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Biomedical subjects

P Smets

Publications and source records attributed to P Smets.

At least 37 records · Page 2Linked to original sources

Toxicity and activity of purified trichosanthin.

Trichosanthin was purified from fresh Chinese root tubers of Trichosanthes kirilowii and evaluated for anti-HIV activity. Trichosanthin inhibited syncytium formation between infected H9 cells and uninfected Sup-T1 cells from 0.5 to 4 micrograms/ml. Trichosanthin also inhibited HIV replication in H9 and CEM-SS cells at 1 microgram/ml, but was toxic for MT-4 cells (HTLV-I-positive), at doses greater than 0.25 microgram/ml. This new purification procedure confirms the anti-HIV activity of trichosanthin on some cell lines in different biological assays.

Amino Acids↗

Klebsiella pneumoniae glycoprotein RU-41740 enhances resistance of mice against Mycoplasma arthritidis-induced arthritis.

The effect of a purified glycoprotein extract from Klebsiella pneumoniae with non-specific immunostimulating properties (RU 41740) on the development and course of mycoplasma arthritis was investigated. Male A/J mice aged 2-3 months were given RU-41740 either intraperitoneally (i.p.) or orally prior to injection with Mycoplasma arthritidis. RU-41740 injected i.p. at 0.1 mg kg-1 or given orally at 1 mg kg-1 prior to the infection and subsequently on alternate days enhanced the resistance of mice to mycoplasma arthritis (P less than 0.001). Doses of 1 mg kg-1 i.p. or 10 mg kg-1 orally did not modify the course of the arthritis significantly, probably due to immunosuppressive factors from monocytes. It is suggested that RU-41740 protects the mice by stimulating macrophages. This immunostimulant might prove useful in the treatment of mycoplasma diseases, especially in the immunocompromised host.

Adjuvants, Immunologic↗

The European Stroke Prevention Study: results according to sex.

The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid tid with placebo in the prevention of stroke or death after one or more attacks of recent transient ischemic attacks or stroke of atherothrombotic origin. From the 2,500 patients in the intention-to-treat analysis, the proportion of women was 42%, and from the 1,861 patients in the explanatory analysis it was 44%. The endpoint incidence was significantly higher in men than in women. The endpoint reduction was statistically significant only in the intention-to-treat analysis with total endpoints. However, there was a marked percentage reduction of endpoints in both men and women in explanatory analysis. The risk reduction of strokes was 49% for men and 41% for women, and the reduction of total endpoints was 39% in men and 30% in women. Thus, antiplatelet therapy is effective in the prevention of stroke or death in both sexes.

Aspirin↗

Improved prediction of left ventricular mass by regression analysis of body surface potential maps.

Electrocardiographic left ventricular (LV) hypertrophy involving ST-T abnormalities, in addition to high QRS voltages, is associated with increased risk of cardiovascular disease mortality. Unfortunately, conventional electrocardiographic criteria have limited utility in the quantitative assessment of LV hypertrophy. Body surface potential maps, which contain diagnostic information not present in commonly used lead systems, were recorded from 117 thoracic sites and 3 limb electrodes in 72 normal subjects and 84 patients with LV hypertrophy. Multiple regression analysis was performed separately for 54 women and 102 men on 120-lead data, using as features instantaneous voltages on time-normalized P, PR, QRS and ST-T waveforms. Leads and features for optimal prediction of echocardiographically determined LV mass were selected. A total of 6 features from 3 torso sites in men, and from the same 3 sites plus 2 others in women, yielded correlations between echocardiographic and electrocardiographic estimates of LV mass of 0.89 and 0.88, respectively. The standard errors of the estimate (SEE), or average errors in predicting LV mass from the regression equations, were 31 and 22 g, respectively. The single most potent predictor in both sexes was a mid-QRS voltage measured on a lead positioned 10 cm below V1; QRS duration, late QRS and early-to-mid T-wave amplitudes recorded in the lower left flank contributed significantly to the performance of both regression models. The optimal electrode sites for electrocardiographic prediction of LV mass were outside the conventional lead locations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of RU 41740 on autologous hemopoietic reconstitution of sublethally irradiated mice.

