Blood Histamine Levels Research Articles

Circulating basophils in patients with type IIb autoimmune chronic spontaneous urticaria have a lower histamine content

AbstractBackgroundPatients suffering from chronic spontaneous urticaria (CSU) are typically classified as type I or type IIb autoimmune CSU, but further patient stratification is hindered by the lack of biomarkers.ObjectivesWe investigated whether the histamine content of individual basophils differ between patient subtypes in CSU to evaluate its potential as a biomarker.MethodsA total of 101 patients diagnosed with CSU were included in the study. The histamine content per circulating basophil was derived from the basophil count in peripheral blood and levels of total cellular blood histamine. These measures, together with results from the serum‐induced basophil histamine release assay (s‐BHRA), were correlated to information on demographics, clinical characteristics, patient reported outcomes and laboratory analyses.ResultsThe histamine content per basophil was significantly different between s‐BHRA positive and ‐negative patients (0.175 vs. 1.40 pg/cell, p < 0.001) and showed a significant negative correlation to the degree of basophil activation in s‐BHRA (ρ = −0.209, p = 0.036). Furthermore, the amount of histamine in individual basophils was found to be significantly correlated with levels of total cellular blood histamine (ρ = 0.376, p < 0.001), eosinophil counts (ρ = 0.205, p = 0.040), levels of thyroid stimulating hormone (ρ = −0.246, p = 0.014) and titre of antibodies against thyroid peroxidase (ρ = −0.216, p = 0.031) and thyroglobulin (ρ = −0.203, p = 0.044).ConclusionsLow content of intracellular histamine in circulating basophils is associated with known markers of type IIb autoimmune CSU. Further studies are required to assess whether the amount of histamine in basophils can be used to monitor or predict response to treatment in patients.

Successful treatment of JAK1-associated inflammatory disease

Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. Amolecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. Avariant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Severe perioperative anaphylaxis: Incidence in a tertiary hospital in Spain over a 20-year period. A historical cohort study.

To assess the incidence of severe perioperative anaphylaxis, the mechanisms involved, the value of laboratory/skin tests, and the most effective treatments. A historical cohort study conducted in a tertiary public hospital in Spain. Patients that had undergone anaesthesia during the 20-year period were included. In these patients, 66 cases of severe anaphylaxis were found. In patients with suspicion of severe anaphylaxis, levels of blood histamine at less than 15min and serum tryptase at 2, 6, and 24h following the reaction were determined. Skin and specific IgE tests were performed between 4 and 8 weeks later. Over the 20-year period, 288 594 anaesthetic procedures were performed. We observed cases of 66 severe anaphylaxis reaction (59% men; age, 60.8±17.3 years. Symptoms observed were cardiovascular (86%), respiratory (73%), and mucocutaneous (56%). Elevated serum tryptase levels were associated with degree of severity at 2 (P<.0001) and 6h (P=.026) and were highest in IgE-mediated reactions (P=.020). All patients required treatment, and 3 events were fatal. In 84.8% of patients, skin and/or specific IgE tests were positive for antibiotics (35.8%), non-steroidal anti-inflammatory drugs (23.1%), neuromuscular blocking agents (15.4%) and latex (15.4%). The incidence of severe anaphylaxis in our hospital was 1 in 4.373 anaesthetic procedures, with a death rate of 4.5%. All cases required treatment. Serum tryptase was a good predictor of reaction severity. The most frequent causative agents were antibiotics, non-steroidal anti-inflammatory drugs, neuromuscular blocking agents and latex.

LYTIC COCKTAIL ATTENUATES CATECHOLAMINE SURGE AFTER SEVERE BURNS BY BLOCKING HISTAMINE H1 RECEPTOR/PKA/CREB/TYROSINE HYDROXYLASE SIGNALING IN CHROMAFFIN CELLS.

