piperidines and Hypersensitivity

Introduction: Allergic conditions frequently require treatment with antihistamines. First-generation antihistamines can potentially interfere with restful sleep, cause “morning after” effects, impair learning and memory, and reduce work efficiency. Second-generation antihistamines, such as bilastine, have been demonstrated to decrease allergy symptoms effectively without causing night-time sleep disturbances and related adverse events.\ \ Method: A real-world case project was developed to help optimize patient care by recognizing the role bilastine can play for allergic conditions where antihistamine treatment is needed. The presented real-world patient cases conducted by the panel members are supported with evidence from the literature, where available. Any discussion concerning off-label use should be considered an expert opinion only.\ \ Results: The real-world cases presented here used bilastine in conditions such as perennial and seasonal allergic rhinitis, chronic urticaria, as well as urticarial vasculitis and pruritus associated with inflammatory skin conditions. The treated patients were between 9 and 76-years old providing information on a full spectrum of patients that require treatment with antihistamines.\ \ Conclusions: The presented real-world cases using the second-generation antihistamine, bilastine, demonstrated favorable outcomes for the treated patients. While effectively relieving symptoms, the antihistamine was reported to be safe and well-tolerated.\ \ J Drugs Dermatol. 2020;19(2)145-154. doi:10.36849/JDD.2020.4835

Topics: Adolescent; Adult; Aged; Benzimidazoles; Child; Histamine Antagonists; Humans; Hypersensitivity; Middle Aged; Piperidines; Urticaria; Young Adult

Bilastine is a potent inhibitor of the histamine H1 receptor. It was recently approved in 28 countries of the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children older than 12 years. Data from preclinical studies confirmed its selectivity for the histamine H1 receptor over other receptors, and demonstrated antihistaminic and antiallergic properties in vivo. Studies in healthy volunteers and patients have shown that bilastine does not affect driving ability, cardiac conduction or alertness. Bilastine has demonstrated a good safety profile, without serious adverse effects or antimuscarinic effects in clinical trials. There were no significant changes in laboratory tests, electrocardiograms or vital signs. In clinical studies, oral treatment with bilastine 20 mg once daily improved allergic rhinitis with greater efficacy than placebo and comparable to cetirizine and desloratadine. Bilastine 20 mg was more effective than placebo and equivalent to levocetirizine in chronic urticaria, relieving symptoms, improving quality of life and controlling sleep disorders.

Topics: Adult; Animals; Anti-Allergic Agents; Benzimidazoles; Drug Interactions; Histamine H1 Antagonists, Non-Sedating; Humans; Hypersensitivity; Piperidines; Randomized Controlled Trials as Topic

Oral bepotastine is a second-generation histamine H(1) receptor antagonist that also suppresses some allergic inflammatory processes. Numerous short- and long-term clinical trials and surveillance studies have shown that twice-daily bepotastine is an effective and generally well tolerated antihistamine in the treatment of patients with allergic rhinitis, chronic urticaria or pruritus associated with skin conditions (eczema/dermatitis, prurigo or pruritus cutaneus). Bepotastine 20 mg/day was significantly more effective than terfenadine 120 mg/day in patients with perennial allergic rhinitis, as evaluated by the final global improvement rating and several other endpoints in a phase III trial. In phase III trials in patients with chronic urticaria, bepotastine 20 mg/day was more effective than placebo in improving levels of itching and eruption, and as effective as terfenadine 120 mg/day with regard to the final global improvement rating and other endpoints. In a noncomparative trial in patients with pruritus associated with skin diseases, the majority of bepotastine recipients in the overall population, as well as in the specific skin disease subgroups (eczema/dermatitis, prurigo or pruritus cutaneus), had a final global improvement rating of moderate or greater. Bepotastine was generally well tolerated in adult and paediatric patients with allergic conditions.

Topics: Administration, Oral; Anti-Allergic Agents; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Pruritus; Pyridines; Rhinitis, Allergic, Perennial; Urticaria

Topics: Amyloid beta-Peptides; Animals; Crystallography, X-Ray; Drug Design; Humans; Hypersensitivity; Inflammation; Intramolecular Oxidoreductases; Lipocalins; Molecular Chaperones; Muscular Dystrophies; Pain; Piperidines; Prostaglandin D2; Protein Conformation; Sleep

Ebastine is a second-generation antihistamine which undergoes transformation to its active metabolite, carebastine. Its antihistaminic and antiallergic effects have been demonstrated in in vitro and in vivo studies, in addition to data obtained from clinical trials. Patients with allergic rhinitis or chronic idiopathic urticaria experienced significant improvement in their symptoms with ebastine 10 or 20 mg once daily. Some studies in patients with seasonal allergic rhinitis (SAR) have indicated trends towards greater efficacy with the 20 mg than the 10 mg dose, although only 1 study has shown statistically significant benefits. In comparative trials in patients with SAR, ebastine 10 mg was as effective as most other second-generation antihistamines, including astemizole, azelastine, cetirizine, loratadine and terfenadine. Ebastine 20 mg/day was significantly superior to loratadine 10 mg/day in patients with SAR according to effects on secondary efficacy variables in comparative studies; 1 study found significantly greater changes from baseline in mean total symptom score with ebastine 20 mg (-43 vs -36% with loratadine, p = 0.045). In patients with perennial allergic rhinitis, ebastine 10 or 20 mg daily was significantly more effective than loratadine in reducing total symptom scores from baseline 1 comparative study. There have been no reports of serious adverse cardiac effects during ebastine therapy. Increases in corrected QT interval have been observed during clinical trials; however, these have not been considered clinically significant and were generally of similar magnitude to those seen with loratadine. The normal diurnal variation in QTc interval and the problems associated in correcting for changes in heart rate also complicate assessment of this issue. The incidence of adverse events during ebastine treatment is not significantly greater than that observed with placebo or other second-generation antihistamines.. Ebastine 10 mg daily is a well tolerated and effective treatment for allergic rhinitis and chronic idiopathic urticaria. At this dosage, it is as effective as the other second-generation antihistamines against which it has been compared. Ebastine 20 mg has similar tolerability to the 10 mg dose, and trends towards greater efficacy with the higher dose have been shown in some studies. Ebastine does not appear to be associated with any significant cardiac adverse events. Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria.

