Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro

Several sulfated oligo- or polysaccharides such as pentosan polysulfate, fucoidan, dextran sulfate, heparin and iota-, kappa- and lambda-carrageenans proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) in vitro. The most potent anti-HIV-1 activity was recorded for the oligosaccharide pentosan polysulfate, its 50% antiviral effective dose (ED50) being 0.19 microgram/ml in MT-4 cells. It inhibited HIV-1 antigen expression in HUT-78 cells at an ED50 of 0.02 microgram/ml, and complete inhibition of HIV-1 antigen expression was obtained at a concentration of 4.0 micrograms/ml. No toxicity for MT-4 cells was observed with pentosan polysulfate at a concentration of 2500 micrograms/ml. The anticoagulant activity of pentosan polysulfate was more than ten-fold lower than that of heparin (14.4 and 177 U/mg, respectively). In fact, pentosan polysulfate achieved its anti-HIV-1 activity at a concentration that is 370-fold below its anticoagulant threshold (1 U). Pentosan polysulfate inhibits virus adsorption to the cells, as was demonstrated by monitoring the association of radiolabeled HIV-1 virions with MT-4 cells.     

The mannose-specific plant lectins from Cymbidium hybrid and Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro.

A series of four mannose(Man)-, three N-acetylglucosamine (GlcNAc)n-, ten N-acetylgalactosamine/galactose(GalNAc/Gal)-, one 5-acetylneuraminic acid (alpha-2,3-Gal/GalNAc)- and one 5-acetylneuroaminic acid(alpha-2,6-Gal/Gal-NAc)-specific plant agglutinins were evaluated for their antiviral activity in vitro. the mannose-specific lectins from the orchid species Cymbidium hybrid (CA), Epipactis helleborine (EHA) and Listera ovata (LOA) were highly inhibitory to human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4, and showed a marked anti-human cytomegalovirus (CMV), respiratory syncytial virus (RSV) and influenza A virus activity in HEL, HeLa and MDCK cells, respectively. The 50% effective concentration (EC50) of CA and EHA for HIV ranged from 0.04 to 0.08 micrograms/ml, that is about 3 orders of magnitude below their toxicity threshold (50% inhibitory concentration for MT-4 cell growth: 54 to 60 micrograms/ml). Also, the (GlcNAc)n-specific lectin from Urtica dioica (UDA) was inhibitory to HIV-1-, HIV-2-, CMV-, RSV- and influenza A virus-induced cytopathicity at an EC50 ranging from 0.3 to 9 micrograms/ml. The GalNAc/Gal-, alpha-2,3-Gal/GalNAc- or alpha-2,6-Gal/GalNAc-specific lectins were not inhibitory to HIV or CMV at non-toxic concentrations. CA, EHA and UDA proved to be potent inhibitors of syncytium formation between persistently HIV-1- and HIV-2-infected HUT-78 cells and CD4+ Molt/4 (clone 8) cells (EC50: 0.2-2 micrograms/ml). Unlike dextran sulfate, the plant lectins CA, EHA and UDA did not interfere with HIV-1 adsorption to MT-4 cells and RSV- and influenza A virus adsorption to HeLa and MDCK cells, respectively. They presumably interact at the level of virion fusion with the target cell.     

Inhibitory effect of tannic acid sulfate and related sulfates on infectivity, cytopathic effect, and giant cell formation of human immunodeficiency virus.

The acquired immune deficiency syndrome (AIDS) is thought to result from infection of T cells by a pathogenic human retrovirus, human immunodeficiency virus [HIV (HTLV-III/LAV)]. In this report, we synthesized sulfated plant polyphenols such as tannic acid sulfate, rutin sulfate, ellagic acid sulfate, (-)-epicatechin sulfate, and (-)-epigallocatechin 3-gallate sulfate, and examined the in vitro inhibitory effect on HIV infection using human T-cell lymphotropic virus type-I-carrying MT-4 cells, which are extremely susceptible to HIV infection. Of the compounds tested, tannic acid sulfate was the most effective and had low cytotoxicity. Tannic acid sulfate completely inhibited the cytopathic effect of HIV and the HIV-specific antigen expression in MT-4 cells at the concentration of 6 micrograms/ml. In addition, this sulfate inhibited giant cell formation in coculture at the concentration of 5 micrograms/ml.     

