Biomedical subjects

T Mazzei

Publications and source records attributed to T Mazzei.

At least 37 records · Page 2Linked to original sources

PubMed1999

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Adolescent↗

PubMed1999

Clarithromycin: pharmacokinetic and pharmacodynamic interrelationships and dosage regimen.

In the last decade three important pharmacodynamic parameters: T>MIC, Cmax/MIC and AUC/MIC, have been shown to correlate well with in-vitro antimicrobial efficacy and that found in animal models, differentiating among groups of antibiotics with diverse mechanisms of action such as exposure time or concentration-dependent effect. The macrolide antimicrobial agents display variable concentration-dependent killing, indicating the increasing importance of the Cmax parameter. Clarithromycin, whose T>MIC and AUC influence its clinical efficacy, is in an intermediate position between its progenitor, erythromycin, and the azalides. This paper reviews pharmacokinetic and pharmacodynamic characteristics of clarithromycin, examining the potential impact of these properties on the dose and the optimal interval between administrations.

Anti-Bacterial Agents↗

PubMed1999

Marked variation of thymidylate synthase and folylpolyglutamate synthetase gene expression in human colorectal tumors.

Patients with advanced colorectal cancer are currently being treated with 5-fluorouracil (5-FU)-based chemotherapy. A growing number of patients with resectable disease receive adjuvant therapy with 5-FU/levamisole (LEV) or 5-FU/folinic acid (LV). However, many patients still fail on these treatments, due to occurrence of natural or acquired tumor resistance. Among clinically relevant mechanisms of resistance to fluoropyrimidines, increased expression of thymidylate synthase (TS) has been emphasized. Another potentially relevant mechanism involves a decrease in folylpolyglutamate synthetase (FPGS) expression. To establish the value of these genes as prognostic factors and predictors of the outcome of 5-FU-based chemotherapy in colorectal cancer, we measured their expression in colorectal tumors from patients undergoing surgery and postoperative chemotherapy and compared it with that in normal colonic mucosa. This was done by a semi quantitative, nonradioisotopic polymerase chain reaction (PCR) method using beta-actin as an internal standard and expressed as a TS/beta-actin or a FPGS/beta-actin mRNA ratio. In tumor samples from 21 colorectal cancer patients, TS gene expression varied 118-fold. The median TS/beta-actin ratio was, in fact, 41.36 x 10(-3) (range 2.49 x 10(-3) to 294.54 x 10(-3)). Little variation in TS gene expression was observed in corresponding normal colic mucosa; the TS/beta-actin gene ratio was lower (median 26.16 x 10(-3); range 8.49 x 10(-3) to 69.49 x 10(-3)). Among tumor explants from 20 patients, FPGS expression varied over 161-fold. A similar marked variation was also observed in normal colonic mucosal samples (over 185-fold). Overall and disease-free survival data suggest an inverse association between the level of tumor TS and FPGS expression and clinical prognosis. The availability of this sensitive and accurate assay for gene expression should now make it possible to extend these laboratory/clinical correlations to larger populations.

Adult↗

PubMed1998

Differential inhibitory effects on human endometrial carcinoma cell growth of luteinizing hormone-releasing hormone analogues.

In addition to its function as a key hormone in the regulation of the pituitary-gonadal axis, luteinizing hormone-releasing hormone (LHRH) probably also affects various extrapituitary tissues. LHRH binding sites and in vitro antiproliferative effects of LHRH analogues have been reported in human endometrial cancer. The effects of the LHRH agonist leuproreline and LHRH antagonist antide were studied on the cell growth, DNA synthesis, and cell cycle distribution of the human endometrial cancer cell lines HEC-1A and HEC-1B by the sulforhodamine B (SRB) method, [3H]thymidine assay incorporation, and propidium iodide DNA staining, respectively. In the presence of 1.0-100 microM leuproreline the proliferation of HEC-1A cells was significantly reduced as early as 3 days after drug exposure, with a minimum growth value of 69.9 +/- 3.6% (mean +/- SE) at the highest concentration tested (100 microM). Similar antiproliferative effects were obtained following a 6-day treatment with the LHRH antagonist antide. Also, inhibitory effects on [3H]thymidine incorporation into the DNA of the HEC-1A cell line were noted after a 6-day exposure to both LHRH analogues, in the above-mentioned concentration range. Cell cycle analysis of HEC-1A cells cultured in the presence of 10 microM leuproreline and antide showed a slight accumulation of cells in the G0/G1 phase, while the proportions of cells in the S and G2/M phases concomitantly decreased. No significant effects on proliferation, DNA synthesis, and cell cycle distribution were observed in HEC-1B cells with either leuproreline or antide (up to 100 and 10 microM, respectively) after a 6-day exposure. Both Northern blot analysis and reverse transcription polymerase chain reaction failed to detect expression of mRNA for the LHRH receptor in both HEC-1A and HEC-1B cell lines. In addition, the LHRH analogues did not affect the intracellular free calcium concentration, indicating that the classic signal transduction for LHRH is absent or impaired in HEC-1A cells. The observed direct inhibitory actions on HEC-1A cells support the concept that the two LHRH analogues may exert biological effects via cellular effectors distinct from the "classic" LHRH receptor. Although the mechanism by which these direct actions are produced is still obscure, these results might help to establish the basis for new approaches to the therapy of endometrial cancer.

