@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={Background 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. Hypothesis/Objective 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). Animals Each drug was administered to six healthy, fasted mixed‐breed dogs in a research facility, using a cross‐over design. Methods and materials Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine‐mediated cutaneous wheal formation. Results 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. Conclusion Oral absorption of diphenhydramine was approximately three times greater with a longer half‐life when it was administered as the combination product dimenhydrinate.}, 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={Background 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. Objective 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. Methods 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. Results 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 8 h 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. Conclusions 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} }