@article{ehling_baeumer_papich_2019, title={Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine-induced wheal formation: a pilot study}, volume={30}, ISSN={["1365-3164"]}, DOI={10.1111/vde.12727}, abstractNote={Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine.To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (≈5 mg/kg diphenhydramine).Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design.Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation.There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (± 20) and 124 (± 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (± 7.1) and 11.6 (± 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs.Oral absorption of diphenhydramine was approximately three times greater with a longer half-life when it was administered as the combination product dimenhydrinate.Les antihistaminiques de type 1 (H1) tels que la diphénhydramine sont fréquemment utilisés pour le traitement du prurit chez le chien, bien que l'efficacité thérapeutique pour les troubles allergiques rapportée soit hautement variable. Le diménhydrinate est un sel de diphénhydramine et de 8-chlorothéophylline décrit comme ayant une meilleur absorption orale que la diphénhydramine. HYPOTHÈSES/OBJECTIFS: Déterminer les propriétés pharmacocinétiques et pharmacodynamiques de la diphénhydramine des chiens après administration intraveineuse (1mg/kg) et orale (5 mg/kg) et lorsque donné oralement sous forme de diménhydrinate à la dose de 10 mg/kg (≈5 mg/kg diphénhydramine).Chaque médicament a été administré à jeun à six chiens croisés sains dans un centre de recherche avec une étude croisée. MATÉRIEL ET MÉTHODE: Des échantillons sanguins ont été prélevés pour analyse pharmacocinétique de diphénhydramine et chlorothéophylline à des intervalles définis. La réponse pharmacocinétique a été mesurée par la formation de plaques cutanées médiées par l'histamine. RÉSULTATS: Il y avait une grande variabilité des données et un chien présentait des valeurs extrèmes non exploitables. Les disponibilités moyennes de diphénhydramine étaient 7,8% et 22,0% après administration orale respectivement de diphénhydramine et diménhydrinate tandis que les concentrations maximales moyennes étaient 36 (± 20) et 124 (± 46) ng/mL. Les demi-vies d’élimination terminales de diphénhydramine et diménhydrinate étaient respectivement 5.0 (± 7.1) et 11.6 (± 17.7) h. Les concentrations plasmatiques de diphénhydramine ne corrélaient pas avec la diminution de pourcentage de la formation de plaque liée à l'histamine. Les concentrations plasmatiques atteintes par la théophylline sont considérées comme thérapeutiques chez le chien.L'absorption orale de diphénhydramine était approximativement trois fois plus importante avec une demi-vie plus longue quand administrée comme combiné de diménhydrinate.INTRODUCCIÓN: los antagonistas de los receptores de histamina tipo 1 (H1), como la difenhidramina, se utilizan con frecuencia para el tratamiento del prurito en perros, aunque se indica que la eficacia terapéutica para los trastornos alérgicos es muy variable. Dimenhidrinato es una sal de difenhidramina y 8-cloroteofilina, y se ha publicado que tiene una absorción oral superior de difenhidramina. HIPÓTESIS/OBJETIVO: determinar las propiedades farmacocinéticas y farmacodinámicas de la difenhidramina en perros después de la administración intravenosa (1 mg/kg) y oral (5 mg/kg), y cuando se administra por vía oral como dimenhidrinato en una dosis de 10 mg/kg (5 mg/kg de difenhidramina). ANIMALES: cada medicamento se administró a seis perros sanos, de raza mestiza en un centro de investigación, utilizando un método de estudio cruzado. MÉTODOS Y MATERIALES: se recogieron muestras de sangre para el análisis farmacocinético