RU 41740, a glyco-protein extract of Klebsiellae pneumoniae 01 K2 strain, is known to have immunomodulator activities. It acts on macrophages as well as on B and T-cells, and enhances their cytokine production, particularly interleukin 1 (IL-1). The fact that cytokines have an effect on hemopoiesis led us to suspect an effect of RU 41740 on hemopoietic reconstitution. In this study, a model of autologous reconstitution of a hemopoietic system after sublethal irradiation in mice was used. C57 BL/6 mice were treated orally with RU 41740 (10 mg/kg/day) before or after irradiation (6.5 Gy). LPS of Klebsiella pneumoniae was used as a positive control. The hemopoietic reconstitution occurred more rapidly in treated animals especially when RU 41740 was given before irradiation.

Animals↗

Murine monoclonal antibodies to Klebsiella pneumoniae protect against lethal endotoxemia and experimental infection with capsulated K. pneumoniae.

To prepare monoclonal antibodies (MAbs) directed against the core-lipid A fractions of smooth lipopoly-saccharide (LPS) from Klebsiella pneumoniae O1:K2, we immunized BALB/c mice with the LPS-associated proteins plus LPS. This preparation exposed the core-lipid A moiety, which is normally hidden in the micellar structure of classical LPS preparations. Among 10 MAbs selected for their reactivity with LPS-associated proteins plus LPS from K. pneumoniae O1:K2, 6 (3A3, 3C2, 3C4, 7D2, 11C3, and 12B6) were directed against the core fraction and 2 (6C5 and 10A5) were directed against the lipid A fraction. Only one (2A4) recognized the O antigen, and one (6D5) had an undefined specificity. When injected before challenge with K. pneumoniae O1:K2 LPS in galactosamine-sensitized mice, five of the MAbs (3C4, 6D5, 7D2, 11C3, and 12B6) provided protection in this model of lethal endotoxemia. MAb 7D2 was also protective in an experimental infection with capsulated K. pneumoniae O1:K2.

Animals↗

Immunological activities of RU-41740, a glycoprotein extract from Klebsiella pneumoniae. III. Role of LPS-like and LPS-non-related molecules.

RU-41740, a glycoprotein complex extracted from Klebsiella pneumoniae, is an immunomodulating agent which acts on B cells and macrophages. It has been shown that RU-41740 is composed mainly of two macromolecular fractions, F1, having an LPS-related structure, and P1, with a proteoglycan structure. In the present paper, the effects of these molecules on B cells and on IL-1 and tumour necrosis factor (TNF), production by macrophages were compared. Data reveal that both fractions were mitogenic for murine B cells and induced IL-1 and TNF production by macrophages. The LPS-like fraction (F1) was sensitive to polymyxin B and was unable to activate macrophages and spleen cells from LPS non-responder mice. The P1 fraction was mitogenic for B cells and induced the production of IL-1 and TNF activities by macrophages from LPS non-responder C3H/HeJ mice. The cytotoxic activity was due to TNF alpha, since treatment with anti-TNF alpha antiserum abrogated the lytic activity of supernatants from stimulated macrophages. The differences observed between P1 and F1 fractions in terms of sensitivity to polymyxin B and activity towards C3H/HeJ spleen cells and macrophages suggest that the two structurally distinct molecules isolated from RU-41740 could act at different sites on immunocompetent cells.

Adjuvants, Immunologic↗

Protective effects of murine monoclonal antibodies in experimental septicemia: E. coli antibodies protect against different serotypes of E. coli.

Murine monoclonal antibodies that bind outer membrane antigens of the J5 mutant of Escherichia coli O111:B4 were derived from spleen cells of BALB/c mice immunized with killed whole cells and boosted with lipopolysaccharide (LPS) and LPS-associated proteins. Seven hybridomas were selected for their reactivity against the J5 LPS; they cross-reacted with O111, O55, O127, and O128 E. coli LPS. One (B7B3) also reacted with the Serratia marcescens LPS and Klebsiella pneumoniae lipid A. A protective effect was obtained with D6B4 antibody in a lethal endotoxemia model induced by LPS from O111, O127, and O128 E. coli serotypes in D-galactosamine-sensitized mice. D6B4 and D6B3 antibodies protected mice infected with E. coli O111:B4, when administered before infection. The D6B4 antibody was also protective when administered after infection. The antibodies D6B3 and D4B5 were protective in heterologous infection induced by E. coli O2:K1.

Animals↗

The effect of RU 41740 on the in vitro maturation of human B-cells.