Antineoplastic Agents, Hormonal↗

PubMed1998

Efficacy and safety of high dose intravenous ciprofloxacin in the treatment of bacterial pneumonia. Italian Ciprofloxacin Study Group.

One hundred and fifty three hospitalized patients were enrolled in an open, prospective, multi-center study on the efficacy and safety of intravenous ciprofloxacin (400 mg i.v., b.i.d.) for acute bacterial pneumonia: 93 (63%) patients were valid for efficacy out of 148 valid for intention-to-treat analysis. The most commonly isolated organisms from 93 valid-for-efficacy patients were Pseudomonas aeruginosa (17%), Haemophilus influenzae and parainfluenzae (17%), Streptococcus aureus (14%) and Streptococcus pneumoniae (11%). Cure was achieved in 89/93 (95.7%) valid-for-efficacy patients; effective eradications were obtained in 42 (45%) and presumed eradications in 48 (52%) of the 93 patients. Mild or moderate adverse events (AE) occurred in 13/153 (8.5%) patients assessable for safety; all but one AE were rapidly reversible and only one treatment-stop (0.65%) was decided. The treatment of acute bacterial pneumonias with high-dose parenteral ciprofloxacin appears to be efficacious and well tolerated.

Anti-Infective Agents↗

PubMed1998

Antibiotic-induced release of bacterial cell wall components in the pathogenesis of sepsis and septic shock: a review.

This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock. After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyze the parameters of betalactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit.

Anti-Bacterial Agents↗

PubMed1998

Cytotoxic effects of gold(III) complexes on established human tumor cell lines sensitive and resistant to cisplatin.

Gold(III) complexes, isostructural and isoelectronic with platinum(II) complexes, are potentially attractive as anticancer agents. We have synthesized a group of square planar gold(III) complexes, all containing at least two gold-chloride bonds in cis-position, and tested their in vitro cytotoxicity on a panel of established human tumor cell lines. Remarkably, all these compounds showed significant cytotoxic effects. In particular, the complexes containing the salycilaldiminate ligand induced tumor cell growth inhibitory effects comparable to or even greater than cisplatin. All gold(III) complexes substantially retained their antitumor potency against two cisplatin-resistant tumor cell lines (CCRF-CEM/R leukemia and A2780/R ovarian carcinoma); only minimal cross-resistance with cisplatin was observed. When considering the mechanism of action, it is reasonable to assume that the cytotoxicity of these gold(III) complexes derives from DNA binding. Preliminary spectroscopic results are consistent with this hypothesis; indeed, circular dichroism experiments show that both the salycilaldiminate- and the pyridine-containing gold(III) complexes bind calf thymus DNA in vitro and alter reversibly its B-type solution conformation. These results, however, must be treated with caution; solution studies indicate that gold(III) compounds are poorly stable under physiological conditions, possibly implying that, when injected, only a small amount will reach, unchanged, the DNA target. The results of our investigations are discussed in the perspective of future work on the cytotoxic and antitumor properties of gold(III) compounds.

Antineoplastic Agents↗

PubMed1997

Evaluation of methotrexate sensitivity in human leukemia cell lines by an adenosine triphosphate bioluminescence assay.

