piperidines and Dermatitis--Contact

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

Topics: Administration, Oral; Adult; Affect; Attention; Benzimidazoles; Cross-Over Studies; Dermatitis, Contact; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Hydroxyzine; Injections, Intradermal; Intradermal Tests; Male; Perception; Piperidines; Psychomotor Performance; Reaction Time; Reference Values; Young Adult

Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed.. This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire.. Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier.. Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

Topics: Adult; Butyrophenones; Chemistry, Pharmaceutical; Dermatitis, Contact; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Pain Measurement; Patient Acceptance of Health Care; Piperidines; Skin; Tablets; Treatment Outcome

Topics: Adult; Alopecia Areata; Dermatitis, Contact; Hair; Humans; Male; Piperidines; Pyrimidines; Pyrroles; Silicone Gels; Treatment Outcome

Contact hypersensitivity (CHS) is a type of cutaneous inflammation that is exacerbated by neurogenic factors. Both mu- and kappa-opioids enhance CHS to a greater extent in females than males. It was hypothesized that potentiated neurokinin 1 (NK1) receptor signaling following opioid treatment accounts for sex differences in the magnitude of CHS. Following morphine or spiradoline treatment the NK1 receptor antagonist SR140,333 significantly attenuated the magnitude of CHS in females but not males. By contrast, the NK2 antagonist SR48968 had no effect on morphine modulation of CHS. Taken together, these data indicate that NK1 receptor signaling is a key mediator of sex differences in opioid-induced enhancement of CHS.

Topics: Analgesics, Opioid; Animals; Benzamides; Dermatitis, Contact; Drug Interactions; Female; Male; Morphine; Neurokinin-1 Receptor Antagonists; Piperidines; Pyrrolidines; Quinuclidines; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sex Characteristics; Signal Transduction; Specific Pathogen-Free Organisms; Substance P

The ability of azaspiranes to modulate the acute inflammatory response in models of skin inflammation was examined.. The in vivo experiments involved the use of 5-6 age-matched male Balb/c inbred mice (22-25 g) per treatment group and a control group of 8-10 animals. In vitro mechanistic studies used RBL-1 and U937 cells lines and freshly isolated human monocytes.. Arachidonic acid (AA) (2 mg/20 microl in acetone) or PMA (phorbol myristate acetate) (4 microg/20 microl) were applied topically. SK&F 106615 and SK&F 106610 were administered topically either dissolved in acetone or dimethylacetamide just after the application of the irritant. Isolated cells were treated with the compounds dissolved in DMSO.. The thickness and influx of neutrophils into the treated ears was measured as was the effects of the azaspiranes on 5-lipoxygenase activity, cyclooxygenase activity, prostaglandin and leukotriene synthesis, and the activation of the transcription factor NF-kappaB.. SK&F 106615 and SK&F 106610 significantly reduced inflammation in the AA- and PMA-induced inflammation models (p < 0.05) with ED50's of 179 and 120 mg/ear for edema and myeloperoxidase, respectively. The compounds did not inhibit eicosanoid biosynthesis, have a direct effect on 5-lipoxygenase or cyclooxygenase enzymes, or inhibit NF-kappaB.. The potent anti-inflammatory and immunomodulatory activities of the azaspiranes observed in these and other studies appear to be mediated by a novel mechanism.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Cell Line; Cyclooxygenase 1; Dermatitis, Contact; Dinoprostone; Ear; Edema; Humans; Immunosuppressive Agents; Isoenzymes; Leukotriene B4; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Monocytes; NF-kappa B; Peroxidase; Piperidines; Prostaglandin-Endoperoxide Synthases; Spiro Compounds; Tetradecanoylphorbol Acetate

This study addresses the hypothesis that the early symptoms of chemically induced skin irritation are neurally mediated. Several approaches were used to affect nerve transmission in adult Balb/c female mice. These included general anesthesia (i.e., sodium pentobarbital), systemic capsaicin treatment, and pretreatment with specific pharmacological antagonists of the neuropeptides substance P (SP) and neurokinin A (NKA). After these treatments, a strongly irritating dose of dinitrofluorobenzene (DNFB) was applied to the ear and its swelling was measured over several postexposure times as an index of tissue irritation. Ear swelling in Nembutal (30 mg/kg)-anesthetized mice was depressed 62 and 76% at 4 and 24 hr postexposure compared to DNFB-treated unanesthetized animals measured at the same time points. Multiple injections of capsaicin (cumulative dose 30 mg/kg) depressed DNFB-ear swelling relative to non-capsaicin, DNFB-treated controls by 15, 40 (ip), and 44 and 43% (sc) at 4 and 24 hr postexposure, respectively. In mice exposed to acute or multiple injections of the SP antagonist CP-96,345 before DNFB application, ear swelling was depressed (relative to DNFB-treated animals) by 64 and 36% (acute, sc, 10 mg/kg) and 91 and 88% (multiple, ip, cumulative 35 mg/kg) at 0.5 and 1 hr postexposure, respectively. Mice exposed to the NKA antagonist, SR 48968, alone and in combination with the SP antagonist CP-96,345 were also examined after DNFB application. Ear swelling was diminished in mice pretreated with the NKA antagonist (1.0 mg/kg) by 17, 24, 34, and 40% at 0.5, 1, 4, and 24 hr postexposure. When used in combination with the SP antagonist, DNFB-induced ear swelling was reduced by 95% compared to unantagonized, DNFB-exposed mice at the 0.5- and 1-hr time points and remained significantly depressed by 33 and 46% at 4 and 24 hr postexposure. Taken in concert, these data suggest that neuropeptides, especially the tachykinins SP and NKA, modulate the early stages of chemically induced skin irritation.