We have tested the effect of a Klebsiella pneumoniae extract, RU 41740, and its lipopolysaccharidic fraction (LPS-LAP) on the in vitro activation of human B-cells. Two models have been used: the polyclonal activation induced by pokeweed mitogen and the specific antibody production to mannan, a polysaccharide extracted from the cell wall of Candida albicans. We have shown that RU 41740, and especially its lipopolysaccharidic fraction, significantly increases the production of immunoglobulins and specific antibodies. This effect is mediated by T-lymphocytes, since preincubation of isolated T-cells, but not of non-T-cells, resulted in the same effect. Together with the known enhancing effect of LPS-LAP on T-cell proliferation, these data strongly suggest that LPS-LAP increases the production of B-cell-activating lymphokines by T-cells.

Adjuvants, Immunologic↗

Increase in the number and the phagocytic function of guinea pig pulmonary and peritoneal macrophages following oral administration of RU 41740, a glycoprotein extract from Klebsiella pneumoniae.

RU 41740 (Biostim) which is a purified glycoprotein extract from Klebsiella pneumoniae, is an orally active non-specific immunostimulant. In guinea pigs, 8 days after a 7 days oral administration of RU 41740 (10 or 100 mg/kg/day), an increase in the cell population of the pulmonary and peritoneal cavities was observed, especially in that of the macrophages. RU 41740 also enhanced the phagocytic activity of both the alveolar and peritoneal macrophages, when their chemotactic activity was not significantly modified. This increase in the number of pulmonary macrophages and the stimulation of their phagocytic function might explain the protective effect afforded by the oral administration of Biostim against respiratory infections in patients with chronic bronchitis.

Administration, Oral↗

Modulation by RU 41740 of oxidative metabolism and migration of rat polymorphonuclear leukocytes collected after induction of immune and nonimmune inflammations.

The activity of an immunomodulating agent, RU 41740, on the behavior of polymorphonuclear leukocytes (PMNs) elicited by two models of inflammation was studied. We observed the effect produced on migration and oxidative metabolism after incubation in vitro, in various drug concentrations, or administration in vivo. A stimulation of oxidative metabolism and an inhibition of chemotaxis was observed with the two types of PMNs. However Arthus-elicited PMNs were less reactive. This might be related to a nonspecific deactivation of the cells after induction of such an immune inflammatory reaction. This evidenced that PMN reactivity greatly varies with the physiopathological state of the cells.

Animals↗

Hyaluronic acid-degrading enzymes in rat alveolar macrophages and in alveolar fluid: stimulation of enzyme activity after oral treatment with the immunomodulator RU 41740.

RU 41740 (Biostim) is an immunomodulator clinically used for the treatment of chronic bronchitis and recurrent pulmonary infections. In these diseases large amounts of mucus are produced which congest the bronchi. A major glycosaminoglycan constituent of this mucus is hyaluronic acid, one of the largest molecules in nature; its metabolic degradation is carried out by 3 acid hydrolases: hyaluronidase, beta-N-acetylglucosaminidase, and beta-glucuronidase. In the lung these enzymes are especially synthesized and active in alveolar macrophages. It was thus interesting to study the effect of RU 41740 administration on the hyaluronic acid-degrading activity of these cells. This compound was given by gastric gavage to rats and the activities of lung alveolar macrophage and alveolar fluid hyaluronidase, beta-N-acetylglucosaminidase, beta-glucuronidase, and acid phosphatase as a lysosomal marker were determined. The effect on macrophage proliferation was also examined. The results obtained showed that: (1) unstimulated alveolar macrophages display the remarkable property, compared with other cell types, that hyaluronidase activity is about equally distributed between the inside and the outside of the cell; (2) RU 41740 administration increases the total activity of the 4 enzymes studied in the alveolar macrophages without inducing any increase in the number of macrophages; (3) the intracellular activities of beta-N-acetylglucosaminidase and beta-glucuronidase are markedly increased, whereas intracellular hyaluronidase activity is not changed. However, in the extracellular fluid only hyaluronidase activity is highly increased; (4) even the lysosomal marker enzyme acid phosphatase has only its intracellular activity increased. This would suggest the possibility that other lysosomal enzymes may also be increased by this immunomodulator.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗

Purification of the lipopolysaccharide fraction from Klebsiella pneumoniae O1 K2 by high-performance liquid chromatography.

An high-performance liquid chromatography technique was applied to purify the lipopolysaccharide fraction from a lysate of Klebsiella pneumoniae O1 K2 (NCTC 5055). The separation of the lipopolysaccharide fraction from the proteins was carried out with a reversed-phase column. By this method the lipopolysaccharide fraction was obtained in a pure state, devoid of proteins but possessing the same biological properties as the lipopolysaccharide fraction prepared by the classical phenol-water technique.

