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Biomedical subjects

Romano Danesi

Publications and source records attributed to Romano Danesi.

At least 37 records · Page 2Linked to original sources
PubMed2004

A phase I and pharmacokinetic study of irinotecan given as a 7-day continuous infusion in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed.

PURPOSE: The purpose is to determine the plasma pharmacokinetics, the maximum-tolerable dose and to preliminary evaluate the antitumor activity of irinotecan administered as a 7-day continuous infusion every 21 days in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed. EXPERIMENTAL DESIGN: A total of 13 patients entered the study. Three received irinotecan at 20 mg/m(2)/day (dose level I), 6 at 25 mg/m(2)/day (dose level II), and 4 at 22.5 mg/m(2)/day (dose level III). In 8 patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38glu) were measured by high-performance liquid chromatography and main pharmacokinetic parameters, including steady-state concentration, area under the time-concentration curve, and clearance, were calculated and normalized to the dose level of 22.5 mg/m(2)/day. RESULTS: Dose-limiting toxicity was grade 3-4 diarrhea, which occurred in 4 of 6 patients at dose level II and in 2 of 4 patients at dose level III. Therefore, we defined 22.5 mg/m(2)/day the maximum-tolerable dose and 20.0 mg/m(2)/day the recommended dose for Phase II studies. Hematological toxicity was rare. The pharmacokinetic data provided evidence that continuous infusion increased the metabolism of irinotecan to SN-38 with respect to standard 30/90-min administration. Indeed, the steady-state concentration of irinotecan, SN-38, and SN-38glu were 42.7 +/- 25.2, 14.9 +/- 1.9, and 31.7 +/- 3.5 nmol/liter, respectively, and the area under the time-concentration curves of irinotecan, SN-38, and SN-38glu were 6.94 +/- 0.41, 1.92 +/- 0.30, and 4.23 +/- 0.52 hx micro mol/liter, respectively. Twelve patients were evaluable for activity, and we observed 3 (25%) partial responses, 2 (17%) minor responses, and 4 (33%) disease stabilizations. CONCLUSIONS: The administration of irinotecan as a 7-day continuous infusion every 21 days is feasible with diarrhea being the dose-limiting toxicity; recommended dose for Phase II studies is 20.0 mg/m(2)/day. The comparison of the present data with those obtained after a standard 30-90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Antitumor activity in pretreated metastatic colorectal cancer patients is encouraging.

Aged↗
PubMed2004

Phosphonomethylphosphorylmethyl(oxy)-analogues of geranylgeranyl diphosphate as stable and selective geranylgeranyl protein transferase inhibitors.

The diphosphate moiety of geranylgeranyldiphosphate (GGdP) was replaced with metabolically and hydrolytically stable analogous polar portions, in an attempt to obtain new geranylgeranyltransferase (GGTase) inhibitors, which could also be selective over congener enzyme farnesyltransferase (FTase). In particular, the phosphonomethylphosphorylmethoxy derivative showed the highest inhibition potency, accompanied by a satisfactory GGTase/FTase selectivity.

Alkyl and Aryl Transferases↗
PubMed2004

Pharmacogenetics of neoplastic diseases: new trends.

The study of the influence of genotype on drug activity and efficacy (pharmacogenetics) and the genome-wide approach to drug discovery and interpretation of complex pharmacological responses (pharmacogenomics) are gaining momentum in current molecular medicine. The reasons of the variable activity and tolerability of cancer chemotherapy are being unraveled by the discovery of genotypic alterations affecting pharmacokinetics and pharmacodynamics of drugs. Indeed, genetic variability may alter drug catabolism (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase for gemcitabine). Moreover, increased expression of transporter systems (i.e. the ATP binding cassette (ABC) superfamily) is associated with reduction of the cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect. Additional systems could protect tumor cells from drug cytotoxicity, including the DNA repair machinery (nucleotide excision repair (NER) and DNA alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations of drug targets may be associated with a decrease in the effectiveness of chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes and irinotecan, respectively, and increased expression of thymidilate synthase for 5-fluorouracil). Therefore, genetic analysis has the potential to predict treatment efficacy and tolerability. However, major problems encountered in pharmacogenetic and pharmacogenomic studies are the need of extensive validation of available technology, the difficulties in obtaining a suitable amount of tissue from patients during the course of their disease and the extremely complex regulation of gene function. From this perspective, the evaluation of the cellular effect of drugs in relation to protein expression and function (pharmacoproteomics) may be able to overcome these obstacles, and allow the optimisation of cancer chemotherapy in association with a pharmacogenetic approach.

Animals↗
PubMed2004

Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38.

