{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T18:09:29Z","timestamp":1776535769182,"version":"3.51.2"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the\n            <jats:italic>in vivo<\/jats:italic>\n            efficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.\n          <\/jats:p>","DOI":"10.1128\/aac.02605-14","type":"journal-article","created":{"date-parts":[[2014,5,6]],"date-time":"2014-05-06T03:36:16Z","timestamp":1399347376000},"page":"4064-4074","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis"],"prefix":"10.1128","volume":"58","author":[{"given":"Sihyung","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Wenzler","sequence":"additional","affiliation":[{"name":"Medical Parasitology &amp; Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrik N.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huali","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David W.","family":"Boykin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgia State University, Atlanta, Georgia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reto","family":"Brun","sequence":"additional","affiliation":[{"name":"Medical Parasitology &amp; Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.11.44"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60829-1"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000225"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.149872"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00225-09"},{"key":"e_1_3_3_8_2","unstructured":"ThuitaJK. 2013. 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