Effect of curcumin on nasal symptoms and airflow in patients with perennial allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common disorder that can significantly affect patient quality of life. Previous studies have found that curcumin had anti-inflammatory and antioxidant effects and clinical benefits in cancer and asthma. OBJECTIVE: To determine the efficacy of curcumin in the treatment of AR and to explore the molecular mechanisms involved. METHODS: In a randomized, double-blind study, 241 patients with AR received either placebo or oral curcumin for 2 months. The therapeutic effects of curcumin were evaluated by nasal symptoms and nasal airflow resistance. In addition, the production of interferon γ, interleukin (IL) 4, IL-10, and tumor necrosis factor α from mononuclear cells and IL-8, soluble intercellular adhesion molecule, polyethylene glycol 2, and leukotriene C4 from polymorphonuclear neutrophils were compared before and after curcumin treatment. RESULTS: Curcumin alleviated nasal symptoms (sneezing and rhinorrhea) and nasal congestion through reduction of nasal airflow resistance. Curcumin was found to exert diverse immunomodulatory effects, including suppression of IL-4, IL-8, and tumor necrosis factor α and increased production of IL-10 and soluble intercellular adhesion molecule. However, curcumin did not affect the release of prostaglandin E2 and leukotriene C4 from polymorphonuclear neutrophils. CONCLUSION: This pilot study provides the first evidence of the capability of curcumin of improving nasal airflow and modulating immune response in patients with AR.

Effect of Ganoderma lucidum on pollen-induced biphasic nasal blockage in a guinea pig model of allergic rhinitis.

Ganoderma lucidum (GL), an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases. However, the effect of GL on allergic rhinitis has not been well defined. The current study describes the inhibitory effect of GL on the biphasic nasal blockage and nasal hyperresponsiveness induced by repeated antigen challenge in a guinea pig model of allergic rhinitis. Intranasally sensitized guinea pigs were repeatedly challenged by inhalation of Japanese cedar pollen once every week. Ganoderma lucidum was orally administered once daily for 8 weeks from the time before the first challenge. The treatment with GL dose-dependently inhibited the early and late phase nasal blockage at the fifth to ninth antigen challenges. Furthermore, nasal hyperresponsiveness to intranasally applied leukotriene D4 on 2 days after the eighth antigen challenge was also inhibited by the treatment with GL. However, Cry j 1-specific IgE antibody production was not affected by the treatment. In conclusion, we demonstrated that the pollen-induced biphasic nasal blockage and nasal hyperresponsiveness were suppressed by the daily treatment with GL in the guinea pig model of allergic rhinitis. These results suggest that GL may be a useful therapeutic drug for treating patients with allergic rhinitis.

Absence of nasal blockage in a Japanese cedar pollen-induced allergic rhinitis model mouse.

BACKGROUND: Japanese cedar pollen-induced allergic rhinitis in a guinea pig model clearly induced not only sneezing but also biphasic nasal blockage. To date, there have only been a few reports on models of murine allergic rhinitis which clearly show nasal blockage. Therefore, in order to try and develop such a model, we administered multiple dosages of intranasal pollen or purified antigen protein Cry j 1. METHODS: B10.S mice were sensitized by intranasal instillations of either pollen extract or Cry j 1 twice a day for 7 days, which was adsorbed on Al(OH)(3). Subsequently, once a week, the mice were given multiple intranasal instillation challenges of either the pollen suspension or Cry j 1 and the frequency of sneezing was observed after respective challenges were made. Specific airway resistance (sRaw) was measured as an indicator for nasal blockage. Cry j 1-specific IgE levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The serum Cry j 1-specific IgE level showed clear elevation only in the group sensitized by Cry j 1 + Al(OH)(3) and then challenged by Cry j 1. No elevations were seen in the groups sensitized by pollen extract + Al(OH)(3) followed by a pollen suspension challenge. There was an immediate increase in sneezing after challenges in all of the sensitized-challenged groups. Nevertheless, no increases in sRaw in any of the groups were detected at any of the time points during the 8 hours following the challenges. CONCLUSIONS: Cry j 1 may be more effective than crude antigens for efficient sensitization/challenge in mice. No increase in sRaw occurred, even in mice that possessed high amounts of Cry j 1-specific IgE and that exhibited sneezing.

