Biomedical subjects

G Cruciani

Publications and source records attributed to G Cruciani.

At least 19 recordsLinked to original sources

PubMed2001

Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study.

PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

Aged↗

PubMed2001

QSAR study and VolSurf characterization of anti-HIV quinolone library.

Antiviral quinolones are promising compounds in the search for new therapeutically effective agents for the treatment of AIDS. To rationalize the SAR for this new interesting class of anti-HIV derivatives, we performed a 3D-QSAR study on a library of 101 6-fluoro and 6-desfluoroquinolones, taken either from the literature or synthesized by us. The chemometric procedure involved a fully semiempirical minimization of the molecular structures by the AMSOL program, which takes into account the solvatation effect, and their 3D characterization by the VolSurf/GRID program. The QSAR analysis, based on PCA and PLS methods, shows the key structural features responsible for the antiviral activity.

Anti-HIV Agents↗

PubMed2001

Synthesis, in vitro skin permeation studies, and PLS-analysis of new naproxen derivatives.

PURPOSE: To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02-15). To compare their physicochemical properties with naproxen esters (16-22) and their respective skin permeation behavior. To study structure-permeation relationships via partial least squares (PLS)-analysis. METHODS: Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in-vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS-analysis was performed to derive structure-permeation relationships. RESULTS: None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS-analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation. CONCLUSIONS: PLS-analysis is a valuable tool to derive significant, internally predictive quantitative models for structure-permeation relationships of naproxen derivatives in the above described skin permeation assay.

Animals↗

PubMed2000

GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors.

Traditional methods for performing 3D-QSAR rely upon an alignment step that is often time-consuming and can introduce user bias, the resultant model being dependent upon and sensitive to the alignment used. There are several methods which overcome this problem, but in general the necessary transformations prevent a simple interpretation of the resultant models in the original descriptor space (i.e. 3D molecular coordinates). Here we present a novel class of molecular descriptors which we have termed GRid-INdependent Descriptors (GRIND). They are derived in such a way as to be highly relevant for describing biological properties of compounds while being alignment-independent, chemically interpretable, and easy to compute. GRIND are obtained starting from a set of molecular interaction fields, computed by the program GRID or by other programs. The procedure for computing the descriptors involves a first step, in which the fields are simplified, and a second step, in which the results are encoded into alignment-independent variables using a particular type of autocorrelation transform. The molecular descriptors so obtained can be used to obtain graphical diagrams called "correlograms" and can be used in different chemometric analyses, such as principal component analysis or partial least-squares. An important feature of GRIND is that, with the use of appropriate software, the original descriptors (molecular interaction fields) can be regenerated from the autocorrelation transform and, thus, the results of the analysis represented graphically, together with the original molecular structures, in 3D plots. In this respect, the article introduces the program ALMOND, a software package developed in our group for the computation, analysis, and interpretation of GRIND. The use of the methodology is illustrated using some examples from the field of 3D-QSAR. Highly predictive and interpretable models are obtained showing the promising potential of the novel descriptors in drug design.

Butyrophenones↗

PubMed2000

GRID/CPCA: a new computational tool to design selective ligands.

We present a computational procedure aimed at understanding enzyme selectivity and guiding the design of drugs with respect to selectivity. It starts from a set of 3D structures of the target proteins characterized by the program GRID. In the multivariate description proposed, the variables are organized and scaled in a different way than previously published methodologies. Then, consensus principal component analysis (CPCA) is used to analyze the GRID descriptors, allowing the straightforward identification of possible modifications in the ligand to improve its selectivity toward a chosen target. As an important new feature the computational method is able to work with more than two target proteins and with several 3D structures for each protein. Additionally, the use of a 'cutout tool' allows to focus on the important regions around the active site. The method is validated for a total number of nine structures of the three homologous serine proteases thrombin, trypsin, and factor Xa. The regions identified by the method as being important for selectivity are in excellent agreement with available experimental data and inhibitor structure-activity relationships.

Algorithms↗

PubMed2000

A 3D-QSAR study on the structural requirements for binding to CB(1) and CB(2) cannabinoid receptors.