Pharmacokinetics and clinical effects of cefixime in pediatrics

Pharmacokinetics and clinical effects of cefixime (CFIX), a new oral cephalosporin antibiotic, in pediatric field were investigated. The result obtained were summarized as follows. CFIX (5% granules) was given to each of 5 children twice in a single dose of 1.5 or 3.0 mg/kg in a cross-over trial. The mean peak serum concentration of CFIX was 0.64 micrograms/ml at 4 hours after given the dose of 1.5 mg/kg and 1.15 micrograms/ml at 4 hours after the dose of 3.0 mg/kg. The mean half-life and the mean AUC values were 2.72 hours and 4.10 micrograms X hr/ml, respectively after the dose of 1.5 mg/kg, and 2.77 hours and 8.26 micrograms X hr/ml after the dose of 3.0 mg/kg. The urinary recovery was investigated in 5 children after the dose of CFIX of 1.5 mg/kg and in 4 children after the dose of 3.0 mg/kg. The mean peak urinary concentrations of CFIX and the mean 12-hour urinary recovery rates were 10.6-67.9 micrograms/ml at 2-10 hours and 15.7% after the dose of 1.5 mg/kg, and were and were 6.16-230 micrograms/ml at 2-8 hours and 18.9% after the dose of 3.0 mg/kg, respectively. CFIX was given to 6 children twice in a single dose of 50 mg either in the form of 5% granules or in capsules in a cross-over trial. The mean peak serum concentrations, half-life and AUC values were 1.26 micrograms/ml at 4 hours, 3.09 hours and 9.63 micrograms X hr/ml, respectively after the dose of 50 mg CFIX in 5% granules, and were 1.16 micrograms/ml at 4 hours, 2.87 hours, and 7.82 micrograms X hr/ml, respectively after the dose of 50 mg in capsules. The urinary recovery was investigated in 5 children. The mean peak urinary concentrations and the mean 12-hour urinary recovery rates were 19.1-114 micrograms/ml at 4-10 hours and 15.7%, respectively after the dose of 50 mg in 5% granules, and were 8.16-89.0 micrograms/ml at 4-10 hours and 11.3%, respectively after the dose of 50 mg in capsules. Clinical efficacy of CFIX was investigated in a total of 26 children including 2 with tonsillitis, 2 with acute bronchitis, 2 with scarlet fever and 20 with urinary tract infection. Each of children were given orally a dose of 2.6 mg/kg CFIX 2-3 times a day for 11 days in average.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antiviral activity of sulfated polysaccharides against African swine fever virus.

The polyanionic substances lambda and kappa carrageenan, pentosan polysulfate, fucoidan, dextran sulfate and heparin were investigated for their inhibitory effect on the replication of African swine fever virus (ASFV) in vitro. Lambda carrageenan was the most efficacious with a selectivity index, as based on the ratio of the 50% cytotoxic concentration to the 50% antiviral effective concentration, of 120, followed by pentosan polysulfate with 30, kappa carrageenan 13.3 and fucoidan 10. Dextran sulfate and heparin were almost inactive. In general, the substances had low toxicity for Vero cells. The studies with radiolabeled ASF virions suggest that the sulfated polysaccharides inhibit virus adsorption. Inhibition of virus replication was found for all the polysaccharides only when the substances were present during virus adsorption, with the exception of lambda and kappa carrageenan, which were also inhibitory when added immediately after the adsorption period.     

Inhibition of herpes simplex virus types 1 and 2 replication in vitro by mercurithio analogs of deoxyuridine.

