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Keith J. Simons - One of the best experts on this subject based on the ideXlab platform.
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skin concentrations of H1 Receptor Antagonists
The Journal of Allergy and Clinical Immunology, 2001Co-Authors: Estelle F R Simons, Norman A Silver, Keith J. SimonsAbstract:Abstract Background: H 1 -Receptor Antagonists are widely used in the treatment of allergic skin disorders. Objective: We sought to evaluate the extent of fexofenadine and diphenhydramine distribution into the skin concomitantly with their peripheral H 1 -Receptor antagonist activity. Methods: In a prospective, randomized, double-blind, parallel-group study, 7 men received 120 mg of fexofenadine, and 7 received 50 mg of diphenhydramine. Before dosing; at 1, 3, 6, 9, and 24 hours after the first dose; and at 168 hours (steady-state), 12 hours after the seventh and last daily dose, blood samples and skin punch biopsy specimens were obtained, and epicutaneous tests with histamine phosphate, 1 mg/mL, were performed. Results: Fexofenadine penetrated the skin to a significantly greater extent than diphenhydramine at 6, 9, 24, and 168 hours ( P ≤ .05). Maximum skin/plasma ratios of both the H 1 -Antagonists (41.3 ± 7.8 for fexofenadine and 8.1 ± 4.4 for diphenhydramine) were obtained at 24 hours. Fexofenadine also produced significantly greater suppression of wheals at 3, 6, and 9 hours and of flares at 3, 6, 9, and 168 hours compared with diphenhydramine ( P ≤ .05). Conclusion: In disorders in which the presence and the effects of H 1 -Receptor Antagonists in the skin are clinically relevant, our results support the use of fexofenadine and indicate the need to re-examine the role of diphenhydramine. (J Allergy Clin Immunol 2001;107:526-30.)
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Clinical pharmacology of the H1-Receptor Antagonists cetirizine and loratadine in children.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2000Co-Authors: F. E. R. Simons, L Johnston, Keith J. SimonsAbstract:H1-Receptor Antagonists are widely used in children but are not as well-studied in children as they are in adults. Our objective was to determine the onset and duration of action and the relative potency of the H1-Receptor Antagonists cetirizine and loratadine in children. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of cetirizine and loratadine using suppression of the histamine-induced wheal and flare as the primary outcome. In 15 allergic children, mean age 9 years, compared with baseline, cetirizine (10 mg) suppressed the wheals and flares significantly from 0.25 to 24 h, achieving nearly 100% of flare suppression from 2 to 24 h, inclusive, and loratadine (10 mg) suppressed the wheals and flares significantly from 0.75 to 24 h, inclusive. Cetirizine suppressed the wheals and flares significantly more than loratadine from 0.25 to 1 h, inclusive, and at 0.5, 1, 2, 3, 5, 6, 7, and 24 h, respectively. Placebo also suppressed the wheal and flare significantly at some assessment times. Cetirizine and loratadine both have excellent antihistaminic activity in children, with a rapid onset of action and a 24-h duration of action in this population.
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central nervous system effects of H1 Receptor Antagonists in the elderly
Annals of Allergy Asthma & Immunology, 1999Co-Authors: Estelle F R Simons, T. G. Fraser, John Maher, Neelan Pillay, Keith J. SimonsAbstract:Background The potential adverse central nervous system effects of H 1 -Receptor Antagonists have not been optimally studied in the elderly. Objective We hypothesized that newer H 1 -Receptor Antagonists such as cetirizine and loratadine would cause less central nervous system dysfunction than the older H 1 -Receptor Antagonists diphenhydramine and chlorpheniramine in this population, as they do in younger subjects. Methods We performed a randomized, double-blind, single-dose, placebo-controlled, 5-way crossover study in 15 healthy elderly subjects (mean age 71 ± SD 5 years). On study days at least 1 week apart, they received cetirizine 10 mg, loratadine 10 mg, diphenhydramine 50 mg, chlorpheniramine 8 mg, or placebo. Outcome measures, recorded before and 2 to 2.5 hours after dosing were latency of the P300 event-related potential in which increased latency reflects a decreased rate of cognitive processing, visual analogue scale for subjective somnolence, and histamine skin tests for measurement of peripheral H 1 -blockade. Results The changes in P300 following each treatment yielded variances that were not equal ( P > .05), precluding usual statistical analysis of the means. These variances were ranked: chlorpheniramine > diphenhydramine > loratadine > placebo > cetirizine. The rank of mean differences in the visual analogue scale increase from pre-dose baseline was: diphenhydramine > chlorpheniramine > cetirizine > loratadine > placebo. All H 1 -Receptor Antagonists suppressed the histamine-induced wheal and flare significantly compared to baseline. Conclusion In the elderly, the new H 1 -Receptor Antagonists cetirizine and loratadine are less likely to cause adverse central nervous system effects than the old H 1 -Antagonists chlorpheniramine or diphenhydramine, but this requires confirmation using additional objective tests of central nervous system function.