A 3D-QSAR study was carried out on 20 cannabinoids for which the binding affinities (K(i)) with respect to CB(1) and CB(2) receptors, determined in the same cell line, were available. For the first time three series of significantly different chemical structures such as Delta(9)-THC analogues, anandamides, and indoles were included in a single 3D-QSAR model, to obtain information on the interactions of all ligands with both CB(1) and CB(2) receptors and on their receptor selectivity. Delta(9)-THC was chosen as the structural template for alignment. The 3D-structure-activity correlation obtained by the GOLPE procedure provided a partial least squares (PLS) model with a very good predictive ability for the CB(1) receptor affinity of all compounds. The model allowed us to identify seven different regions in the space that contribute to explain the above binding affinities. External validation of the interpretation of the 3D-QSAR model was derived from a response-independent procedure such as principal components analysis (PCA). The CB(2) receptor model evidenced, besides the seven regions found for the CB(1) receptor, a new characteristic region for the CB(2) receptor. Another PCA, using 10 GRID probes, provided further evidence of receptor selectivity regions. One region opposite to the amidic NH of CB(1) selective O585 appears to be responsible for the CB(1) selectivity, while an interaction region opposite to the carbonyl of CB(2) selective JWH-015 appears to be involved in the CB(2) binding selectivity.

Arachidonic Acids↗

PubMed2000

Predicting blood-brain barrier permeation from three-dimensional molecular structure.

Predicting blood-brain barrier (BBB) permeation remains a challenge in drug design. Since it is impossible to determine experimentally the BBB partitioning of large numbers of preclinical candidates, alternative evaluation methods based on computerized models are desirable. The present study was conducted to demonstrate the value of descriptors derived from 3D molecular fields in estimating the BBB permeation of a large set of compounds and to produce a simple mathematical model suitable for external prediction. The method used (VolSurf) transforms 3D fields into descriptors and correlates them to the experimental permeation by a discriminant partial least squares procedure. The model obtained here correctly predicts more than 90% of the BBB permeation data. By quantifying the favorable and unfavorable contributions of physicochemical and structural properties, it also offers valuable insights for drug design, pharmacological profiling, and screening. The computational procedure is fully automated and quite fast. The method thus appears as a valuable new tool in virtual screening where selection or prioritization of candidates is required from large collections of compounds.

Blood-Brain Barrier↗

PubMed2000

VolSurf: a new tool for the pharmacokinetic optimization of lead compounds.

A method for the modeling and prediction of pharmacokinetic properties based on computed molecular interaction fields and multivariate statistics has been investigated in different experimental datasets. The program VolSurf was used to correlate 3D molecular structures with physico-chemical and pharmacokinetic properties. In membrane partitioning, VolSurf produced a two-component model explaining 94% of the total variation with a predictive q(2) of 0.90. This result was achieved without conformational sampling and without any quantum-chemical calculation. For the prediction of blood-brain barrier penetration the VolSurf model was able to predict the BBB profile for most of the drugs in the external prediction set. In Caco-2 and MDCK permeation experiments, VolSurf was used with success to establish statistical models and to predict the behaviour of new compounds. The method thus appears as a valuable new property filter in virtual screening and as a novel tool in optimizing the pharmacokinetic profile of pharmaceutically relevant compounds.

Animals↗

PubMed2000

3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands.

Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes identified the most important enzyme-ligand interactions that account for the differences in activity within the series. A GRID/GOLPE analysis was then performed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and confirmed the advantages of incorporating structural information from series of ligand-receptor complexes into 3D-QSAR methodologies.

Binding Sites↗

PubMed2000

Schedule dependent toxicity and efficacy of combined gemcitabine/paclitaxel treatment in mouse adenocarcinoma.

Increased interest in combining drugs with different targets has emerged over recent years. Our study aims at evaluating the effectiveness of combined gemcitabine/paclitaxel treatment taking into consideration doses, schedules, and toxicity. A spontaneous mammary carcinoma was transplanted into the right-hind foot of C3D2F1 mice. Paclitaxel (in doses from 20 to 80 mg/kg b.w.) and gemcitabine (in doses from 30 to 480 mg/kg b.w.) were administered i.p. in single or fractionated treatments. Toxicity and tumor growth delay (TGD) were the endpoints. TGDs for different gemcitabine doses in single administration (120, 240, and 360 mg/kg) overlapped (TGD approximately = 2.5 days). Toxicity was very high in daily administration. Results with gemcitabine alone showed the efficacy of treatments every 3 days. TGDs in fractionated treatments of 60 and 120 mg/kg x 4 were of approximately equals 16 days. Also in this case, tumor growth curves overlapped pointing out the uselessness of the high drug doses. For combined treatments, we used only fractionated protocols, administering gemcitabine every 3 days. Paclitaxel was administered alone in one or two fractions and with different sequences in respect to gemcitabine administration. With 120 mg/kg of gemcitabine all the protocols showed an increased unacceptable toxicity. The best result was obtained administering paclitaxel 40 mg/kg on days 1 and 15 and gemcitabine 60 mg/kg on days 3, 6, 9, and 12 (TGD = 38.2 days). The light toxicity and the high efficacy obtained with this protocol indicate the possible use of gemcitabine/paclitaxel treatment in clinical practice.