The in vitro antiviral activity of several 5-mercurithio analogs of 2'-deoxyuridine (dUrd) on the replication of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) were examined. Of those compounds tested, the thioglycerol analog of 5-mercuri-2'-deoxyuridine (HgdUrd) was most effective in inhibiting the replication of HSV-1 in KB cells with a 50% inhibitory dose (ID50) of 0.001 micrograms/ml while the glutathione analog of HgdUrd was the most effective in inhibiting the replication of HSV-2 with a ID50 of 0.075 micrograms/ml. Conversely in HeLa TK- cells, the mercaptoguanosine analog of HgdUrd was the most effective compound in inhibiting virus replication with ID50S of 0.098 and 0.001 micrograms/ml for HSV-1 and HSV-2 respectively. These results suggest that these mercurithio analogs of dUrd are as effective as acyclovir in preventing the replication of these herpesviruses.     

Inhibitory effect of selected antiviral compounds on arenavirus replication in vitro

Several compounds, belonging to different classes of nucleoside analogues and sulfated polysaccharides, were evaluated for their inhibitory effects on the replication of the arenaviruses Junin and Tacaribe in VERO cells. S-Adenosylhomocysteine (AdoHcy) hydrolase inhibitors [i.e. adenosine dialdehyde, carbocyclic 3-deazaadenosine (C-c3 Ado), neplanocin A, 3-deazaneplanocin A, 9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], (RS)-3-adenin-9-yl-hydroxypropanoic acid isobutyl ester [(RS)-AHPA], the 2',3'-dihydroxycyclopentenyl derivatives of adenine (DHCA) and 3-deazaadenine (DHCDA)] inhibited arenavirus replication within the concentration range of 1-10 micrograms/ml, while not being toxic for cell morphology or cellular DNA synthesis at a concentration of 100-400 micrograms/ml. Based on the ratio of the concentrations required to inhibit cell proliferation and virus replication, only (S)-DHPA, DHCA, C-c3 Ado and adenosine dialdehyde could be considered as truly selective inhibitors. Tubercidin, cyclopentenyl cytosine, pyrazofurin and ribavirin also inhibited viral cytopathogenicity at concentrations that were well below the cytotoxic threshold. Carbodine (cyclopentyl cytosine) also proved to be a potent inhibitor of arenavirus replication, but it was not as selective as cyclopentenyl cytosine. Very potent and selective inhibitors were the sulfated polysaccharides dextran sulfate, lambda-carrageenan, fucoidan, heparin and pentosan polysulfate: they inhibited virus replication at a concentration of 0.1-2.8 micrograms/ml, whereas the compounds were not inhibitory to cell growth even at a concentration of 200 micrograms/ml.     

A study of the absorption and excretion of fosfomycin sodium in children

Fosfomycin sodium (FOM-Na, Forocyle-S) was administered at 25 mg/kg or 50 mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analysis was carried out using the one-compartment model. 1. Average concentrations in the blood serum after injections with 25 mg/kg and 50 mg/kg were 55.3 +/- 6.3 micrograms/ml and 118.8 +/- 31.1 micrograms/kg 30 minutes after injection, respectively, and their half-lives were 1.04 +/- 0.15 hours and 0.98 +/- 0.17 hours, respectively. Six hours after injection, the levels were 2.7 +/- 1.6 micrograms/kg and 6.2 +/- 5.5 micrograms/kg, respectively. With 1 hour intravenous drip infusion of 25 mg/kg and 50 mg/kg, average concentrations the blood serum were 34.2 +/- 14.9 micrograms/ml and 89.7 +/- 6.7 micrograms/ml, respectively, and their half-lives were 0.87 +/- 0.24 hour and 0.69 +/- 0.10 hour, respectively. Six hours after the administration, the levels were 2.7 +/- 1.8 micrograms/ml and 6.7 +/- 0.8 micrograms/ml. There was a clear dose response in the concentration levels in the blood in those given the drug at 25 mg/kg and 50 mg/kg in either method of administration. 2. Average levels in urine after injection of 25 mg/kg and 50 mg/kg were 5,778 +/- 2,257 micrograms/ml and 6,268 +/- 3,329 micrograms/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701 +/- 765 micrograms/ml and 1,588 +/- 1,324 micrograms/ml, respectively. Average excretion, rates into the urine were 72.8 +/- 11.0 and 73.9 +/- 11.1%, respectively. In case of 1 hour drips infusion of 25 mg/kg and 50 mg/kg, average concentrations in the urine 0-2 hours after administration were 3,570 +/- 1,540 micrograms/ml and 11,800 micrograms/ml, respectively, and averages for 4-6 hours were 211 +/- 124 micrograms/ml and 1,300 micrograms/ml. Average rates of excretion into the urine for the first group was 57.9 +/- 16.3% and the second group was 78.4%. Clear dose response was observed in changes of drug concentration levels in the urine with 25 mg/kg and 50 mg/kg doses through either administration method, and in terms of excretion into the urine, no noticeable differences were observed between the different amounts administered or different administration methods.(ABSTRACT TRUNCATED AT 400 WORDS)     