To verify a recently developed in vitro tumor chemosensitivity assay (TCA) based on adenosine triphosphate (ATP) measurement for detection of methotrexate (MTX) sensitivity or resistance in human leukemias and solid tumors in which the antifol is indicated, we investigated the ability of the assay to discriminate between sensitivity and resistance to this antifolate in human leukemia cell lines sensitive (parental CCRF-CEM/S) and resistant (CCRF-CEM/E, CCRF-CEM/T and CCRF-CEM/P sublines) to MTX by virtue of known biochemical mechanisms. Correlation experiments with a standard cell growth inhibition assay and a radiometric method for measurement of thymidylate (dTMP) synthesis ([5-3H]-2'-deoxyuridine tritium release assay) were performed. No significant differences were observed in the IC50 values for the four cell lines tested as determined by cell growth evaluation (cell number counts) and the ATP-TCA after a 72 h MTX exposure. After short-term (4 h) high-dose MTX exposure, no significant correlation between ATP-TCA and the classic [5-3H]-2'-deoxyuridine tritium release assay was observed in both CCRF-CEM/S and CCRF-CEM/P cells. CCRF-CEM/T and CCRF-CEM/E displayed, instead, complete resistance with both methods. When using conditions proposed for clinical application (long-term exposure, i.e. 144 h) the ATP-TCA permitted the identification of cell lines highly resistant to MTX (CCRF-CEM/F and CCRF-CEM/E), while intermediate MTX resistance due to altered polyglutamylation was not detectable. Detection of this kind of resistance was obtained, as expected, using a short-term exposure (4 h) to MTX followed by a long-term efflux (72 h) in drug-free medium. On the basis of these results, ATP-TCA appears to be a suitable method for the evaluation of cytotoxicity induced by MTX.

Adenosine Triphosphate↗

PubMed1996

Clinical pharmacokinetics of meropenem after the first and tenth intramuscular administration.

We investigated the pharmacokinetics of meropenem after the first and tenth i.m. administration in patients with respiratory tract infections. Ten patients (mean age 63.8 +/- 5.2 years) received meropenem 500 mg tds for at least ten doses, and plasma and urine antibiotic concentrations were determined by microbiological assay. After the first injection a mean peak plasma concentration of 7.93 +/- 1.29 mg/L was observed at 1 h. Trough levels at 8 h (0.29 +/- 0.16 mg/L) were detectable in five of ten treated patients. The mean terminal half-life was 1.08 +/- 0.2 h with an area under the curve (AUC) value of 23.8 +/- 4.59 mg/L.h, and a cumulative urinary recovery at 8 h of 48.43 +/- 3.12%. There was no evidence of change in the pharmacokinetics of meropenem after repeated i.m. administration, though the mean peak plasma concentration and AUC value were slightly increased. The accumulation ratio (assessed using AUC values) was 1.18 +/- 0.19 after multiple doses and was considered to be of little kinetic and clinical importance. Moreover, many of the trough concentrations of meropenem were below the limit of detection of the assay. After i.m. administration meropenem concentrations exceeded 0.5 mg/L for longer than previously described following i.v. infusion. No adverse events were reported.

Aged↗

PubMed1995

Methotrexate chemosensitivity by ATP luminescence in human leukemia cell lines and in breast cancer primary cultures: comparison of the TCA-100 assay with a clonogenic assay.

Chemosensitivity assays are widely used to predict the ability of tumor cell lines to respond to potential or existing cytotoxic drugs. In this study we have compared the cell cloning assay first described by Salmon and Hamburger with a recently developed assay which measures viable cell number by ATP luminescence. Methotrexate (MTX) was chosen as the test agent, since cell lines with varying degrees of sensitivity to this agent were readily available. The results shown good correlation between the two assays, both of which are able to discriminate between the various cell lines used. MTX inhibition of primary breast carcinomas and cell lines shows a steep dose-response curve with a threshold concentration above which increasing dose does not increase sensitivity. In solid tumors, the plateau is usually reached at a level well below 100% inhibition. The ATP luminescence assay allows discrimination of MTX sensitivity between breast carcinomas and has considerable technical advantages over the cloning assay.

Adenocarcinoma↗

PubMed1995

In vitro postantibiotic effect and postantibiotic leukocyte enhancement of tobramycin.

