Biomedical subjects

B Parodi

Publications and source records attributed to B Parodi.

25 records · Page 2Linked to original sources

PubMed1984

In vitro stimulation of IgE production at a single precursor level by human alloreactive T helper clones.

Human alloreactive proliferating T cell clones were isolated by a combination of allogeneic stimulation and interleukin 2-dependent growth. When cultured with B cells and macrophages bearing the appropriate alloantigens, the helper clones induced the production of high levels of IgE, while in the absence of the appropriate stimulation B cells produced undetectable IgE levels. Allogeneic peripheral blood T cells did not provide any help, but rather suppressed the IgE production induced by the alloreactive clones. The development of culture conditions where the help provided by specific T cell clones is non-limiting and suppressor-cytotoxic T cells are absent allowed the set up of limiting dilution experiments to determine the frequency of the B cells activated to high rate IgE production. One in 2,200-6,000 B cells in the peripheral blood of normal donors was activated to produce measurable amounts of IgE. This experimental system will allow the clonal analysis of the IgE antibody repertoire, in different physiological and pathological conditions.

B-Lymphocytes↗

PubMed1983

Activation of human B lymphocytes: frequency of antigen-specific B cells triggered by alloreactive or by antigen-specific T cell clones.

Human T cell clones specific for tetanus toxoid (TT) or for alloantigens were isolated and expanded in culture using antigen stimulation and soluble growth factors. When stimulated by the specific antigen, the clones were able to proliferate in the absence of exogenous growth factors and to provide help to B cells. The alloreactive and TT-specific clones were compared for their capacity to help an anti-TT as well as a polyclonal antibody response. The frequency of the B cells activated to the production of specific antibody was determined by limiting dilution analysis in cultures containing limiting numbers of responding B cells and optimal numbers of cloned T helper cells. In these conditions a single activated b cell was able to produce about 10 ng of antibody. TT-specific clones, in the presence of low TT concentrations, selectively induced a number of TT-specific B cells to produce IgG antibody in the absence of a detectable polyclonal B cell activation. On the other hand the alloreactive clones activated higher numbers of TT-specific B cells as a part of a strong polyspecific B cell activation. In this case the antibody production did not require the presence of TT in culture; furthermore cells producing antibodies of unrelated specificities were also activated in allostimulated cultures. IgG anti-TT were produced only by immune donors, while IgM anti-TT were produced by immune and nonimmune donors, providing the B cells were activated by alloreactive clones. These data demonstrate that human memory B cells can be triggered by both antigen-specific and alloreactive T cells to antibody production. The alloreactive clones can therefore be used to analyze at the clonal level the repertoire of a pool of B cells that contain most, if not all, the memory antibody specificities.

Antibody Formation↗

PubMedDate not supplied

Synthesis and antitumor activity of a new cis-diammineplatinum (II) complex containing procaine hydrochloride.

This paper refers to some of the chemical and biological properties of a new platinum (II) complex where the aromatic amino group of procaine is involved in the coordination with platinum and whose structure was defined by UV, IR, 1H-NMR, and elemental analysis. This new cationic platinum-triamine complex (DPR) displays excellent solubility (> 50 mg/ml) and stability in water. DPR has significant in vitro cytotoxicity against murine P388 leukemic cell line, human K562 erythroleukemic cell line and human Jurkat T cell line. The in vitro cytotoxic effects of DPR on P388 and Jurkat leukemic cells were comparable to those of cis-diamminedichloroplatinum (II) (DDP), while its activity on K562 cells was significantly better than that of DDP [IC50 = 1.07 +/- 0.36 (SD) microM vs 2.62 +/- 0.23 (SD) microM, P < 0.01]. The in vitro Pt accumulation rate for P388 cells was twice as rapid after DPR than after DDP exposure, while no difference in cellular platinum efflux was observed. The antitumor activity of DPR was tested in vivo against P388 leukemic cells in BDF1 mice and gave a % ILS value (75%) similar to that of the maximum tolerated dose (MTD) of DDP (8 mg/Kg). A comparative study of plasma urea nitrogen (PUN) levels and kidney morphological analysis in tumor-bearing mice receiving the LD50 dose of both drugs (39.3 mg/Kg and 16.5 mg/Kg for DPR and DDP, respectively), showed DPR to be less nephrotoxic than DDP. These results indicate that this new cationic platinum-triamine complex containing primary amine ligand is surprisingly active both in vitro and in vivo. In summary, the good characteristics of DPR in terms of high solubility, encouraging anticancer activity and absence of nephrotoxic effects make DPR a promising new platinum anticancer agent for preclinical development.

Animals↗

PubMedDate not supplied

Effect of normal saline on cisplatin pharmacokinetics and antitumor activity in mice bearing P388 leukemia.