Topics: Animals; Anti-Allergic Agents; Butyrophenones; Humans; Hypersensitivity; Piperidines

Ebastine is a long-acting nonsedating second generation histamine H1 receptor antagonist which binds preferentially to peripheral H1 receptors in vivo. It has shown antihistamine and antiallergic activity in healthy volunteers and patients with allergies, and protected against histamine-induced bronchoconstriction in patients with asthma. Significant symptom improvement is observed in patients with seasonal or perennial allergic rhinitis or chronic idiopathic urticaria following administration of ebastine 10 mg/day, or 20 mg/day in severe rhinitis. In clinical trials, the efficacy of ebastine 10 or 20 mg/day was generally similar to standard dosages of terfenadine, cetirizine, astemizole and loratadine in patients with seasonal allergic rhinitis, astemizole, terfenadine and ketotifen in patients with chronic idiopathic urticaria, and ketotifen, terfenadine, chlorpheniramine and mequitazine in patients with perennial allergic rhinitis. The most frequent adverse events reported during ebastine therapy are drowsiness, headache and dry mouth, the incidence being similar to that reported in placebo recipients. Serious adverse cardiac events, observed on rare occasions with some other histamine H1 receptor antagonists, have not been reported with ebastine, and there has been no evidence of QTc interval prolongation related to ebastine therapy. Thus, once-daily ebastine offers an effective and well-tolerated alternative to other second generation antihistamines in current use for the first-line treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria.

Topics: Animals; Butyrophenones; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines

Mosquito bites usually cause wealing and delayed bite papules. Cetirizine decreases wealing, bite papules and pruritus but the effect of other antihistamines on mosquito bites is unknown. We studied the effect of ebastine in 30 mosquito bite-sensitive adult subjects. Ebastine 10 mg or 20 mg and placebo were given for 4 days in a cross-over fashion. Aedes aegypti bites were given on forearms. The size of the bite lesions and pruritus (visual analogue score) were measured at 15 min, 2, 6, and 24 h after the bites. Twenty-five subjects were evaluable in the study. At 15 min ebastine decreased significantly the size of the bite lesion (p = 0.0017) and pruritus (p<0.0001). The effects of 10 mg and 20 mg of ebastine were similar. No significant effect was found at 2, 6 or 24 h, but when the measurements at all four time points were compiled the size of the bite lesion and pruritus score decreased significantly. Sedation occurred during ebastine treatment in 6 (21%) and during placebo treatment in 2 (7%) subjects. The present results show that prophylactically given ebastine is effective against immediate mosquito bite symptoms.

Topics: Adult; Aedes; Animals; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Hypersensitivity; Insect Bites and Stings; Male; Middle Aged; Piperidines; Premedication

The peripheral H1-inhibiting effects of cetirizine 10 mg and ebastine 10 mg were compared at the skin level after single oral administration. The study was performed in 9 healthy subjects under double-blind randomized crossover conditions. Both drugs were significantly effective up to 24 h. The suppressive effect of cetirizine was significantly more rapid and more marked.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Butyrophenones; Capsules; Cetirizine; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Hydroxyzine; Hypersensitivity; Male; Multivariate Analysis; Piperidines; Placebos; Skin; Skin Tests; Time Factors

Terfenadine was evaluated for the relief of symptoms in patients with allergic pollinosis on a double-blind basis. Terfenadine 20 mg tid was as effective as Chlorpheniramine maleate 4 mg tid. Chlorpheniramine consistently showed a higher incidence of sedation than placebo. None of the terfenadein dosage schedules up to 200 mg tid caused sedation significantly different from that of placebo. Terfenadine appears to be the first antihistamine to lack significant central nervous system effects.

Topics: Benzhydryl Compounds; Chlorpheniramine; Clinical Trials as Topic; Double-Blind Method; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Placebos; Pollen; Terfenadine

To determine the efficacy of ketotifen as an oral anti-asthmatic agent, experimental and therapeutic long-term trials were carried out. Four models were used in the expirmental therapeutic trials nad the antihistaminic agent clemastine and disodium cromoglycate were used as comparative substances. It was demonstrated that ketotifen provides protection against bronchopasm induced by allergens, histamine and exercise, but not against that induced by acetylcholine. In the therapeutic long-term trials, the efficacy and tolerance of ketotifen were compared with that of clemastine and disodium cromoglycate for a period of 6 months. In another study ketotifen was administered for 1 year. Ketotifen proved very effective in decreasing the frequency and duration of asthmatic attacks, concomitant medication could be reduced and the patients improved subjectively. From these trials it can be concluded that ketotifen is a safe and effective oral anti-anaphylactic agent for use in the long-term treatment of bronchial asthma.

Topics: Acetylcholine; Aerosols; Asthma; Clemastine; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Forced Expiratory Volume; Histamine; Humans; Hypersensitivity; Physical Exertion; Piperidines; Thiophenes; Vital Capacity

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.

Topics: Adolescent; Adult; Aged; Animals; Asthma; Bone Marrow; Cell Differentiation; Chemokines, CC; Eosinophils; Female; Healthy Volunteers; Hematopoietic Stem Cells; Humans; Hypersensitivity; Inflammation; Lung; Macrophage Inflammatory Proteins; Male; Mice; Mice, Knockout; Middle Aged; Ovalbumin; Phenylurea Compounds; Piperidines; Receptors, CCR1; Signal Transduction; Young Adult

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in

Topics: Animals; Biomarkers, Tumor; Cimetidine; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypersensitivity; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Mast Cells; Mice; Phosphoric Diester Hydrolases; Piperidines; Promethazine; Rabbits; Rats; Skin Diseases; Spider Venoms; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1