The occurrence of a postantibiotic effect (PAE) and postantibiotic leukocyte enhancement (PALE) of tobramycin, a natural aminoglycoside clinically used since the early 1970s, has been investigated in comparison to gentamicin on recent clinical isolates of Staphylococcus aureus (both methicillin-susceptible and -resistant strains) and of Gram-negative fermenting and non-fermenting rods. A concentration-dependent PAE was observed with both antibiotics, regardless of the bacterial species used, with some variability based on their intrinsic resistance. Tobramycin, at concentrations equal to or higher than the minimum inhibitory concentration (MIC), exhibited a rather long PAE (ranging from 1.9 to 10.9 h) which was often significantly longer than that observed with gentamicin (ranging from 1.0 to 7.5h). Moreover, pre-exposure to tobramycin led to enhanced polymorphonuclear leukocyte phagocytosis and killing with a 2- to 27-fold increase in activity compared to controls. These results suggest that tobramycin might be conveniently used with once-daily dosing for the treatment of infections due to sensitive pathogens.

Analysis of Variance↗

PubMed1995

Tissue penetration and pulmonary disposition of tobramycin.

The pharmacokinetics of tobramycin, including the penetration into suction blister fluid (SBF), has been investigated in 12 patients with a mean age of 69.8 +/- 4.6 yrs, after a single i.m. administration of either 150 or 300 mg. Tobramycin demonstrated a concentration-independent pharmacokinetics and a high diffusion into the extravascular compartment with a penetration index (obtained by the SBF and serum AUC ratio) of 135% with no significant differences between the two groups of patients. Tobramycin was also administered as a single or multiple i.m. dose of 300 mg in 10 intensive care patients undergoing fiberoptic bronchoscopy for diagnostic purposes. The aminoglycoside mean concentration 6h after the single or last administration ranged from 5.3 to 5.5 mg/l and from 3.0 to 3.3 mg/l in alveolar lining fluid (ALF) and macrophages (AM), respectively, thus demonstrating that the once-daily dosage schedule leads to high and persistent levels in the bronchial alveolar tree, exceeding the minimum inhibitory concentrations in vitro for susceptible respiratory pathogens.

Adolescent↗

PubMed1995

Betalactam therapy and intestinal flora.

Betalactams, mainly when orally administered, may lead to intestinal flora modifications related to their spectrum of activity, rate of absorption and degradation. therefore it is important to investigate the possible influence of recently developed oral cephem derivatives on normal human microflora. We have investigated the impact on normal human intestinal flora in a 10-day course with cefetamet-pivoxil (CET, 500 mg BID) in comparison to cefixime (CFX, 400 mg qD) or cefuroxime axetil (CA, 250 mg BID) in 24 patients suffering from acute exacerbation of chronic bronchitis. Stool specimens were taken before (day 0), at the end (day 10) and 14 days after treatment (day 24) and quali-quantitative microflora composition was determined with a detection limit of 10 CFU/g dry weight. Treatment with CET caused slight and non-significant modifications of normal intestinal flora. On the contrary CFX and CA significantly affect Enterobacteriaceae and clostridia with a concomitant increase in enterococci for CFX. With both CFX and CA there was a new appearance of Salmonella spp. as well as Clostridium difficile in 4 and 2 cases, respectively. Therefore CET seems to affect normal bowel flora minimally in comparison to other oral cephalosporins. This aspect might contribute to the low incidence of GI related side effects in patients treated with CEt for longer than 1 week.

Administration, Oral↗

PubMed1994

Phase II trial of 5-fluorouracil and the natural l isomer of folinic acid in the treatment of advanced colorectal carcinoma.

Between February 1991 and July 1992, 79 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study of combined 5-fluorouracil (5-FU) and l-folinic acid (FA). 5-FU 370 mg/m2/day was administered for 5 consecutive days as an intravenous (i.v.) bolus injection preceded by l-FA 100 mg/m2/day with the same administration modality. Treatment was given every 4 weeks until progression. 79 patients were evaluable for toxicity and 64 for response. 2 patients (3%) achieved a complete remission and 8 (12.5%) a partial remission, 33 (52%) had stable disease and 21 patients (33%) had progressive disease. Median duration of remission was 32.5 weeks and median survival for all evaluable patients was 64.5 weeks. Substantial to severe side-effects occurred in 39% of patients. Dose-limiting toxicity (grade 3-4) was mainly diarrhoea (18%) and mucositis (15%). Nausea/vomiting, cutaneous toxicity, leucopenia, alopecia and conjunctivitis of grade 3-4 occurred respectively in 6, 4, 2.5, 1 and 1% of cases. Toxicity appeared to be substantially similar to that characteristic of combined 5-FU and the chiral mixture of d,l-FA. Efficacy was within the range of that observed with the 5-FU/d,l-FA combination, although at the lower level.

