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Biomedical subjects

R Pauwels

Publications and source records attributed to R Pauwels.

At least 127 records · Page 7Linked to original sources
PubMed1990

Airway hyperreactivity, an introduction.

Asthma is characterized by the presence of airway inflammation and an increased responsiveness to many different stimuli. The hyperresponsiveness to indirect stimuli such as adenosine, bradykinin, neuropeptides, sulphur dioxide suggest that the hyperresponsiveness in asthma results from the complex interaction between inflammatory cells, neurons and smooth muscle cells. Several mechanisms may be involved in the influence of airway inflammation on airway responsiveness: increased mucosa permeability: enhanced exposure of irritant receptors, modulation of airway smooth muscle behavior by inflammatory mediators, mucosal edema, enhanced release of neurotransmitters, increased local reflex activity, decreased breakdown of neurotransmitters, etc. We have investigated the interaction between airway inflammation and responsiveness in two animal models: acute exposure to endotoxin and chronic exposure to aerosolized antigen. Both models demonstrate the complexity of interaction between inflammatory processes and demonstrate positive controlling mechanisms that inhibit the increase in airway responsiveness due to airway inflammation. The lack of such controlling mechanisms may be involved in the development of the asthmatic airway hyperresponsiveness.

Administration, Inhalation↗
PubMed1990

The pharmacology of airway hyperresponsiveness and inflammation.

Hyperresponsiveness is a key abnormality in asthma and deserves recognition both in the clinical presentation of asthma and its pathogenesis. Available evidence strongly suggests that inflammatory processes are important in producing this aspect of disordered airway physiology. Pharmacologic studies have greatly increased our knowledge of mechanisms involved in hyperresponsiveness but fall short of a complete explanation of the phenomenon. It is most likely that hyperresponsiveness, as measured in the laboratory, has many different components and that any single mechanism will be an insufficient explanation.

Airway Resistance↗
PubMed1990

Dextran sulfate and other polyanionic anti-HIV compounds specifically interact with the viral gp120 glycoprotein expressed by T-cells persistently infected with HIV-1.

Eighty to 100% of persistently HIV-1-infected HUT-78 cells express the viral glycoprotein gp120 as demonstrated with anti-gp 120 monoclonal antibody (mAb) and fluorescence-activated cell sorter (FACS) analysis. Several polyanionic anti-HIV compounds, i.e., dextran sulfate, pentosan polysulfate, heparin, aurintricarboxylic acid (ATA), suramin, and Evans blue, which are known to inhibit the adsorption of HIV particles to CD4+ cells, prevented the binding of anti-gp120 mAb to the persistently HIV-1 infected HUT-78 cells. This effect was dose-dependent and reversible. Except for ATA, the polyanionic compounds did not interfere with the binding of Leu3a/OKT4A mAB, indicating that they do not directly bind to the CD4 receptor. Thus, the inhibitory effect of dextran sulfate and its congeners on the interaction of the HIV gp120 with the cellular CD4 receptor can be ascribed to a specific binding ("shielding") of gp120.

Antibodies, Monoclonal↗
PubMed1990

Anti-HIV-1 activity of antiviral compounds, as quantitated by a focal immunoassay in CD4+ HeLa cells and a plaque assay in MT-4 cells.

The inhibitory effects of a series of antiviral compounds on human immunodeficiency virus type 1 (HIV-1) were evaluated in a plaque assay (PA) in MT-4 cells and a focal immunoassay (FIA) in CD4+ HeLa cells. Similar 50% inhibitory concentrations (IC50) were obtained for the sulfated polysaccharides when measured by PA or FIA: the IC50 values of dextran sulfate and pentosan polysulfate were 0.8 microgram/ml and 0.35 microgram/ml, respectively. Also, comparable IC50 values (ranging from 1.42 to 2.71 microM) were obtained for purine 2',3'-dideoxyribosides (i.e. DDA, DDI and DDG) when evaluated by PA or FIA. In contrast, the IC50 values of pyrimidine 2',3'-dideoxyribosides were invariably 4- to 10-fold lower when monitored by PA than FIA: the IC50s of AZT, D4T and DDC in the PA were 0.015, 0.094 and 0.038 microM, respectively, and in the FIA were 0.062 microM, 0.29 microM and 0.46 microM, respectively. The differential anti-HIV-1 activities found with AZT, D4T and DDC in the PA and FIA systems may at least be related in part to differences in the metabolism of the compounds (i.e. phosphorylation by thymidine kinase or 2'-deoxycytidine kinase) between MT-4 and CD4+ HeLa cells. The novel anti-HIV-1 compounds tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO) derivatives, R82150 and R82913, and the acyclouridine derivative 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) were also more inhibitory to HIV-1 in the PA than FIA system. The IC50 values of R82150, R82913 and HEPT, as based on PA, were 0.005, 0.003 and 0.79 microM, respectively. Their IC50 values, as based on FIA, were 0.020 microM, 0.015 microM and 3.77 microM, respectively. The TIBO derivatives emerged as the most effective HIV-1 inhibitors of the compounds tested whether assayed by PA or FIA.

