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Romano Danesi

Publications and source records attributed to Romano Danesi.

49 records · Page 3Linked to original sources
PubMed2003

Cardiac toxicity of antineoplastic anthracyclines.

Anthracyclines play a major role in the treatment of solid malignancies, but their clinical use is limited by acute or chronic cardiac toxicity. This is not due to the same molecular action involved in the antineoplastic effect, i.e. topoisomerase II inhibition, but can be attributed to different mechanisms: free radical generation, stimulation of sarcoplasmic reticulum calcium release, binding to anionic phospholipids, alteration of sphingolipid metabolism, modulation of gene expression. Anthracycline metabolites, particularly 13-hydroxy derivatives, might contribute to impair iron and calcium homeostasis. Unresolved issues are the relative importance of such injurious mechanisms and the relationship between acute and chronic toxicity. Attempts to reduce anthracycline toxicity have been focused on the development of new derivatives, on the adoption of peculiar delivery systems, and on the association with substances able to interfere with the mechanism responsible for cardiotoxicity. Many anthracyclines have been synthesized and screened, but no major improvement in therapeutic index has been obtained. A possible exception might be represented by the new disaccharidic derivatives, which have provided promising results in preclinical studies. Liposome encapsulation and association with the iron chelator dexrazoxane have also proved to be useful. Novel approaches are targeted at the effects of anthracyclines on nitric monoxide metabolism and on sphingolipid metabolism.

Animals↗
PubMed2002

Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer.

PURPOSE: To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses. RESULTS: Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively. CONCLUSION: This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.

Adult↗
PubMed2002

The effect of osteogenic growth peptide (OGP) on proliferation and adhesion of HEMC-1 human endothelial cells.

Human osteogenic growth peptide (OGP) promotes the growth of osteoblastic, fibroblastic and bone marrow stromal cells. There is no evidence that OGP stimulates the growth or the attachment of endothelial cells to the extracellular matrix. The aim of this study was to test OGP on in vitro cultures of human microvascular endothelial HEMC-1 cells and to characterize its potential angiogenic effect when administered alone or in combination with vascular endothelial growth factor (VEGF) or its binding protein alpha(2)-macroglobulin (alpha(2)M). HEMC-1 cells were cultured in vitro under serum-free conditions to study the effects of OGP (10(-14)- 10(-10)M), VEGF (100 ng ml(-1)), alpha(2)M (20 ng ml(-1)) and their combinations on cell proliferation for 48 h. Furthermore, an adhesion assay was performed incubating the HEMC-1 cells with OGP, VEGF, alpha(2)M and their combinations for 24 h. OGP, alpha(2)M and their combination did not stimulate proliferation of HEMC-1 cells; in contrast, VEGF caused a significant enhancement of cell growth ( +37.3 %;P< 0.05). Pre-incubation with VEGF resulted in a fast and increased adhesion of endothelial cells to the matrix as compared to controls ( +87.5 % at 30 min and +86.6 % at 70 min, P< 0.05); in contrast, incubation with OGP alone determined only a significant increase in the attachment at 100 min ( +52 %;P< 0.05). The combinations of these peptides did not cause significant additive effects. These results suggest that OGP, compared to VEGF, induced neither the proliferation nor an increase in attachment of HEMC-1 cells to a matrix, either alone or in combination with VEGF and alpha(2)M. These in vitro findings may suggest a possible administration of OGP, as a haematopoietic factor, to patients affected by pathological conditions involving angiogenesis.

Cell Adhesion↗
PubMed2002

Molecular basis of resistance to azole antifungals.

The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance has prompted investigations of the underlying molecular mechanisms, particularly for the azole compounds central to current therapy. The target site for the azoles is the ERG11 gene product, the cytochrome P450 lanosterol 14alpha-demethylase, which is part of the ergosterol biosynthetic pathway. The resulting ergosterol depletion renders fungal cells vulnerable to further membrane damage. Development of azole resistance in fungi may occur through increased levels of the cellular target, upregulation of genes controlling drug efflux, alterations in sterol synthesis and decreased affinity of azoles for the cellular target. Here, we review the adaptative changes in fungi, in particular Candida albicans, in response to inhibitors of ergosterol biosynthesis. The molecular mechanisms of azole resistance might help in devising more effective antifungal therapies.

Adaptation, Physiological↗
PubMed2002

Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients.

