piperidines and Eosinophilia

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

The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP).. An eosinophilic CRSwNP model was induced using 4-week-old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA-3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL-4, IL-5, IL-12, and interferon-γ, were measured using enzyme-linked immunosorbent assays (ELISA).. Topical tofacitinib administration significantly reduced the number of polyp-like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA-3. Lastly, tofacitinib significantly decreased IL-4 and IL-5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon-γ.. Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs.. N/A. Laryngoscope, 131:E1400-E1407, 2021.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Eosinophils; Humans; Janus Kinases; Male; Mice; Nasal Mucosa; Nasal Polyps; Piperidines; Pyrimidines; Rhinitis; Signal Transduction; Sinusitis; STAT Transcription Factors; Triamcinolone Acetonide

Topics: Aged; Benzimidazoles; Eosinophilia; Histamine Antagonists; Humans; Male; Piperidines; Skin; Skin Diseases

Topics: Adenine; Eosinophilia; Humans; Immunoglobulin E; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

We present a case report of an early-onset drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) induced by vemurafenib (BRAF inhibitor) in a middle-age man affected by a metastatic, BRAF mutant melanoma who was started on first-line metastatic treatment with vemurafenib and cobimetinib.After initiating the treatment, the patient presented an extensive cutaneous rash with eosinophilia and renal impairment. Due the constellation of signs and symptoms, a diagnosis of DRESS syndrome was made which strongly contraindicated the reintroduction of vemurafenib due to its hypersensibility reaction. Thus, vemurafenib was stopped immediately, and we started corticoid treatment with clinical improvement.Due to the contraindication to start vemurafenib again, after multidisciplinary view of the case and having balanced the risks and benefits, we successfully performed a switch to another BRAF inhibitor in a progressively ascending pattern, without any skin toxicity and with a good response of the metastatic melanoma.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Azetidines; Drug Hypersensitivity Syndrome; Eosinophilia; Exanthema; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome; Vemurafenib

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

We recently reported that airway hyperresponsiveness (AHR) induced by a 6-h exposure to sulfuric acid (H(2)SO(4)) was inhibited by either the neurokinin (NK)-1 receptor antagonist, FK888, or the NK-2 receptor antagonist, SR48968, when administered immediately before the exposure. The aims of this study were to determine whether these antagonists have any therapeutic efficiency against AHR after long-term H(2)SO(4) inhalation and to elucidate the mechanisms in ovalbumin sensitized guinea pigs.. Specific airway resistance (sRaw), AHR, and BAL fluid were analyzed after an 8-week exposure to H(2)SO(4) aerosol (82 mg/m(3), pH 1.7, 40 mOsm) or hypotonic saline solution (pH 5.9, 40 mOsm) as a control. The H(2)SO(4) group then received a 2-week treatment with FK888, SR48968, or vehicle.. The AHR and the eosinophil count in BAL fluid were significantly increased in the H(2)SO(4) group compared to control animals, while sRaw was significantly elevated in both groups after the 8-week exposure. Treatment with both FK888 and SR48968 significantly reduced the AHR and tended to inhibit eosinophilia in BAL fluid, but sRaw did not change. The degree of AHR improvement with SR48968 was much larger than with FK888.. Our results show that both NK-1 and NK-2 receptor antagonists inhibited long-term H(2)SO(4)-induced AHR in sensitized guinea pigs, and the effect was much greater with an NK-2 antagonist. We suggest that NK-1 or NK-2 antagonism might partially inhibit the H(2)SO(4)-induced influx of eosinophils into the lung.

Topics: Airway Resistance; Animals; Benzamides; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Dipeptides; Eosinophilia; Guinea Pigs; Indoles; Leukocyte Count; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Sulfuric Acids; Weather

Topics: Allopurinol; Eosinophilia; Female; Folliculitis; Gout Suppressants; Humans; Middle Aged; Piperidines; Suppuration

1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 microg kg(-1), i.v.), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg(-1), i.p.), SR140333 (1 mg kg(-1), s.c.) or CP96345 (15 mg kg(-1), i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 micromol kg(-1), i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg(-1), i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Electric Stimulation; Eosinophilia; Guinea Pigs; Lung; Neurokinin A; Neurokinin-1 Receptor Antagonists; Ovalbumin; Peptide Fragments; Pilocarpine; Piperidines; Quinuclidines; Receptor, Muscarinic M2; Receptors, Muscarinic; Receptors, Tachykinin; Specific Pathogen-Free Organisms; Substance P; Trachea; Vagus Nerve

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o. ) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (Rrs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3-10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.

Topics: Animals; Anti-Allergic Agents; Asthma; Bronchoconstriction; Disease Models, Animal; Eosinophilia; Eosinophils; Female; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity; Ketotifen; Male; Passive Cutaneous Anaphylaxis; Piperidines; Platelet Activating Factor; Pyridines; Rats; Rats, Wistar

Eosinophilic inflammations has been recognized as a characteristic of allergic diseases. The effect of betotastine besilate (betotastine, CAS 125602-71-3, TAU-284), a new potent antihistamine drug, on the model of eosinophilic inflammation which shows eosinophil infiltration into the airway and peripheral blood eosinophilia was examined. The mice sensitized with ovalbumin (OVA) were challenged with aerosolized OVA 12 days after the first sensitization. One day after the challenge, the numbers of leukocytes and eosinophils in bronchoalveolar lavage fluid (BALF) were increased and the increase lasted up to 10 days after the challenge. Additionally, peripheral blood eosinophilia was also observed and the change peaked on the third day after the challenge. Betotastine (10 mg/kg, b.i.d., p.o.) inhibited the increase of eosinophil number in BALF on the third day after the challenge and that in peripheral blood from 1 to 3 days after the challenge. These results suggest that betotastine is an effective drug against eosinophilic inflammation of allergic diseases.

Topics: Animals; Anti-Allergic Agents; Blood Cell Count; Bronchoalveolar Lavage Fluid; Eosinophilia; Eosinophils; Leukocyte Count; Lung; Male; Mice; Ovalbumin; Piperidines; Pyridines; Respiratory Hypersensitivity