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M Tonetti

Publications and source records attributed to M Tonetti.

69 records · Page 4Linked to original sources
PubMed1990

Short-chain fatty acids produced by anaerobic bacteria inhibit phagocytosis by human lung phagocytes.

The effect of short-chain fatty acids on the phagocytic activity of human alveolar macrophages and neutrophils was investigated. These acids, butyric, propionic, and succinic, are produced by anaerobic bacteria. The results indicate that phagocytosis of Staphylococcus aureus by human lung phagocytes is strongly inhibited by the end products of anaerobic catabolism and support the hypothesis that the antiphagocytic activity present in the supernatants of anaerobic cultures may be dependent on the presence of short-chain fatty acids.

Calorimetry↗
PubMed1990

Zero-order delivery with periodontal placement of tetracycline-loaded ethylene vinyl acetate fibers.

The concentration of tetracycline in the gingival fluid was measured in the periodontal pocket following placement of controlled drug delivery monolithic fibers and subgingival irrigation. Following subgingival irrigation with 1% and 10% tetracycline HCl solution, concentrations decayed exponentially with half times of 4.2 and 12.2 h, respectively. Tetracycline fibers maintained a constant average concentration of 1590 micrograms/ml in periodontal pockets over a 10-day period. The observed concentrations were in agreement with those expected from a steady-state model based on release rate characteristic of the fibers and gingival fluid flow rate. After removal of the delivery system, tetracycline concentrations decreased exponentially with half time of 4.5 h. These data describe the delivery characteristics of tetracycline-loaded ethylene vinyl acetate fibers as zero-order for 10 d; following removal, an exponential washout was observed.

Adult↗
PubMed1990

Construction and characterization of adriamycin-loaded canine red blood cells as a potential slow delivery system.

Adriamycin was internalized in canine red blood cells (RBC) by two procedures involving (a) simple diffusion of the drug into cells and (b) hypotonic dialysis followed by isotonic resealing. The two procedures yielded comparable amounts of encapsulated adriamycin, around 35 micrograms/10(9) RBC. Exposure of adriamycin-loaded RBC to 0.16% glutaraldehyde consistently slowed down the rate of efflux of the drug as compared with non-glutaraldehyde-treated cells: after 1 h of incubation at 37 degrees C, greater than 80% of adriamycin was still present inside the glutaraldehyde-treated RBC, while at 24 h it was 66%, compared to 10% and 1%, respectively, in the adriamycin-loaded, non-glutaraldehyde-treated cells. Canine RBC showed a higher rate of transformation of adriamycin than the human cells, the only intracellular metabolite being adriamycinol, which is apparently formed by the NADPH-dependent enzyme aldehyde reductase. Production of adriamycinol was remarkably lower in the glutaraldehyde-treated RBC, as a result of progressive and extensive inactivation of hexose monophosphate shunt activity responsible for NADPH formation. These results, coupled with the known selective targeting of glutaraldehyde-treated RBC to liver, hold promise as to in vivo applications of this drug delivery system in antineoplastic therapy.

Animals↗
PubMed1989

Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

Doxorubicin-loaded, glutaraldehyde-treated murine erythrocytes, once reinjected into circulation, are rapidly taken up by liver and lungs and behave as an organ-targeted, slow delivery system for the encapsulated drug. The antitumor activity of encapsulated doxorubicin (former generic name, adriamycin) was compared with that of the free drug in a murine hepatic and pulmonary tumor model. This was obtained by intrasplenic injection of L1210 lymphoma cells followed by splenectomy. Different schedules of treatment of tumor-bearing mice with erythrocyte-encapsulated or free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin proved to be i.v. bolus administration on the day of splenectomy. Under these conditions, the dose producing 50% inhibition of metastatic growth in the liver, as measured by inhibition of 5-[125I]iodo-2'-deoxyuridine uptake 9 days after tumor induction, was 6.3 mg/kg for free doxorubicin and 0.48 mg/kg for the encapsulated drug. In these conditions pulmonary tumor development was even more efficiently prevented by encapsulated doxorubicin as compared with the free drug. The values of the therapeutic index (TI), defined as the ratio between the maximal tolerated dose (LD10) and the minimal effective dose (ED90, producing 90% inhibition of liver metastatic growth), were 4.2 and 1.8 for encapsulated and free doxorubicin, respectively.

Alanine Transaminase↗
PubMed1988

In vivo liver and lung targeting of adriamycin encapsulated in glutaraldehyde-treated murine erythrocytes.

Treatment of adriamycin-loaded erythrocytes from B6D2F1 mice with 0.1% glutaraldehyde produced the following effects: a considerable decrease in the in vitro leakage of the unmodified drug and a selective liver (and, to a lesser extent, lung) uptake of the encapsulated drug (70% of the injected dose) compared to drug leakage from, and tissue distribution of, carrier erythrocytes not treated with glutaraldehyde. The liver vascular bed was not saturated by five daily intravenous injections of 20 microliters of glutaraldehyde-treated erythrocytes, which allows a total dosage of 200 micrograms of the drug (half the LD50 value) to be administered. No appreciable liver damage results from extensive and prolonged uptake of glutaraldehyde-treated carrier erythrocytes. Entrapment of adriamycin within erythrocytes along with glutaraldehyde treatment of the carrier cells seems to be a promising therapeutic strategy against liver (and lung) tumors.