Effect of TA-270, a novel quinolinone derivative, on antigen-induced nasal blockage in a guinea pig model of allergic rhinitis.

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone) is a novel quinolinone derivative that has been demonstrated to possess an anti-oxidative activity against peroxynitrite, a potent oxidant, that is generated by the reaction of nitric oxide with superoxide anions. The current study describes the inhibitory effect of TA-270 on the biphasic nasal blockage induced by repeated antigen challenge in an allergic rhinitis guinea pig model. In the present in vitro study, TA-270 potently inhibited the oxidative reaction induced by peroxynitrite (IC(50)=79 nM). In addition, TA-270 (0.3-30 mg/kg, p.o.) dose-dependently inhibited peroxynitrite (3 mM, 10 mul/nostril)-induced nasal blockage in guinea pigs. In the antigen-induced allergic rhinitis model, TA-270 (0.3, 3, and 30 mg/kg, p.o.) given 1 h before the antigen challenge suppressed early phase nasal blockage by 36%, 42%, and 63%, respectively. Furthermore, TA-270 (0.3, 3, and 30 mg/kg, p.o.) showed a relatively strong suppression of late phase nasal blockage (39%, 62%, and 72%, respectively). The late phase nasal blockage was significantly inhibited (61%) even when TA-270 (30 mg/kg, p.o.) was administered 18 h before the antigen challenge. In conclusion, TA-270 improved antigen-induced nasal blockage, probably through its peroxynitrite scavenging action, and the effect was sustained for at least 18 h. Thus, TA-270 would be expected to relieve nasal blockage in allergic rhinitis patients.

Effect of local nasal immunotherapy on nasal blockage in pollen-induced allergic rhinitis of Guinea pigs.

BACKGROUND: As a non-injection route for immunotherapy, local nasal immunotherapy has been examined in allergic rhinitis patients. However, it is unclear how the immunotherapy affects sneezing, biphasic nasal blockage and nasal hyperresponsiveness. Thus, we evaluated the therapeutic effects of nasal immunotherapy on the symptoms of guinea pig allergic rhinitis. Additionally, we also evaluated whether the immunotherapy relieved pollen-induced allergic conjunctivitis. METHODS: Sensitized animals were repeatedly challenged by pollen inhalation once every week. After the 7th challenge, the pollen extract was intranasally administered 6 times a week until the 30th challenge. Sneezing frequency was counted after each of the challenges. As an indicator of nasal blockage, changes in specific airway resistance were measured. Nasal hyperresponsiveness was assessed by measuring leukotriene D(4)-induced nasal blockage. Additionally, during the immunotherapy, we applied pollen onto the ocular surface to induce the allergic conjunctivitis symptoms. RESULTS: At the 11th-30th challenges, the nasal immunotherapy showed inhibition or a tendency to inhibit the biphasic nasal blockage although the inhibitions were variable at respective challenges. The development of nasal hyperresponsiveness was markedly suppressed by the immunotherapy. Nevertheless, neither sneezing nor antigen-specific IgE antibody production was substantially influenced by the immunotherapy. On the other hand, the nasal immunotherapy did not affect the induction of allergic conjunctivitis symptoms. CONCLUSIONS: Local nasal immunotherapy may be clinically useful for allergic nasal blockage associated with nasal hyperresponsiveness. The mechanisms responsible for this effectiveness might not be related to IgE production. Additionally, the effectiveness for nasal tissue was dissociated from that seen for the ocular tissue.

Effects of KP-496, a novel dual antagonist of leukotriene D(4) and thromboxane A (2) receptors on nasal blockage in guinea pig models of allergic rhinitis.

OBJECTIVE AND DESIGN: KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge. METHODS: As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model). RESULTS: Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges. CONCLUSIONS: KP-496 may be clinically effective for nasal blockage in allergic rhinitis.

Involvement of peroxynitrite in pollen-induced nasal blockage in guinea pigs.