Severe burns develop a catecholamine surge, inducing severe damage to the organism, raising the possibility of multisystem organ failure, and even death. The mechanisms of catecholamine surge have not been fully elucidated, and few strategies are generally acceptable to reduce catecholamine surge postburn. Thus, it is valuable to investigate the underlying mechanisms of catecholamine surge postburn to develop targeted interventions to attenuate it. We have found that the lytic cocktail alleviates the surge of catecholamine and organ injury after severe burn; however, the underlying mechanisms were still unclear. Moreover, the lytic cocktail has side effects, such as significant arterial hypotension and breathing depression, limiting its clinical application. This study aims to investigate the therapeutic mechanism of the lytic cocktail in regulating catecholamine levels postburn. We find that promethazine, a classic histamine H1 receptor blocker and a component of the lytic cocktail, can effectively reduce catecholamine surge and organ injury postburn. Our study confirms that blood histamine levels increase after severe burns. We find that histamine can amplify the catecholamine surge by elevating tyrosine hydroxylase expression and catecholamine synthesis in chromaffin cells through the histamine H1 receptor/Protein Kinase A /cAMP-response element binding protein signaling pathway. In summary, for the first time, we find that histamine plays a vital role in catecholamine surge postburn. We also confirm that the lytic cocktail effectively alleviates catecholamine surge and organ injury postburn through promethazine.

Anafilaxia perioperatoria severa: Incidencia en un hospital terciario en España durante 20 años. Estudio de cohorte histórico

ObjectiveTo assess the incidence of severe perioperative anaphylaxis, the mechanisms involved, the value of laboratory/skin tests, and the most effective treatments. MethodsA historical cohort study conducted in a tertiary public hospital in Spain. Patients that had undergone anaesthesia during the 20-year period were included. In these patients, 66 cases of severe anaphylaxis were found. In patients with suspicion of severe anaphylaxis, levels of blood histamine at less than 15 minutes and serum tryptase at 2, 6, and 24 hours following the reaction were determined. Skin and specific IgE tests were performed between 4 and 8 weeks later. ResultsOver the 20-year period, 288 594 anaesthetic procedures were performed. We observed cases of 66 severe anaphylaxis reaction (59% men; age, 60.8 ± 17.3 years. Symptoms observed were cardiovascular (86%), respiratory (73%), and mucocutaneous (56%). Elevated serum tryptase levels were associated with degree of severity at 2 (p < 0.0001) and 6 hours (p = 0.026) and were highest in IgE-mediated reactions (p = 0.020). All patients required treatment, and 3 events were fatal.In 84.8% of patients, skin and/or specific IgE tests were positive for antibiotics (35.8%), non-steroidal anti-inflammatory drugs (23.1%), neuromuscular blocking agents (15.4%) and latex (15.4%). ConclusionsThe incidence of severe anaphylaxis in our hospital was 1 in 4 373 anaesthetic procedures, with a death rate of 4.5%. All cases required treatment. Serum tryptase was a good predictor of reaction severity. The most frequent causative agents were antibiotics, non-steroidal anti-inflammatory drugs, neuromuscular blocking agents and latex.

Fullerene nanoparticles for the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a long-term, recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting. Repairing the barrier dysfunction of the colon and reducing intestinal inflammation are considered key objectives to cure UC. Here we demonstrate a novel therapeutic strategy based on a C60 fullerene suspension (C60FS) to treat dinitrobenzene sulfonic acid-induced UC in an animal model. C60FS can repair the barrier dysfunction of UC and effectively promote the healing of ulcers; it also manifests better treatment effects compared with mesalazine enema. C60FS can reduce the numbers of basophils in the blood of UC rats and mast cells in the colorectal tissue, thereby effectively alleviating inflammation. The expression of H1R, H4R, and VEGFR2 receptors in colorectal tissues is inhibited by C60FS, and the levels of histamine and prostaglandin in the rat blood are reduced. This work presents a reliable strategy based on fullerene to cure UC and provides a novel guide for UC treatment.