Antiviral Agents↗
PubMed1990

Novel sulfated polysaccharides: dissociation of anti-human immunodeficiency virus activity from antithrombin activity.

Novel sulfated polysaccharides, sulfated bacterial glycosaminoglycan (Org 31581) and chemically degraded heparin (Org 31733), have proved to be potent and selective inhibitors of human immunodeficiency virus (HIV) in vitro. Their 50% inhibitory concentrations for HIV type 1 (HIV-1) in MT-4 cells were 0.67 and 0.52 micrograms/ml, respectively. These values are comparable to those obtained for dextran sulfate and standard heparin (0.39 and 0.89 micrograms/ml, respectively). Org 31581 and Org 31733 showed much less antithrombin activity than did dextran sulfate and standard heparin. These results indicate that the anti-HIV activity of sulfated polysaccharides can be dissociated from their antithrombin activity. Org 31581 and Org 31733 were equally inhibitory to HIV-2 and HIV-1 and were also inhibitory to the replication of human cytomegalovirus. Syncytium formation, induced by cocultivation of MOLT-4 (clone 8) cells with chronically HIV-1-infected HuT 78 cells, was also inhibited by Org 31581. As previously demonstrated with dextran sulfate and heparin, both Org 31581 and Org 31733 blocked virus adsorption to the host cells. These compounds offer great promise as candidate drugs for the chemotherapy of HIV infections.

Blood Coagulation↗
PubMed1990

Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency virus replication and giant cell formation.

Novel synthetic sulfated polymers, namely, sulfated polyvinyl alcohol (PVAS) and sulfated copolymers of acrylic acid with vinyl alcohol (PAVAS), proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in vitro. The compounds completely inhibited HIV-1-induced cytopathogenicity in MT-4 cells and HIV-1 antigen expression in CEM cells at a concentration of 0.8 micrograms/ml. They were equally effective against HIV-2 replication. In addition, and in contrast to azidothymidine, PAVAS and PVAS suppressed HIV-1-induced giant cell (syncytium) formation, a process that may account for the depletion of T4 lymphocytes in patients with acquired immunodeficiency syndrome. PAVAS and PVAS completely blocked giant cell formation at a concentration of 4 micrograms/ml, whereas for dextran sulfate a concentration of 100 micrograms/ml was required to achieve complete inhibition of giant cell formation. As has been demonstrated previously for the sulfated polysaccharides, the mechanism of action of PAVAS and PVAS resides in the inhibition of virus adsorption to the cells.

Acrylic Resins↗
PubMed1990

The penetration of aminoglycosides into the alveolar lining fluid of rats. The effect of airway inflammation.

The concentration-time profile of gentamicin and tobramycin in the alveolar lining fluid (ALF) of rats was determined after intravenous bolus injection using bronchoalveolar lavage (BAL). BAL can be used for evaluating the penetration of both aminoglycosides into the ALF if highly sensitive detection methods are used, and an endogenous marker (urea) can be applied to avoid the unpredictable dilutional effect of the lavage procedure. The concentration of gentamicin and tobramycin in ALF reached a peak after 5 and 10 min, respectively, and remained high when plasma concentrations were declining, suggesting an accumulation reservoir in the lung acini. The ratio of the AUC of the concentration-time profile in ALF and plasma was 0.67 and 0.45 for gentamicin and tobramycin, respectively. The penetration of both aminoglycosides into the ALF was significantly higher after induction of airway inflammation by inhalation of endotoxin. The ratio of the AUC in ALF and plasma in the endotoxin-exposed animals was 0.76 and 0.55 for gentamicin and tobramycin, respectively. The ratio of the AUC of the concentration-time profile of gentamicin in ALF to that of tobramycin was 1.27 without inflammation and 1.44 after endotoxin exposure. Thus, both with and without inflammation, gentamicin penetrates better into the ALF than does tobramycin.