AIMS: To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism. METHODS: Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m-2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m-2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined. RESULTS: An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 micromol l-1 h [95% CI for the difference: 0.29, 0.71],+0.66 micromol l-1 h [95% CI for the difference: 0.47, 0.85] and +0.82 micromol l-1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m-2, respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61+/-0.1 micromol l-1 h). A significant increase in epirubicin AUC (+0.74 micromol l-1 h [95% CI for the difference: 0.14, 1.34] and +1.09 micromol l-1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB) (-25.35 l h-1 m-2[95% CI for the difference: -50.18, -0.52] and -35.9 l h-1 m-2[95% CI for the difference -63,4,-8,36]) occurred in combination with paclitaxel 200 and 225 mg m-2 with respect to the AUC (3.16+/-0.6 micromol l-1 h) and CLTB (74.4+/-28.4 l h-1 m-2) of epirubicin followed by paclitaxel 30 h later. An Emax relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 micromol l-1 (tC0.1). The tC0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood. CONCLUSIONS: Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the Emax relationship between neutropenia and tC0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.

Adult↗
PubMed2002

Cholinergic toxic syndrome by the anticancer drug irinotecan: acetylcholinesterase does not play a major role.

BACKGROUND: The anticancer drug irinotecan induces cholinergic side effects that are currently ascribed to the blockade of acetylcholinesterase. This study investigated (1) the pattern of acetylcholinesterase activity in patients receiving treatment with irinotecan and (2) the relationship between acetylcholinesterase activity and plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G). METHODS: Twenty-five patients with advanced colorectal cancer were treated with 250 mg/m(2) irinotecan administered by intravenous infusion for 60 minutes. Blood samples were collected before drug infusion and at 15 minutes and 45 minutes after the start of drug infusion. Blood acetylcholinesterase activity was determined by a colorimetric enzymatic assay, and irinotecan, SN-38, and SN-38G concentrations were determined in plasma by HPLC. The in vitro effects of irinotecan and other drugs on human acetylcholinesterase were also assessed. RESULTS: Compared with basal values, the activity of acetylcholinesterase in blood specimens collected during irinotecan infusion at 15 minutes (-0.76%) and at 45 minutes (-1.50%) showed no changes. No relationships were established between the activity of blood acetylcholinesterase at 15 or 45 minutes and plasma concentrations of irinotecan, SN-38, or SN-38G measured at the same time points. In vitro, the activity of acetylcholinesterase was inhibited by 100-micromol/L irinotecan (-24.8%) and markedly reduced by 1-micromol/L physostigmine (-86.7%), whereas neither SN-38 nor camptothecin had an effect. CONCLUSIONS: Although the use of erythrocyte acetylcholinesterase as a surrogate marker of acetylcholinesterase activity in the nervous system has not been firmly established, our findings do not support the hypothesis that the toxic cholinergic syndrome associated with irinotecan treatment depends on acetylcholinesterase blockade.

Acetylcholinesterase↗
PubMed2002

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer.

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

Adenocarcinoma↗
PubMed2002

Relationship between plasma concentrations of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil and toxicity of 5-fluorouracil infusions in cancer patients.

This study investigated the relationship among the pharmacokinetics of 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU); the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells; and treatment-related toxicity in 26 patients with surgically resected colorectal cancer treated with short daily infusions of 5-FU adjuvant chemotherapy, each cycle consisting of 5 consecutive days every 4 weeks. After the first chemotherapeutic cycle, severe stomatitis and diarrhea occurred in 5 patients and were related to the variations in the systemic disposition of the drug rather than to DPD activity. These patients showed a significant decrease in 5-FU clearance, and an increase in the 5-FU/5-FDHU area under the time-concentration curve (AUC) ratio, as compared with patients who experienced mild toxicities, whereas a low DPD activity was observed in only 2 patients. In conclusion, the results of this study demonstrate that the alterations in 5-FU and 5-FDHU pharmacokinetics are related to severe toxicities in patients treated with short intravenous infusion of 5-FU.

Aged↗
PubMed2002

Antimicrobial peptides: therapeutic potential for the treatment of Candida infections.

The increasing frequency of fungal infections in immunocompromised patients together with the emergence of strains resistant to currently used antifungal drugs point to an increased need for a new class of antimycotics. Antimicrobial peptides are promising candidates for the treatment of fungal infections since they have both mechanisms of action distinct from available antifungal agents and the ability to regulate the host immune defence systems as well. This review focuses on Candida albicans as a large amount of work on the mechanisms of action of classical antifungals as well as antimicrobial peptides, such as defensins, protegrins, histatins and lactoferrin (LF)-derived peptides, has been performed in this yeast. Analogues of these antimicrobial peptides and combinations of antimicrobial peptides with classical antimycotics are under investigation for treatment of candidiasis.

Anti-Bacterial Agents↗
PubMed2002

Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs.

The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy. The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.

Antibiotics, Antineoplastic↗