Adenocarcinoma↗

PubMed1999

Hyperthermia enhances the response of paclitaxel and radiation in a mouse adenocarcinoma.

PURPOSE: The aim of our study was to investigate if the efficacy of paclitaxel and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia. MATERIALS AND METHODS: Paclitaxel was administered i.p. in doses from 30 to 60 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local hyperthermia (41 degrees, 42 degrees, 43 degrees C) was carried out by immersing tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90 Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD(50), radiation dose needed to induce local tumor control in 50% of irradiated animals) were the endpoints. RESULTS: A significant increase of dose-dependent growth delay was observed in paclitaxel and 43 degrees C hyperthermia combined treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg. Combined treatments with hyperthermia at 41 degrees and 42 degrees C were less effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min and 4 h after hyperthermic treatments produced similar results (TGDs varying from 22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment (paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD(50) of 14. 1 Gy, in respect to the TCD(50) of 53.1 obtained with X-ray alone, was the most effective. CONCLUSIONS: Hyperthermia enhanced the effectiveness of paclitaxel in all the tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg combined with a hyperthermic treatment of 1 h at 43 degrees C. Trimodality treatment, evaluated in terms of percentage of cures, shows a very high enhancement ratio.

Analysis of Variance↗

PubMed1999

6-Substituted benzopyrans as potassium channel activators: synthesis, vasodilator properties, and multivariate analysis.

During the last 10 years compounds have been discovered which can activate or block KATP channels. In particular, K channel activators (KCA) have been found to be smooth muscle relaxants with their main utility in hypertension and bronchodilation. In this paper we describe the synthesis of new KCA of the benzopyran type with a fixed 4-substituent and a systematic variation in the 6-position. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. In both biological test systems, they exhibit potency ranges of more than 3 log units. Structure-activity relationships are investigated by principal component analysis (PCA) and partial least-squares (PLS) analysis. Most striking outliers in an initial PLS analysis of the entire database were the unsubstituted 6-H compound 13 as well as 34 and 35. For the remaining set of 31 compounds, a 3-component PLS model explains the variance in biological activity to 81% in the aortic and to 82% in the tracheal test system. 6-Substituents influence affinity by a direct (presumably dipolar) interaction with the receptor site. According to the 2D-plot of the partial PLS weights, a strong electronegativity as well as high values for the integy moment and for the heat of formation in water dominate the first component; low values for substituent size (as defined by globularity or surface) are in addition favorable for high potency. High lipophilicity and low minimum energies of interaction dominate the second component. Chemical descriptors for the biological potency of the test set in rat aorta and rat trachea are very similar according to the almost identical projection of the Y-variables onto the X-component space.

Animals↗

PubMed1999

Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The aim of this work was to validate a previously constructed prognostic score for terminally ill cancer patients in order to determine its value in clinical practice. The Palliative Prognostic Score (PaP Score) was tested on a population of 451 evaluable patients consecutively entered in the hospice programs of 14 Italian Palliative Care Centers. The score subdivided patients into three specific risk classes based on the following six predictive factors of death: dyspnea, anorexia, Karnofsky Performance Status (KPS), Clinical Prediction of Survival (CPS), total white blood count (WBC), and lymphocyte percentage. The performance of the PaP Score index in the training and testing sets was evaluated by comparing mortality rates in the 3 prognostic risk categories. The score was able to subdivide the validation-independent case series into three risk groups. Median survival was 76 days in group A (with a 86.6% probability of 30-day survival), 32 days in group B (with a 51.6% probability of 30-day survival), and 14 days in group C (with a 16.9% probability of 30-day survival). Survival medians were remarkably similar to those of the training set (64 days in group A, 32 days in group B, and 11 days in group C). In the complex process of staging terminally ill patients, the PaP Score is a simple instrument which permits a more accurate quantification of expected survival. It has been validated on an independent case series and is thus suitable for use in clinical practice.

Algorithms↗

PubMed1999

Experimental design and multivariate calibration in the development, set-up and validation of a differential pulse polarographic and UV spectrophotometric method for the simultaneous plasmatic determination of the therapeutic metronidazole-pefloxacin combination.