一些保肝药物对原代培养大鼠肝细胞糖原合成功能的影响

本文参照PO Seglen的方法并加以修改,建立了原代培养大鼠肝细胞糖原合成功能的测定体系。观察到联苯双酯既能使正常肝细胞合成糖原增加88%,又能保护肝细胞完全拮抗四氯化碳对其功能的损伤;银耳多糖能使四氯化碳对肝细胞糖原合成功能的损伤减轻57%;去甲斑蝥素10μg/ml能增加肝细胞糖原合成,浓度增加到100μg/ml时,此作用减弱,1000μg/ml则明显抑制糖原的合成,而且在10～100μg/ml浓度时,即能加强四氯化碳的损伤作用;100μg/ml CL₁₅₀₀和熊果酸二钠单独应用可增加肝细胞糖原合成,但与四氯化碳同时应用,反而加重对糖原合成的抑制作用。     

A newly developed immunofluorescent assay for determining the Pichinde virus-inhibitory effects of selected nucleoside analogues

An immunofluorescent assay (IFA) for Pichinde virus (PCV), a member of the family Arenaviridae, was developed for antiviral drug assays against the virus. The assay was performed by adding fluorescein-labeled anti-PCV monoclonal antibody to virus-infected cells at 24 h after the initial infection and counting the infected cells with an epifluorescence microscope. The average 50% effective dose (ED50) for a series of nucleoside analogues tested against PCV using this IFA was: 2-beta-D-ribofuranosylselenazole-4-carboxamide (selenazofurin), less than 1.0 microgram/ml; 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin), 6.0 micrograms/ml; ammonium 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide- 5'-phosphate hydrate (ribavirin-5'-monophosphate), 15.8 micrograms/ml; ammonium 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5'-hemisuccinate (ribavirin-5'-hemisuccinate), 14.7 micrograms/ml; ammonium 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5'-(2,3- dimethyl)hemisuccinate [ribavirin-5'-(2,3-dimethyl)hemisuccinate], 213.5 micrograms/ml; 4-hydroxy-1-beta-D-ribofuranosyl-2-pyridone (3-deazauridine), 5.2 micrograms/ml; and (S)-9-(2,3-dihydroxypropyl)adenine, ([S]-DHPA), 471.0 micrograms/ml. In comparison, the ED50 of ribavirin using inhibition of marginal PCV-induced cytopathogenic effect after 12 days was 6.0 micrograms/ml and using plaque reduction after 5 days was 2.5 micrograms/ml, indicating that this IFA was of comparable sensitivity to these other tests.     

The adsorption of quinine and quinidine to activated charcoal with and without magnesium sulfate

The effect of magnesium sulfate on the in vitro adsorption of quinine and quinidine to activated charcoal (AC) was studied. Solutions of quinine and quinidine were prepared at concentrations of 5 and 10 micrograms/ml and at simulated toxic concentrations of 62.5, 125 and 250 micrograms/ml in distilled water. Drug-charcoal slurries were vortex mixed, centrifuged and analysed for free drug in the supernatant. Quinine had adsorption capacities of 78.2 to 100% with 12.5 or 50 mg AC; 12.5 or 50 mg AC adsorbed 29.5-87.2% of the quinidine. Quinine (250 micrograms/ml) had adsorption capacities of 0.0, 21.1, 52.4, 78.3 or 93.8% to 12.5, 50, 125, 250 or 500 mg AC, respectively. There was a corresponding increase quinine and quinidine adsorption at increasing concentrations of AC. The adsorption of quinine and quinidine seemed dose dependent. Magnesium sulfate (7.5 mg/ml) enhanced the adsorption of quinine to AC, but increased the amount of AC required for quinidine-charcoal adsorption.     