Adult↗

PubMed1994

Penetration of cefotetan into suction skin blister fluid and tissue homogenates in patients undergoing abdominal surgery.

The penetration of cefotetan (2-g intravenous bolus) into the suction blister fluid and tissue homogenates of 11 patients was investigated. Mean concentrations in tissue were significantly lower than contemporary suction blister fluid levels. These data show that the determination of beta-lactam concentrations by the tissue homogenate method may seriously underestimate the actual antibiotic levels in extracellular fluid.

Abdomen↗

PubMed1994

Inhibition of MDR1 gene expression by antimessenger oligonucleotides lowers multiple drug resistance.

The multiple drug resistance of neoplastic cells is mediated by overexpression of the human MDR1 gene, which encodes the transmembrane efflux pump P-glycoprotein. In both cell lines and human tumors the MDR phenotype closely correlates with MDR1 mRNA and P-glycoprotein levels. Reversion of the MDR phenotype was attempted in human colorectal adenocarcinoma doxorubicin (Dx)-resistant cells (Lo Vo/Dx) by long-term administration of an equimolecular mixture of three unmodified ODNs (18mer) targeted to adjacent binding sites of the MDR1 mRNA and carried by a synthetic cationic lipid (DOTAP). Three different experimental parameters were used to evaluate the antimessenger agent's effectiveness in comparison with a random sequence ODN: the level of cell resistance to Dx; the level of P-glycoprotein (determined by flow cytometry); the level of MDR1 mRNA (determined by quantitative RT-PCR). Experimental data indicate that the level of both the MDR1 mRNA and the P-glycoprotein is reduced by approximately 50% by treatment of Lo Vo/Dx cells with a 10 microM total concentration of the aODN mixture every 24 h for 15 days. In agreement with these findings, sensitivity to Dx of the antimessenger agent-treated Lo Vo/Dx cells was almost doubled in comparison with random sequence ODN-treated controls.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Cationic lipids improve antisense oligonucleotide uptake and prevent degradation in cultured cells and in human serum.

The power of antisense phosphodiester oligonucleotides (aODN) as regulatory molecules of gene expression is strongly limited by their low cellular uptake and very rapid nuclease-mediated degradation. This study deals with the effect of artificial cationic lipids on ODN cellular uptake and degradation in cell cultures and in human serum. At the ODN levels normally used in antisense-mediated gene regulation experiments, a cationic lipid, DOTAP, enhances the rate of ODN uptake more than 25 fold, but at lower ODN levels the effect of DOTAP is absent. These findings are consistent with a mechanism of ODN internalization by receptor-mediated saturable endocytosis that is bypassed by DOTAP. ODN degradation by nucleases is markedly prevented by DOTAP both in cultured cells and in human serum. Other cationic lipids, namely DOTMA and DOGS, exhibit very similar behaviour. The relatively slight cellular toxicity revealed by cationic lipids contribute to render these molecules very suitable for aODN vehiculation.

3T3 Cells↗

PubMed1993

Antimicrobial chemoimmunoprophylaxis in colorectal surgery with cefotetan and thymostimulin: prospective, controlled multicenter study. Italian Study Group on Antimicrobial Prophylaxis in Abdominal Surgery.

Surgical antimicrobial prophylaxis was performed with a controlled study on 859 evaluable patients randomized into two groups treated with chemoprophylaxis only or chemo- and immunoprophylaxis in colorectal surgery. Immuno and chemoprophylactic treatment (425 patients) consisted of 70 mg i.m. thymostimulin per day for 7 days beginning 48 h before surgery plus 2 g cefotetan at the moment of induction of anesthesia; the other group (434 patients) received only the single dose of antibiotic. Results in the two different groups were significantly different regarding abdominal abscess and the total infectious episodes in the surgical site with lower frequency in patients receiving both thymostimulin and the antibiotic (cefotetan). Moreover the respiratory tract infections were more than double in those patients not treated with perioperative immunotherapy. Stratifying patients on the basis of grade of skin test reaction, we observed a significantly lower percentage of surgical site infection in hypoergic patients receiving chemo- and immunoprophylaxis.

Adjuvants, Immunologic↗