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I Poggesi

Publications and source records attributed to I Poggesi.

33 records · Page 2Linked to original sources
PubMed1996

Pharmacokinetics of reboxetine in healthy volunteers. Single against repeated oral doses and lack of enzymatic alterations.

The pharmacokinetics of reboxetine have been investigated in 12 healthy male volunteers after a single 2 mg dose of reboxetine and at steady state, following the last administration of a multiple-dose regimen (2mg twice a day for 5 1/2 d). Reboxetine was analysed in plasma and urine samples collected up to 72 h post-dosing using an HPLC method with UV detection. The urinary excretion rate of 6-beta-hydroxycortisol, used as a marker for cytochrome P450IIIA activity, was also tested, and any possible alteration was correlated to reboxetine plasma levels. The dosing regimen was well tolerated by all subjects. Reboxetine pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the multiple-dosing regimen, no significant deviations from expectation based on linear superposition was observed. The accumulation ratio, based on repeated-dose/single-dose ratios of Cmax, AUC(0-12 h), and C(12 h) was approximately two. A slight rise was recorded for the average excretion rate of 6-beta-hydroxycortisol over 48 h by the end of treatment; however, the difference was not statistically significant and the mean excretion rates were within the normal reference range. Thus a significant induction of P450IIIA was not indicated.

Administration, Oral↗
PubMed1996

Cytological evidence for 5-azacytidine-induced demethylation of the heterochromatic regions of human chromosomes.

This work was aimed at studying the effects of the demethylating agent 5-azacytidine (5-azaC) on the constitutive heterochromatin of human chromosomes at the cytological level. Metaphase preparations from peripheral blood lymphocyte and lymphoblastoid cultures obtained by standard methods were treated with the agent. Labelling of the heterochromatic regions was achieved by the indirect immunostaining method using anti-5-methylcytosine (5MeC) monoclonal antibodies and peroxidase-tagged second antibodies. 4-Chloro-1-naphthol (4C1N) was used as the substrate. The rate of methylation of individual chromosomes or chromosome groups was measured as the frequency of binding of anti-5MeC antibodies to specific chromosome regions. The following results were obtained: (i) in control cultures high intra- and interindividual variability in the binding frequencies of anti-5MeC antibodies to the short arm region of the acrocentrics was observed; (ii) 5-azaC consistently affects the methylation status of the constitutive heterochromatin; (iii) preferential demethylation occurs in the heterochromatic regions of specific chromosomes; (iv) under our experimental conditions the demethylating effect of 5-azaC appears not to be related to the well-known uncoiling effect of this drug.

5-Methylcytosine↗
PubMed1995

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Adult↗
PubMed1995

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Adult↗
PubMed1995

Low environmental radiation background impairs biological defence of the yeast Saccharomyces cerevisiae to chemical radiomimetic agents.

Background radiation is likely to constitute one of the factors involved in biological evolution since radiations are able to affect biological processes. Therefore, it is possible to hypothesize that organisms are adapted to environmental background radiation and that this adaptation could increase their ability to respond to the harmful effects of ionizing radiations. In fact, adaptive responses to alkylating agents and to low doses of ionizing radiation have been found in many organisms. In order to test for effects of adaptation, cell susceptibility to treatments with high doses of radiomimetic chemical agents has been studied by growing them in a reduced environmental radiation background. The experiment has been performed by culturing yeast cells (Saccharomyces cerevisiae D7) in parallel in a standard background environment and in the underground Gran Sasso National Laboratory, with reduced environmental background radiation. After a conditioning period, yeast cells were exposed to recombinogenic doses of methyl methanesulfonate. The yeast cells grown in the Gran Sasso Laboratory showed a higher frequency of radiomimetic induced recombination as compared to those grown in the standard environment. This suggests that environmental radiation may act as a conditioning agent.

Background Radiation↗
PubMed1995

Persistence of increased levels of ribosomal gene activity in CHO-K1 cells treated in vitro with demethylating agents.