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)(7)TAA (UGT1A1(*)28), UGT1A9 766G>A (D256N; UGT1A9(*)5), and UGT1A9 98T>C (M33T; UGT1A9(*)3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 +/- 6466 ng x h/mL and 629 +/- 370 ng x h/mL, respectively, which is in line with earlier findings. For UGT1A9(*)5,novariant alleles were observed, whereas for UGT1A9(*)3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1(*)28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1(*)28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p =.022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1(*)28 polymorphism may identify patients with altered SN-38 pharmacokinetics.

Adult↗
PubMed2004

A benefit-risk assessment of basiliximab in renal transplantation.

Interleukin-2 (IL-2) and its receptor (IL-2R) play a central role in T lymphocyte activation and immune response after transplantation. Research on the biology of IL-2R allowed the identification of key signal transduction pathways involved in the generation of proliferative and antiapoptotic signals in T cells. The alpha-chain of the IL-2R is a specific peptide against which monoclonal antibodies have been raised, with the aim of blunting the immune response by means of inhibiting proliferation and inducing apoptosis in primed lymphocytes. Indeed, basiliximab, one of such antibodies, has proved to be effective in reducing the episodes of acute rejection after kidney and pancreas transplantation. The use of basiliximab was associated with a significant reduction in the incidence of any treated rejection episodes after kidney transplantation in the two major randomised studies (placebo 52.2% vs basiliximab 34.2% at 6 months, European study; placebo 54.9% vs basiliximab 37.6% at 1 year, US trial). Basiliximab and equine antithymocyte globulin (ATG) administration resulted in a similar rate of biopsy-proven acute rejection at 6 months (19% for both) and at 12 months (19% and 20%, respectively). The use of basiliximab appears not to be associated with an increased incidence of adverse events as compared with placebo in immunosuppressive regimens, including calcineurin inhibitors, mycophenolate mofetil or azathioprine and corticosteroids, and its safety profile is superior to ATG. Moreover, a similar occurrence of infections is noted in selected studies (65.5% after basiliximab vs 65.7% of controls), including cytomegalovirus infection (17.3% vs 14.5%), and cytokine-release syndrome is not observed. Finally, economic analysis demonstrated lower costs of overall treatment in patients treated with basiliximab. Therefore, the use of basiliximab entails a very low risk, allows safe reduction of corticosteroid dosage and reduces the short- and mid-term rejection rates. However, the improvement in the long-term survival of kidney grafts in patients treated according to modern immunosuppressive protocols is still to be demonstrated. These conclusions are based on a systematic review of the scientific literature, indexed on Medline database, concerning the mechanism of action, therapeutic activity, safety and pharmacoeconomic evaluation of basiliximab in renal transplantation.

Antibodies, Monoclonal↗
PubMed2003

Stable analogues of geranylgeranyl diphosphate possessing improved geranylgeranyl versus farnesyl protein transferase inhibitory selectivity.

Phosphonoacetamido(oxy) groups have proven to be good mimics of the diphosphate portion in geranylgeranyl protein transferase I (GGTase I) inhibitors. The introduction of small alkyl groups (Me, Et) into the diphosphate mimic moiety caused a further decrease in collateral farnesyl protein transferase (FTase) inhibitory activity, thereby improving GGTase I over FTase selectivity.

Alkyl and Aryl Transferases↗
PubMed2003

Selective anti-endothelial effects of protracted low-dose BAL-9504, a novel geranylgeranyl-transferase inhibitor.

Because the anti-endothelial effects of agents such as interferon alpha, endostatin, and various chemotherapeutic drugs appear to be optimal after protracted, frequent dosing, both in vitro and in vivo, using low concentrations/doses of drugs, we tested the geranylgeranyl transferase inhibitor BAL-9504 ((E,E,E) [2-oxo-2-[[(3,7,11,15-tetramethyl-2,6,10,14 hexadecatetraenyl)-oxy]amino]ethyl] phosphonic acid) in this manner on different human cell types, including endothelial, breast cancer cells and fibroblasts. We found that human endothelial cells were preferentially affected with respect to inhibition of proliferation, induction of apoptosis, suppression of adhesion to fibronectin, and blockade of cell migration, by daily exposure to low concentrations of BAL-9504 for 6 days. These results may have implications in terms of both increasing anti-tumor efficacy, mediated by antiangiogenic mechanisms, and reducing toxic side effects.

Alkyl and Aryl Transferases↗
PubMed2003

Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg.

OBJECTIVES: The administration of antibacterial agents should be optimized on the basis of their distribution to enhance drug exposure and obtain bacterial eradication. This study examines the pharmacokinetics of azithromycin in plasma, lung tissue and bronchial washing in patients after oral administration of 500 mg versus 1000 mg once daily for 3 days. PATIENTS AND METHODS: Samples of plasma, lung tissue and bronchial washing were obtained from a cohort of 48 patients during open-chest surgery for lung resection up to 204 h after the last drug dose, and assayed for antibiotic concentrations. RESULTS: Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 +/- 2.05 versus 18.6 +/- 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue. CONCLUSIONS: Lung exposure to azithromycin is increased proportionally by doubling the dose, which results in a predictable pharmacokinetic behaviour of the drug in the lower respiratory tract.