The effect of normal saline (NS) on the antitumor activity, toxicity and pharmacokinetic of cisplatin (DDP) was investigated in BDF1 mice bearing P388 leukemia. Tumor-bearing mice received 8 or 16 mg/Kg of DDP dissolved in NS or distilled water (DW) intraperitoneally. Control animals were treated with DW or NS alone. The administration of 8 mg/Kg of DDP+NS produced a significantly better survival (P less than 0.05) compared to that observed in mice receiving DDP+DW. The proportion of long-term survivors was 3.5 times higher in the DDP+NS group (39%) compared to the DDP+DW group (11%). The administration of 16 mg/kg DDP+DW was highly toxic, resulting in early deaths (MST = 5 days) and no long-term survivors. NS protected from DDP toxicity without further improving the survival achieved following the injection of 8 mg/kg DDP+NS. Investigation of platinum pharmacokinetics showed that NS significantly decreases both plasma and tissue concentrations of total platinum, mainly through a decrease in the amount of platinum bound to high molecular weight plasma proteins. HPLC studies indicated that mice receiving 8 mg/kg DDP+NS or DDP+DW fail to show clear differences both in the total ultrafilterable platinum and unchanged DDP in plasma ultrafiltrate. Conversely, mice treated with DDP+NS had higher concentrations of platinum-species in plasma ultrafiltrate than mice receiving DDP+DW. These latter results, together with the observation that NS decreases the amount of platinum bound to plasma proteins, suggest that the effect of NS does not solely depend in vivo on the ability of the chloride ion concentration to stabilize the DDP molecule and suppress the formation of DDP metabolites, but also on its ability to prevent DDP toxicity by reducing the protein binding of DDP aquated products.

Animals↗

PubMedDate not supplied

Serum, urine and peritoneal fluid levels of 5-FU following intraperitoneal administration.

Seven patients with advanced colon cancer, refractory to conventional chemotherapy, and malignant disease confined to the intra-abdominal space received a total of 24 consecutive courses of ip 5-Fluorouracil (5-FU). 5-FU 1000 mg was administered in 2 L of warm (37 degrees C) dialysate daily for five consecutive days every 28 days. 5-FU concentrations in serum, peritoneal fluid and urine were measured by high pressure liquid chromatography (HPLC). The mean disappearance half-life of 5-FU from the peritoneal fluid was 1.6 hours with a mean permeability area product (PA) of 22.4 ml/min. The mean peritoneal AUC was 450 +/- 165 times greater than the mean serum AUC. Ip 5-FU treatment is well tolerated, can be safely administered on an outpatient basis and produces a significant pharmacological advantage over conventional routes of administration.

Adult↗

PubMedDate not supplied

Chemical and biological properties of a new cis-diammineplatinum (II) complex containing para-aminobenzoic acid as amino ligand.

In this paper we report on the synthesis, characterization and preliminary pharmacological evaluation of a new platinum (II) complex obtained by reaction of cis-diamminedichloroplatinum(II) (DDP) with para-aminobenzoic acid (PABA). The structure of this platinum compound was defined by UV, IR, 1H-NMR and elemental analysis. DPAB tested in vitro and in vivo against P388 leukemic cells displayed good antiproliferative (IC50 values after 48 h exposure of cells = 3 micrograms/ml) and antitumor activity (T/C% = 150). This compound also possesses desirable physical properties, such as a good solubility and stability in aqueous media, and a low toxicity (LD50 > 1200 mg/kg body weight) combined with a moderate nephrotoxic activity [plasma urea nitrogen (PUN) level: 36 +/- 8(SD) mg/100 ml]. DPAB was cleared from plasma ultrafiltrate (UF-plasma) very rapidly [clearance (CL), 55.3 ml x min-1 x kg-1], showing a half-life of 13.6 min. Platinum exposure (AUC) in the kidney was 2.6 times greater than that found in UF-plasma. AUCS for liver, stomach and UF-plasma were similar, while the AUC value for the spleen was 1.7 times lower than that of UF-plasma. These preliminary results seem to hold interest for further preclinical evaluation of the biological activity of this new platinum compound.

4-Aminobenzoic Acid↗

PubMedDate not supplied

Cis-diamminedichloroplatinum (II)-procaine pharmacokinetic interaction in mice bearing P388 leukemia.

The distribution and elimination kinetics of cis-diamminedichloroplatinum (II) (DDP) in female BDF1 mice bearing 6-day P388 leukemia were investigated in the presence and absence of procaine hydrochloride (P.HCl) exposure. DDP was administered as a single i.p. dose of 8 mg/kg in a 0.9% NaCl solution 6 days after tumor inoculum. P.HCl was administered as a single i.v. dose of 40 mg/kg immediately after DDP. The combined treatment with P.HCl produced marked changes in the plasma concentration-time profile of Pt. The unbound fraction of Pt was significantly increased both in the ascites fluid and plasma following DDP + P.HCl administration. P.HCl treatment induced a significant reduction (P < 0.01) in the rate constant of the protein-bound of Pt in plasma of tumored mice. Urinary excretion of Pt was unaffected by P.HCl, and there was no significant P.HCl-induced modification in the concentrations of Pt in the P388 leukemic cells. A statistically significant reduction of kidney and spleen Pt content was observed in female mice exposed to a dose of 8 mg/kg DDP + P.HCl. A similar reduction was observed in kidneys and testes of tumored mice receiving 16 mg/kg DDP along with 40 mg/kg P.HCl, which also showed lower renal and testicular cisplatin-DNA adducts after DDP + P.HCl than after DDP treatment. Potential explanations for the ability of P.HCl to interfere with the pharmacokinetics and biodistribution of DDP are discussed.

Animals↗