Animals↗
PubMed1990

Scintigraphic, spirometric, and roentgenologic effects of radiotherapy on normal lung tissue. Short-term observations in 14 consecutive patients with breast cancer.

The effects of radiotherapy on lung function, ventilation/perfusion scans, and chest radiography were studied prospectively in 15 patients who underwent either modified radical mastectomy or tumorectomy, followed by radiotherapy for breast cancer. In all patients, pulmonary function studies, chest x-ray films, and lung scintigraphic studies were performed prior to and at the end of radiotherapy as well as three months later. No consistent or significant alteration in either parameter was detected. No patient developed clinical symptoms suggestive of radiation-induced lung changes, although in one of them, major radiologic features were found that were consistent with radiation pneumonitis; those changes disappeared completely in the course of the subsequent months. It is concluded that the tangential beam technique for postoperative irradiation as used in these patients is largely safe as regards pulmonary function, perfusion, and ventilation.

Adult↗
PubMed1990

Establishment of a bioassay to determine serum levels of dextran sulfate and pentosan polysulfate, two potent inhibitors of human immunodeficiency virus.

Dextran sulfate and pentosan polysulfate are two promising candidate anti-acquired immune deficiency syndrome (AIDS) drugs that have already been the subject of initial clinical trials in patients with AIDS. There is at present no reliable assay method to monitor blood drug levels in humans following the administration of either drug. We have now developed a sensitive bioassay system based on the inhibitory activity of the compounds against human immunodeficiency virus type 2 (HIV-2) in MT-4 cells. This method permits the detection in (rabbit) serum samples of dextran sulfate and pentosan polysulfate concentrations as low as 3.0 and 0.5 micrograms/ml, respectively. Pharmacokinetic studies with dextran sulfate and pentosan polysulfate in rabbits indicated that the half-life of these compounds after intravenous bolus injection is approximately 1 h 24 min.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Sulfated polysaccharides as potent inhibitors of HIV-induced syncytium formation: a new strategy towards AIDS chemotherapy.

Multinucleated giant cell (syncytium) formation induced by the interaction between the gp120 glycoprotein expressed on the surface of cells infected with human immunodeficiency virus type (HIV-1) and the CD4 receptor of uninfected CD4-positive (CD4+) cells may play an important role in the depletion of T4 lymphocytes in acquired immune deficiency syndrome (AIDS) patients. Using a double fluorescence cell-staining technique and analysis of the cells by the fluorescence-activated cell sorter (FACS), we have demonstrated that giant cell formation between persistently HIV-1-infected HUT-78 cells and uninfected MOLT-4 cells results in a selective destruction of the uninfected CD4+ MOLT-4 cells. Apparently, bystander CD4+ cells may serve as targets for the killing effect of the HIV-1-infected cells, and this killing effect is preceded by fusion between the target (uninfected) and aggressor (infected) cells. Pentosan polysulfate, dextran sulfate, and various other sulfated polysaccharides, but not heparin, have proved to inhibit this cell fusion process and hence protect the target CD4+ cells against destruction by the killer HIV-1-infected cells. Azidothymidine does not interfere with this process. Assuming that fusion between HIV-infected and uninfected CD4+ cells is a crucial event in the pathogenesis of AIDs, any compounds that specifically interfere with this process may be therapeutically advantageous in the treatment of this disease.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pharmacokinetics of antibiotics in the lungs.

This paper reviews current knowledge on the relationship between local penetration or antibiotics and therapeutic efficacy in pulmonary and bronchial infections. The antimicrobial drug concentration at the site of infection is supposedly determinative for the efficacy of the antibiotic treatment but the number of studies in respiratory infections supporting this hypothesis is limited. The mechanisms responsible for the pulmonary deposition or orally or systemically administered antibiotics include passive diffusion, active transport, bulk flow and permeation. The penetration of antimicrobial drugs into the respiratory tract is influenced by both host-related factors, such as inflammation or mechanical injury, and drug-related factors, such as molecular weight. In addition, local bio-inactivation can occur. The final bioactive antibiotic concentration at the site of the respiratory infection is, therefore, the result or a very complex dynamic process. Different sampling and measuring methods have been used for the assessment of antibiotic concentrations at the site of respiratory infections. Concentrations in sputum, bronchial secretions and biopsy specimens have been correlated with serum concentrations and clinical outcome. Bronchoalveolar lavage could be a promising technique for evaluating antibiotic drug concentrations in alveolar lining fluid. For many antibiotics, data concerning penetration and pharmacokinetic behaviour in the respiratory tract are lacking.