de la difenhidramina y la cloroteofilina a intervalos definidos. La respuesta farmacodinámica se midió mediante formación de abones cutáneos mediadas por histamina. RESULTADOS: hubo una gran variabilidad en los datos y un perro fue un caso atípico extremo. La disponibilidad sistémica media de la difenhidramina fue de 7,8% y 22,0% después de la administración oral de difenhidramina y dimenhidrinato, respectivamente, mientras que las concentraciones máximas promedio fueron de 36 (± 20) y 124 (± 46) ng/mL. Las vidas medias de eliminación terminal de la difenhidramina y el dimenhidrinato fueron de 5,0 (± 7,1) y 11,6 (± 17,7) h, respectivamente. Las concentraciones de difenhidramina en plasma no se correlacionaron con el porcentaje de reducción en la formación de abones inducidos por histamina. La teofilina alcanzó concentraciones plasmáticas consideradas terapéuticas para perros. CONCLUSIÓN: la absorción oral de difenhidramina fue aproximadamente tres veces mayor con una vida media más larga cuando se administró como el producto de combinación dimenhidrinato.Histamin Typ-1 (H1) Rezeptor Antagonisten, wie Diphenhydramin werden häufig zur Behandlung von Juckreiz bei Hunden eingesetzt, ihre therapeutische Wirksamkeit bei allergischen Erkrankungen wird als höchst unterschiedlich beschrieben. Demenhydrinat ist ein Salz des Diphenhydramins und 8-Chlorotheophyllins. Es gibt Berichte, dass es die per os Absoprtion von Diphenhydramin stark verbessert.Eine Feststellung der pharmakokinetischen und pharmakodynamischen Eigenschaften von Diphenhydramin bei Hunden nach intravenöser Verabreichung (1 mg/kg) sowie einer Verabreichung per os (5 mg/kg), sowie eine per os Verabreichung als Dimenhydrat bei einer Dosis von 10 mg/kg (≈5 mg/kg Diphenhydramin).Jedes Medikament wurde sechs gesunden, nüchternen Mischlingshunden in einer Versuchsanstalt unter Verwendung eines Cross-over Designs verabreicht.Es wurden Blutproben zur pharmakokinetischen Analyse von Diphenhydramin und Chlorotheophyllin in definierten Intervallen genommen. Die pharmakodynamische Antwort wurde mittels Histamin-mediierter kutaner Quaddelbildung gemessen.Es bestand eine große Variabilität bei den Daten und ein Hund stellte einen extremen Ausreißer dar. Die durchschnittlichen systemischen Verfügbarkeiten von Diphenhydramin waren 7,8% und 22,0% nach einer per os Verabreichung von Diphenhydramin bzw Dimenhydrinat, während die durchschnittlichen maximalen Konzentrationen 36 (± 20) und 124 (± 46) ng/mL betrugen. Die terminalen Halbwertszeiten der Elimination von Diphenhydramin bzw Dimenhydrinat waren 5,0 (± 7,1) bzw 11,6 (± 17,7). Die Diphenhydramin Konzentrationen im Plasma korrelierten nicht mit der prozentualen Reduzierung der Histamin-induzierten Quaddelbildung. Das Theophyllin erreichte Plasmakonzentrationen, die als therapeutisch für Hunde angesehen werden.Die per os Absorption von Diphenhydramin war etwa dreimal größer mit einer längeren Halbwertszeit als eine Verabreichung im Kombinationsprodukt Dimenhydrinat.背景: 组胺1型(H1)受体拮抗剂,如苯海拉明,常用于治疗犬的瘙痒,但有报道称,对过敏性疾病的治疗效果非常不确定。茶苯海明是苯海拉明和8-氯代茶碱的一种盐,据报道,其产生能被较好口服吸收的苯海拉明。 假设/目的: 确定犬静脉注射(1 mg/kg)和口服(5 mg/kg)苯海拉明后的药代动力学和药效学特性,并以10 mg/kg的剂量口服给予茶苯海明(≈5mg/kg苯海拉明)。 动物: 将每种药物通过交叉设计,给予六只研究所内健康、禁食的杂种犬。 方法和材料: 采集血液样本,以规定的间隔对苯海拉明和茶碱进行药代动力学分析。通过组胺介导形成皮肤风疹,测量药效学反应。 结果: 数据有很大的可变性,一只犬有极端异常值。口服苯海拉明和茶苯海明后,苯海拉明的平均全身可用量分别为7.8%和22.0%,而平均最大浓度分别为36(±20)和124(±46)ng/mL。苯海拉明和茶苯海明的终末消除半衰期分别为5.0(±7.1)和11.6(±17.7)h。血浆苯海拉明浓度与组胺诱导的风疹减少百分比无关。茶碱达到被认为对犬有治疗作用的血浆浓度。 