for loratadine and cetirizine, and 10(-8) M for ranitidine. The inhibitory potency of H1-blockers on cytokines from HMC-1 cells was TNF-alpha >IL-8> or =IL-6> or =IL-3, with no significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-alpha and GM-CSF, the sequence was IL-6 >IL-8 after preincubation. Dexamethasone inhibited all cytokines, but ranitidine only TNF-alpha and IL-3. Antihistamines had no effect on calcium flux in resting or stimulated cells. At the mRNA level, inhibition was only seen with KU812 cells and IL-8 in the presence of azelastine at 10-(10) M. These data show thus distinct inhibitory patterns for different antihistamines during cytokine production from human mast cells and basophils which may contribute to the anti-inflammatory effects of these drugs during treatment of allergic diseases.
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The action spectrum of solar urticaria varies among cases. In addition, light spectra outside the activating wavelengths can influence the wheal formation in selected patients.
To determine the efficacy and safety of azelastine nasal spray, 1 spray per nostril twice daily, in patients with SAR.
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Mast cells are involved in allergic inflammation by secreting histamine, proteases and several cytokines, including interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and IL-8. Certain histamine-1 receptor antagonists, such as azelastine present in the ophthalmic solution Optivar, have been reported to inhibit histamine and tryptase secretion, but its effect on inflammatory cytokine release from normal human umbilical cord blood-derived cultured mast cells (hCBMC) are not well known.
We examined effects of six oral anti-allergy drugs used to treat bronchial asthma on fMet-Leu-Phe (N-formyl-methionyl-leucyl-phenylalanine)-induced superoxide (O2-) generation and mobilization of intracellular free calcium ([Ca2+]i) in human neutrophils. We also evaluated the direct action of these drugs on NADPH (reduced nicotinamide-adenine dinucleotide phosphate)-oxidase activity in cell lysate (cell-free system). Ketotifen (25 approximately 200 microM) enhanced fMet-Leu-Phe-stimulated O2- generation and [Ca2+]i mobilization, although it directly inhibited NADPH oxidase in the cell-free study. Low concentrations of oxatomide (5-20 microM) enhanced O2- generation, but concentrations > 25 microM inhibited O2- generation. In concentrations below 20 microM, oxatomide had no effects on fMet-Leu-Phe-stimulated [Ca2+]i mobilization, but at concentrations above 25 microM, it inhibited [Ca2+]i mobilization. Oxatomide inhibited NADPH oxidase activity at all concentrations examined. Azelastine, pemirolast, tranilast, and repirinast inhibited O2- generation and [Ca2+]i mobilization. Azelastine and pemirolast directly inhibited NADPH oxidase, but tranilast and repirinast did not. Our results indicated that except for ketotifen and low concentration of oxatomide, oral anti-allergy drugs used to treat bronchial asthma inhibited fMet-Leu-Phe-induced O2- generation in human neutrophils. Based on IC50 values, potency of drugs was as follows: oxatomide > azelastine > tranilast > pemirolast > repirinast.
Azelastine, a newly synthesized antiallergic agent, strikingly inhibited the production of leukotriene B4 and C4 (LTB4 and LTC4) in murine peritoneal cells which had been stimulated by calcium ionophore A23187. The 50% inhibitory concentrations (IC50) of the agent were approximately 1.0 x 10(-5) M. In addition, azelastine significantly inhibited also 5-lipoxygenase activity in peritoneal cells with an IC50 of 1.0 x 10(-5) M, but not on LTC4 synthetase, LTA4 hydrolase or phospholipase A2 activity. Furthermore, azelastine showed little effect on either 12-lipoxygenase activity or thromboxane synthesis in human platelets. These results suggest that at least the drug's antiallergic effects can be attributed to its inhibiting action of 5-lipoxygenase in regard to arachidonate metabolism.
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A novel intranasal formulation of azelastine HCl (AZE, an antihistamine) and fluticasone propionate (FP, a corticosteroid) in a single spray (MP-AzeFlu [Dymista®]) was studied in four randomized, double-blind, placebo-controlled trials of patients with seasonal allergic rhinitis conducted in the US. Study sites were distributed so that all major US geographic regions and the prevalent pollens within these regions were represented. Spring and summer studies included patients aged 12 years and older with allergy to grass and tree pollens. Fall studies enrolled patients with allergy to weeds, in particular ragweed. In addition, a study was conducted during the winter months in patients with allergy to mountain cedar pollen in TX, USA. Regardless of allergy season or prevalent pollen, MP-AzeFlu improved nasal symptoms of allergic rhinitis (AR) to a significantly greater degree than AZE or FP, two treatments that currently are recommended as the first-line AR therapy. MP-AzeFlu improved all individual AR symptoms and was significantly better than FP and AZE for nasal congestion relief, which is generally accepted as the most bothersome symptom for AR patients. The onset of action was within 30 minutes. MP-AzeFlu also provided clinically important improvement in the overall Rhinoconjunctivitis Quality of Life Questionnaire score and significantly improved ocular symptoms of rhinitis compared to placebo. Favorable characteristics of the MP-AzeFlu formulation as well as superior clinical efficacy make it an ideal intranasal therapy for AR.
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A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
The combination azelastine-fluticasone nasal spray provided statistically significant improvement in the TNSS and additive clinical benefit compared with either agent alone in patients with moderate-to-severe seasonal allergic rhinitis.
The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70 µm and zeta potential +24.55 to +49.56 mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug's presence in cul de sac with improved therapeutic efficacy.