{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T06:08:54Z","timestamp":1775714934234,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,7,6]],"date-time":"2024-07-06T00:00:00Z","timestamp":1720224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Dopamine beta\u2010hydroxylase (D\u03b2H) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A single\u2010centre, prospective, double\u2010blind, randomized, placebo\u2010controlled, crossover study evaluated the effect of 400\u2009mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days \u22121 and 10. Plasma and 24\u2009h\u2010urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma D\u03b2H activity, were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to placebo, zamicastat showed a\u2009\u2212\u20094.62\u2009mmHg decrease in systolic blood pressure during the cold stimulus <jats:italic>vs<\/jats:italic>. rest phases on Day 10 of CPT (<jats:italic>P<\/jats:italic>\u2009=\u2009.020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (\u22122.62\u2009mmHg; <jats:italic>P<\/jats:italic>\u2009=\u2009.025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63\u2009ng\/L; <jats:italic>P<\/jats:italic>\u2009=\u2009.040) and after CPT (19.22\u2009ng\/L; <jats:italic>P<\/jats:italic>\u2009=\u2009.001) as well as the estimated plasma EPI change from baseline after CPT (<jats:italic>P<\/jats:italic>\u2009=\u2009.040). Inhibition of plasma D\u03b2H activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24\u2010h urinary excretion of EPI (<jats:italic>P<\/jats:italic>\u2009=\u2009.002) and NE (<jats:italic>P<\/jats:italic>\u2009=\u2009.001) were observed. Zamicastat <jats:italic>C<\/jats:italic><jats:sub>\u03c4<\/jats:sub> geometric mean \u00b1 GSD ranged from 45.86\u2009\u00b1\u20091.46\u2009ng\/mL on Day 3 to 58.64\u2009\u00b1\u20091.52\u2009ng\/mL on Day 10, with moderate inter\u2010individual variability (CV: 32.6%\u201336.6%). Steady state was already achieved on Day 6.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16167","type":"journal-article","created":{"date-parts":[[2024,7,6]],"date-time":"2024-07-06T12:30:01Z","timestamp":1720269001000},"page":"2781-2792","source":"Crossref","is-referenced-by-count":3,"title":["Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double\u2010blind, randomized, placebo\u2010controlled study in healthy subjects"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5828-8535","authenticated-orcid":false,"given":"Marlene","family":"Fonseca","sequence":"first","affiliation":[{"name":"BlueClinical Phase I  Porto Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheila","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Research and Development, Bial\u2010Portela &amp; C\u00aa S.A., Coronado (S. 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