Aminoglycosides↗
PubMed1989

Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative.

A novel 6-substituted acyclouridine derivative, 1-[(2-hydroxy-ethoxy) methyl]-6-phenylthiothymine (HEPT), has proved to be a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) in vitro. HEPT inhibits HIV-1 replication in various T4 cell cultures as well as peripheral blood lymphocytes and macrophages. The 50% antiviral effective concentration for HIV-1 (HTLV-IIIB) in MT-4 cells is 7.0 microM, while the 50% cytotoxic concentration for mock-infected MT-4 cells is 740 microM. Although HEPT is inhibitory to various strains of HIV-1, it has no effect on the replication of other retroviruses including HIV type 2. In contrast with the dideoxynucleoside (i.e. azidothymidine) 5'-triphosphates, the triphosphate of HEPT does not interact with HIV-1 reverse transcriptase. The mechanism of action of HEPT remains subject of further study.

Antiviral Agents↗
PubMed1989

Tetrazolium-based plaque assay for HIV-1 and HIV-2, and its use in the evaluation of antiviral compounds.

A modification of the MT-4 cell plaque assay for human immunodeficiency virus (HIV) is described, which gave reproducible results with all 4 HIV-1 strains and the two HIV-2 strains that were used. The main feature of this new method is the use of a tetrazolium (MTT) staining procedure. The number of plaques read after 4-6 days was essentially the same as the number of infectious units derived from the 50% cell culture infective dose (CCID50) in MT-4 suspension cultures. For a selected group of antiviral compounds the 50% plaque-inhibitory doses were comparable with the 50% inhibitory doses (ID50) in suspension cultures. In the plaque assay HIV-1 (HTLV-IIIB) and HIV-2 (LAV-2ROD) were equally susceptible to azidothymidine (AZT), and the same was true for didehydrodideoxythymidine (D4T). For these compounds it was irrelevant whether they were already present during the initial HIV adsorption phase or added immediately thereafter. Pentosan polysulfate proved about 20-fold more inhibitory to HIV-2 than HIV-1. There was a 5-fold increase in activity if present during the virus adsorption stage.

Antiviral Agents↗
PubMed1989

3'-Fluoro-2',3'-dideoxy-5-chlorouridine: most selective anti-HIV-1 agent among a series of new 2'- and 3'-fluorinated 2',3'-dideoxynucleoside analogues.

A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the corresponding inosine derivatives nor 8-bromination of 2',3'-dideoxyadenosine resulted in increased anti-HIV-1 activity. Nor did introduction of a 2'-fluorine in the erythro or threo configuration lead to improved anti-HIV-1 activity of the parent 2',3'-dideoxynucleosides. 1-(2-Fluoro-2,3-dideoxy-beta-D-threo-pentofuranosyl)cytosine and 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine were only marginally active. However, 3'-fluoro-2',3'-dideoxyuridine (FddUrd) proved to be potent and a relatively nontoxic inhibitor of HIV-1. 5-Halogenated derivatives of FddUrd were prepared in attempts to further increase its anti-HIV potency and selectivity. Of these 5-halogenated derivatives, 3'-fluoro-2',3'-dideoxy-5-chlorouridine emerged as the most selective inhibitor of HIV-1 replication. Its selectivity index was comparable to that of azidothymidine when evaluated under the same conditions.