Nitric oxide (NO) has been implicated in early and late phase nasal blockage in a Japanese cedar pollen-induced experimental allergic rhinitis guinea pig model. In this study, we investigated the role of peroxynitrite, which is formed by a rapid reaction of NO with superoxide anion, in the antigen-induced biphasic nasal blockage. Sensitized guinea pigs were repeatedly challenged by pollen inhalation once every week. The peroxynitrite scavenger, ebselen (30 mg/kg), or the xanthine oxidase inhibitor, allopurinol (50 mg/kg), was intraperitoneally administered 30 min before the antigen challenge. The late phase nasal blockage induced 4 h after the challenge was largely suppressed by ebselen (57% inhibition; P<0.05) and allopurinol (47% inhibition; P<0.05), but neither ebselen nor allopurinol influenced the early phase response. On the other hand, the intranasal instillation of peroxynitrite (10(-3) and 10(-2) M, 10 microl/nostril) caused a remarkable dose-dependent nasal blockage in the sensitized guinea pig. These results suggest that peroxynitrite plays a major role in the late phase nasal blockage induced by the antigen challenge in sensitized guinea pigs.

Different mechanisms between thromboxane A2- and leukotriene D4-induced nasal blockage in guinea pigs.

Although thromboxane (TX)A2 is involved in allergic rhinitis, the mechanisms inducing nasal blockage have not been elucidated. We evaluated the roles of nasal mucosal vascular changes following intranasal instillation of the TXA2 analog U-46619 or leukotriene (LT)D4 to induce nasal blockage in a guinea pig model of allergic rhinitis. Both U-46619- and LTD4-induced nasal blockages in sensitized animals were swiftly and completely suppressed by a vasoconstrictor, naphazoline. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester relieved LTD4-induced nasal blockage, but not U-46619-induced nasal blockage. Although both agonists produced vasodilatation of nasal mucosa in vivo, LTD4 caused vasodilatation while U-46619 caused vasoconstriction in vitro. Both LTD4- and U-46619-induced nasal blockages in vivo should depend on vasodilatation of nasal mucosa. LTD4-induced nasal blockage is induced by direct vasodilatation via nitric oxide. In contrast, U-46619-induced nasal blockage may be associated with contraction of a certain vein that should exist at the exit of capacitance vessels, leading to congestion of the nasal mucosa.

Efficacy of Tinospora cordifolia in allergic rhinitis.

The efficacy of Tinospora cordifolia (TC) extract in patients of allergic rhinitis was assessed in a randomized double blind placebo controlled trial. Seventy-five patients were randomly given either TC or placebo for 8 weeks. They were clinically examined and Hb %, TLC, DLC and nasal smear was done. At the end of trial baseline investigations were repeated, drug decoded and results analyzed. With TC treatment 100% relief was reported from sneezing in 83% patients, in 69% from nasal discharge, in 61% from nasal obstruction and in 71% from nasal pruritus. In placebo group, there was no relief in 79% from sneezing, in 84.8% from nasal discharge, in 83% from nasal obstruction, and in 88% from nasal pruritus. The difference between TC and placebo groups was highly significant. TLC increased in 69% patients in drug treated group and in only 11% with placebo. After TC, eosinophil and neutrophil count decreased and goblet cells were absent in nasal smear. After placebo, decrease in eosinophil and neutrophil count was marginal and goblet cells were present. TC significantly decreased all symptoms of allergic rhinitis. Nasal smear cytology and leukocyte count correlated with clinical findings. TC was well tolerated.

Effects of TAK-427 on acute nasal symptoms and nasal obstruction in guinea pig model of experimental allergic rhinitis.

TAK-427 (2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate) is a novel anti-allergic agent that has both histamine H1-receptor antagonist and anti-inflammatory activities. In this study, we evaluated the efficacy of TAK-427 on acute nasal responses and nasal obstruction using various guinea pig models of allergic rhinitis. TAK-427 inhibited the histamine-induced nasal reactions with an ID50 value of 0.633 mg/kg, p.o. TAK-427 (0.1-10 mg/kg, p.o.) and most histamine H1-receptor antagonists tested inhibited the increase in intranasal pressure, nasal hypersecretion, sneezing and nasal itching caused by a single antigen challenge in sensitized guinea pigs. In addition, TAK-427 (0.3, 30 mg/kg, p.o.) significantly inhibited the development of nasal obstruction when sensitized guinea pigs were repeatedly challenged via inhalation with Japanese cedar pollen, whereas the histamine H1-receptor antagonist, azelastine (1 mg/kg, p.o.), and ketotifen (1 mg/kg, p.o.) were without effect. These results suggest that TAK-427 might not only suppress acute nasal symptoms but also ameliorate nasal obstruction via the effects other than those as a histamine H1-receptor antagonist.