To explore the effects of aloperine (ALO) on allergic airway inflammation, we investigated whether its mechanism is related with NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. Histochemical staining and inflammatory cell count were used to observe lung histopathological changes in mice. ELISA was used to detect the content of inflammatory cytokines and IgE in the mouse bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness (AHR) to inhale methacholine was measured by the plethysmography in conscious mice. Immunohistochemical method was used to detect the expression levels of Nrf2 and HO-1 in lung tissues. The key proteins of MAPK, NF-κB, and Nrf2/HO-1 in lung tissues were quantitatively analyzed by Western blot. Finally, the in vitro effect of ALO on the production of pro-inflammatory mediators and cytokines by lipopolysaccharide-stimulated RAW 264.7 cells was also evaluated. In the ovalbumin (OVA)-induced asthma mouse model, ALO reduced the exudation and infiltration of inflammatory cells and suppressed goblet cell hyperplasia. ALO-treated asthmatic mice also decreased the protein levels of interleukin (IL)-4, IL-5, IL-13, IFN-γ, and IgE in BALF and attenuated AHR. Furthermore, ALO inhibited the expression of key proteins of MAPK and NF-κB pathways, and increased the expression of Nrf2/HO-1 in OVA-challenged mice. Additional in vitro study has shown that ALO abrogates the macrophage production of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, IL-6, and IL-1β. Taken together, ALO attenuated allergic airway inflammation through regulating NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. The results suggest the utility of ALO as an anti-inflammatory agent for the treatment of asthma.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Heme Oxygenase-1; Humans; Hypersensitivity; Inflammation; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Piperidines; Quinolizidines; Respiratory System; Signal Transduction

Topics: Animals; Caspase 1; Cell Line; Cytokines; Deoxyribonucleases, Type II Site-Specific; Enzyme Activation; Histamine H2 Antagonists; Humans; Hypersensitivity; Inflammation Mediators; Male; Mast Cells; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines

Allergy is an abnormal immune response to an allergen. Type I hypersensitivity is an immunoglobulin (Ig) E-mediated allergic disorder. Fructus piperis is derived from the ripe fruit of the pepper, which is widely used as a spice in human diets and is also administered as a medicine in many countries. Piperine has been shown to have anti-oxidant, anti-depressant, anti-tumor, and anti-inflammatory activities. However, the effect of piperine on IgE-mediated allergic responses has not been reported. Here, the rat basophilic leukemia cells by membrane chromatography (RBL-2H3/CMC) coupled to high performance liquid chromatography/mass spectrometry (HPLC/MS) to discover and identify piperine can bind to RBL-2H3 cell membranes. Piperine inhibited the expression of cytokines, and the release of both β-hexosaminidase and histamine, which could be stimulated by antigen in RBL-2H3 mast cells. We found that the levels of intracellular Ca(2+) also decreased. Furthermore, RT-PCR showed that the mRNA expression levels of IL-4, IL-13, and TNF-α were significantly suppressed by piperine. The inhibitory effect of piperine on IgE-mediated degranulation and cytokine production by RBL-2H3 cells may be caused by the inhibition of IgE-mediated signaling pathways, including the phosphorylation of Lyn, p38, Erk, and Ras. In summary, piperine can inhibit antigen-induced allergic reactions that control degranulation.

Topics: Alkaloids; Animals; Benzodioxoles; beta-N-Acetylhexosaminidases; Calcium; Cell Degranulation; Cell Line, Tumor; Cytokines; Histamine; Hypersensitivity; Immunoglobulin E; Mast Cells; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Signal Transduction

This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and - challenged peri-bronchial vascular inflammation and remodeling in mice.. After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)- pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases-9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intraperitoneal OVA on day 1 and day 8, challenged with OVA nebulization and treated with KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NOmetabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar regions. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1.. Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.

Topics: Airway Remodeling; Animals; Bronchi; Cyclic GMP-Dependent Protein Kinases; Female; Guanylate Cyclase; Hypersensitivity; Intercellular Adhesion Molecule-1; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperidines; Pneumonia; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vascular Cell Adhesion Molecule-1; Xanthines

Cannabinoids have recently been identified as potential neuronal modulators of pruritic response, representing a potential target in the treatment of itch associated with a variety of pathophysiologic conditions. While the selective CB(1) receptor antagonist rimonabant is an established pruritic agent in both animal and clinical testing, its receptor mechanism of action and anatomical loci remain unclear.. The purpose of this study was to determine whether CB(1) receptor blockade is critical to rimonabant-induced scratching and to identify differences in scratching response based on different routes of administration. Furthermore, experiments were designed to elucidate any evidence as to whether rimonabant elicits scratching behavior through common immunologic hypersensitivity mechanisms.. Rimonabant was equally effective at producing scratching via intraperitoneal and local subcutaneous injection. This compound also produced an intense scratching response when administered intrathecally, but had no effects after intracerebroventricular administration. Repeated administration of rimonabant led to a decreased magnitude of scratching. While rimonabant-induced scratching was not attenuated either by pretreatment with the H(1) receptor antagonist loratadine or in mast cell-deficient mice, it lacked efficacy in CB(1) (-/-) mice.. Rimonabant is a potent and fully effective pruritogen when administered spinally or systemically and requires CB(1) receptors to induce scratching, suggesting an important spinal CB(1) receptor component of action. The lack of responsiveness to H(1) antagonism or mast cell deficiency supports previous findings that cannabinoids modulate itch through neuronal mechanisms, and not by traditional hypersensitivity activation.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Female; Histamine H1 Antagonists; Hypersensitivity; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Loratadine; Male; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Piperidines; Pruritus; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhanced resolution of eosinophilic inflammation by deliberate induction of eosinophil apoptosis using pharmacological agents has not been previously demonstrated. Here we investigated the effect of a novel cyclin-dependent kinase inhibitor drug, AT7519, on human and mouse eosinophil apoptosis and examined whether it could enhance the resolution of a murine model of eosinophil-dominant inflammation in vivo.. Eosinophils from blood of healthy donors were treated with AT7519 and apoptosis assessed morphologically and by flow-cytometric detection of annexin-V/propidium iodide staining. AT7519 induced eosinophil apoptosis in a concentration dependent manner. Therapeutic administration of AT7519 in eosinophil-dominant allergic inflammation was investigated using an established ovalbumin-sensitised mouse model of allergic pleurisy. Following ovalbumin challenge AT7519 was administered systemically at the peak of pleural inflammation and inflammatory cell infiltrate, apoptosis and evidence of macrophage phagocytosis of apoptotic eosinophils assessed at appropriate time points. Administration of AT7519 dramatically enhanced the resolution of allergic pleurisy via direct induction of eosinophil apoptosis without detriment to macrophage clearance of these cells. This enhanced resolution of inflammation was shown to be caspase-dependent as the effects of AT7519 were reduced by treatment with a broad spectrum caspase inhibitor (z-vad-fmk).. Our data show that AT7519 induces human eosinophil apoptosis and enhances the resolution of a murine model of allergic pleurisy by inducing caspase-dependent eosinophil apoptosis and enhancing macrophage ingestion of apoptotic eosinophils. These findings demonstrate the utility of cyclin-dependent kinase inhibitors such as AT7519 as potential therapeutic agents for the treatment of eosinophil dominant allergic disorders.