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Clinical pharmacology of new histamine H1 Receptor Antagonists.
Clinical pharmacokinetics, 1999Co-Authors: Keith J. SimonsAbstract:The recently introduced H1 Receptor Antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 Antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2,β) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2,β values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2,β of ∼7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of ∼15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2,β of ∼14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2,β of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2,β of ∼13 hours and duration of action of at least 24 hours. Most orally administered new H1 Receptor Antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 Antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 Receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 Antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 Antagonists with optimal effectiveness and safety.
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Comparison of the central nervous system effects produced by six H1-Receptor Antagonists.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 1996Co-Authors: F. E. R. Simons, T. G. Fraser, J. D. Reggin, Keith J. SimonsAbstract:Summary Background A comprehensive comparative study of the central nervous system (CNS) properties of newer H1-Receptor Antagonists is needed. Objective Our objective was to investigate the central nervous system eifects of u single manufacturer's recommended dose of six H1-Receptor Antagonists, using appropriate controls. Methods Fifteen healthy subjects received astemizole 10mg, cetirizine 10mg, ketotifen 2mg, loratadine 10 mg, terfenadine 60mg, diphenhydramine 50mg or placebo. Before and 2-1.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. Results In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H1-Receptor Antagonists suppressed the histamine-induced weal significantly compared with baseline. Conclusions The H1-Receptor Antagonists tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H1-blockade.
F. E. R. Simons - One of the best experts on this subject based on the ideXlab platform.
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Clinical pharmacology of the H1-Receptor Antagonists cetirizine and loratadine in children.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2000Co-Authors: F. E. R. Simons, L Johnston, Keith J. SimonsAbstract:H1-Receptor Antagonists are widely used in children but are not as well-studied in children as they are in adults. Our objective was to determine the onset and duration of action and the relative potency of the H1-Receptor Antagonists cetirizine and loratadine in children. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of cetirizine and loratadine using suppression of the histamine-induced wheal and flare as the primary outcome. In 15 allergic children, mean age 9 years, compared with baseline, cetirizine (10 mg) suppressed the wheals and flares significantly from 0.25 to 24 h, achieving nearly 100% of flare suppression from 2 to 24 h, inclusive, and loratadine (10 mg) suppressed the wheals and flares significantly from 0.75 to 24 h, inclusive. Cetirizine suppressed the wheals and flares significantly more than loratadine from 0.25 to 1 h, inclusive, and at 0.5, 1, 2, 3, 5, 6, 7, and 24 h, respectively. Placebo also suppressed the wheal and flare significantly at some assessment times. Cetirizine and loratadine both have excellent antihistaminic activity in children, with a rapid onset of action and a 24-h duration of action in this population.
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non cardiac adverse effects of antihistamines H1 Receptor Antagonists
Clinical & Experimental Allergy, 1999Co-Authors: F. E. R. SimonsAbstract:Antihistamines, available without prescription in many countries, are generally considered to be safe medications; however, the old first-generation H1 Antagonists commonly cause adverse central nervous system (CNS) effects, even when administered in usual doses. Patients may not be aware of these effects and do not necessarily develop tolerance to them. In contrast, the new, second-generation H1 Antagonists are relatively free from adverse effects in the CNS, primarily because they do not cross the blood-brain barrier and block the important neurotransmitter function of histamine. Most of the H1 Antagonists in current use are unlikely to cause cardiac toxicity. There is no evidence that H1 Antagonists, which have been approved by regulatory agencies, have carcinogenic, tumour-promoting, or teratogenic effects in humans.