Acquired nasal hyperresponsiveness aggravates antigen-induced rhinitis in the guinea pig.

Whether a state of nasal hyperresponsiveness influences antigen-induced biphasic nasal blockage and sneezing were examined using a guinea pig model of allergic rhinitis. Sensitized animals were challenged with an antigen, Japanese cedar pollen, once every week. Before the 13th challenge, the animals were randomly divided into 2 groups, and then the 13th challenge was performed (Groups A-0 and B-0). The 14th challenge was done on day 2 (Group A-2) and on day 7 (Group B-7) after the 13th challenge, on which nasal hyperresponsiveness was present and absent, respectively. Biphasic nasal blockage and sneezing after the challenge in Group A-2 were more severe than those in Group A-0, while those of Group B-7 were almost the same as those of Group B-0. An anti-histaminic, mepyramine, inhibited sneezing but not the biphasic nasal blockage in Group B-7. A cysteinyl leukotriene (CysLT) antagonist, pranlukast, suppressed the late nasal blockage but not the early blockage and sneezing in Group B-7. In contrast, in Group A-2, mepyramine significantly attenuated not only sneezing but also the early nasal blockage. Pranlukast significantly inhibited both nasal blockage and sneezing in Group A-2. In conclusion, nasal hyperresponsiveness aggravated the antigen-induced nasal responses, to which histamine and CysLTs considerably contributed.

Markedly increased nasal blockage by intranasal leukotriene D4 in an experimental allergic rhinitis model: contribution of dilated mucosal blood vessels.

We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized-challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD4 (10 microl/nostril) at 10(-10) to 10(-6) M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dose-dependently suppressed by N(omega)-nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized-challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized-non-challenged group. The amount of NO2- and NO3- in nasal cavity lavage fluid after LTD4 instillation in the sensitized-challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.

Involvement of nitric oxide in pollen-induced biphasic nasal blockage in sensitised guinea pigs.

We have developed a reproducible allergic rhinitis model showing biphasic nasal blockage on repetitive inhalation challenge with Japanese cedar pollen in sensitised guinea pigs. The role of nitric oxide (NO) in inducing nasal blockage was evaluated with this model. N(omega)-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, intravenously administered before the challenge, significantly inhibited both early and late nasal blockage by approximately 80% and 50%, respectively. When L-NAME treatment was performed after the challenge, the late response was inhibited by approximately 70%. This inhibition was completely reversed by co-administration of L-arginine. However, aminoguanidine and L-N(6)-(1-iminoethyl)lysine, selective inhibitors of inducible NOS, negligibly influenced the degree of nasal blockage. Meanwhile, the alpha-adrenergic agonist, naphazoline, strongly suppressed both early and late nasal blockage. These results indicate that NO, likely produced by constitutive rather than inducible NOS, plays a major role in the occurrence of biphasic nasal blockage, primarily by inducing vasodilatation.

Development of pollen-induced allergic rhinitis with early and late phase nasal blockage in guinea pigs.

OBJECTIVE AND DESIGN: Development of nasal blockage and sneezing during repeated inhalation challenges with Japanese cedar pollens was evaluated in guinea pigs. SUBJECTS: Male Hartley guinea pigs. TREATMENT: Guinea pigs were sensitized by intranasal instillation of cedar pollen extracts + Al(OH)3 2 times a day for 7 days. The animal was then forced to inhale the pollens for challenge, which was restrictively trapped in the upper airways, once a week. METHODS: Change of specific airway resistance (sRaw), sneezing frequency, and titers of anaphylactic antibodies in the serum were measured after each of the 30 challenges. RESULTS: At the first challenge, no obvious increase in sRaw was observed. However, the second and third challenges to the animals caused modest biphasic elevations of sRaw, with peaks at the first and the fourth to sixth hour. At the fourth to tenth challenges, marked elevations of sRaw were observed. However, with repetition of the inhalation challenge, the early and the late responses became almost indistinguishable because of partial overlapping as the responses expanded. All guinea pigs sneezed immediately after each pollen inhalation challenge. Apparent increases of both circulating gamma1 and IgE antibodies were seen after the seventh challenge. CONCLUSIONS: These results indicate that the experimental allergic rhinitis established in the present study can be a valuable model for analyzing the pathogenesis of the disease and developing new therapeutic drugs.