Gervasoni M, Pirola R, Pollera C, Villa S, Cignarella G, Mantegazza P, Poli G, Bareggi S R
Department of Pharmacology, Chemotherapy and Medical Toicology, School of Medicine, University of Milan, Italy.
J Pharm Pharmacol. 2004 Mar;56(3):323-8. doi: 10.1211/0022357022854.
Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our group from Congo Red (CR), that is active in preventing the pathological conversion of normal prion protein (PrP). As the precise mechanisms controlling the ways in which prions are distributed and infect the brain and other organs are not fully understood, studying the pharmacokinetics of drugs that are active against prions may clarify their targets and their means of inhibiting prion infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and brain after single or repeated intraperitoneal or subcutaneous administration, as determined by means of specific and sensitive fluorimetric HPLC. A single intraperitoneal administration led to peak plasma CRA concentrations after 15 min, followed by biphasic decay with an apparent half-life of 4.3 h. After subcutaneous administration, T(max) was reached after 30 min, and was followed by a similar process of decay: Cmax and the AUC0-last were 25% those recorded after intraperitoneal administration. The mean peak concentrations and AUCs of CRA after a single intraperitoneal or subcutaneous administration in peripheral tissue (spleen) were similar to those observed in blood, whereas brain concentrations were about 2% those in plasma. After repeated intraperitoneal or subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to those observed at the same times after a single dose. After repeated intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid at concentrations of 1.8 +/- 0.2 microg(-1) mL, which is similar to, or slightly higher than, those found in brain. Brain concentrations may be sufficient to explain the activity of CRA on PrP reproduction in the CNS. However, peripheral involvement cannot be excluded because the effects of CRA are more pronounced after intraperitoneal than after intracerebral infection.
3,4-二氨基萘-1-磺酸钠（CRA）是我们团队由刚果红（CR）合成的一种化合物，它在预防正常朊病毒蛋白（PrP）的病理转化方面具有活性。由于控制朊病毒在大脑和其他器官中分布及感染方式的精确机制尚未完全明确，研究抗朊病毒活性药物的药代动力学可能会阐明其作用靶点及抑制朊病毒感染的方式。本文描述了通过特异性和灵敏的荧光高效液相色谱法测定的单次或重复腹腔内或皮下给药后CRA在血浆、脾脏和大脑中的药代动力学。单次腹腔内给药后15分钟血浆CRA浓度达到峰值，随后呈双相衰减，表观半衰期为4.3小时。皮下给药后，30分钟后达到T(max)，随后是类似的衰减过程：Cmax和AUC0-last分别为腹腔内给药后记录值的25%。单次腹腔内或皮下给药后外周组织（脾脏）中CRA的平均峰值浓度和AUC与血液中观察到的相似，而大脑中的浓度约为血浆中的2%。重复腹腔内或皮下给药后，血浆、大脑和脾脏中的Cmax值与单次给药后相同时间观察到的值相似。重复腹腔内给药后，在脑室脑脊液中也发现了CRA，浓度为1.8±0.2μg(-1) mL，与大脑中发现的浓度相似或略高。大脑中的浓度可能足以解释CRA对中枢神经系统中PrP复制的活性。然而，不能排除外周参与，因为腹腔内感染后CRA的作用比脑内感染后更明显。