Topics: Animals; Apoptosis; Cells, Cultured; Eosinophils; Female; Flow Cytometry; Humans; Hypersensitivity; Leukocytes; Mice; Mice, Inbred BALB C; Piperidines; Pyrazoles

We set out to establish the in vivo histamine H(1) receptor antagonistic (antihistaminic) and antiallergic properties of bilastine.. In vivo antihistaminic activity experiments consisted of measurement of: inhibition of increase in capillary permeability and reduction in microvascular extravasation and bronchospasm in rats and guinea pigs induced by histamine and other inflammatory mediators; and protection against lethality induced by histamine and other inflammatory mediators in rats. In vivo antiallergic activity experiments consisted of measurement of passive and active cutaneous anaphylactic reactions as well as type III and type IV allergic reactions in sensitised rodents.. In the in vivo antihistaminic activity experiments, bilastine was shown to have a positive effect, similar to that of cetirizine and more potent than that of fexofenadine. The results of the in vivo antiallergic activity experiments showed that the properties of bilastine in this setting are similar to those observed for cetirizine and superior to fexofenadine in the model of passive cutaneous anaphylactic reaction. When active cutaneous anaphylactic reaction experiments were conducted, bilastine showed significant activity, less potent than that observed with cetirizine but superior to that of fexofenadine. Evaluation of the type III allergic reaction showed that of the antihistamines only bilastine was able to inhibit oedema in sensitised mice, although its effect in this respect was much less potent than that observed with dexamethasone. In terms of the type IV allergic reaction, neither bilastine, cetirizine nor fexofenadine significantly modified the effect caused by oxazolone.. The results of our in vivo preclinical studies corroborate those obtained from previously conducted in vitro experiments of bilastine, and provide evidence that bilastine possesses antihistaminic as well as antiallergic properties, with similar potency to cetirizine and superior potency to fexofenadine.

Topics: Animals; Benzimidazoles; Bradykinin; Bronchial Spasm; Capillary Permeability; Cetirizine; Dermatitis; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Antagonists; Hypersensitivity; Male; Mice; Molecular Structure; Oxazolone; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H1; Serotonin; Structure-Activity Relationship; Terfenadine; Time Factors

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.

Topics: Animals; Biological Availability; Caco-2 Cells; Calcium; Chemotaxis, Leukocyte; CHO Cells; Cricetinae; Cyclohexanes; Eosinophils; Female; Humans; Hypersensitivity; In Vitro Techniques; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Permeability; Phenylurea Compounds; Piperidines; Receptors, CCR3; Receptors, Chemokine; Stereoisomerism; Structure-Activity Relationship; Urea

The effect of the adenosine triphosphate sensitive K+ (K(ATP)) channel opener (3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-piperidinyl)-N-phenyl-1-benzopyran-6-sulphonamide (KCO912) on airway hyperresponsiveness induced using either a combination of allergen immunization (i.p.) followed by aerosol allergen challenge or immunization alone was investigated. Rabbits were immunized with Alternaria tenuis for the first 3 months of life. Airway responsiveness to histamine was measured 24 h before and after A. tenuis aerosol challenge. Fifteen minutes before the second challenge, rabbits were pre-treated with 10 microg of KCO912 or vehicle by inhalation. Allergen challenge induced airway hyperresponsiveness in vehicle pre-treated rabbits and pre-treatment with KCO912 abolished the airway hyperresponsiveness. The effect of KCO912 (10 microg) or vehicle on baseline airway hyperresponsiveness to the adenosine A(1) receptor agonist, cyclopentyl adenosine (CPA), induced by immunization with A. tenuis alone, was also assessed. Rabbits, immunized with A. tenuis alone, exhibited baseline airway hyperresponsiveness as demonstrated by an increase in airway resistance to CPA. Treatment with KCO912 did not alter the allergen-induced airway responsiveness to CPA. This study demonstrates that KCO912 can inhibit allergen-induced exacerbations of airway hyperresponsiveness.

Topics: Adenosine; Adenosine Triphosphate; Allergens; Alternaria; Animals; Antigens, Fungal; Benzopyrans; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Hypersensitivity; Piperidines; Potassium Channels; Rabbits

1. The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind-paw of mice sensitised to this antigen (50 microg OVA+5 mg Al(OH)(3), s.c., 14 days beforehand) was investigated. 2. Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2+/-14.6 s at 0.3 microg; 152.6+/-35.6 s at 1 microg) than nonsensitised animals (29.3+/-7.4 s at 1 microg). Nocifensive responses of sensitised mice to 0.3 microg OVA were inhibited by morphine (3 mg kg(-1), s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80). 3. Pretreatment with i.v. bosentan (mixed ET(A)/ET(B) receptor antagonist; 52 micromol kg(-1)) or A-122722.5 (selective ET(A) receptor antagonist; 6 micromol kg(-1)) reduced OVA-induced licking from 124.8+/-20.6 s to 45.7+/-13.0 s and 64.2+/-12.1 s, respectively, whereas A-192621.1 (selective ET(B) receptor antagonist; 25 micromol kg(-1)) enhanced them to 259.2+/-39.6 s. 4. Local i.pl. pretreatment with BQ-123 or BQ-788 (selective ET(A) or ET(B) receptor antagonists, respectively, each at 3 nmol) reduced OVA-induced licking (from 106.2+/-15.2 to 57.0+/-9.4 s and from 118.6+/-10.5 to 76.8+/-14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA-sensitised, but not in nonsensitised, animals. 5. Compound 48/80 (0.3 microg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 microg). Treatment with BQ-123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ-788 (3 nmol) was ineffective. 6. Thus, immune-mediated Type I hypersensitivity reactions elicit mast cell- and endothelin-dependent nociception in the mouse hind-paw, which are mediated locally by both ET(A) and ET(B) receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ET(A)/ET(B) or selective ET(A) receptor antagonists, but is sharply potentiated by systemic selective ET(B) receptor antagonist treatment. The apparently distinct roles played by ET(B) receptors in this phenomenon at local and other sites remain to be characterised.