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histamine and H1 Receptor Antagonists in allergic disease
1996Co-Authors: F. E. R. SimonsAbstract:Histamine Receptors and histamine: histamine Receptors molecular identification of the histamine H1-Receptor in humans histamine in allergic diseases. H1-Receptor Antagonists - basic science: structure and classification/H1-bolckade anti-allergic effects in vitro anti-allergic effects in vivo. H1-Receptor Antagonists - clinical science: pharmacokinetics and clinical pharmacology allergic rhinoconjunctivitis asthma chronic urticaria anaphylaxis antihistamines (H1-Receptor Antagonists) in children. H1-Receptor Antagonists - adverse effects: central nervous system cardiovascular system.
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Comparison of the central nervous system effects produced by six H1-Receptor Antagonists.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 1996Co-Authors: F. E. R. Simons, T. G. Fraser, J. D. Reggin, Keith J. SimonsAbstract:Summary Background A comprehensive comparative study of the central nervous system (CNS) properties of newer H1-Receptor Antagonists is needed. Objective Our objective was to investigate the central nervous system eifects of u single manufacturer's recommended dose of six H1-Receptor Antagonists, using appropriate controls. Methods Fifteen healthy subjects received astemizole 10mg, cetirizine 10mg, ketotifen 2mg, loratadine 10 mg, terfenadine 60mg, diphenhydramine 50mg or placebo. Before and 2-1.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. Results In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H1-Receptor Antagonists suppressed the histamine-induced weal significantly compared with baseline. Conclusions The H1-Receptor Antagonists tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H1-blockade.
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individual differences in central nervous system response to antihistamines H1 Receptor Antagonists
Annals of Allergy Asthma & Immunology, 1995Co-Authors: F. E. R. Simons, J. D. Reggin, T G Fraser, Keith J. SimonsAbstract:Hypothesis : We hypothesized that the objectively documented central nervous system response to antihistamines (H 1 -Receptor Antagonists) could not be predicted reliably by an individual's subjective perception of somnolence after ingestion of these medications. Methods : In a double-blind, placebo-controlled, single-dose, four-way crossover study, cetirizine 10 mg, hydroxyzine 50 mg, diphenhydramine 50 mg, or placebo were administered to 20 healthy subjects. Before and two to two and one-half hours after dosing, the latency of the P300 event-related potential (P300) at the central (Cz) and parietal (Pz) scalp electrodes, and the visual analogue scale for somnolence were recorded. Epicutaneous tests with histamine were performed, and serum H 1 -Receptor antagonist concentrations were also measured. Results : Neither cetirizine nor placebo significantly increased the mean P300 latency or somnolence as recorded on the visual analogue scale compared with predose baseline (P >.05), although increases were seen in some subjects after each of these treatments. Hydroxyzine and diphenhydramine increased the mean P300 latency and somnolence significantly (P <.05) compared with baseline ; increases were observed in most, but not all subjects. Hydroxyzine increased P300 latency and somnolence significantly compared with placebo and with cetirizine. Diphenhydramine increased somnolence significantly compared with placebo. Overall, correlation between the objective test, P300 latency, and the subjective assessment, somnolence as recorded on the visual analogue scale, was statistically significant but clinically unimportant. Identification of central nervous system adverse effects after one potentially sedating H 1 -Receptor antagonist did not predict central nervous system adverse effects after the others. Conclusions : Inter-individual objective and subjective central nervous system responses to H 1 -Receptor Antagonists are wide-ranging. The subjective responses can be misleading and do not necessarily predict the abnormalities that can be documented objectively after the same H 1 -Receptor antagonist or a different H 1 -antagonist.
