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The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10\u2013100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>\n                      To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation\n                      <jats:italic>in vitro<\/jats:italic>\n                      , quantified pentamidine CNS delivery of a sub-set of formulations\n                      <jats:italic>in vitro and in vivo<\/jats:italic>\n                      , and progressed one pentamidine-Pluronic formulation for further evaluation using an\n                      <jats:italic>in vivo<\/jats:italic>\n                      single dose brain penetration study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Principal Findings<\/jats:title>\n                    <jats:p>\n                      Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline\n                      <jats:sub>2<\/jats:sub>\n                      receptor. The reduction in insulin secretion in MIN6 \u03b2-cells by pentamidine may be secondary to pentamidine-mediated activation of \u03b2-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w\/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect\n                      <jats:italic>in vitro<\/jats:italic>\n                      . However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0009276","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T05:28:21Z","timestamp":1618550901000},"page":"e0009276","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug"],"prefix":"10.1371","volume":"15","author":[{"given":"Lisa","family":"Sanderson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-4021","authenticated-orcid":true,"given":"Marcelo","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayathri N.","family":"Sekhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-6757","authenticated-orcid":true,"given":"Rachel C.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hollie","family":"Burrell-Saward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1129-090X","authenticated-orcid":true,"given":"Mehmet","family":"Fidanboylu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8697-234X","authenticated-orcid":true,"given":"Bo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-7122","authenticated-orcid":true,"given":"Lea Ann","family":"Dailey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0578-8090","authenticated-orcid":true,"given":"C\u00e9cile A.","family":"Dreiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1028-4804","authenticated-orcid":true,"given":"Chris","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Christie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4933-5958","authenticated-orcid":true,"given":"Shanta J.","family":"Persaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Yardley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7239-3403","authenticated-orcid":true,"given":"Margarita","family":"Valero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-0154","authenticated-orcid":true,"given":"Sarah A.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"pntd.0009276.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0001007","article-title":"The human african trypanosomiasis control and surveillance programme of the world health organization 2000\u20132009: The way forward.","volume":"5","author":"PP Simarro","year":"2011","journal-title":"PLoS Negl Trop Dis."},{"key":"pntd.0009276.ref002","unstructured":"WHO. 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