Inhibitory effects of catechin isolated from Acacia catechu on ovalbumin induced allergic asthma model

Purpose Polyphenols possess anti-allergic activities. Catechin is one of the polyphenols that are abundantly present in the Acacia catechu. In this study, the authors investigated the effect of catechin isolated from A. catechu in an experimental mouse model of ovalbumin (OVA)-induced allergic asthma. Design/methodology/approach Catechin was isolated from A. catechu, and phytochemical analysis was carried out by ultraviolet visible and thin-layer chromatography (TLC), high pressure thin-layer chromatography was used for the determination of an amount of catechin present. In a first set of an experiment, the authors have carried out dose-dependent evaluation of catechin on histamine synthesis in normal rats. In another study, allergic asthma was induced in BALB/c mice by intraperitoneal injection of 50 mg OVA dissolved in 4 mg aluminum hydroxide dissolved in 0.2 ml saline on Days 0 and 14. Catechin was given orally at the dose of 100 mg/kg, once a day from Day 1 to Day 35 and after which various respiratory parameters such as tidal volume, respiratory rate and airflow rate, biochemical parameters such as histamine release from mast cells, bronchoalveolar (BAL) lavage fluid analysis and histopathology of lungs were carried out. Findings Catechin showed significant (p &lt; 0.05) improvement in respiratory parameters such as tidal volume, respiratory rate and airflow rate, as well as biochemical and hematological parameters such as blood histamine, serum bicarbonate and nitric oxide levels as compared to the disease control group. The treatment also showed inhibitory effects on histamine synthesis in rat peritoneal as well as BAL mast cells. Also, a significant (p &lt; 0.05) improvement in lung histopathology was observed with catechin. Originality/value From the present study, the authors can conclude that catechin exhibited potent anti-allergic activity by inhibition of histamine synthesis by inhibition of histidine decarboxylase enzyme. The study suggests that catechin has therapeutic potential for the treatment of allergic inflammatory disease in humans.

Modulation of allergic responses by mitochondrial STAT3 inhibitors.

Recently, we have shown that mast cell mitochondrial STAT3 could serve as a new target for the regulation of the allergic response as it plays an essential role in immunologically mediated degranulation of mast cells. In the present work, we explored how two recently developed mitochondrial STAT3 inhibitors (Mitocur-1 and Mitocur-3) modulate the allergic response. Experiments were performed both invitro in cultured human/mouse mast cells and with rat basophilic leukemia (RBL) cells and also invivo in mice. The effect of mitochondrial STAT3 inhibition on mast cell function was determined via checking degranulation and several cytokines secretion levels. Here, we show that treatment of rodent and human cultured mast cells with low concentrations of mitochondrial STAT3 inhibitors had no effect on STAT3 target gene expression. However, these inhibitors caused a significant reduction in mast cell exocytosis and cytokine release, due to a decrease in OXPHOS activity and STAT3 serine 727 phosphorylation. It was also observed in an OVA mouse model of allergic asthma that one of the inhibitors used significantly reduced eosinophilia and neutrophilia compared to the control mice group. Furthermore, it was observed that treatment with this inhibitor resulted in a significant reduction in blood histamine levels in mice after IgE-Ag challenge. The present data strongly suggest that the development of mitochondrial STAT3 inhibitors could serve as a potential treatment for allergy-associated diseases.

Immunological evaluation of Gum kondagogu (Cochlospermum gossypium): A tree gum with potential applications in food and pharma industry

Gum kondagogu (KG) is a natural polysaccharide derived as an exudate from the bark of the tree Cochlospermum gossypium (Bixaceae family). The toxicological assessment of KG established that this gum to be nontoxic, while the immunological response to KG was yet to be explored, as the protein content of KG has been reported to be 5.0–6.3% (w/w). The current investigation evaluates immunogenic aspects of three grades of gum (KG-I, II and III) in a rodent model. The immunogenicity of KG was evaluated in comparison with ovalbumin, which is a known food allergen. As a measure of immunological response, delayed-type hypersensitivity (DTH) reaction, blood histamine levels and antibody (IgG) response were assessed. The DTH reaction of KG-III gum was found to be similar to that of ovalbumin, as measured by mean skin fold thickness of each ear sensitised with test and reference immunogens. KG-I and II did not elicit any DTH reaction. Statistically significant difference in histamine and IgG levels were observed between the control (PBS), ovalbumin and KG-III rat groups (p < 0.05). The experimental observations showed similar immune response between KG-III and ovalbumin in experimental groups sensitised with respective immunogens. Immune response to KG-III gum could be attributed to the impurities originating from the bark during the process of exudation. As there is no statistical significant immunological response to KG-I and II, these grades of gum may find potential applications in food and pharmaceutical industry.