Evaluation of the toxicity and antiviral activity of carbocyclic 3-deazaadenosine against respiratory syncytial and parainfluenza type 3 viruses in tissue culture and in cotton rats

The toxicity and antiviral efficacy of carbocyclic 3-deazaadenosine (Cc3Ado) against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) virus infections were tested in tissue culture and in cotton rats. The mean median efficacious dose (ED50) of Cc3Ado in HEp2 cells against RSV and PIV3 was 9 and 14 micrograms/ml, respectively. These values were 85- and 55-fold less than the median inhibitory (toxic) dose (ID50) of Cc3Ado in this cell line (750 micrograms/ml), and similar to values obtained for ribavirin. Cc3Ado exhibited no significant antiviral activity against influenza A, influenza B, adeno type 5 or adeno type 7 viruses (all ED50 were greater than 1000 micrograms/ml). In cotton rats, animals given greater than or equal to 1 mg/kg/day Cc3Ado intraperitoneally on days 1, 2 and 3 after experimental challenge with virus, consistently had significant reductions in pulmonary RSV and PIV3 titers compared to pulmonary virus titers in comparably treated control animals. The minimum efficacious dose of ribavirin given under the same conditions was 30 mg/kg/day. Cc3Ado was also efficacious in cotton rats when given orally by gavage, or when different administration schedules were used. The median efficacious dose of Cc3Ado when given orally was 10 mg/kg/day. No significant toxic effects were noted in cotton rats, even in animals given 20 mg/kg daily for eight consecutive days.     

Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients.

OBJECTIVE: The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling. DESIGN AND SETTING: A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200 mg of saquinavir-SGC or 600 mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship. RESULTS: A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 micrograms/L (CV 40%). Saquinavir-SGC 1200 mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20,000 micrograms/L.h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count. CONCLUSION: Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200 mg, corresponding to 3600 mg/day.     

Intraperitoneal injection of dextran sulfate as an anti-adherent drug for the prevention of peritoneal metastasis of cancer shows low toxicity in animals

Intraperitoneal dextran sulfate with a mean molecular weight of 5 x 10(5) has been developed for use in an anti-adherent therapy against peritoneal carcinomatosis. The present study examined acute toxicity of i.p. injection of dextran sulfate in mice and rabbits. The 10, 50 and 90% lethal dose values are 0.213 (0.146-0.252), 0.336 (0.291-0.405) and 0.530 mg/g (0.431-0.873 mg/g: 95% confidence interval) in mice, respectively. These are markedly larger than the efficacious dose of 0.005-0.01 mg/g obtained previously. Death or symptoms of intoxication were seen within 3 days after administration of toxic doses. Rabbits received i.p. injection of dextran sulfate at 0.02 mg/g, which was close to the efficacious dose. At 2, 4, 6, 8 and 13 days after administration, blood was taken for biochemical and hematological analyses. Dextran sulfate at 0.02 mg/g induced no remarkable abnormal findings. These results suggest that the i.p. dextran sulfate is safe as an anti-adherent agent against peritoneal metastasis of cancer.     

Cytotoxicity studies on T-3262 in cultured Chinese hamster cells

T-3262 is an antibacterial drug which belongs to the group of pyridonecarboxylic acids. In this study, we investigated cytotoxicity of T-3262 for inhibition of cell growth and effects on viability of, and morphological changes in cultured Chinese hamster cells (V79 cells). The following results were obtained. 1. The 50% inhibition dose of T-3262 for cell growth (ID50, cultured for 48 hours) was 12 micrograms/ml, showing that the inhibitory effect of T-3262 on the cell growth was stronger than that of enoxacin (ENX: ID50 44 micrograms/ml), norfloxacin (NFLX: ID50 105 micrograms/ml) or ofloxacin (OFLX: ID50 145 micrograms/ml). 2. The number of cells increased and dead cells were scarcely seen at the highest concentration tested in culture medium (40 micrograms/ml of T-3262 for 48 hours). At this concentration, degeneration of cytoplasm (atrophy and round shape) and decrease of mitotic cells were observed. These morphological changes were similar to those of the cells treated 400 micrograms/ml of NFLX or OFLX for 48 hours. 3. After the removal of T-3262 from culture medium, the cells began to grow actively and recovered from the morphological changes. The similar phenomenon was observed with ENX treated cells but not with fluorouracil or mitomycin C treated cells.     

