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Biomedical subjects

G Poli

Publications and source records attributed to G Poli.

At least 325 records · Page 18Linked to original sources
PubMedDate not supplied

Bioavailability and pharmacokinetics of a fixed combination of delapril/indapamide following single and multiple dosing in healthy volunteers.

The study objective was to obtain detailed information on the bioavailability and pharmacokinetics of the new fixed combination of delapril and indapamide following single and multiple dosing. For this reason, the study was performed in two parts, separated by a medication-free period of at least 7 days. In the single dose part, one tablet, containing 30 mg delapril and 2.5 mg indapamide, was administered to 12 male volunteers; in the multiple dose part, the volunteers received one tablet of the test preparation, once daily over 7 days. Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods. In addition, urine samples were collected following single and multiple dosing for evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine. For the area under the curve, calculated from time 0 to infinity (AUC(0-infinity)) the study revealed, following single dosing, mean values of delapril and its metabolites M1, M2 and M3 of 281, 2178, 739 and 716 h.ng/ml, respectively; for indapamide the mean value was 1597 h.ng/ml. The corresponding mean values found after multiple dose administration were 272, 2071, 857 and 598 h.ng/ml for delapril and its metabolites, respectively and 1536 h.ng/ml for indapamide. Evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine (Ae) demonstrated mean values following single dosing (observation period 36 h) of 705, 4521, 454 and 4203 micrograms, respectively; the corresponding values after multiple dose administration (observation period 24 h) of the test preparation were 655, 4679, 469 and 4801 micrograms, respectively. The most important pharmacokinetic parameters AUC(0-infinity) and Ae were statistically compared by analysis of variance (ANOVA) and 90% confidence intervals were calculated. It may be concluded from the results of this study, that the bioavailability and pharmacokinetic parameters of the test preparation after single dosing and after multiple doses correspond well. The undesired side effects observed are known to occur after administration of the test preparation. The occurrence was a little more frequent after multiple dose application in comparison with the single dose administration.

Adult↗
PubMedDate not supplied

Comparative bioavailability of two oral formulations of ipriflavone in healthy volunteers at steady-state. Evaluation of two different dosage schemes.

Ipriflavone (IP) is an isoflavone derivative with antiosteoporotic activity. This drug is extensively metabolized in humans and only negligible concentrations of unchanged IP can be detected in plasma. Metabolites M1 and M5 are predominant, while met abolites M2 and M3 are detected in minor amounts. The aim of this study was to compare the bioavailability of IP and its metabolites M1, M2, M3, and M5 at steady-state after administration of 200 mg tablets three times daily and 300 mg Scherer capsules twice daily during meals. IP plasma levels were below the limit of quantitation in 6 subjects out of 12 after administration of IP 200 mg tablets. On the other hand, after administration of the Scherer capsules IP plasma levels were quantifiable in all the volunteers. As regards IP metabolites, a mean increase in bioavailability, equal to 35%, was observed after administration of the Scherer capsules. Plasma level fluctuations, reflecting changes in absorption rate at steady-state, remained unvaried. The good bioavailability and fluctuation indexes of the Scherer capsules permit a simplification of the dosage scheme, reducing the daily administrations from three times to twice daily, thus improving the patients' compliance. In clinical practice this characteristic is not negligible, con sidering the mean age of the patients and the long-term treatment. Due to the high therapeutic index of IP, the increase in bioavailability does not cause any risk of accumulation or overdosage.

Administration, Oral↗
PubMedDate not supplied

Food effect on the oral bioavailability of Manidipine: single dose, randomized, crossover study in healthy male subjects.

