Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection

Abstract

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 fail 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.Polysulfated polyanions, including heparin, pentosan polysulfate, and dextran sulfate, are potent inhibitors of human immunodeficiency virus (HIV) infectivity and syncytium formation in vitro (2,13,23,30). In addition, these compounds inhibit other retroviruses, herpes simplex viruses, cytomegalovirus, and paramyxoviruses (4). These compounds are believed to block virus binding and penetration into target cells (3, 23) and, specifically, to block the binding of the HIV envelope protein to the CD4 receptor (25). They may also exert activity at a second step in infectivity, such as membrane fusion (8, 28).Potential advantages of polysulfated polysaccharides as antiviral agents include their broad-spectrum activity and simple chemical structure, which allows production costs to be low compared with those of the available nucleoside analogs or synthetic polypeptides. Clinical trials of oral dextran sulfate in HIV-infected patients (1) were terminated soon after the drug was shown to be poorly absorbed (21) In order to assess the potential anti-HIV activity of parenteral polysulfated polysaccharides, we selected dextran sulfate as a prototypical agent for study in patients with AIDS or AIDS-related complex (ARC). We chose dextran sulfate because it is...

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

“…This effect of DXS was already described earlier (16) and might participate in our model in the regulation of coagulation disorders, which are known to play an important part in the early phase of AVR. Systemic inhibition of the coagulation cascade can limit the use of DXS in a clinical setting (27), but in our model, injecting DXS every 2nd day up to day 13 after transplantation did not cause major bleeding complications. In addition, no signs of acute toxicity of i.v.…”

Role of Curdlan Sulfate in the Binding of HIV‐1 gp120 to CD4 Molecules and the Production of gp120‐Mediated TNF‐α

“…Accordingly, soluble recombinant virus receptor molecules such as recombinant CD4 andCD4-immunoadhesin (a chimeric protein of human CD4 molecules and immunoglobulin), and sulfated polysaccharides such as dextran sulfate (DS: sulfated 1,6-a-D-glucan), have been tested involving clinical trials of HIV-1 infected patients (3,19,22). However, despite an inhibitory effect on HIV-1 infection in vitro, these agents are not widely employed because of their insufficient anti-HIV-1 activity in vivo and adverse effects including thrombocytopenia (7,11). Although treatment using nucleoside analogs, protease inhibitors and combinations of these agents is extremely useful for suppressing virus load expansion, HIV-1 has been known to develop a resistance to these agents (9).…”

Polymeric Anti‐HIV Therapeutics

“…[66,69,70] Due to these high in vitro potencies, clinical trials were rapidly set up in the late 1980s to study the efficacy upon systemic administration in HIV-1 infected patients. [129,130] Dextran sulfate (1) was selected as the drug of choice due to low anticoagulant activity compared to heparin (2) and because previous clinical experience in administration of the drug provided a better understanding of the pharmacokinetics and toxicity. However, the initial trials of orally administered (1) were soon terminated due to poor Anti-HIV assay performed using TZM-bl assay.…”

“…[130] In addition, administration of 1 caused toxic side effects such as reversible thrombocytopenia and alopecia and was shown to possess a short systemic half-life. [130] Flexner et al advised that caution should be taken with regard to the further development of all sulfated polyanionic compounds for systemic administration. [130] Since the most common mode of HIV transmission is via sexual contact, [131] application of polymeric compounds as topical anti-HIV microbicides (more accurately known as 'virustats' [132] ) has proven to be a popular alternative route of administration.…”

“…[130] Flexner et al advised that caution should be taken with regard to the further development of all sulfated polyanionic compounds for systemic administration. [130] Since the most common mode of HIV transmission is via sexual contact, [131] application of polymeric compounds as topical anti-HIV microbicides (more accurately known as 'virustats' [132] ) has proven to be a popular alternative route of administration. As illustrated in Figure 8a, HIV acquisition can result if the virus traverses the vaginal (or rectal) epithelium.…”