Chiaki Kamei - One of the best experts on this subject based on the ideXlab platform.
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effects of histamine H1 Receptor Antagonists on delayed spatial win shift task in rats
European Journal of Pharmacology, 2010Co-Authors: Akiko Okada, Akane Kato, Chiaki KameiAbstract:Abstract We investigated the effects of histamine H1 Receptor Antagonists in 3 different stages of spatial working memory in comparison with scopolamine. The effects of drugs were measured using an eight-arm radial maze with a delayed spatial win-shift task in rats. Drugs were injected 10 min before the training phase (timing 1), immediately after the training phase (timing 2), or 10 min before the test phase (timing 3). Intrahippocampal injection of pyrilamine and diphenhydramine resulted in significant effects on the number of correct choices and across-phase errors in all 3 timings. Scopolamine impaired the number of correct choices and across-phase errors in timing 1 and 3; however, no significant effect was observed in timing 2. These results indicate that pyrilamine and diphenhydramine impaired encoding, retention and retrieval processes of spatial working memory, whereas scopolamine did not impair the retention process.
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Effects of histamine H1 Receptor Antagonists on hippocampal theta rhythm during spatial memory performance in rats
European Journal of Pharmacology, 2007Co-Authors: Takayoshi Masuoka, Azusa Mikami, Masa Yasuda, Kazuaki Shinomiya, Chiaki KameiAbstract:Abstract The effects of histamine H 1 Receptor Antagonists (promethazine, diphenhydramine, chlorphenilamine and triprolidine) on hippocampal theta rhythm during eight-arm radial maze performance were investigated using rats. Promethazine showed a significant increase in the number of total errors and working memory errors at doses of 10 and 20 mg/kg, and a significant increase was also observed in reference memory errors at a dose of 20 mg/kg. Diphenhydramine and chlorphenilamine at a dose of 20 mg/kg and triprolidine at a dose of 35 mg/kg also caused significant increases in the number of total, reference memory and working memory errors. Promethazine, diphenhydramine and chlorphenilamine, having potent anti-muscarinic Receptor properties, increased hippocampal theta power during radial maze performance at a dose of 20 mg/kg. On the other hand, triprolidine, which has weak anti-muscarinic Receptor properties compared with other histamine H 1 Receptor Antagonists, decreased theta power at a dose of 35 mg/kg. These results suggest that anti-muscarinic Receptor properties rather than anti-histamine H 1 Receptor properties may affect hippocampal theta power during spatial memory deficit induced by promethazine, diphenhydramine and chlorphenilamine.
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Influences of histamine H1 Receptor Antagonists on maximal electroshock seizure in infant rats.
Biological & Pharmaceutical Bulletin, 2007Co-Authors: Takashi Ishikawa, Kenshi Takechi, Ashequr Rahman, Jun Ago, Naotaka Matsumoto, Aya Murakami, Chiaki KameiAbstract:The influences of histamine H1 Receptor Antagonists on maximal electroshock seizure were studied using infant rats. In this study, electroconvulsion was induced by stimulating rats using ear-clip electrodes, and the durations of electroencephalogram (EEG) seizure, tonic extensor (TE) seizure and clonic (CL) seizure induced by maximal electroshock were measured. Diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused a dose-dependent and significant prolongation of both EEG seizure and TE seizure induced by maximal electroshock. On the other hand, epinastine and fexofenadine caused no such effects, even at a dose of 50 mg/kg. All drugs used in this study showed no significant effect on CL seizure induced by maximal electroshock. From these findings, it is suggested that epinastine and fexofenadine may cause no harmful influence on epilepsy, even when used in a little child.