结论: 茶苯海明当作为组合产品给药时,其口服吸收半衰期较长,大约是口服苯海拉明的三倍。.Os antagonistas de receptores histamínicos do tipo-1 (H1) como a difenidramina são utilizados frequentemente no tratamento do prurido em cães, ainda que a eficácia terapêutica no tratamento de alergopatias seja relatada como altamente variável. O dimenidrinato é um sal da difenidramina e 8-cloroteofilina, e relatos sugerem que este possui absorção oral superior à da difenidramina. HIPÓTESE/OBJETIVO: Determinar as propriedades farmacocinéticas e farmacodinâmicas da difenidramina em cães após administração intravenosa (1 mg/kg) e oral (5 mg/kg), e quando administrado por via oral como dimenidrinato em uma dose de 10 mg/kg (≈5 mg/kg difenidramina).Cada fármaco foi administrado a seis cães mestiços saudáveis de um centro de pesquisa, em jejum, utilizando um delineamento experimental cruzado. MÉTODOS E MATERIAIS: Amostras de sangue foram coletadas para análise farmacocinética de difenidramina e cloroteofilina em intervalos definidos. A resposta farmacocinética foi mensurada pela formação de pápulas mediadas por histamina na pele.Houve uma grande variação nos dados e um cão destoou extremamente dos demais, sendo considerado um ponto fora da curva (outlier).A média das disponibilidades sistêmicas de difenidramina foram 7,8%e 22,0% após administração de difenidramina e dimenidrinato, respectivamente, enquanto as concentrações máximas médias foram 36 (± 20) e 124 (± 46) ng/mL. As meias-vidas de eliminação terminal de difenidramina e dimenidrinato foram 5,0 (± 7,1) e 11,6 (± 17,7) h, respectivamente. As concentrações plasmáticas de difenidramina não correlacionaram com a porcentagem de redução na formação de pápulas induzidas por histamina. A teofilina alcançou concentrações consideradas terapêuticas para cães. CONCLUSÃO: A absorção oral de difenidramina foi aproximadamente três vezes maior com uma meia-vida mais longa quando administrada em combinação com o produto dimenidrinato.背景: ジフェンヒドラミンなどのヒスタミン1型(H1)受容体拮抗薬は、犬の掻痒治療に頻繁に使用されるが、それでもアレルギー性疾患に対する治療効果は非常に変動的であると報告されている。ジメンヒドリナートはジフェンヒドラミンおよび8-クロロテオフィリンの塩であり、ジフェンヒドラミンの優れた経口吸収を生じさせることが報告されている。 仮説/目的: 本研究の目的は、ジフェンヒドラミンを 静脈内(1 mg/kg)および経口(5 mg/kg)、ならびにジメンヒドリナートを10mg / kgの用量で経口投与された場合(約5mg / kgのジフェンヒドラミン)の犬におけるジフェンヒドラミンの薬物動態学的および薬力学的特性を決定することである。 被験動物: 研究施設内の6頭の健常な絶食状態の雑種犬に、各薬剤をクロスオーバーデザインによって投与した。 方法および材料: ジフェンヒドラミンおよびクロロテオフィリンの薬物動態解析のため、定義された間隔で血液サンプルを採取した。薬力学的応答は、ヒスタミン媒介皮膚膨疹形成によって測定した。 結果: データには大きなばらつきがあり、1頭の犬が極端な異常値を示した。ジフェンヒドラミンおよびジメンヒドリナートの経口投与後のジフェンヒドラミンの平均全身アベイラビリティはそれぞれ7.8%と22.0%であったが、平均最高濃度は36(±20)と124(±46)ng / mLであった。ジフェンヒドラミンおよびジメンヒドリナートの消失半減期はそれぞれ5.0(±7.1)と11.6(±17.7)hであった。血漿ジフェンヒドラミン濃度は、ヒスタミン誘発性膨疹形成の減少率と相関しなかった。テオフィリンは、犬の治療に役立つと考えられる血漿濃度に達した。 結論: ジフェンヒドラミンをコンビネーションプロダクトであるジメンヒドリナートとして投与した場合、ジフェンヒドラミンの経口吸収は約3倍大きく、より長い半減期を有した。.}, number={2}, journal={VETERINARY DERMATOLOGY}, author={Ehling, Sarah and Baeumer, Wolfgang and Papich, Mark G.}, year={2019}, month={Apr}, pages={91-+} }
 @article{ehling_fukuyama_ko_olivry_bäumer_2019, title={Neuromedin B Induces Acute Itch in Mice via the Activation of Peripheral Sensory Neurons}, volume={99}, ISSN={0001-5555}, url={http://dx.doi.org/10.2340/00015555-3143}, DOI={10.2340/00015555-3143}, abstractNote={Neuromedin B is expressed in nociceptive and itch-sensitive dorsal root ganglia neurons, but its peripheral pruritogenic potential is not well described. The potential of neuromedin B as a pruritogen and pro-inflammatory peptide in the skin was tested in vivo in an acute model in mice and monkeys as well as an allergic dermatitis model in mice. To identify the underlying mechanisms in vitro real time PCR analysis for neuromedin B and its receptor expression in murine mast cells and dorsal root ganglia as well as functional calcium imaging in the ganglia was applied. Neuromedin B induces itch when injected intradermally, and the peripheral signal is likely transmitted through the activation of dorsal root ganglia. Thus, neuromedin B could be an interesting new therapeutic target for peripheral processing of itch at the level of sensory neurons.}, number={6}, journal={Acta Dermato Venereologica}, publisher={Acta Dermato-Venereologica}, author={Ehling, S and Fukuyama, T and Ko, M and Olivry, T and Bäumer, W}, year={2019}, pages={587–893} }