和漢薬「小青竜湯」の鼻アレルギーに対する効果 : 第1報「小青竜湯」投与による血中IgE, ヒスタミンおよびcAMPの変動

和漢薬「小青竜湯」の鼻アレルギーに対する効果 : 第1報「小青竜湯」投与による血中IgE, ヒスタミンおよびcAMPの変動

Identification of a Neuronal Receptor Controlling Anaphylaxis.

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

아토피 피부염의 동물 모델인 NC/Nga Mice에서의 우묵사스레피의 면역조절 효과

본 연구에서는 1-chloro-2,4-dinitrobenzene (DNCB)로 유도한 아토피 피부염 동물 모델인 NC/Nga mice에 대한 Eurya emarginata 에탄올 추출물(EE-70E)의 면역 조절 효능을 확인하고자 하였다. DNCB를 5주간 도포하여 유도한 아토피 동물 모델인 NC/Nga mice에 EE-70E를 3주간 경구 투여한 후 scratching behavior 및 clinical skin severity score, 혈청 면역지표(IL-4, IL-13, IL-17, histamine, IgG1, IgE)의 농도를 측정하였다. DNCB를 도포하여 3주동안 경구 투여한 결과, EE-70E의 200 및 400mg/kg 용량에서 clinical skin severity의 감소, scratching behavior의 감소 및 혈중 IL-4 및 IL-13, IL-17, histamine, IgE의 농도가 대조군과 비교하여 유의성 있게 농도의존적으로 감소하는 결과가 관찰되었다(p<0.05). EE-70E의 경구투여는 NC/Nga mice 아토피 피부염 동물모델에서 면역조절 작용 및 아토피 피부염의 개선 효과를 가짐을 나타냈다. 따라서 EE-70E은 아토피 피부염에 유용한 천연자원으로서 기대된다. In this study, a test for the immunity control effect by ethanolic extract of Eurya emarginata (EE-70E) on NC/Nga mice as the models for atopic dermatitis was conducted with the following results. Atopic dermatitis in NC/Nga mice was induced by repeated application of 1-chloro-2,4-dinitrobenzene (DNCB) for 5 weeks. Mice were orally administered EE-70E or terfenadine, positive control for 3 weeks. Scratching behavior, clinical skin severity, and the levels of IL-4, L-13, IL-17, total serum IgG1, and total serum IgE were measured. The oral administration with EE-70E doses of 200 or 400 mg/kg significantly decreased scratching behavior scores and clinical skin severity score in a dose-dependent manner (p<0.05). The administration of EE-70E at 400 mg/kg significantly decreased cytokines within the blood serum, that is, IL-4, L-13, and IL-17 compared to the control group (p<0.05). The level of blood histamine was statistically significantly decreased. Administration of EE-70E at 400 mg/kg significantly decreased the levels of total serum IgE (p<0.05). The above results indicated that EE-70E was effective in improving the symptoms of atopic dermatitis through various immunity control mechanisms.

Anti-nuclear antibodies positive serum from systemic lupus erythematosus patients promotes cardiovascular manifestations and the presence of human antibody in the brain.

