Pharmacokinetic Analysis of Dextran Sulfate in Rats as Pertains to Its Clinical Usefulness for Therapy of HIV Infection

Modified cyclodextrin sulphate (mCDS) in which lipophilic groups were introduced to cyclodextrin sulphate (CDS) was synthesized and proved more inhibitory to the replication of HIV-1 and HIV-2 than CDS or dextran sulphate (DS). The anti-coagulant activity of mCDS was lower than that of DS. Cyclodextrin phosphate (CDP) showed anti-HIV activity similar to that of CDS, and its anti-coagulant activity was even lower than that of mCDS. Flow cytometric analysis suggested that the mechanism of the anti-HIV-1 action of CDS, mCDS, and CDP is based on inhibition of HIV-1 binding to the cells. The peak blood concentration after oral administration of mCDS11(potassium tris[6-benzylthio-6-deoxy]-β-cyclodextrin hexadecasulphate) to rabbits was about 1000 times higher than the concentration showing anti-HIV activity. The retention time in the blood was also long (blood half-life: 4 h). These results point to the potential usefulness of oral mCDS administration in the prophylaxis and/or therapy of HIV infections.

Section: Discussionmentioning

confidence: 99%

“…However, a clinical trial with oral OS administration showed no effect in patients with AIDS or ARC (Abrams et el., 1989). Other studies showed that following oral administration to humans or rats, OS is not readily absorbed (Lorentsen et al, 1989;Hartman et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Modified Cyclodextrin Sulphates(mCDS11) have Potent Inhibitory Activity against HIV and High Oral Bioavailability

Otake

Schols

Witvrouw

et al. 1994

“…inefficacy were low absorption rate from the intestine and rapid degradation of the drug in the blood (Lorentsen et al, 1989;Hartman et al, 1990).…”

mentioning

confidence: 99%

Characterization of Human Immunodeficiency Virus Type 1 Resistant to Modified Cyclodextrin Sulphate (mCDS71) in Vitro

Mori

Otake

Oishi

et al. 1999

Drug resistance of human immunodeficiency virus type 1 (HIV) to modified cyclodextrin sulphate (mCDS71) has been analysed with respect to both the in vitro appearance of resistance to the compound and the mechanism of the acquisition of resistance. Resistant strains could be obtained in all three strains (NL432, KK-1 and A018) tested after serial passages in MT-4 cells with a gradual increase of the concentration of mCDS71. Cross-resistance both to mCDS71 and dextran sulphate 8000 was observed. As a result of sequencing analysis of the gp120 V3-C5 region of resistant strains, the mechanism of resistance can be explained in several ways: (i) substitution of sugar chain-binding amino acids, N and S; (ii) three to five amino acid deletion in V4 loop; and (iii) several mutations in V3 and V4 regions. The real cause of the resistance may be a combination of these three mechanisms. The results suggest that the target of mCDS71 is relatively widely distributed on the viral surface glycoprotein.

“…A dextran sulfate formulation (Mw 8000 KOa) has been investigated in clinical trials in AIOS patients for activity against HIV-1, but was not efficacious when administered orally (Abrams et al, 1989) or intravenously (Flexner et al, 1991). This inactivity is related to the vulnerability of the molecule to metabolism particularly when delivered orally (Hartman et al, 1990). Although heparin is regularly used therapeutically to control blood coagulation, no definitive studies have been reported concerning its antiviral effects in man.…”

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of Herpes Simplex Virus by MDL 101028, a Novel Biphenyl Disulfonic Acid Urea Co-Polymer

Ahmed¹,

Cardin²,

Bridges³

et al. 1995

A novel low-molecular-weight sulfonic acid polymer, MDL 101028, was investigated for antiviral activity against herpes simplex virus (HSV) type 1 and type 2 in human embryonic diploid fibroblasts (MRC-5) and in a line of monkey kidney cells (Vero). Potent antiviral activities were obtained when treatment was restricted to the adsorption phase of virus propagation as measured by plaque reduction assay, and this was confirmed by experiments at high multiplicity of infection. Inhibition of virus binding to host cells by MDL 101028 was compared to that of heparin, a known antagonist of virus attachment. Both compounds showed dose-dependent inhibition, with IC50 values of 1.1 and 0.43 μg ml−1, respectively. The effect on cell-to-cell fusion was investigated using a syncytial-positive (syn+) phenotypic mutant of HSV-1 (strain 17i). MDL 101028 (3-1 μm) dramatically halted the spread of syncytial lesions; this effect was accompanied by the destruction of the syncytium and regrowth into the lesion by uninfected Vero cells. In contrast, heparin (10 μg ml−1) only partially reduced the spread of syncytia. Protection was also observed with MDL 29797 (100 μg ml−1), an antagonist of glycoprotein maturation. Unexpectedly, only a marginal effect was observed with acyclovir (10 μg ml−1), a potent inhibitor of viral DNA synthesis and HSV growth. As an extension to the current therapy for herpes simplex infection, acyclovir, the potent anti-fusion activity of MDL 101028 may have a clinical use in tissues or organs in which cell-to-cell fusion contributes to the pathology.