The effect of food on the oral bioavailability of a manidipine 20 mg tablet was studied after a single administration in 12 male healthy subjects. The clinical trial was conducted as an open, randomised, crossover study. In two different administration sessions, the subjects received a 20 mg manidipine tablet either in the fasting state or after a standardized breakfast. Plasma samples were collected before and at different times after each administration for up to 24 h. The concentrations of manidipine and its pyridine metabolite (M-XIII metabolite) were determined by HPLC with coulometric detection. The tolerability of manidipine was good. Only two cases of mild headache, one with each treatment, were reported. Food significantly improved the absorption, with an increase in AUC from 19.1 to 27.2 ng.h/ml (geometric mean, p<0.01) but did not modify the rate of absorption (tmax unchanged, median = 1.5 h). Peak plasma concentration was also increased (from 6.2 to 7.8 ng/ml), but the difference was not statistically significant (p=0.18). Other pharmacokinetic parameters (apparent elimination half-life and mean residence time) remained unchanged. The increase in bioavailability of manidipine administered with food is related to its high lipophilicity and may be explained through a solubilization effect produced by food and bile secretions.

Adult↗
PubMedDate not supplied

14C-NaVP and 14C-PEV repeated dose study in rat. Pharmacokinetic study in rats after repeated oral administrations of 14C-valproic acid sodium salt and 14C-valproic acid pivaloyl oxymethyl ester.

The absorption, excretion and tissue distribution of radioactivity after repeated oral equimolar doses of 14C-valproic acid sodium salt (NaVP) or 14C-valproic acid pivaloyl oxymethyl ester (PEV) was investigated in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 microg eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 microg eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting from 4 h onwards, radioactivity levels after PEV treatment were higher than those after NaVP (AUCtau = 113.3 h.microg eq./ml after PEV vs 71.9 h.microg eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivity recovered (0-432 h interval) in urine accounted for 79.3% (PEV) and 56.1% (NaVP) while, in faeces accounted for 9.1% (PEV) and 26.1% (NaVP) of total administered dose (14 days). The difference is attributable to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excreted in expired air, as observed in single dose studies. Radioactivity excreted in bile (0-8 h interval of the last 14th day) accounted for 5.1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observed after PEV administration is probably due to an inhibition of the glucuronation of valproic acid (or other metabolites) caused by the pivalic acid. Due to the presence of the enterohepatic recycle, the radioactivity levels in intestine, 0.5 and 2 h after administration, were higher after NaVP administration. According to higher plasma levels, the radioactivity concentrations in liver, kidneys and some fat tissues were found to be slightly higher after PEV administration. At 120 h after the last treatment of both compounds, relevant tissue concentrations were observed in mesenteric lymphnodes, perirenal and brown fat. The tissue-plasma radio activity ratio appeared quite similar for the two compounds.

Administration, Oral↗
PubMedDate not supplied

The role of lipid peroxidation in liver damage.

The consequences of the peroxidative breakdown of membrane lipids have been considered in relation to both the subcellular and tissue aspects of liver injury. Mitochondrial functions can be impaired by lipid peroxidation probably through the oxidation of pyridine nucleotides and the consequent alteration in the uptake of calcium. Several enzymatic functions of the endoplasmic reticulum are also affected as a consequence of peroxidative events and among these are the activities of glucose 6-phosphatase, cytochrome P-450 and the calcium sequestration capacity. Moreover, a release of hydrolytic enzymes from lysosomes and a decrease in the fluidity of plasma membranes can contribute to the liver damage consequent to the stimulation of lipid peroxidation. Extensive studies carried out in vivo and integrated with the use of isolated hepatocytes have shown that lipid peroxidation impairs lipoprotein secretion mainly at the level of the dismission from the Golgi apparatus, rather than during their assembly. However, such an alteration appears to give a late and not essential contribution to the fat accumulation. A more critical role is played by peroxidative reactions in the pathogenesis of acute liver necrosis induced by several pro-oxidant compounds as indicated by the protective effects against hepatocyte damage exerted by antioxidants. In addition, even in the cases where lipid peroxidation has been shown not to be essential in causing cell death there is evidence that it can still act synergistically with other damaging mechanisms in the amplification of liver injury.

Animals↗
PubMedDate not supplied

4-hydroxynonenal and transforming growth factor-beta1 expression in colon cancer.

