Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug
Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug
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针对被忽视的疾病重新配制药物。
DOI：
10.1101/573329
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Sanderson L
中科院分区：
文献类型：
--
作者：
Sanderson L
人类非洲锥虫病（HAT或昏睡病）是由寄生虫布氏锥虫引起的。这种疾病有两个阶段，一个是被感染的采采蝇叮咬后的血淋巴阶段，接着是寄生虫穿透大脑的中枢神经系统阶段，如果不治疗会导致死亡。由于血脑屏障，治疗是阶段特异性的，毒性较小的药物如用于治疗阶段1的喷他脒。我们研究计划的主要目的是开发一种喷他脒静脉注射制剂，使CNS暴露增加约10-100倍，从而对2期HAT模型有效。这一目标候选人概况符合被忽视疾病药物倡议（DNDi）的建议。为此，我们评估了普朗尼克-喷他脒制剂的理化和结构特征，选择了合适的候选药物进行体外疗效和毒性评价，定量了一组体外和体内制剂的喷他脒CNS递送，并使用体内单剂量脑渗透研究进一步评价了一种喷他脒-普朗尼克制剂。针对40个中枢神经系统靶点筛选喷他脒并未发现任何重大神经毒性问题，然而，喷他脒对咪唑啉2受体具有高亲和力。在MIN 6 β细胞中观察到的喷他脒导致的胰岛素分泌减少可能继发于喷他脒介导的β细胞咪唑啉受体活化和细胞活力受损。F68（0.01%w/v）-喷他脒制剂对胰岛素分泌的抑制作用与单独的喷他脒相似，并且在体外具有相加的杀锥虫作用。然而，所有Pluronics试验（P85、P105和F68）均未显著增强喷他脒的脑暴露。因此，我们在进行体内疗效和毒性研究之前关闭了研究。重要的是，这项由MRC DPFS资助的研究产生了一系列结果，这些结果与进一步开发嵌段共聚物作为纳米载体、改善BBB药物渗透和了解喷他脒的副作用有关。
Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasiteTrypanosoma brucei sspp. 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 primary objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10-100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative (DNDi) recommendations. To do this, we evaluated the physicochemical and structural characteristics of Pluronic-pentamidine formulations, selected appropriate candidates for efficacy and toxicity evaluationin vitro, quantified pentamidine CNS delivery of a sub-set of formulationsin vitroandin vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using anin vivosingle dose brain penetration study. Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2receptor. The observed reduction in insulin secretion with pentamidine in MIN6 β-cells maybe secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effectin vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine. We therefore closed the study before progressing toin vivoefficacy and toxicity studies. Importantly, this MRC DPFS funded study has resulted in the generation of a set of results which are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.
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δ2 谷氨酸受体的药理学：喷他脒和质子的作用。
DOI：
10.1124/jpet.102.045799
发表时间：
2003
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Williams,Keith;Dattilo,Michael;Sabado,ThomasN;Kashiwagi,Keiko;Igarashi,Kazuei
通讯作者：
Igarashi,Kazuei
血脑和血脑脊液屏障处脱氧核糖核苷的饱和摄取系统的鉴定
影响因子：
2.9
作者：
S. A. Williams;M. Segal
通讯作者：
M. Segal
1,5-Bis(4-amidinophenoxy)pentane (pentamidine) 是 [3H]idazoxan 与咪唑啉 I2 结合位点结合的有效抑制剂。
影响因子：
5
作者：
DOROTHY H. Wood;J. Hall;Beate G. Rose;R. Tidwell
通讯作者：
R. Tidwell
影响因子：
5
作者：
Nalos, Lukas;de Boer, Teun P.;van der Heyden, Marcel A. G.
通讯作者：
van der Heyden, Marcel A. G.
DOI：
10.3109/10731199509117673
发表时间：
1995-01-01
影响因子：
--
作者：
LOWE, KC;FURMIDGE, BA;THOMAS, S
通讯作者：
THOMAS, S