 @article{butler_ehling_barbar_thomas_hughes_smith_pogorelov_aryal_wetsel_lascelles_et al._2017, title={Distinct neuronal populations in the basolateral and central amygdala are activated with acute pain, conditioned fear, and fear-conditioned analgesia}, volume={661}, ISSN={["1872-7972"]}, url={https://dx.doi.org/10.1016/j.neulet.2017.09.025}, DOI={10.1016/j.neulet.2017.09.025}, abstractNote={Fear-conditioned analgesia (FCA) is modulated by brain areas involved in the descending inhibitory pain pathway such as the basolateral (BLA) and central amygdala (CEA). The BLA contains Ca2+/calmodulin-dependent protein kinase II (CaMKII) and parvalbumin (PV) neurons. CEA neurons are primarily inhibitory (GABAergic) that comprise enkephalin (ENK) interneurons and corticotropin-releasing factor (CRF) – neurons that project to the periaqueductal grey. The purpose of our experiment was to determine the pattern of activation of CaMKII/PV and ENK/CRF neurons following the expression of acute pain, conditioned fear, and FCA. A significant reduction was observed in nociceptive behaviors in mice re-exposed to a contextually-aversive environment. Using NeuN and cFos as markers for activated neurons, CaMKII, PV, ENK, or CRF were used to identify neuronal subtypes. We find that mice expressing conditioned fear displayed an increase in c-Fos/CaMKII co-localization in the lateral amygdala and BLA compared to controls. Additionally a significant increase in cFos/CRF co-localization was observed in mice expressing FCA. These results show that amygdala processing of conditioned contextual aversive, nociceptive, and FCA behaviors involve different neuronal phenotypes and neural circuits between, within, and from various amygdala nuclei. This information will be important in developing novel therapies for treating pain and emotive disorders in humans.}, journal={NEUROSCIENCE LETTERS}, author={Butler, R. K. and Ehling, S. and Barbar, M. and Thomas, J. and Hughes, M. A. and Smith, C. E. and Pogorelov, V. M. and Aryal, D. K. and Wetsel, W. C. and Lascelles, B. D. X. and et al.}, year={2017}, month={Nov}, pages={11–17} }
 @article{ehling_rossbach_dunston_stark_baumer_2016, title={Allergic inflammation is augmented via histamine H4 receptor activation: The role of natural killer cells in vitro and in vivo}, volume={83}, ISSN={["1873-569X"]}, DOI={10.1016/j.jdermsci.2016.04.011}, abstractNote={Natural Killer cells (NK cells) are identified as pivotal mediators in allergic skin diseases and accumulate in lesions of atopic dermatitis (AD) patients. Histamine levels are increased in these lesions and histamine is involved in chemotaxis in dendritic cells and NK cells.The aim of this study was to determine if the histamine H4 receptor (H4R) mediates NK cell chemotaxis and whether it influences interplay between NK cells and dendritic cells during the early phase of allergic inflammation.Chemotactic function of the H4R as well as the influence of the H4R on the cytokine profile of an NK cell-dendritic cell co-culture was studied in vitro. The effect of H4R activation on NK cell migration, NK cell-dendritic cell interaction and cytokine levels in the skin was further characterized in the murine TDI model of allergic dermatitis. Additionally, the impact of the H4R on dermal NK cells was determined in the ovalbumin (OVA)- induced allergic dermatitis model, comparing wild type and H4R knockout mice.The selective H4R agonist ST-1006 induced NK cell chemotaxis in vitro, which was inhibited with the H4R