Anti-Bacterial Agents↗
PubMed2003

Conformationally restrained ceramide analogues: effects of lipophilic modifications on the antiproliferative activity.

Conformationally restrained analogues of ceramide containing thiouracil or uracil moieties in their polar head, substituted with an ethyl group in their 6-positions, proved to inhibit cell proliferation and induce apoptosis. A series of new thiouracil and uracil analogues of ceramide possessing several 6-alkyl- or 6-arylalkyl-substituents, were synthesized and tested as inhibitors of cell proliferation. The lipophilic substituents introduced in the 6-position were pure alkyls (n-propyl, n-butyl, i-butyl, neo-pentyl), or aryl-alkyls (2-phenylethyl). Although a significant antiproliferative activity was maintained in most compounds synthesized, none of them showed any improvement with respect to their 6-ethyl-substituted counterparts.

Carbohydrate Conformation↗
PubMed2003

Ceramide analogues in apoptosis: a new strategy for anticancer drug development.

A survey on the role played by ceramide within the sphingolmyelin pathway is here reported, taking into account its importance as an intracellular effector molecule in apoptosis. Recently, several analogs of ceramide, able to pass the cell membrane and then to induce apoptosis, have been developed as a new potential approach in anticancer therapy.

Animals↗
PubMed2003

Pharmacogenomics of ABC transporters and its role in cancer chemotherapy.

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

ATP-Binding Cassette Transporters↗
PubMed2003

Molecular targeted treatments for fungal infections: the role of drug combinations.

Invasive mycoses are associated with a high mortality rate, and their incidence is increased in immunologically deficient patients. From a diagnostic and therapeutic perspective, these infections represent a significant challenge to medicine. In addition to new antifungal agents, drug combinations are an important therapeutic resource, which might be exploited clinically, owing to the multiplicity of fungal targets against which currently available agents are active. In this review, we examine the experimental data regarding the combination of conventional antifungal agents with cytokines, antibacterial agents, calcineurin inhibitors and drugs under development characterized by novel mechanisms of action.

Amphotericin B↗
PubMed2003

Pharmacogenetics and proteomics of anticancer drugs in non-Hodgkin's lymphoma.

The variability of tumor responses to chemotherapeutic agents is a topic of major interest in current cancer research. Advances in the knowledge of dysregulation of key molecular pathways in cancer cells have enabled techniques to be developed that can profile tumor cells for their genetic background, allowing selection of anticancer agents on an individual basis. The next generation of anticancer treatments might therefore be tailored according to the molecular alterations identified in tumor cells of individual patients. However, before these alterations can be exploited from a therapeutic point of view, it is necessary to understand how such alterations influence the cellular pathways that control sensitivity to chemotherapeutic agents. Pharmacogenetics and pharmacoproteomics, novel disciplines that investigate the relationship between gene and protein expression in tumor cells and the response to anticancer agents, will be instrumental in developing optimal chemotherapeutic regimens for patients with non-Hodgkin's lymphoma.

Antineoplastic Agents↗
PubMed2003

Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer.

In mammalian cells, the process of malignant transformation is characterized by the loss or down-regulation of tumor-suppressor genes and/or the mutation or overexpression of proto-oncogenes, whose products promote dysregulated proliferation of cells and extend their life span. Deregulation in intracellular transduction pathways generates mitogenic signals that promote abnormal cell growth and the acquisition of an undifferentiated phenotype. Genetic abnormalities in cancer have been widely studied to identify those factors predictive of tumor progression, survival, and response to chemotherapeutic agents. Pharmacogenetics has been founded as a science to examine the genetic basis of interindividual variation in drug metabolism, drug targets, and transporters, which result in differences in the efficacy and safety of many therapeutic agents. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. However, these studies have yielded contradictory results because of the small number of molecular determinants of drug response examined, and in several cases this approach was revealed to be reductionistic. This limitation is now being overcome by the use of novel techniques, i.e., high-density DNA and protein arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics represents the natural evolution of pharmacogenetics since it addresses, on a genome-wide basis, the effect of the sum of genetic variants on drug responses of individuals. Development of pharmacogenomics as a new field has accelerated the progress in drug discovery by the identification of novel therapeutic targets by expression profiling at the genomic or proteomic levels. In addition to this, pharmacogenetics and pharmacogenomics provide an important opportunity to select patients who may benefit from the administration of specific agents that best match the genetic profile of the disease, thus allowing maximum activity.

Antineoplastic Agents↗