The rate of ribosomal gene activity was evaluated by silver staining of the Nucleolus Organisers (NOs) in cultured CHO-K1 cells after a 12 h pulse with two demethylating agents (L-ethionine and 5-azacytidine). Silver staining of the NOs was measured every 24 h, from 24 up to 110 h after seeding. The purpose was to test the hypothesis that drug-induced demethylation is associated to heritable modifications of rDNA activity. Ribosomal gene activity was shown to be significantly increased by both agents. The increase persisted throughout the experiments, thereby suggesting the heritability of this epigenetic modification. The analysis of heritable DNA damage or modification is an important task in studying the risk of cancer onset and the mechanisms of cancer induction. In these studies two main results were obtained: (i) heritable DNA variations can be induced by both mutational and epigenetic changes; (ii) the modified end-point was not negatively selected.

Animals↗
PubMed1994

High-performance liquid chromatographic assay of the magnetic resonance imaging contrast agent gadobenate in plasma, urine and bile.

Gadobenate dimeglumine (Gd-BOPTA-Dimeg) is currently under evaluation as an intravascular paramagnetic contrast agent for magnetic resonance imaging. The anion Gd-BOPTA2- is the moiety of Gd-BOPTA-Dimeg responsible for contrast enhancement. An HPLC method for assaying gadobenate (Gd-BOPTA2-) in plasma, urine and bile samples is described. The analysis is based on the reversed-phase chromatographic separation of the ion pair Gd-BOPTA(2-)-tetrabutylammonium from the endogenous components of biological fluids and its detection by UV absorption at 210 nm. The mean accuracy and precision of the method were in the range -3.4 to +5.0% and 0.2-3.5%, respectively. The method detection limits for Gd-BOPTA2- in plasma (0.8 ml), urine (0.2 ml) and bile (1.0 ml) were 1.1, 7.6 and 1.7 microM (corresponding to 0.73, 5.1 and 1.1 micrograms/ml), respectively.

Animals↗
PubMed1994

Pharmacodynamics and relative bioavailability of cabergoline tablets vs solution in healthy volunteers.

The effect of formulation on the urinary pharmacokinetics, pharmacodynamics, and relative bioavailability of cabergoline was investigated. Twelve healthy female volunteers, aged 23-35 years, were treated, according to an open, randomized, crossover design, with cabergoline (1-mg single oral dose) both as tablets and as a solution. The two administrations were separated by a 4-week wash-out period. Cabergoline and prolactin were measured in urine and plasma, respectively, by specific radioimmunoassays. Blood samples were collected before and up to 30 days after dosing. Urine was collected before and up to 8 days after dosing. Cabergoline elimination half-lives calculated from urinary data were 68 and 63 h after administration of the tablets and the solution, respectively. Urinary excretion of unchanged cabergoline accounted, on average, for 1.92% (range, 0.14-3.26) and 1.80% (range, 0.67-3.09) of the dose after administration of the tablets and the aqueous solution, respectively. Relative bioavailability of tablets vs solution was 99% (geometric mean with the 90% confidence intervals of 68-144%). Prolactin levels in 10 out of 12 subjects fell below the detection limit of the assay (1.5 micrograms/L) after both treatments. The mean maximum prolactin decrease (ca. 70%) was achieved by 2 or 3 h after dosing; the effect persisted up to 9 days, being completely exhausted 23-28 days after dosing. The analysis of variance performed on the pharmacodynamic effects of the two cabergoline formulations indicated that the percent decreases of plasma prolactin levels were not significantly different for tablets and solution. These results indicate that the pharmacodynamics and relative bioavailability of cabergoline are not influenced by formulation, as tablets or solution.

Adult↗
PubMed1994

Activity of terbinafine against Pneumocystis carinii in vitro and its efficacy in the treatment of experimental pneumonia.