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effects of second generation histamine H1 Receptor Antagonists on the sleep wakefulness cycle in rats
European Journal of Pharmacology, 2004Co-Authors: Yuki Shigemoto, Kazuaki Shinomiya, Mitsunobu Mio, Nobuhide Azuma, Chiaki KameiAbstract:The present study was performed to examine the sedative effects of second-generation histamine H(1) Receptor antagonist using power spectrum analysis in the rat. Similar to ketotifen, olopatadine caused a decrease in sleep latency at a dose of 50 mg/kg, while epinastine and cetirizine showed no significant effect even at a dose of 50 mg/kg. On the other hand, no significant difference was observed in the total times of wakefulness, non-rapid eye movement sleep and rapid eye movement sleep by any drugs used in the experiments. The number of sleep phases and interval between sleep phases were also unchanged by these drugs. Ketotifen and olopatadine inhibited [(3)H]mepyramine binding to rat brain homogenates in parallel with a decrease in sleep latency. No significant effect was observed with epinastine and cetirizine on [(3)H]mepyramine binding. These findings suggest that the differences in the central nervous system (CNS) depressant effect observed in second generation H(1) Receptor Antagonists may be due to their liability to penetrate into the CNS.
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Effects of second-generation histamine H1 Receptor Antagonists on the active avoidance response in rats.
Clinical and experimental pharmacology & physiology, 2003Co-Authors: Miyuki Nishiga, Yoko Fujii, Masako Konishi, Maria Alejandra Hossen, Chiaki KameiAbstract:Summary 1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation histamine H1 Receptor Antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation histamine H1 Receptor Antagonists.
Junzo Kamei - One of the best experts on this subject based on the ideXlab platform.
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effects of histamine H1 Receptor Antagonists on depressive like behavior in diabetic mice
Pharmacology Biochemistry and Behavior, 2006Co-Authors: Shoko Hirano, Shigeo Miyata, Kenji Onodera, Junzo KameiAbstract:We previously reported that streptozotocin-induced diabetic mice showed depressive-like behavior in the tail suspension test. It is well known that the central histaminergic system regulates many physiological functions including emotional behaviors. In this study, we examined the role of the central histaminergic system in the diabetes-induced depressive-like behavior in the mouse tail suspension test. The histamine contents in the hypothalamus were significantly higher in diabetic mice than in non-diabetic mice. The histamine H(1) Receptor antagonist chlorpheniramine (1-10 mg/kg, s.c.) dose-dependently and significantly reduced the duration of immobility in both non-diabetic and diabetic mice. In contrast, the selective histamine H(1) Receptor Antagonists epinastine (0.03-0.3 microg/mouse, i.c.v.) and cetirizine (0.01-0.1 microg/mouse, i.c.v.) dose-dependently and significantly suppressed the duration of immobility in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity was not affected by histamine H(1) Receptor Antagonists in either non-diabetic or diabetic mice. In addition, the number and affinity of histamine H(1) Receptors in the frontal cortex were not affected by diabetes. In conclusion, we suggest that the altered neuronal system mediated by the activation of histamine H(1) Receptors is involved, at least in part, in the depressive-like behavior seen in diabetic mice.
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effects of first and second generation histamine H1 Receptor Antagonists on the pentobarbital induced loss of the righting reflex in streptozotocin induced diabetic mice
Journal of Pharmacological Sciences, 2005Co-Authors: Junzo Kamei, Shoko Hirano, Akiyoshi Saitoh, Shigeo Miyata, Kenji OnoderaAbstract:Abstract The second-generation histamine-H1-Receptor Antagonists, such as epinastine and cetirizine, are used as non-sedating antihistamines for treating allergic symptoms due to their poor ability to penetrate blood-brain barrier. Because it has been reported that the blood-brain barrier system is disturbed in diabetes, it is possible that second-generation histamine-H1-Receptor Antagonists may easily penetrate the blood-brain barrier and cause potent sedation in diabetics. In the present study, we investigated the effects of first-generation (diphenhydramine) and second-generation (epinastine and cetirizine) histamine-H1-Receptor Antagonists on the duration of pentobarbital-induced loss of the righting reflex (LORR) in non-diabetic and diabetic mice. Systemic treatment with diphenhydramine (3 – 30 mg/kg, s.c.), and intracerebroventricular treatment with epinastine (0.03 – 0.3 μg/mouse) and cetirizine (0.03 – 0.3 μg/mouse) dose-dependently and significantly increased the duration of pentobarbital-induced LORR in both nondiabetic and diabetic mice. Although systemic treatment with epinastine (3 – 30 mg/kg, s.c.) and cetirizine (3 – 30 mg/kg, s.c.) did not affect the duration of pentobarbital-induced LORR in nondiabetic mice, these treatments significantly prolonged it in diabetic mice. Our results suggest that the systemic administration of second-generation histamine-H1-Receptor Antagonists may produce a central nervous system depressant effect in diabetes.
