Oral Dextran Sulfate (UAOO1) in the Treatment of the Acquired Immunodeficiency Syndrome (AIDS) and AIDS-Related Complex

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%

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

Otake

Schols

Witvrouw

et al. 1994

“…Serum drug concentrations achieved by these sulfated polymers were highly dependent on the route of administration. Clinical trials of oral OS (Abrams et al, 1989) and PS (Peters et al, 1989) were terminated soon after the drug was shown to be poorly absorbed (bioavailability < 1%) (Lorentsen et al, 1989). No significant changes in surrogate markers (p24) or clinical endpoints (CD4), suggesting anti-HIV activity, were recorded from those trials.…”

Section: Clinical Efficacymentioning

confidence: 99%

Antiviral Portrait Series: 4. Polysuifates as Inhibitors of HIV and Other Enveloped Viruses

Witvrouw¹,

Desmyter²,

Clercq

1994

101

Polysulfates are highly potent and selective inhibitors of the in vitro replication of HIV and other enveloped viruses. They not only inhibit the cytopathic effect of HIV, but also prevent HIV-induced syncytium (giant cell) formation. They also act synergistically with other anti-HIV drugs. The anti-HIV activity of polysulfates is a result of their shielding of the positively charged sites in the V3 loop of the viral envelope glycoprotein gp120. When polysulfates were administered intravenously to rabbits, their half-life was approximately 2h. Although they are very poorly absorbed following oral administration, they can be made orally bioavailable with the appropriate chemical modifications. Also, polysulfates may lose (much of) their anticoagulant activity upon chemical modification without giving up their anti-HIV activity. Their efficacy in the therapy and/or prophylaxis of retroviral infections remains to be demonstrated both in animal models and in humans.

“…Aurintricarboxylic acid predominantly interacts with the CD4 receptor (Schols et al, 1989), whereas dextran sulphate has a shielding effect on the viral gp120 protein (Schols et al, 1990). Despite the low clinical activity of dextran sulphate when orally administered (Abrams et al, 1989), this polyanionic molecule is the prototype for other anionic derivatives that can block viral replication by inhibiting viral binding. Inhibition of viral capsid assembly might be an alternative mechanism, as was shown recently for a sulphonic acid derivative (Teschke et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Song

Witvrouw

Schols

et al. 1997

SummaryVarious water-soluble polysulphonated and polycarboxylated porphyrins and some of their metallated derivatives have been prepared and their antiviral properties against human immunodeficiency virus (HIV-1, HIV-2), simian immunodeficiency virus and other viruses are reported. Besides these polyanionic compounds, two new series of porphyrins were included and studied from the perspective of bio-availability modulation: (i) acetylsulphonamido derivatives endowed with weak acidity properties (deprotonation gives the corresponding anionic derivatives in a pH range 4.5-8.5) and (ii) compounds with the anionic charge transiently masked by esterification (acetoxymethyl-and pivaloyloxymethylesters). Among the more active compounds in inhibiting HIV-induced cytopathic effects, the sulphonated and carboxylated porphyrin complexes were found to interact directly with the HIV protein gp 120 and not with the CD4 cellular receptor.