Antiviral Agents↗
PubMed1989

Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the replication of human immunodeficiency virus (HIV) in vitro in human T-lymphocyte MT-4, H9, and ATH8 cells. PMEA also inhibits Moloney murine sarcoma virus (Mo-MSV)-induced transformation of murine C3H embryo fibroblasts. Moreover, PMEA causes a dose-dependent suppression of tumor formation and associated mortality in mice inoculated with Mo-MSV. At a dose of 50 or 20 mg/kg per day PMEA effected a 90-100% protection of the mice against Mo-MSV-induced tumor formation and mortality. Even with a PMEA dose as low as 1 to 5 mg/kg per day, tumor formation was significantly delayed and the survival rate was significantly enhanced. In parallel experiments, azidothymidine exhibited a comparable inhibitory effect on Mo-MSV-induced tumor formation and associated death only at a 25-fold higher dose than PMEA. Because PMEA has stronger in vivo antiretrovirus potency and selectivity than azidothymidine and various other compounds currently being subjected to clinical trials, PMEA studies should be pursued to assess the potential of this compound in the treatment of acquired immunodeficiency syndrome (AIDS) and other retrovirus infections in humans.

Adenine↗
PubMed1989

Specific interaction of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell receptor.

The triphenylmethane derivative aurintricarboxylic acid (ATA), but not aurin, selectively prevented the binding of OKT4A/Leu-3a monoclonal antibody (mAb) and, to a lesser extent, OKT4 mAb to the CD4 cell receptor for human immunodeficiency virus type 1 (HIV-1). The effect was seen within 1 min at an ATA concentration of 10 microM in various T4+ cells (MT-4, U-937, peripheral blood lymphocytes, and monocytes). It was dose-dependent and reversible. ATA prevented the attachment of radiolabeled HIV-1 particles to MT-4 cells, which could be expected as the result of its specific binding to the HIV/CD4 receptor. Other HIV inhibitors such as suramin, fuchsin acid, azidothymidine, dextran sulfate, heparin, and pentosan polysulfate did not affect OKT4A/Leu-3a mAb binding to the CD4 receptor, although the sulfated polysaccharides suppressed HIV-1 adsorption to the cells at concentrations required for complete protection against HIV-1 cytopathogenicity. Thus, ATA is a selective marker molecule for the CD4 receptor. ATA also interfered with the staining of membrane-associated HIV-1 glycoprotein gp120 by a mAb against it. These unusual properties of a small molecule of nonimmunological origin may have important implications for the study of CD4/HIV/AIDS pathogenesis and possibly treatment.

Adsorption↗
PubMed1989

Syncytium formation and destruction of bystander CD4+ cells cocultured with T cells persistently infected with human immunodeficiency virus as demonstrated by flow cytometry.

We have developed a flow cytometric method for demonstrating cell fusion between human immunodeficiency virus type 1 (HIV-1)- or HIV-2-infected HUT-78 cells and uninfected CD4-bearing MOLT-4 cells. Syncytium formation due to an interaction between the gp120 glycoprotein expressed on HIV-infected HUT-78 cells and the CD4 receptor present on MOLT-4 cells, resulted in an immediate decrease in the number of MOLT-4 cells; after a 24 h incubation period almost all MOLT-4 cells had disappeared from the culture. To show that the target MOLT-4 cells and not the aggressor HUT-78 cells were destroyed, specific monoclonal antibodies (MAbs) that reacted with antigens expressed on either MOLT-4 or HUT-78 cells were used. The formation of giant cells and the concomitant disappearance of MOLT-4 cells was blocked by MAbs specific for OKT4A and Leu3a, and, to a much lower level, by the MAbs specific of OKT4 and gp120. MAbs specific for OKT3, Leu2a, HLA-DR, Leu18 and LeuM3 did not prevent the disappearance of MOLT-4 cells. Sera from two AIDS patients containing antibodies to the HIV envelope glycoproteins did not protect MOLT-4 cells against the destructive effect of the HIV-infected HUT-78 cells. The fusion index, the percentage fusion inhibition and the 50% fusion inhibitory concentration of the MAbs can be accurately determined with the flow cytometric assay. The method can be readily implemented to evaluate any therapeutic treatment by examining its capacity to block cell-to-cell fusion, and hence destruction of the target bystander cells. Five anti-HIV compounds which have been previously shown to interfere with HIV binding to cells (namely pentosan polysulphate, heparin, suramin, aurintricarboxylic acid and Evans Blue) were further evaluated by this new method. With the exception of heparin, all of these compounds were found to inhibit cell-to-cell fusion and the concomitant destruction of the target bystander cells. Azidothymidine failed to inhibit fusion or bystander T cell destruction.

Antibodies, Monoclonal↗