PHARMACOKINETICS, TOXICITY, AND ACTIVITY OF INTRAVENOUS DEXTRAN SULFATE IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION
PHARMACOKINETICS, TOXICITY, AND ACTIVITY OF INTRAVENOUS DEXTRAN SULFATE IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION
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DOI：
10.1128/aac.35.12.2544
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发表时间：
1991-12-01
影响因子：
4.9
通讯作者：
LIETMAN, PS
中科院分区：
文献类型：
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作者：
FLEXNER, C;BARDITCHCROVO, PA;LIETMAN, PS
多硫酸多糖是抗病毒药物开发的有吸引力的候选者，因为它们对人类免疫缺陷病毒（HIV）、疱疹病毒和其他包膜病毒的有效体外活性。为了确定原型多硫酸多糖的潜在抗HIV活性，我们通过连续静脉输注给予10名有症状的HIV感染者最大耐受剂量的硫酸葡聚糖长达14天。由于肠外硫酸葡聚糖是一种抗凝剂，因此调整输注以使活化部分凝血活酶时间产生最大可接受的增加。用该方案实现的血浆中药物浓度比体外游离HIV感染性的50%抑制浓度高200倍。尽管如此，在接受药物治疗超过3天的所有8例受试者中，循环HIV抗原（p24）水平均升高（中位比例升高，73.5%;范围，32 - 130%）;与未接受治疗的历史对照的大型队列相比，这种升高非常显著（Fisher精确检验，P < 0.001）。所有受试者都需要频繁降低输注速率，以维持恒定的活化部分凝血活酶时间;血浆硫酸葡聚糖水平不随输注速率降低而下降，表明估计的药物清除率随时间推移而下降。连续静脉注射硫酸葡聚糖是有毒的，在所有8名接受药物超过3天的受试者中产生了严重但可逆的血小板减少症，其中5名受试者出现了广泛但可逆的脱发。由于其毒性和缺乏对替代标记物的有益作用，硫酸葡聚糖不太可能在治疗症状性HIV感染中发挥实际作用。
Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P < 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fall as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.