In vivo studies on human colon adenocarcinoma showed decreased transforming growth factor-beta1 (TGF-beta1) antiproliferative cytokine content in tumour tissue related to malignancy progression, with a corresponding decrease in lipid peroxidation aldehydic end-product, 4-hydroxynonenal (HNE). The tumour mechanism to escape TGF-beta1-mediated growth inhibition may be due to an altered TGF-beta1 receptor system. Subsequent in vitro analyses showed a differential distribution of TGF-beta1 receptors depending on the human colon cancer cell line considered (CaCo-2 or HT-29): compared to HT-29 cells, CaCo-2 cells showed a decrease of the two main TGF-beta1 receptors, RI and RII. Notwithstanding their partial TGF-beta1 RI and RII deficiency, treatment of CaCo-2 cells with adequate doses of the cytokine (10 ng/ml) was able to induce apoptosis. Of note, co-treatment of these cells with 1 microM HNE increased the apoptotic effect. The constant low concentration of TGF-beta1 in the tumour mass may be related to the low content of antiproliferative HNE observed in colon cancer: the latter phenomenon, which reduces TGF-beta1 production in the tumour area, may represent a favourable condition for neoplastic progression. The enhancement of TGF-beta1-induced apoptosis by HNE in CaCo-2 cells supports this hypothesis. The different transcriptional components regulated by the distinct signaling pathways of these two molecules might be proposed; in particular, crosstalk between the MAPK and the Smad pathway could modulate and co-operate in the transcription of target genes involved in regulation of cell proliferation.

Adenocarcinoma↗
PubMedDate not supplied

4-Hydroxynonenal in the pathomechanisms of oxidative stress.

Here we review the current knowledge on the biochemistry and molecular pathology of oxidative stress with specific regard to a major aldehydic end-product stemming from peroxidation of biomembranes, that is 4-hydroxynonenal (HNE). This multifunctional molecule, which derives from the most represented class of polyunsaturated fatty acids in the membranes, is potentially able to undergo a number of reactions with proteins, phospholipids, and nucleic acids. Despite an active metabolism in most of the cell types, HNE can be detected in several biological tissues by means of sufficiently precise methods, although with different sensitivity. In particular, relatively high steady-state levels of HNE are often detectable in a large variety of human disease processes, pointing to some involvement of the aldehyde in their pathogenesis. Among the prominent pathobiochemical effects of HNE is its remarkable stimulation of fibrogenesis and inflammation, which indicates a potential contribution of the aldehyde to the pathogenesis of several chronic diseases, whose progression is indeed supported by inflammatory reactions and characterized by fibrosis. Further, of interest appears to be the ability of HNE to modulate cell proliferation through interference with the activity of cyclins and protein kinases and with the apoptotic machinery. Finally, on the basis of the already achieved evidence, pursuing investigation of the role of HNE in signal transduction and gene expression seems very promising.

Aldehydes↗
PubMedDate not supplied

Neutrophil recruitment in the reperfused-injured rat liver was effectively attenuated by repertaxin, a novel allosteric noncompetitive inhibitor of CXCL8 receptors: a therapeutic approach for the treatment of post-ischemic hepatic syndromes.

Hepatic reperfusion injury represents a crucial problem in several clinical situations including liver transplantation, extensive hepatectomy and hypovolemic shock with resuscitation. Repertaxin is a new non-competitive allosteric blocker of interleukin-8 (CXCL8) receptors, which by locking CXCR1/R2 in an inactive conformation, prevents receptor signaling and polymorphonuclear leukocyte (PMN) chemotaxis. The present study shows that repertaxin dramatically prevents rat post-ischemic hepatocellular necrosis (80% of inhibition) and PMN infiltration (96% of inhibition) at a clinically-relevant time (24 h) of reperfusion. Treatment with repertaxin by continuous infusion is demonstrated to be the optimal route of administration of the compound especially in view of its clinical therapeutic use. Because repertaxin has proven to be safe and well tolerated in different animal studies and in phase I studies in human volunteers, it is in fact a candidate novel therapeutic agent for the prevention and treatment of hepatic post-ischemic injury.

Alanine Transaminase↗
PubMedDate not supplied

Prevention of carbon tetrachloride-induced lipid peroxidation in liver microsomes from dehydroepiandrosterone-pretreated rats.