Topics: Animals; Antigens; Bosentan; Dose-Response Relationship, Drug; Endothelins; Hyperalgesia; Hypersensitivity; Indicators and Reagents; Male; Mice; Oligopeptides; Ovalbumin; p-Methoxy-N-methylphenethylamine; Pain; Peptides, Cyclic; Piperidines; Sulfonamides; Viper Venoms

The role of substance P in adverse pulmonary reactions induced by an anticancer agent paclitaxel was investigated in rats and humans who undertook post-operative chemotherapy for ovarian cancer. In rats, paclitaxel caused a marked plasma extravasation and edema in lungs with a concomitant decrease in arterial partial oxygen pressure, which were reversed by an NK1 antagonist LY303870. Substance P level in rat plasma and bronchoalveolar lavage fluid increased after paclitaxel injection. In 13 patients, plasma level of substance P but not histamine significantly (P < 0.05) increased during paclitaxel infusion. Therefore, substance P rather than histamine may be involved in paclitaxel hypersensitivity.

Topics: Animals; Antineoplastic Agents; Bronchoalveolar Lavage Fluid; Female; Histamine; Humans; Hypersensitivity; Indoles; Male; Neurokinin-1 Receptor Antagonists; Ovarian Neoplasms; Paclitaxel; Piperidines; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Retrospective Studies; Substance P

We report a patient who presented with multiple small submucosal nodules with granulomatous inflammation in the minor salivary glands of the oral cavity. A 43-year-old woman presented with a 1-week history of multiple small submucosal nodules in her oral cavity after having taken medicine for abdominal pain. The patient did not have a history of fever, rectal bleeding, skin lesions or arthritis, but did have a history of drug allergy and bronchial asthma. Histopathological examination of the submucosal nodules showed sialadenitis with marked infiltration of lymphocytes, eosinophilic cells, macrophages and Langhans-type or foreign-body-type multinucleate giant cells. The macrophages tended to be aggregated and appeared to have caused immature granuloma formation without caseous necrosis. Degranulated eosinophilic cells were numerous. Sarcoidosis, Crohn's disease, tuberculosis and atypical mycobacterial infection were not identified by medical examination. Three weeks after discontinuing the medication the patient was seen again at a follow-up visit. Multiple submucosal small nodules and other symptoms were not evident at that time. This case report may represent a new entity of salivary gland disease that we tentatively refer to as 'allergic granulomatous sialadenitis'.

Topics: Abdominal Pain; Adult; Anti-Ulcer Agents; Diagnosis, Differential; Enzymes; Female; Granuloma; Humans; Hypersensitivity; Inflammation; Liver Diseases; Piperidines; Ranitidine; Salivary Glands, Minor; Sialadenitis

Mast cell activation, bronchoconstriction, inflammation and airway hyperreactivity are prominent features of non-atopic hypersensitivity reactions in mouse airways. We studied the role of tachykinin receptors in mice that were skin-sensitized with dinitrofluorobenzene (or vehicle) and challenged intranasally with dinitrobenzene sulfonic acid. Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge. In contrast, treatment with the tachykinin NK2 receptor antagonist SR48968 did not affect the dinitrofluorobenzene-induced hypersensitivity reaction. We have previously shown that mast cells play a crucial role in the development of non-atopic asthma. However, we did not observe an inhibitory effect of the tachykinin receptor antagonists or the genetic absence of tachykinin NK1 receptors on mast cell protease release. In conclusion, distal from mast cell activation, the tachykinin NK1 receptor is crucial for the infiltration of pulmonary neutrophils and the development of tracheal hyperreactivity in non-atopic asthma.

Topics: Administration, Intranasal; Airway Obstruction; Animals; Benzamides; Dinitrofluorobenzene; Hypersensitivity; In Vitro Techniques; Indoles; Inflammation; Isoindoles; Leukocytes; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Trachea

To compare antihistaminic and antiallergic activity of antihistaminic drugs of the latest generation (ebastin, cetirisine, fexofenadine, loratadine) and antihistaminic drugs of the first generation (clemastin) in the same patients with pollenosis.. Skin prick-titration with 10-dilution histamine and specific allergen, provocative nasal titration with 2-dilution histamine and allergen before and after a single intake of H1-antagonists were made in 30 patients in stable clinical remission of pollenosis during maximal antihistamine activity of the above drugs.. Systemic administration of the known H1-antagonists suppresses histamine sensitivity of both skin and nasal mucosa in the same degree. Drugs with more potent antihistaminic activity (fexofenadin and cetirisin) inhibited allergen-induced reactions more effectively. The order of the tested drugs by suppression of allergen-provoked skin and nasal reactions (by lowering antiallergic activity) is the following: fexofenadin and cetirisin > ebastin and loratadin > clemastin.. The above drugs of the latest generation seem to posses antiallergic activity not only due to antihistaminic effect but also due to other mechanisms. Different suppressive action of H1-antagonists reflects also individual sensitivity to different drugs. The factor of individual sensitivity of the patients to a pharmacological action of the drug may be crucial in the selection of the most effective medicine for each patient. This is confirmed by the data of individual sensitivity of the patient to antihistaminic and antiallergic action of H1-antagonists. The illustrated method may be helpful for individual selection of H1-antagonists for treatment of patients with allergic diseases.