Background:Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies (ANAs) in the serum of patients. These antibodies may cross over into the brain resulting in the development of neuropsychiatric symptoms and result in abnormal pathology in other organs such as the heart and kidneys.Objective:The objective of this study was to determine if SLE pathology could be detected in the hearts and brains of rats injected with positive human ANA serum.Materials and Methods:Lewis rats (n = 31) were selected for this study due to documented research already performed with this strain in the investigation of serum sickness, encephalitis and autoimmune related carditis. Rats were injected once a week with either ANA positive or negative control serum or saline. Hearts were examined for initial signs of heart disease including the presence of lipid deposits, vegetation, increased ventricular thickness and a change in heart weight. Brains were examined for the presence of human antibody and necrotic lesions. Animals were observed for outward signs of neuropathy as well. Blood samples were taken in order to determine final circulating concentrations of IgG and monitor histamine levels.Results:Animals injected with ANA were significantly higher for lipid deposits in the heart and an increased ventricular thickness was noted. One animal even displayed Libman-Sacks endocarditis. Brains were positive for the presence of human IgG and diffuse internal lesions occurred in 80% of the ANA positive serum injected animals examined. Blood histamine levels were not significantly different, but actually lower than controls by the end of the experiment.Conclusion:Since human antibodies were detected in the brain, further studies will have to identify which antibody cross reactions are occurring within the brain, examine cell infiltration as well as characterize the antibodies associated with more destructive consequences such as lesion formation.

Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice

Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis.

Possible Role of Mast Cells and Neuropeptides in the Recovery Process of Dextran Sulfate Sodium-induced Colitis in Rats

To clarify the role of mast cells and neuropeptides substance P (SP), somatostatin (SS), and vasoactive intestinal peptide (VIP) in dextran sulfate sodium (DSS)-induced colitis in rats. Experimental colitis was induced in Sprague-Dawley rats (180-200 g, n=20) by oral ingestion of 4% (w/v) DSS in drinking water for 7 days. Control rats (n=5) drank water and were sacrificed on day 0. Mast cell number, histamine levels in whole blood and tissue, tissue levels of SP, SS and, VIP in the distal colon of the rats were measured on day 8, day 13, and day 18 of experimentation. Oral administration of 4% DSS solution for 7 days resulted in surface epithelial loss and crypt loss in the distal colon. Mast cell count increased on day 8 (1.75±1.09/mm vs. 0.38±0.24/mm, P<0.05) and day 13 (1.55±1.01/mm vs. 0.38±0.24/mm, P<0.05) after DSS treatment. Whole blood histamine levels were increased on day 8 (266.93±35.62 ng/mL vs. 76.87±32.28 ng/mL, P<0.01) and gradually decreased by day 13 and day 18 after DSS treatment. Histamine levels in the distal colon were decreased on day 8 (1.77±0.65 ng/mg vs. 3.06±0.87 ng/mg, P<0.05) and recovered to control levels by day 13 after DSS treatment. SP level in the distal colon gradually increased and were raised significantly by day 13 (8777.14±3056.14 pg/mL vs. 4739.66±3299.81 pg/mL, P<0.05) after DSS treatment. SS and VIP levels in the distal colon were not changed. Mast cell degranulation followed by histamine release may play an important role in the pathogenesis of colitis induced by DSS. SP may be a significant substance in the progression of inflammation and the recovery process of DSS-induced colitis.

생쥐에서 ovalbumin과 디젤배기가스 입자로 유도된 기도염증과 기도 과민성에 대한 반하 물 추출물의 항천식 효과

Objectives : Asthma is a chronic, complex respiratory disease, caused by airway obstruction, airway eosinophilic inflammation(AEI), and airway hyperresponsiveness(AHR). This study was conducted to determine whether oral administration of crude water extracts of Pinellia ternate Breitenbach(PTB) has an antiasthmatic potential in the treatment of asthma in mice. Methods : Asthmatic AEI and AHR were induced by systemic sensitization to ovalbumin(OVA) by intratracheal instillation with 0.1 mg/mL suspension of diesel exhaust particles(DEP) once a week for 10 weeks in BALB/c mice. Crude PTB water extracts(50 mg/kg and 200 mg/kg) were orally administered 5 times a week for 10 weeks. Cyclosporin(10 mg/kg) was administrered the same manner as a positive control. Results : Long-term treatment with crude PTB water extracts suppressed the infiltration of inflammatory cells, including eosinophils, into airways from blood. It also reduced asthmatic AEI and AHR by attenuating the increase in the levels of cytokines such as interleukin(IL)-4, IL-5 and IL-13 in bronchoalveolar lavage fluid(BALF), as well as the levels of histamine and OVA-specific IgE in blood. However, the effect of crude PTB water extracts(200 mg/kg) was not likely to be stronger than that of cyclosporin(10 mg/kg). Conclusion : These results suggest that crude PTB water extracts have inhibitory effects on AEI and AHR in a mouse model of asthma and may act as a potential Th2 cytokine antagonist, and have a therapeutic effect on allergic asthma.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.

