title: Curdlan sulfate (CRDS) in a 21-day intravenous tolerance study in human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infected patients: indication of anti-CMV activity with low toxicity.
abstract: This study evaluated tolerance (and possible efficacy) for 21 days of i.v. administration at three dose levels of curdlan sulfate (CRDS) (a semisynthetic sulfated polysaccharide), administered over 30 minutes, in HIV and CMV (in some cases) infected individuals with CD4 levels < 500 cells/mm3. Half of the subjects were previously treated with reverse transcriptase inhibitors (RTI) (which were continued during the CRDS administration) and half the patients had no prior RTI treatment. Evaluation of other sulfated polysaccharides in HIV had been discontinued due to side effects and lack of activity. Three groups of HIV patients (also including subsets with CMV infection) were treated separately with 50 mg/70 Kg, 100 mg/70 Kg and 200 mg/70 Kg of CRDS infused i.v. over thirty minutes daily for 21 days. In each dose group, half of the patients selected were being treated with a RTI and half were on no RTI. Patients were monitored for CD4 cell levels, viral load in some cases, and safety parameters in blood. Samples of urine and semen were additionally taken for CMV by culture and for PCR assay in subsets of participants. CRDS in this 21 day study was well-tolerated and produced few reportable side effects. Systematic decreases in platelets and increases in p24 antigen previously seen with dextran sulfate were not observed in this study with CRDS. In the 21 patients testing positive for CMV at the start of the study, 12 were CMV negative at the end of 21 days. In an untreated historical control group, 0/36 went from CMV positive to negative over a period of 13-15 years. The anti-CMV activity of CRDS in this study, therefore, had a p value < 0.001, based on these historical controls. The marked temporary increases in CD4 levels seen in the single dose and the seven-day CRDS studies on HIV patients were also seen for 21 days in the current study (p = 0.0001). Treatment with CRDS seems promising against CMV in HIV infected patients, even with once daily dosing of this two-hour half-life drug. CRDS was well tolerated and its lack of toxicity makes it an attractive candidate for CMV-infected HIV patients. Multiple daily dosing, or the continuous infusion of CRDS, could lead to increased effectiveness against both HIV and CMV, especially in combination with other agents. Given the toxicity of existing anti-CMV agents, and considering the emerging importance of CMV in atherosclerotic disease, further studies on CRDS are warranted.
authors.affiliation: AJI Pharma USA, Inc., Teaneck, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gordon
authors.forename: S
authors.initials: S
authors.lastname: Deeks
authors.forename: C
authors.initials: C
authors.lastname: De Marzo
authors.forename: J
authors.initials: J
authors.lastname: Goodgame
authors.forename: M
authors.initials: M
authors.lastname: Guralnik
authors.forename: W
authors.initials: W
authors.lastname: Lang
authors.forename: T
authors.initials: T
authors.lastname: Mimura
authors.forename: D
authors.initials: D
authors.lastname: Pearce
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018791:CD4 Lymphocyte Count; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D004361:Drug Tolerance; D005260:Female; D005936:Glucans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D047071:beta-Glucans
chemical_list: D000998:Antiviral Agents; D005936:Glucans; D047071:beta-Glucans; C063130:curdlan sulfate