Dehydroepiandrosterone (DHEA), a lipid soluble steroid, administered to rats (100 mg/kg b.wt) by a single intraperitoneal injection, increases to twice its normal level in the liver microsomes. Microsomes so enriched become resistant to lipid peroxidation induced by incubation with carbon tetrachloride in the presence of a NADPH-regenerating system: also the lipid peroxidation-dependent inactivation of glucose-6-phosphatase and gamma-glutamyl transpetidase due to the haloalkane are prevented. Noteworthy, the liver microsomal drug-metabolizing enzymes and in particular the catalytic activity of cytochrome P450IIE1, responsible for the CCl4-activation, are not impaired by the supplementation with the steroid. Consistently, in DHEA-pretreated microsomes the protein covalent binding of the trichloromethyl radical (CCl3 degrees), is similar to that of not supplemented microsomes treated with CCl4. It thus seems likely that DHEA protects liver microsomes from oxidative damage induced by carbon tetrachloride through its own antioxidant properties rather than inhibiting the metabolism of the toxin.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Immunologic reconstitution by interleukin-2: facts and open questions.

Interleukin-2 (IL-2), one of the most potent immunoregulatory and inflammatory cytokines, is being tested in phase III clinical trials in order to demonstrate its efficacy in combination with current antiviral agents in preventing the occurrence of opportunistic infections and death in individuals infected by the human immunodeficiency virus (HIV). In the meantime, its capacity to boost the number of CD4+ T cells in peripheral blood has been confirmed by a number of individual phase I/II trials conducted in different countries by independent investigators. In the face of this remarkable result, little is known of the effects exerted by this cytokine once administered to infected individuals in terms of its impact on different immunologic functions. The recent acquisitions on the important role played by latently infected cells in in vivo infection in reinitiating HIV replication and cytopathicity once antiviral therapy is suspended or becomes suboptimal, has shed new light on the possibility of utilizing immunologic strategies, including IL-2, for eradicating the virus from latent reservoirs. Results from a clinical trial conducted at our Institute indicate a decrease in lymphocyte-associated HIV DNA after IL-2 administration, supporting this hypothesis.

Anti-HIV Agents↗
PubMedDate not supplied

Microbial growth and air pollution in carbonate rock weathering. Preliminary results of a in situ experimental study.

Preliminary results on limestone weathering caused by air pollution and microbial colonization are presented in this study. Outdoor exposure experimental assays were performed on Scaglia limestone samples. Samples were exposed in two areas in Perugia (Italy) that differ for degree of urban air pollution. At different times of exposure, ranging from 1 to 12 months, microbial contamination and textural modifications of sampled surfaces were evaluated by microbiological procedures, X-ray diffraction, and scanning electron microscopy. After one year of exposure a significant fungal colonization and the presence of weathering products (i.e. gypsum) were detected on sampled surfaces.

Air Pollutants↗
PubMedDate not supplied

[Pharmacotherapy of sepsis].

Despite an increasingly understanding of the pathogenetic mechanisms of sepsis, its mortality remains extremely high, caused mainly by hemodynamic impairment-related alterations frequently present in severe sepsis. Currently, treatment of sepsis is based on hemodynamic support, antibiotic therapy, surgical excision of infectious foci and immunomodulatory therapy. In fact, a massive host inflammatory infection response has recently emerged to substantially contribute to the development of septic shock and multiple organ dysfunction. Many clinical trials on various pharmacological agents have been conducted: glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombin III (AT III), anti-endotoxin monoclonal antibodies, nitric oxide inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor (TNF) antibodies. Apart from some likely favourable findings connected to low doses of glucocorticoids, most studies yielded disappointing results. Nevertheless, the use of recombinant human activated protein C (drotrecogin-alpha) has recently proven to have a mortality reduction effect particularly in patients with severe sepsis and dysfunction of at least two organs. Furthermore, the early treatment of hemodynamic instability with volume expanders and vasopressors (early goal-directed therapy), and a strict glycemic control represent important measures in order to significantly reduce mortality from severe sepsis and septic shock, and are fundamental guidelines recommended by most scientific societies (Surviving Sepsis Campaign).

Anti-Bacterial Agents↗