Partial least squares regression (PLS1 and PLS2) and GOLPE variable selection procedures were used for the treatment of differential pulse polarographic and UV spectrophotometric data obtained from the analysis of the therapeutic combination of metronidazole and pefloxacin. The analytical method used for the determination was set up using experimental design strategies (Doehlert's design, full factorial design, fractional face center cube design, etc.) and by involving the simultaneous optimization of several responses (desirability function). Method validation was also performed, determining accuracy, precision, linearity and range, detection and quantification limits and robustness. The quantitative prediction abilities in determining metronidazole and pefloxacin plasma levels of the PLS1 and PLS2 models were tested on spiked plasma samples and good results were obtained (metronidazole, 97.5%, RSD = 4.8%, n = 3; pefloxacin, 100.6%, RSD = 3.6%, n = 3). The use of multivariate calibration was particularly useful for spectrophotometric quantification because of the highly overlapping spectra of the binary mixture.

Anti-Bacterial Agents↗

PubMed1999

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.

Adult↗

PubMed1999

Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: results of an Italian Prostate Cancer Project study.

PURPOSE: To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade (MAB) in the treatment of advanced prostatic cancer. PATIENTS AND METHODS: Previously untreated patients with histologically proven stage C or D disease (American Urological Association Staging System) were randomly allocated to receive either bicalutamide or MAB. After disease progression, patients treated with bicalutamide were assigned to castration. The primary end point for this trial was overall survival. Secondary end points included response to treatment, disease progression, treatment safety, quality-of-life (QOL), and sexual function. RESULTS: A total of 108 patients received bicalutamide and 112 received MAB. There was no difference in the percentage of patients whose prostate-specific antigen returned to normal levels. At the time of the present analysis (median follow-up time, 38 months; range, 1 to 60 months), 129 patients progressed and 89 died. There was no difference in the duration of either progression-free survival or overall survival. However, a survival trend favored bicalutamide in stage C disease but MAB in stage D disease. Overall and subgroup trends were confirmed by multivariate analysis. Serious adverse events and treatment discontinuations were more common in patients receiving MAB (P =.08 and P =.04, respectively). Fewer patients in the bicalutamide group complained of loss of libido (P =. 01) and of erectile dysfunction (P =.002). Significant trends favored bicalutamide-treated patients also with respect to their QOL, namely relative to social functioning, vitality, emotional well-being, and physical capacity. CONCLUSION: Bicalutamide monotherapy yielded comparable results relative to standard treatment with MAB, induced fewer side effects, and produced a better QOL.

Adult↗

PubMed1998

Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis.

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.

Animals↗

PubMed1998

Enhancement of radiation response by paclitaxel in mice according to different treatment schedules.

PURPOSE: The aim of our study was to determine if paclitaxel could be used as a radiosensitizer in vivo. MATERIALS AND METHODS: Paclitaxel was tested as a single agent and combined with an X-ray treatment. Paclitaxel was administered i.p. in doses from 30 to 120 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Tumor growth delay (TGD) or tumor control dose (TCD50, radiation dose needed to induce local tumor control in 50% of irradiated animals) and moist desquamation dose (MDD50, radiation dose needed to induce serious moist desquamation in 50% of the non-tumor-bearing feet) were the endpoints. DNA flow cytometric analysis was performed. RESULTS: DNA analysis demonstrated a G2/M block of tumor cells and a depletion of cells in S phase, with a maximum at 24 h from paclitaxel administration. Administering paclitaxel, in graded doses, 15 min before a 10-Gy X-ray treatment resulted in a linear regression line, almost parallel to that with paclitaxel alone, with a growth delay of about 6 days. In contrast, varying the X-ray dose with a constant paclitaxel injection (45 mg/kg b.w.) treatment showed some degree of synergism as the linear regression curves diverged. Interval time and sequence between paclitaxel administration and a 10 Gy X-ray treatment did not influence TGD. Protocols with paclitaxel at 30, 45, or 60 mg/kg were combined with radiation treatments at various doses (from 10 to 65 Gy). Values of TCD50 varied from 50.8 Gy for X-ray alone to 31.8 Gy for paclitaxel 60 mg/kg + X-ray. No differences were observed among MDD of different protocols. CONCLUSIONS: These results suggest that, under some conditions, paclitaxel combined with radiation can show superadditive effects and this result combined with the lack of severe normal tissue damage indicate that a favorable therapeutic gain can be obtained.

Animals↗