{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:45:03Z","timestamp":1787013903953,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03DA031090"],"award-info":[{"award-number":["R03DA031090"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS076517"],"award-info":[{"award-number":["R01NS076517"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL118561"],"award-info":[{"award-number":["R01HL118561"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH096463"],"award-info":[{"award-number":["R01MH096463"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000904","name":"Lynde and Harry Bradley Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000904","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001166","name":"Richard and Ethel Herzfeld Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006817","name":"University of Wisconsin-Milwaukee","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006817","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    We report a 28\u2010day repeat dose immunotoxicity evaluation of investigational drug\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301, a novel oral asthma drug candidate that targets gamma amino butyric acid type A receptors (\n                    <jats:styled-content style=\"fixed-case\">\n                      GABA\n                      <jats:sub>A<\/jats:sub>\n                      R\n                    <\/jats:styled-content>\n                    ) in the lung. The study design employed oral administration of mice twice daily throughout the study period with 100\u00a0mg\/kg\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301 mixed in peanut butter. Compound dosing did not reveal signs of general toxicity as determined by animal weight, organ weight or haematology. Peanut butter plus test drug (in addition to ad libitum standard rodent chow) did not affect weight gain in the adult mice, in contrast to weight loss in 5\u00a0mg\/kg prednisone\u2010treated mice. Spleen and thymus weights were unchanged in\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301\u2010treated mice, but prednisone significantly reduced the weight of those organs over the 28\u2010day dosing. Similarly, no differences in spleen or thymus histology were observed following\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301 treatment, but prednisone treatment induced morphological changes in the spleen. The number of small intestine Peyer's patches was not affected by\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301 treatment, an important factor for orally administered drugs. Circulating lymphocyte, monocyte and granulocyte numbers were unchanged in the\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301\u2010treated animals, whereas differential lymphocyte numbers were reduced in prednisone\u2010treated animals.\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301 treatment did not alter IgG antibody responses to dinitrophenyl following dinitrophenyl\u2010keyhole limpet haemocyanin immunization, indicating that systemic humoral immune function was not affected. Taken together, these studies show that repeated daily administration of\n                    <jats:styled-content style=\"fixed-case\">MIDD<\/jats:styled-content>\n                    0301 is safe and not associated with adverse immunotoxicological effects in mice.\n                  <\/jats:p>","DOI":"10.1111\/bcpt.13206","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T17:20:43Z","timestamp":1548782443000},"page":"75-84","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>MIDD<\/scp>\n                    0301 \u2013 A first\u2010in\u2010class anti\u2010inflammatory asthma drug targets\n                    <scp>\n                      GABA\n                      <sub>A<\/sub>\n                    <\/scp>\n                    receptors without causing systemic immune suppression"],"prefix":"10.1111","volume":"125","author":[{"given":"Nicolas M.","family":"Zahn","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec T.","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon N.","family":"Mikulsky","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mae E.","family":"Stepanski","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander S.","family":"Kehoe","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanguan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Schussman","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed S.","family":"Rashid Roni","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revathi","family":"Kodali","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C.","family":"Stafford","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A.","family":"Steeber","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leggy A.","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"751","article-title":"Guidelines for asthma management: a review and comparison of 5 current guidelines","volume":"53","author":"Myers TR","year":"2008","journal-title":"Respir Care"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80911"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1752-699X.2011.00263.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1586\/eci.11.27"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.7b01013"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.07.045"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2014.10.002"},{"key":"e_1_2_7_9_1","unstructured":"https:\/\/wwwproteinatlasorg\/ENSG00000187730-GABRD\/tissue."},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0109OC"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1604"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00131.2011"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00107.2017"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2015.04.001"},{"key":"e_1_2_7_15_1","doi-asserted-by":"crossref","unstructured":"YocumGT Perez\u2010ZoghbiJF DanielssonJ et\u00a0al.A Novel GABAA Receptor Ligand MIDD0301 with Limited Blood\u2010Brain Barrier Penetration Relaxes Airway Smooth Muscle Ex Vivo and In Vivo. American journal of physiology Lung cellular and molecular physiology.2018.","DOI":"10.1152\/ajplung.00356.2018"},{"key":"e_1_2_7_16_1","unstructured":"http:\/\/wwwichorg\/products\/guidelines\/safety\/safety-single\/article\/immunotoxicity-studies-for-human-pharmaceuticalshtml."},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301942"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13059"},{"key":"e_1_2_7_19_1","unstructured":"ArnoldLA StaffordD CookCM et\u00a0al.GABA(A) receptor modulators and methods to control airway hyperresponsiveness and inflammation in asthma. WO2018\/035246 A1.2018."},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.7b00183"},{"key":"e_1_2_7_21_1","first-page":"17","article-title":"Stress produced by gavage administration in the rat","volume":"39","author":"Brown AP","year":"2000","journal-title":"Contemp Top Lab Anim Sci"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2010.04.001"},{"key":"e_1_2_7_23_1","first-page":"42","article-title":"Laboratory routines cause animal stress","volume":"43","author":"Balcombe JP","year":"2004","journal-title":"Contemp Top Lab Anim Sci"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2009.01193.x"},{"key":"e_1_2_7_25_1","unstructured":"CFW (Swiss Webster mice) strain code: 024 Charles River description."},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/84.4.433"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108159"},{"key":"e_1_2_7_28_1","first-page":"46","article-title":"Serum clinical chemistry and hematology reference values in outbred stocks of albino mice from three commonly used vendors and two inbred strains of albino mice","volume":"42","author":"Serfilippi LM","year":"2003","journal-title":"Contemp Top Lab Anim Sci"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2008.08.017"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.6b00159"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201602001"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/0148607101025006338"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200038050-00001"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11691"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2010.0331"}],"updated-by":[{"DOI":"10.1111\/bcpt.13400","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000}}],"container-title":["Basic &amp; Clinical Pharmacology &amp; Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbcpt.13206","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcpt.13206","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T09:02:52Z","timestamp":1694336572000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bcpt.13206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,21]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,7]]}},"alternative-id":["10.1111\/bcpt.13206"],"URL":"https:\/\/doi.org\/10.1111\/bcpt.13206","archive":["Portico"],"relation":{},"ISSN":["1742-7835","1742-7843"],"issn-type":[{"value":"1742-7835","type":"print"},{"value":"1742-7843","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,21]]},"assertion":[{"value":"2018-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}