antagonist JNJ7777120. In vivo, mice treated with TDI plus ST-1006 topically onto the ear, showed significantly enhanced ear swelling and an increased number of NK cells compared to just allergen challenged ears. CCL17 levels in the ear were also significantly increased 8h after allergen challenge. Histology revealed that the main source for increased CCL17 were dendritic cells. These effects could be blocked using the H4R antagonist JNJ7777120. In the chronic model of allergic dermatitis, OVA induced NK cell migration into lesional skin sites. The number of NK cells was lower in OVA-sensitized H4R knockout mice compared to wild type mice.These results identify the H4R as a new target controlling NK cell migration and NK cell-dendritic cell interaction in the skin during early allergic inflammation. These results further suggest that blocking the H4R in the skin might be beneficial in diseases like AD.}, number={2}, journal={JOURNAL OF DERMATOLOGICAL SCIENCE}, author={Ehling, Sarah and Rossbach, Kristine and Dunston, Stanley M. and Stark, Holger and Baumer, Wolfgang}, year={2016}, month={Aug}, pages={106–115} }
 @article{laduke_ehling_cullen_baeumer_2015, title={Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes}, volume={76}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.76.7.649}, abstractNote={To investigate the cytotoxic effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine hepatocytes.Commercially available cryopreserved canine primary hepatocytes.The study consisted of 2 trials. In trial 1, hepatocytes were incubated with azathioprine, 6-mercaptopurine, or 6-thioguanine at 1 of 6 concentrations (0.468, 0.937, 1.875, 3.750, 7.500, or 15.000 μmol/L) for 24, 48, or 72 hours. At each time, cell viability and lactate dehydrogenase (LDH) activity were determined for each thiopurine-concentration combination, and alanine aminotransferase (ALT) activity was determined for cells incubated with each thiopurine at a concentration of 15 μmol/L. In trial 2, hepatocytes were incubated with azathioprine, 6-mercaptopurine, or 6-thioguanine at 1 of 3 concentrations (18.75, 37.50, or 75.00 μmol/L) for 24 hours, after which the free glutathione concentration was determined for each thiopurine-concentration combination and compared with that for hepatocytes incubated without a thiopurine (control).Incubation of hepatocytes with each of the 3 thiopurines adversely affected cell viability in a time- and concentration-dependent manner; however, this decrease in cell viability was not accompanied by a concurrent increase in LDH or ALT activity. Likewise, free glutathione concentration for hepatocytes incubated for 24 hours with supratherapeutic thiopurine concentrations (> 18.75 μmol/L) did not differ significantly from that of control cells.Results indicated that thiopurines adversely affected the viability of canine hepatocytes in a time- and concentration-dependent manner but had a nonsignificant effect on the LDH and ALT activities and free glutathione depletion of those hepatocytes.}, number={7}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={LaDuke, Kathleen E. and Ehling, Sarah and Cullen, John M. and Baeumer, Wolfgang}, year={2015}, month={Jul}, pages={649–655} }
 @article{fukuyama_ehling_cook_baeumer_2015, title={Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis}, volume={354}, ISSN={["1521-0103"]}, DOI={10.1124/jpet.115.223784}, abstractNote={The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow-derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.}, number={3}, journal={JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS}, author={Fukuyama, Tomoki and Ehling, Sarah and Cook, Elizabeth and Baeumer, Wolfgang}, year={2015}, month={Sep}, pages={394–405} }