Bacterial Proteins↗

Effects exerted by RU 41740 on oxidative metabolism and migration of rat polymorphonuclear leukocytes collected after induction of one acute non specific inflammatory reaction.

The activity of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, endowed with immuno-modulating properties, has been investigated on polymorphonuclear (PMN) leukocyte functions. This report deals with the effect of RU 41740 on oxidative metabolism (assessed by chemiluminescence, 02 consumption and O2- production) and on chemotaxis and random migration (using agarose and Boyden chamber techniques). PMNs were collected from the rat pleural cavity after induction of one acute inflammatory reaction (pleurisy induced by injection of a suspension of calcium pyrophosphate crystals). Experiments were performed in parallel after in vivo treatment or incubation in vitro. RU 41740 enhanced PMN oxidative metabolism and inhibited PMN chemotaxis while random migration was only affected using agarose assay at high concentration. This effect on PMN migration was observed with at least two attractants. These observations have been obtained either after incubation in vitro or administration in vivo. The minimal effective dose was 1 mg/kg in vivo and 0.1 microgram/ml in vitro. These data suggest that RU 41740 acts directly on PMN membrane receptors.

Animals↗

Effects of RU 41740 aerosol treatment on mouse bronchoalveolar cells, and protection afforded against influenza virus infection.

RU 41740, an immunomodulating compound extracted from Klebsiella pneumoniae, was previously shown to enhance mice resistance to bacterial and viral lung infections. To explore lung defense mechanisms, we studied the influence of RU 41740 aerosol treatment on the bronchoalveolar cell populations. Five successive daily RU 41740 aerosol treatments induced a large accumulation of leukocytes in the lungs 4h after the last treatment. Polymorphonuclear leukocytes predominated. The numbers of lymphocytes and monocytes rose significantly. A single RU 41740 aerosol treatment significantly raised the number of polymorphonuclears only. A luminol-dependent chemiluminescence assay was used to test the effect of RU 41740 on the opsonized zymosan induced response of alveolar macrophages. In vitro, addition of RU 41740 enhanced this chemiluminescence. After a single RU 41740 aerosol treatment of mice, the chemiluminescence of purified alveolar macrophages from these mice increased significantly. The protective effect of five daily RU 41740 aerosol treatments against influenza virus infection was believed to be due to the great intensity of the cellular response and the polymorphonuclear influx. The alveolar macrophage activation observed might also explain the enhanced resistance of mice to influenza virus infection.

Adjuvants, Immunologic↗

Enhancement of bronchoalveolar cell recovery and stimulation of alveolar macrophage chemiluminescence and resistance to influenza virus after treatment with RU 41821 aerosol.

Aerosol treatment with RU 41821, a glycoprotein extract from Klebsiella pneumoniae, was tested in mice for its effect on the kinetics of the induction of bronchoalveolar cells (i.e., alveolar macrophages, monocytes, lymphocytes, and polymorphonuclear leukocytes). RU 41821 led to an increase in the total number of bronchoalveolar cells. The largest increase was observed for polymorphonuclear leukocytes, and more moderate increases occurred in the numbers of alveolar macrophages, monocytes, and lymphocytes. The alveolar macrophages recruited in response to RU 41821 were activated, as indicated by luminol-dependent chemiluminescence in response to stimulation by opsonized zymosan. The effects of five RU 41821 aerosol treatments and those of a single treatment were further examined in vivo by aerosol infection of mice inoculated with a mouse-pathogenic influenza virus. The maximum protective effect was obtained after five once-a-day treatments and was correlated with the largest increase in the total number of bronchoalveolar cells.

Aerosols↗

Pharmacological modulation of prostaglandin production by phagocytic cells of the thymic reticulum in relation to immunoregulation.

We cultured phagocytic cells derived from the thymic reticulum in order to study the regulation of prostaglandin (PG) production by antiinflammatory or immunostimulating agents. The kinetics of PGE2, 6-keto-PGF1 alpha and PGF2 alpha production were measured by specific radioimmunoassays of the supernatants harvested from cells treated with dexamethasone, a steroidal antiinflammatory drug and by two non steroidal inhibitors (indomethacin and sulindac) or by various immunostimulating agents, one of them, RU 41740 is currently being used in humans. Our results revealed that each of these drugs exerts a differential effect on the PG production, with a striking action on PGE2 synthesis, a lesser effect on 6-keto-PGF1 alpha production and almost no effect on PGF2 alpha synthesis. The possible mechanisms responsible for this complex regulation of PG production are discussed.

Adjuvants, Immunologic↗