Topics: Administration, Cutaneous; Animals; Benzamides; Biphenyl Compounds; Capsaicin; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Dose-Response Relationship, Drug; Ear, External; Female; Irritants; Mice; Mice, Inbred BALB C; Neurokinin A; Neuropeptides; Piperidines; Skin; Substance P; Synaptic Transmission

The antiallergic action of 2-[2-[4-(diphenylmethyl)-1-piperadinyl] ethoxy] benzoic acid maleate (ZCR-2060) was investigated on allergic cutaneous reactions and nasal vascular permeability in mice and rats. ZCR-2060 markedly inhibited immediate allergic cutaneous reactions, including passive cutaneous anaphylaxis (PCA) in rats and mice; histamine-, compound 48/80- and calcium ionophore A 23187-induced cutaneous reactions in rats; and biphasic skin reactions mediated by monoclonal IgE antibody and epicutaneous challenge with antigen in mice, but did not affect 5-hydroxytryptamine-induced cutaneous reaction in rats. The antigen-induced nasal vascular permeability increase in actively and passively sensitized rats and histamine-induced nasal vascular permeability increase in rats (allergic rhinitis model) were clearly inhibited in a dose-dependent fashion by ZCR-2060. Moreover, ZCR-2060 significantly inhibited antigen-induced anaphylactic histamine release from rat peritoneal mast cells and carrageenin-induced paw edema in rats. These results suggest that ZCR-2060 has antiallergic effects on allergic cutaneous reactions and experimental rhinitis, probably due to histamine H1-receptor blockage and the inhibition of histamine release.

Topics: Animals; Antibodies, Monoclonal; Ascaris; Benzoates; Capillary Permeability; Carrageenan; Dermatitis, Contact; Edema; Female; Histamine Release; Immunoglobulin E; Male; Mast Cells; Mice; Mice, Inbred BALB C; Nasal Mucosa; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rhinitis, Allergic, Seasonal

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

A topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear surface induces nonallergic inflammation, i.e. ear edema. Oral administration of 3-30 mg/kg of 1-([5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadieno yl]-aminoethyl)-4-diphenylmethoxypiperidine (TMK 688), a potent 5-lipoxygenase inhibitor with antihistamine activity, inhibited TPA-induced ear edema in a dose-dependent manner. TMK688 inhibited not only 5-lipoxygenase activity but also epidermal cyclooxygenase activity. 1-([5'-(3"-methoxy-4"-hydroxyphenyl)-2',4'-pentadienoyl]-aminoe thy l)- 4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688, had more potent 5-lipoxygenase inhibitory activity but less potent cyclooxygenase inhibitory activity than TMK688. Oral administration of TMK688 (30 mg/kg) markedly inhibited TPA-stimulated LTB4 formation in mouse skin but TPA-stimulated PGE2 formation only slightly. Our experimental results suggest that both cyclooxygenase inhibitory activity and antihistamine activity of TMK688 are not essential to its anti-inflammatory action. The anti-inflammatory effect of orally administered TMK688 is due most probably to the anti-5-lipoxygenase activity of TMK688 and its active metabolite TMK777.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Cyclooxygenase Inhibitors; Dermatitis, Contact; Dinoprostone; Dose-Response Relationship, Drug; Female; Leukotriene B4; Lipoxygenase Inhibitors; Mice; Piperidines; Tetradecanoylphorbol Acetate

Topics: Administration, Topical; Anesthetics; Anti-Inflammatory Agents; Benzocaine; Dermatitis; Dermatitis, Contact; Humans; Hydrocortisone; Hydroxybenzoates; Lidocaine; Morpholines; Ointments; Piperidines; Safety

Topics: Adult; Dermatitis, Atopic; Dermatitis, Contact; Humans; Male; Piperidines

Topics: Adult; Burns, Chemical; Dermatitis, Contact; Dermatitis, Occupational; Ethyl Chloride; Humans; Male; Necrosis; Penile Diseases; Piperidines; Scrotum; Sulfides

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

Topics: Dermatitis, Contact; Piperidines