Animals↗
PubMed1987

Short-chain fatty acids produced by anaerobic bacteria alter the physiological responses of human neutrophils to chemotactic peptide.

The effect of some short-chain fatty acids (SCFA) produced by anaerobic bacteria, namely acetic, propionic, isobutyric, butyric, isovaleric and succinic acids, on production of light and release of lysozyme by human neutrophils exposed to chemotactic peptide fMet-Leu-Phe was investigated. A short period of incubation of neutrophils with SCFA led to marked inhibition of both granulocytic chemiluminescence and degranulation (P less than 0.001). Ultrastructural studies of neutrophils, incubated with concentrations of SCFA inhibiting the chemotactic response, chemiluminescence and release of lysozyme (30 mmol/l), effected alterations in cellular morphology with formation of protrusions of varying shape. The data reported indicate that SCFA might be regarded as important pathogenicity factors. The observed effect on neutrophils could also partially explain the ability of anaerobes to inhibit their own phagocytosis and killing as well as that of the aerobic species present in mixed infections.

Bacteria, Anaerobic↗
PubMed1985

Hexose monophosphate shunt-stimulated reduction of methemoglobin by divicine.

Reduced divicine (2,6-diamino-4,5-dihydroxypyrimidine), an aglycone implicated in the pathogenesis of favism, reduces methemoglobin efficiently in intact erythrocytes and in hemolysates. Oxidized divicine produces the same effect when glucose or an NADPH-generating system is added to intact erythrocytes or to hemolysates. Although NADPH, NADH, and GSH have no direct methemoglobin-reducing activity in vitro, they convert oxidized divicine to the reduced hydroquinone species, which is responsible for the electron transfer to methemoglobin. Reduction of methemoglobin is optimally observed under nitrogen since, in the presence of oxygen, reduced divicine undergoes autoxidation. Several lines of evidence rule out the reduction of methemoglobin by divicine through an enzyme-catalyzed process, although it is certainly sustained by the hexose monophosphate shunt activity of erythrocytes through the generation of both NADPH and GSH. Thus, the strong enhancing effect that glucose produces on the divicine-dependent methemoglobin reduction within intact normal erythrocytes is completely absent in erythrocytes from glucose-6-phosphate dehydrogenase-deficient subjects. This distinctive behavior might account for the enhanced methemoglobin levels that are found both in vitro in glucose-6-phosphate dehydrogenase-deficient erythrocytes exposed to divicine and in vivo as a typical feature of the acute hemolytic crisis of favic patients.

Catalase↗
PubMedDate not supplied

Enhanced antitumor activity of adriamycin by encapsulation in mouse erythrocytes targeted to liver and lungs.

Adriamycin was encapsulated within human and murine (B6D2F1 female mice) erythrocytes using a procedure based on hypotonic hemolysis followed by isotonic resealing and reannealing. Following drug encapsulation the murine erythrocytes were treated with glutaraldehyde to obtain: a) control of Adriamycin efflux from loaded erythrocytes, b) appropriate hepatic and pulmonary targeting of the in vivo re-infused cells. The antitumor effect of equivalent amounts of bolus (i.v.) administered Adriamycin, 1) free, 2) encapsulated within erythrocytes, 3) encapsulated within glutaraldehyde-treated erythrocytes, was compared using an in vivo model of metastasis based on selective hepatic and pulmonary dissemination of intrasplenically injected L1210 cells in B6D2F1 mice. The therapeutic index (TI) of Adriamycin encapsulated within glutaraldehyde-treated erythrocytes increased by more than two-fold over that of the free drug.

Animals↗
PubMedDate not supplied

Construction of glucose oxidase-loaded human erythrocytes: a model of oxidative cytotoxicity.

Human red blood cells were loaded with Glucose oxidase from Aspergillus niger by a standardized procedure of encapsulation involving transient hypotonic hemolysis followed by isotonic resealing. The amount of loaded enzyme activity, as evaluated by O2 consumption at 5 mM glucose, ranged from 40 to 75 mumoles O2/hr/ml of packed red cells at 37 degrees C. The red cells loaded with Glucose oxidase were found to behave as efficient glucose-consuming bioreactors. Moreover, at 5 mM glucose, no clear mechanism of H2O2-induced damage was apparent, with the exception of a significantly increased formation of methemoglobin (10% approximately) and of a several-fold stimulated intracellular rate of hexose monophosphate shunt activity, indicating glutathione peroxidase-mediated draining of reduced glutathione for removal of bursts of H2O2. The Glucose oxidase-loaded red cells represent a convenient model system for cytotoxicity studies aiming at clarifying the effects of intracellularly formed H2O2.

Aspergillus niger↗