Topics: Adult; Anti-Allergic Agents; Butyrophenones; Cetirizine; Clemastine; Female; Histamine H1 Antagonists; Humans; Hypersensitivity; Loratadine; Male; Piperidines; Pollen; Terfenadine

Topics: Anti-Inflammatory Agents; Butyrophenones; Cells, Cultured; Cetirizine; Chymases; Eosinophils; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity; Intercellular Adhesion Molecule-1; Interleukin-3; Interleukin-8; Loratadine; Mast Cells; Piperidines; Potassium Channel Blockers; Potassium Channels; Prostaglandin D2; Pyridines; Recombinant Fusion Proteins; Recombinant Proteins; Serine Endopeptidases; Terfenadine; Time Factors; Tryptases

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

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

MDL 105,212 has been identified as a potent, nonpeptide NK-1 and NK-2 receptor antagonist that inhibits effects of substance P and neurokinin A in vitro and in vivo (Kudlacz et al., 1996). In the present study, the compound inhibited capsaicin-induced respiratory effects after p.o. administration (5-50 mg/kg) to conscious guinea pigs; nearly complete inhibition of dyspnea and cough was observed 1 hr after 50 mg/kg p.o., and efficacy persisted for approximately 11 hr. MDL 105,212 reduced pulmonary insufflation pressure and microvascular leakage in ovalbumin-sensitized animals in response to antigen-challenge relative to vehicle-treated animals. Attenuation of early-phase allergic responses may result from MDL 105,212 inhibition of antigen-induced histamine release from sensitized guinea pig lung observed in vitro. Airway hyperresponsiveness to methacholine occurred 24 hr after antigen-challenge in ovalbuminsensitized guinea pigs; this effect was inhibited by pretreatment with MDL 105,212 (50 mg/kg p.o.) 1 hr before ovalbumin exposure without affecting increased bronchoalveolar lavage eosinophil numbers. These data suggest that sensory neuropeptides play a role in some aspects of allergic airway responses and that tachykinin receptor antagonists may be useful in treatment of atopic respiratory diseases.

Topics: Animals; Bronchoconstriction; Capsaicin; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Release; Hypersensitivity; Male; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Pyrrolidines; Receptors, Neurokinin-2; Respiration

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

1. Using a guinea-pig model of allergic asthma, in which the animals display early (0-5 h) and late phase (8-23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2. Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3. After the early response, there was no change in cardiac muscarinic M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 autoreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine-induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Topics: Administration, Inhalation; Allergens; Animals; Asthma; Benzodiazepinones; Bronchial Hyperreactivity; Diamines; Disease Models, Animal; Electric Stimulation; Female; Gallamine Triethiodide; Guinea Pigs; Heart; Histamine; Hypersensitivity; In Vitro Techniques; Male; Muscarinic Antagonists; Muscle, Smooth; Neuromuscular Junction; Parasympatholytics; Pilocarpine; Piperidines; Pirenzepine; Receptors, Muscarinic; Trachea

The anti-allergic activity of ebastine, a novel antihistamine, was assessed in comparison with several antihistamines. 1) Orally administered ebastine dose-dependently inhibited 7-day homologous passive cutaneous anaphylaxis (PCA), experimental allergic rhinitis and experimental asthma in guinea pigs or rats (ED50-values were 2.17, 0.29 and 0.35 mg/kg, respectively); and its anti-allergic activity was more potent than those of terfenadine and mequitazine. Moreover, its PCA-inhibitory activity was still observed 24 hr after the administration. 2) Orally administered ebastine also inhibited histamine-induced skin reaction in rats (ED50: 1.10 mg/kg). 3) In isolated guinea pig trachea, ebastine had no effect on histamine-induced contraction, but carebastine, a main metabolite of ebastine, inhibited this contraction (IC50: 0.12 microM). 4) Carebastine (30-100 microM) suppressed the histamine release from rat peritoneal mast cells and human basophils. 5) Ebastine at a high oral dose showed slight inhibition of the specific binding of 3H-mepyramine to the histamine H1-receptor in rat brain. This binding-inhibitory activity of ebastine was little more potent than that of terfenadine, but much less potent than those of mequitazine and ketotifen. These results indicated that ebastine has potent and long acting anti-allergic activity with few side effects based on the antihistaminic activity in the central nervous system. Furthermore, it was suggested that these effects of ebastine are due to the action of a main metabolite, carebastine.

Topics: Administration, Oral; Animals; Butyrophenones; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; In Vitro Techniques; Male; Phenothiazines; Piperidines; Pyrilamine; Rats; Rats, Wistar; Terfenadine

A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.

Topics: Animals; Carboxylic Acids; Central Nervous System Diseases; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity; In Vitro Techniques; Male; Mice; Mice, Inbred Strains; Piperazines; Piperidines; Rats; Rats, Wistar

The antihistaminic effect of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]ethoxy] benzoic acid maleate (ZCR-2060), a newly synthesized antiallergic agent, was investigated in both in vitro and in vivo studies. ZCR-2060 clearly antagonized histamine-induced contraction of isolated guinea pig ileum and trachea. In contrast, carbachol-, BaCl2- and 5-hydroxytryptamine-induced contractions of isolated guinea pig ileum were slightly inhibited by higher concentrations of ZCR-2060. 3H-Mepyramine specific binding to membranes from guinea pig lung and brain were markedly inhibited by ZCR-2060 in a concentration-dependent fashion. In the in vitro studies, the antihistaminic effect of ZCR-2060 was greater than those of cetirizine and terfenadine, but was less than that of ketotifen. In the in vivo studies, ZCR-2060 significantly inhibited the histamine-induced cutaneous reaction in rats, when administered orally 1 hr before the histamine injection. Moreover, ZCR-2060 has a long-lasting antihistaminic effect. In the in vivo studies, the antihistaminic effect of ZCR-2060 was found to be greater than that of cetirizine and terfenadine, and it was the same as that of ketotifen. Thiopental-induced sleep and spontaneous ambulatory activity in mice, however, were unaffected by ZCR-2060 at higher doses. These results indicate that ZCR-2060 has a potent, selective and long acting histamine H1-receptor antagonistic action without causing any unwanted CNS side effect.

Topics: Animals; Benzoates; Brain; Dermatitis, Contact; Exploratory Behavior; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; In Vitro Techniques; Lung; Male; Membranes; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Muscle Contraction; Muscle, Smooth; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Sleep; Thiopental

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

A new series of piperidineacrylate derivatives was prepared and evaluated for antiallergic activity. Most of the compounds showed potent activities in the rat passive cutaneous anaphylaxis (PCA) assay. In particular, ethyl 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidineacrylate (1a) was more potent than oxatomide and terfenadine in this assay, and was selected for further study. Some pharmacological properties of 1a are presented.