Inhibitory effect of substituted dextrans on MCF7 human breast cancer cell growth in vitro.

Substituted dextrans can reproduce some of the properties of heparin and can thus be used to alter cellular growth. We studied the effect of heparin (H108), dextran (D), carboxymethylbenzylamide dextran (CMDB) and carboxymethylbenzylamide sulfonate dextran (CMDBS) on the growth of human mammary cells of the MCF7 tumor line. The cells were cultured in minimum Eagle's medium containing 2% fetal calf serum without biopolymer, or with increasing concentrations of H108, D, CMDB or CMDBS. Growth curves were accurately based on cell counting using a Coulter counter. Cell distribution in the various phases of the cycle was analyzed by flow cytometry. Dose-dependent growth inhibitory effects (400-4000 micrograms/ml) were observed. The effect on MCF7 tumor cells was most apparent with CMDBS. The percentage of cells in the S phase decreased with preferential blocking in the G0/G1 phase. Pre-clinical studies can be anticipated as there is an absence of in vivo toxicity.     

Anti-HIV activity of dextran sulphate as determined under different experimental conditions

Dextran sulphate is a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1). Its anti-HIV-1 activity has been investigated under varying experimental conditions. MT-4 cells were infected with HIV-1 at different multiplicities of infection (MOI), and treated with either dextran sulphate, 3'-azido-2',3'-dideoxythymidine (AZT), or anti-HIV-1 serum obtained from an ARC patient. Dextran sulphate suppressed HIV-1 replication (as monitored by viral antigen expression) when the MOI was 0.01 or 0.1. It was ineffective at an MOI of 1.0. The anti-HIV-1 serum was only partially effective at an MOI of 0.01 and ineffective at an MOI of 0.1 or 1.0. AZT proved effective at all three MOIs. Co-cultures of uninfected and HIV-1-infected MT-4 cells were protected against destruction by dextran sulphate at a concentration of 10 and 100 micrograms/ml. To fully suppress viral antigen expression a concentration of 100 micrograms/ml was needed. When used at this concentration, a 1-h contact of dextran sulphate with the cells during the virus adsorption period sufficed to suppress HIV-1 antigen expression. In this sense, dextran sulphate behaved like the anti-HIV-1 serum. Dextran sulphate also behaved like OKT-4A in that they both inhibited HIV-1 attachment to the MT-4 cells, whereas OKT-4 failed to do so. However, dextran sulphate did not affect the binding of OKT-4A to the cells. The present results support the concept that dextran sulphate owes its anti-HIV-1 activity mainly to inhibition of virus binding to its target cells. The anti-HIV-1 activity of dextran sulphate is highly dependent on its sulphate content.     

Effect of Dextran Sulfate on Renal Accumulation of Gentamicin

The effect of dextran sulfate of three molecular weights (1000, 5000, and 90,000) on the accumulation of gentamicin in rat kidney was investigated using a continuous infusion technique. During the infusions of both gentamicin and gentamicin-dextran sulfate mixtures, the gentamicin plasma concentration was maintained at 10 µg/ml. The renal cortical accumulation of gentamicin was significantly lower when dextran sulfate (1000, 5000) was coadministered. The inhibition of cortical gentamicin accumulation increased with increasing dextran sulfate dose, and it was proportional to the amount of dextran sulfate excreted into the urine. Analysis by electrophoresis on cellulose acetate membrane indicated that gentamicin binds to dextran sulfate in rat urine. Therefore, gentamicin–dextran sulfate binding within the lumen of the proximal tubules may reduce the renal reabsorption and possibly the renal toxicity of gentamicin.