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antipruritic activity of the κ opioid Receptor agonist trk 820
European Journal of Pharmacology, 2002Co-Authors: Yuko Togashi, Hideo Umeuchi, Kiyoshi Okano, Naoki Ando, Yoshitaka Yoshizawa, Toshiyuki Honda, Kuniaki Kawamura, Takashi Endoh, Jun Utsumi, Junzo KameiAbstract:The effects of the κ-opioid Receptor agonist, TRK-820, (−)-17-(cyclopropylmethyl)-3, 14β-dihydroxy-4, 5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, on the itch sensation were compared with those of histamine H1 Receptor Antagonists, using the mouse pruritogen-induced scratching model. Peroral administration of TRK-820 reduced the numbers of substance P- or histamine-induced scratches dose dependently. No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments, indicating that the inhibition of scratches was not due to the effect on general behavior. Furthermore, the scratching inhibitory activity of TRK-820 was dose dependently antagonized by the specific κ-opioid Receptor antagonist, nor-binaltorphimine, suggesting that the inhibitory activity was mediated via κ-opioid Receptors. Histamine H1 Receptor Antagonists, chlorpheniramine and ketotifen, did not inhibit substance P-induced scratches, or did so only partially. Both antihistamines inhibited the histamine-induced scratches completely. These results suggest that TRK-820 has antipruritic activity which is mediated by κ-opioid Receptors, and is effective in both antihistamine-sensitive and -resistant pruritus.
Erwin W. Gelfand - One of the best experts on this subject based on the ideXlab platform.
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the role of histamine H1 and h4 Receptors in allergic inflammation the search for new antihistamines
Nature Reviews Drug Discovery, 2008Co-Authors: Robin L Thurmond, Erwin W. Gelfand, Paul J DunfordAbstract:Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 Receptor, and H1-Receptor Antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine Receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-Receptor Antagonists and a possible synergy between H1 and H4-Receptor Antagonists in targeting various inflammatory conditions.
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Anti-inflammatory activity of H1-Receptor Antagonists: review of recent experimental research
Current medical research and opinion, 2004Co-Authors: Erwin W. Gelfand, Sireesh Appajosyula, Suzanne MeevesAbstract:SUMMARYObjective: To compare the anti-inflammatory effects of fexofenadine with other H -Receptor Antagonists in vitro.Data sources: Published literature.Study selection: Recent experimental studies on anti-inflammatory effects of H1-Receptor Antagonists. Databases searched: Medline, Medscape. Period covered: 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine.Results: Second- and third-generation H1-⁁ Receptor Antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects.Conclusions: Experimental research suggests that second- and third-generation H1-Receptor Antagonists may achieve anti-inflammatory effects in a clinical context. Further studies are required to support this conclusion.
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role of histamine in the pathophysiology of asthma immunomodulatory and anti inflammatory activities of H1 Receptor Antagonists
The American Journal of Medicine, 2002Co-Authors: Erwin W. GelfandAbstract:Cumulative clinical and laboratory evidence on histamine and its actions suggests that it has a pathophysiologic role in asthma. These findings have renewed interest in the potential therapeutic role of H1 antihistamines in this disease. A murine model of allergen-induced airway inflammation and methacholine-induced airway hyperresponsiveness has been used to clarify mechanisms of airway function, to identify potential therapeutic targets, and to investigate the effects of the H1-Receptor antagonist fexofenadine. Findings suggest that there may be a role for second-generation antihistamines in treating asthma, with patient selection as well as dosing both important therapeutic considerations. Because high-dose therapy may be required to achieve a clinical response, agents with the widest therapeutic window and the lowest potential for sedation would offer the greatest therapeutic potential.