Topics: Acrylates; Animals; Guinea Pigs; Hypersensitivity; Magnetic Resonance Spectroscopy; Male; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Rats, Sprague-Dawley

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

A new antiallergic agent with thromboxane A2 antagonistic activity, KW4099, was synthesized by a simple method. Its optical resolution was accomplished with the use of (+)- or (-)-2,2'-(1,1'-binaphthyl)phosphoric acid as a resolving agent.

Topics: Dibenzoxepins; Hypersensitivity; Piperidines; Stereoisomerism; Thromboxane A2

AHR-13268D (4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1- piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED50s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED50 = 0.29%. In the rat passivefoot anaphylaxis test. AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED50s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity. In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC50 = 0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC50 approximately 300 microM). AHR-13268B was bioavailable (approximately 88%) from capsules or from oral solutions.

Topics: Aerosols; Anaphylaxis; Animals; Antigens; Ascaris; Benzoates; Biological Availability; Electroencephalography; Female; Food Hypersensitivity; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; Immunoglobulin E; Lung; Male; Piperidines; Rats; Rats, Inbred Strains; Skin Tests

High-performance liquid chromatographic (HPLC) methods were developed for the analysis of two compounds in a series of new antiallergenic agents, 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone and its active acidic metabolite in plasma. The methods utilize ultraviolet or fluorescence detection, liquid-liquid extraction or solid-phase extraction and reversed-phase HPLC. The drugs were quantitated in samples from bioavailability studies performed in dogs. Calibrations were in the ng/ml concentration range for both compounds in plasma.

Topics: Animals; Biological Availability; Chromatography, High Pressure Liquid; Dogs; Humans; Hypersensitivity; Microchemistry; Piperidines; Quality Control

A series of 4-(diarylhydroxymethyl)-1-[3-(aryloxy)propyl]piperidines was synthesized and evaluated for antiallergy activity. Several analogues had potent activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity. In particular 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone (1, AHR-5333) was more potent than oxatomide and terfenadine in this assay.

Topics: Anaphylaxis; Animals; Benzhydryl Compounds; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Guinea Pigs; Hypersensitivity; Male; Passive Cutaneous Anaphylaxis; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Terfenadine

A new series of 3-heteroarylacrylamides 2 and 4 was prepared and the inhibitory activities against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase (5-LO) were tested. Most of the compounds exhibited an anti-PCA activity superior to or equivalent to ketotifen and had a 5-LO inhibitory activity. The 3-heteroarylacrylamide derivatives including 3-(3-pyridyl)acrylamides represent a new structural class of compound that exhibits not only an in vivo anti-PCA activity but also an in vitro 5-LO inhibitory activity.

Topics: Acrylamides; Animals; Heterocyclic Compounds; Hypersensitivity; Passive Cutaneous Anaphylaxis; Piperazines; Piperidines; Rats; Structure-Activity Relationship

Whole body extracts of imported fire ants (IFAWBE) are the only reagents currently available for diagnosis and immunotherapy of patients with anaphylaxis to these Hymenoptera. To characterize better IFAWBE of the species Solenopsis invicta, we evaluated the sera of 29 patients with systemic or large local reactions to imported fire ant (IFA) stings. Forty-eight percent (14/29) of these sting-sensitive patients were IFAWBE RAST positive (greater than or equal to 6% binding of total radioactivity added). With a pool of sera with an initial IFAWBE-RAST value of 16.2% binding, we evaluated RAST inhibition by IFA venom (IFAV), IFAWBE, and the venom component, transpiperidine. Maximum RAST inhibition obtained was 84% with 300 micrograms/ml of IFAV, 95% with 5 mg/ml of protein IFAWBE, and insignificant with undiluted transpiperdine. We conclude that IFAWBE contains large quantities of immunoreactive venom components other than transpiperidine and that the allergenicity of IFAWBE and venom resides in the small amount of protein present in IFAV.

Topics: Adult; Animals; Ant Venoms; Ants; Arthropod Venoms; Binding Sites, Antibody; Binding, Competitive; Female; Humans; Hypersensitivity; Immunoglobulin E; Male; Piperidines; Radioallergosorbent Test; Radioimmunoassay; Tissue Extracts

Topics: Anaphylaxis; Animals; Arthus Reaction; Histamine H1 Antagonists; Hypersensitivity; Lipoxygenase Inhibitors; Piperidines

Effects of 2-methyl-3-piperidino-beta-propionaphtone hydrochloride (KZ-111), 3-isobutyryl-2-isopropylpyrazolo-[1, 5-a]pyridine (KC-404) and FPL-55712 on experimental allergic reactions were investigated. Homologous passive cutaneous anaphylaxis (PCA) in rats was clearly inhibited by oral and intravenous administrations of KC-404 and KZ-111. FPL-55712 inhibited the PCA reaction only by intravenous injections, but not by oral administration. Maximum inhibition of the PCA reaction by KC-404 and KZ-111 was obtained by administration of these agents 2 hr prior to challenge. The immunological release of histamine from sensitized rat peritoneal mast cells was inhibited by KZ-111 at a concentration of 10(-4) g/ml. KC-404 and FPL-55712 did not inhibit the immunological release of histamine. All three compounds had no effect on the release of histamine from rat peritoneal mast cells and on the generation of SRS from rat polymorphonuclear leucocytes by calcium ionophore A23187. KC-404 and KZ-111 produced a downward displacement of the maximum without a parallel shift in LTD4 induced concentration-response curves of guinea pig ileal and tracheal smooth muscle at concentrations between 10(-6) and 10(-5) g/ml. FPL-55712 at a concentration of 10(-6) g/ml produced a parallel shift of LTD4 induced concentration-response curves to the right in both smooth muscle preparations. The 50% inhibitory concentration to the contraction by LTD4 of each of the three compounds is lower than those of other agonists, histamine, PGF2 alpha and BaCl2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Asthma; Chromones; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; In Vitro Techniques; Male; Muscle Contraction; Passive Cutaneous Anaphylaxis; Piperidines; Pyridines; Rats; Rats, Inbred Strains; SRS-A