The antiprotozoan and antifungal agent, the terbinafine, was investigated for its potential activity against Pneumocystis carinii infection of the A549 cell line culture and on immunosuppressed Sprague Dawley rats in comparison with trimethoprim-sulphamethoxazole and pentamidine isethionate. Terbinafine suppressed P. carinii growth at doses up to 3 g/L within 24 h and it was able to inhibit cyst forms at 60 h post inoculation. With respect to trimethoprim-sulphamethoxazole and pentamidine isethionate P. carinii organisms decreased at the same time interval but cyst form elimination was less apparent than with terbinafine. The results of the in-vitro culture were consistent with the in-vivo observations. Of the 3 groups of rats tested, the occurrence of P. carinii pneumonia was documented in 18 (60%) of the control rats (group 3) which showed a high degree of P. carinii burden and a marked weight loss with respect to the beginning of the experiment. Among terbinafine treated rats (group 1), P. carinii pneumonia was present in one rat (3.3%), while no P. carinii infection occurred in the pentamidine isethionate and in trimethoprim-sulphamethoxazole treatment rat groups (group 2). All the agents investigated showed no particular signs of toxicity. These preliminary results suggest further explorations of the terbinafine in clinical trials for treatment and prophylaxis of P. carinii pneumonia.

Animals↗
PubMed1991

Inheritance of ribosomal gene activity and level of DNA methylation of individual gene clusters in a three generation family.

Ribosomal gene activity and levels of DNA methylation were investigated by cytochemical and immunological methods in the nucleolar organizer regions (NORs) of individually recognised acrocentric chromosomes. Mendelian inheritance of ribosomal gene activity in a three generation family was demonstrated, together with consistent behaviour of individual gene clusters in different carriers, even when environmental conditions were changed. For most chromosomes, an inverse relationship between gene activity and the level of DNA methylation was observed. Exceptions were the two chromosomes 15 and chromosomes 13cp and 22p, all being strongly chromomycin-A3-positive in their short arms. These chromosomes bound to anti-5-MeC antibodies with differential frequencies in the different carriers. The possibility of involvement of repetitive GC-rich DNA in this behaviour is discussed.

Azacitidine↗
PubMed1990

High-performance liquid chromatographic assay of iomeprol in plasma and urine.

A high-performance liquid chromatographic method for assaying the radiographic contrast agent iomeprol in plasma and urine samples is described. Before reversed-phase chromatography, the biological fluids are treated with ion-exchange resins and iopamidol is added as internal standard. The compounds are monitored during elution by ultraviolet-visible spectrometry at 245 nm. The method shows good precision and accuracy and gives similar results to X-ray fluorescence analysis.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Pharmacokinetics of acipimox and of its N-deoxy metabolite following single and repeated oral administration to healthy volunteers.

The aim of the present study was to evaluate the plasma pharmacokinetics of acipimox and of its N-deoxy metabolite (5-methylpyrazine-2-carboxylic acid, MPCA) following single and repeated administration of 250 mg acipimox (thrice daily, for 6 days) to ten healthy volunteers. Mean maximum concentration, the corresponding time, area under the curve extrapolated to infinity and elimination half-life values of acipimox after single administration were equal to 5.74 micrograms/ml (range 2.56-8.38 micrograms/ml), 1.7 h (1-3 h), 16.99 micrograms/ml.h (11.28-22.17 micrograms/ml.h) and 1.15 h (0.79-1.48 h), respectively. Mean area under the curve over one dosing interval (8 h) and elimination half-life values of acipimox after repeated dosing were not significantly different from the corresponding values after the single dose. No significant accumulation was observed following the repeated treatment, since the mean accumulation ratio was 1.08 (range 0.74-1.52). The mean maximum concentration and corresponding time values in the 7 out of 10 subjects with detectable metabolite levels after the single dose were 0.19 microgram/ml (0.10-0.34 microgram/ml) and 6.7 h (3-12 h), respectively, whilst after the repeated treatment, detectable concentrations of the metabolite were observed in all subjects, the mean maximum concentration value being equal to 0.48 micrograms/ml (0.11-1.19 microgram/ml). The average ratio of the parent/metabolite area under the curve values (8 h) after repeated dosing was equal to 14 (range 2-56). Inter-subject variability in the extent of metabolite formation was very high.

Administration, Oral↗