Environmental and occupational respiratory diseases – 1055. CD23, TH1/TH2 cytokines in children with bronchial asthma, bronchiolitis and bronchial pneumonia

Results Serum sCD23 was significantly increased (p<0.01) in bronchial asthma (1209.8 ± 68.01 pg/mL), bronchiolitis (1455.52 ± 146.92 pg/mL) and bronchial pneumonia (1406.35 ± 98.26 pg/mL) when compared to controls (691.5 ± 74.94 pg/mL). Serum IgE and blood histamine levels were increased significantly (P<0.05) and IFN-g (Th1 cytokine) was significantly lower (P<0.01) in both bronchial asthma and bronchiolitis than in controls where as IFN-g (Th1 cytokine) increased significantly in bronchial pneumonia compared to the other three groups.

Mechanisims of asthma and allergic disease – 1083. CD23, Total IgE and Th1/Th2 cytokines in asthma patients

Results Serum sCD23 mean±SE was significantly increased (p<0.05) in asthma (581.16 ± 35.72 pg/mL), when compared to controls (429.49 ± 31.29 pg/mL). Similarly serum IgE mean±SE (154.03 ± 33.24) and blood histamine (46.7 ± 7.23) levels were increased significantly (P<0.01) in patients with asthma; while IFN-g, a Th1 cytokine, was significantly lower (P<0.05) in asthma (3.28 ± 0.65) than in controls (9.45 ± 1.58). Pearson’s correlation coefficient showed a significant (P<0.05, r=0.50) association between sCD23, IL-5 with serum IgE concentration, however, IFNg was not correlated with IgE. Serum IL-4 and CD23 in buccal mucosa and stool samples were below detectable levels.

Association of bovine Toll-like receptor 4 with tick infestation rates and blood histamine concentration

We investigated a possible association between bovine Toll-like receptor 4 (TLR4) and resistance to tick infestation in 103 cattle, including BMY cattle (1/2 Brahman, 1/4 Murray Grey, and 1/4 Yunnan Yellow cattle), Brahman, and Red Angus grazing on improved pasture. The tick infestation weight and number of Rhipicephalus microplus and the blood histamine concentration were measured and compared with those of 32 Chinese Holsteins and 30 Simmentals. A 228-bp fragment was amplified and sequenced to analyze the polymorphisms of the TLR4 gene. After SSCP and sequencing analysis, 4 SNPs, i.e., 535(A>C), 546(T>C), 605(T>A), and 618(G>C), were identified, corresponding to GenBank accession Nos. AY297041 and NW_003104150; the latter two SNPs caused Leu→Gln and Gln→His substitutions, respectively. Genotype AA was completely predominant in the Chinese Holstein and Simmental; genotypes AA and AB were detected in Red Angus, while genotypes AA, AB, BB, and BC were detected in Brahman and in BMY cattle. A negative correlation was identified between blood histamine concentration and number of tick infestation; in BMY cattle this negative association was significant. The tick infestation in cattle with genotype BB was significantly lower than in those with genotype AA. Blood histamine concentration in cattle with genotype BB was significantly higher than in those with genotype AA. The TLR4 gene mutation could affect the blood histamine level and activate the immune reaction after tick infestation. Allele B has potential as a molecular marker for tick-resistance originated from Zebu cattle for use in cattle breeding programs.