A study was carried out in 30 hospitalized diabetics suffering from allergic conditions to assess the effects of ketotifen on various laboratory parameters. Ten of the patients were on diet only, 10 on biguanides plus diet, and 10 on sulphonylureas plus diet. Most were overweight. Patients received 4 mg ketotifen daily for 14 days. Oral glucose tolerance tests and other laboratory investigations were carried out before and 7 and 14 days after the start of ketotifen administration. There were no pathological changes measured in blood levels of sodium, potassium, SGPT, SGOT, alkaline phosphatase, cholesterol, triglycerides, creatinine, uric acid, non-protein nitrogen, haemoglobin, haematocrit, white cell count and differential, and platelet count. Glucose tolerance improved somewhat during the repeated oral glucose tolerance test, and there were no significant changes either in the immunoreactive insulin or growth hormone levels during the test. In the diabetics on biguanides, initial blood pressures were raised both in the lying and standing positions. The levels decreased significantly to normal during ketotifen administration. The results indicate that ketotifen can be used without problems in the treatment of diabetics with allergic disorders and its suggested that a long-term study with ketotifen in diabetic patients could be useful.

Topics: Biguanides; Blood; Diabetes Complications; Diabetes Mellitus; Drug Interactions; Female; Glucose Tolerance Test; Histamine H1 Antagonists; Humans; Hypersensitivity; Ketotifen; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Thiophenes

Topics: Asthma; Cromolyn Sodium; Humans; Hypersensitivity; Ketotifen; Piperidines; Thiophenes

It is now apparent that venom and venom components of the Hymenoptera superfamilies of Apida (honeybee) and Vespida (wasps, yellow jackets, and hornets) are becoming increasingly important in the diagnosis and treatment of hypersensitivity reactions. Stings from fire ants (superfamily Formicidae, family Myrmicinae) have also been recognized as causes of systemic reactions in man. Fire ant venom is unique in its composition, consisting mainly of alkaloids in aqueous suspension with only trace amounts of protein. This study compares the skin reactivity of fire ant venom and synthesized alkaloid components with the whole body extract (WBE) of fire ants and other Hymenoptera. The venom as well as the WBE of fire ants was found useful for skin test diagnosis of sensitive individuals. There appear to be cross-reactive or shared antigens between fire ant venom, WBE, and WBE of other Hymenoptera. Successful passive transfer of skin reactivity to nonsensitive individuals was accomplished with sera from sensitive individuals. Loss of this passive transfer by heating sera at 56 degrees C for 4 hr is evidence in favor of IgE mediating the positive skin test to the venom.

Topics: Animals; Ants; Humans; Hypersensitivity; Immunization, Passive; Insect Bites and Stings; Piperidines; Skin Tests; Tissue Extracts; Venoms

Topics: Adult; Child; Child, Preschool; Delirium; Exanthema; Female; Gels; Hallucinations; Histamine H1 Antagonists; Humans; Hypersensitivity; Male; Ointments; Piperidines; Psychoses, Substance-Induced

1. The neuromuscular blocking activities of AH 5183 (2-(4-phenylpiperidino) cyclohexanol) and its N-methyl quaternary analogue (AH 5954) were compared in rapidly stimulated nerve-skeletal muscle preparations of the rat, chicken and cat.2. The evidence indicated that in isolated preparations the neuromuscular block produced by both AH 5183 and AH 5954 was primarily pre-junctional in origin. That produced by AH 5954 was readily reversible either by washing the tissue or by reducing the stimulation frequency, whereas that produced by AH 5183 was difficult to reverse in these ways.3. Low doses of AH 5954 sensitized the rat hemidiaphragm preparation to the neuromuscular blocking action of choline. The neuromuscular block produced by choline was reversible by tetraethylammonium but not by neostigmine. This suggested that the blocking action of choline is at least partly pre-junctional in nature.4. In anaesthetized cats AH 5954 possessed a biphasic neuromuscular blocking action. The initial phase was rapid in onset, suggestive of a post-junctional action, whereas the second phase was prolonged and reversible by choline, suggestive of a prejunctional inhibitory action on the choline transport mechanism. AH 5183 produced no initial blocking action and was irreversible by choline.5. Both AH 5183 and AH 5954 possessed local anaesthetic and alpha-adrenoceptor blocking actions. These actions and the neuromuscular blocking action were affected to different degrees by quaternization, suggesting that the three main actions of the two drugs are independent.6. It was concluded that AH 5954 and AH 5183 act at different pre-junctional sites at the neuromuscular junction, AH 5954 acting extraneuronally by inhibiting choline transport and AH 5183 intraneuronally at the level of the synaptic vesicle membrane.

Topics: Adrenergic alpha-Antagonists; Alcohols; Anesthesia, Local; Animals; Cats; Chickens; Choline; Cyclohexanes; Electric Stimulation; Hypersensitivity; In Vitro Techniques; Muscles; Neostigmine; Neuromuscular Depolarizing Agents; Neuromuscular Junction; Piperidines; Quaternary Ammonium Compounds; Rabbits; Rats; Tetraethylammonium Compounds

Topics: Dermatitis, Contact; Drug Eruptions; Female; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; Male; Piperidines; Urticaria

Topics: Anti-Allergic Agents; Asthma; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Thioxanthenes

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Hypersensitivity; Piperidines

Topics: Anti-Allergic Agents; Humans; Hypersensitivity; Immune System Diseases; Piperidines

Topics: Anti-Allergic Agents; Desensitization, Immunologic; Histamine H1 Antagonists; Hypersensitivity; Piperidines; Tartrates

Topics: Anti-Allergic Agents; Dermatitis, Atopic; Eczema; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Pruritus; Skin Diseases; Tartrates

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Hypersensitivity; Piperidines

Topics: Hypersensitivity; Piperidines; Tripelennamine

Topics: Hypersensitivity; Immune System Diseases; Piperidines; Tripelennamine

Topics: Histamine H1 Antagonists; Hypersensitivity; Immune System Diseases; Piperidines