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Biomedical subjects

R Fumagalli

Publications and source records attributed to R Fumagalli.

175 records · Page 10Linked to original sources
PubMedDate not supplied

Effect of the nifedipine-atenolol association on arterial myocyte migration and proliferation.

The in vitro effect of nifedipine and atenolol, either alone or in combination, on the proliferation and migration of rat aortic smooth muscle cells was investigated. Nifedipine inhibited the replication of arterial myocytes in concentrations ranging between 10 and 100 microM. The inhibition, evaluated as cell number, was dose- and time-dependent with an IC50 of 39 and 34 microM after 48 and 72 h, respectively; the cell doubling time increased with drug concentrations up to 118 h versus 28 h for controls. Atenolol alone failed to reduce arterial myocyte proliferation, and did not influence the effect of nifedipine on cell proliferation. Nifedipine and atenolol alone inhibited in a dose-dependent manner rat aortic myocytes migration induced by fibrinogen as chemotactic agent. When the combination nifedipine-atenolol was investigated, an additive inhibitory effect on cell migration was observed. These results provide in vitro support for a potential effect of this drug association on early steps of atherogenesis.

Animals↗
PubMedDate not supplied

Effects of coffee on plasma lipids, lipoproteins and apolipoproteins.

The acute effects of coffee, cigarette smoking and alcohol on serum lipids, lipoproteins and thromboxane B2 production by platelets were studied in nine healthy volunteers who were non-drinkers of coffee and alcohol and non-smokers. They received, in a single administration, coffee (containing 200 mg of caffeine), alcohol (0.50 ml/kg body wt), or smoked two cigarettes. No differences were observed between baseline and 15, 60 and 80 min values for plasma cholesterol, triglycerides, HDL cholesterol, plasma apolipoproteins A-I and B and thromboxane B2 production. Chronic coffee consumption also did not affect either plasma lipoprotein profile or the interaction of low density lipoproteins with cellular receptors in a group of healthy individuals. These results suggest that coffee itself does not affect acutely the plasma lipoprotein profile in healthy man. This was also true in heavy coffee drinkers.

Adult↗
PubMedDate not supplied

Trapidil derivatives and low density lipoprotein metabolism by human skin fibroblasts and by human hepatoma cell line Hep G2.

The effect of trapidil (RocornalR) and some of its newly developed derivatives (AR 12456, AR 12463, AR 12465, AR 12464) on the receptor-mediated low density lipoprotein (LDL) binding, uptake and degradation was studied in human skin fibroblasts (HSF) and in human hepatoma cell line Hep G2. Compound AR 12456 influenced this pathway in a selective way: it enhanced the uptake and degradation of 125I-LDL by Hep G2 cells in a dose-dependent manner, but inhibited it in HSF. Scatchard analysis of the saturable LDL binding in Hep G2 indicates that the effect of compound AR 12456 is the result of an increased number of LDL binding sites. Compound AR 12465 was less effective on LDL catabolism. Trapidil and the other derivatives were inactive under the same experimental conditions. When Ar 12456 was preincubated with Hep G2 cells and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. These findings suggest that a metabolite(s) of AR 12456 might be responsible for the enhanced expression of LDL receptors in cultured human cells.

Animals↗
PubMedDate not supplied

In vitro inhibition of arterial myocyte growth and stimulation of low density lipoprotein metabolism by SIM 6080, a new calcium antagonist.

We have investigated the in vitro effect of the new calcium antagonist SIM 6080 on proliferation of rat aortic smooth muscle cells and on LDL receptor-mediated catabolism in human fibroblasts. Verapamil was used as the reference compound. SIM 6080 inhibited the proliferation of rat aortic myocytes in concentrations ranging between 1 and 20 microM. The inhibition, evaluated as cell number and nuclear incorporation of [3H]thymidine, was dose and time dependent; the cell doubling time increased with drug concentrations up to 69 h versus 20 h for controls. Similar results on both LDL pathway and smooth muscle cell proliferation were achieved with verapamil, but higher concentrations were needed. The specific uptake and degradation of 125I-LDL was evaluated in human fibroblasts after 48 h incubation with SIM 6080 (1-10 microM). The compound dose dependently enhanced the receptor-mediated 125I-LDL uptake, with a fourfold increase as a maximal effect (10 microM); LDL degradation was less sensitive to the drug. The present results provide evidence that the new calcium antagonist SIM 6080 interferes in vitro with processes involved in atherogenesis.

Animals↗
PubMedDate not supplied

Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lipids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.

Animals↗
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↗
PubMedDate not supplied

Constant mean airway pressure with different patterns of positive pressure breathing during the adult respiratory distress syndrome.

Twenty-one ARDS patients were divided into two groups of severity according to FIO2 and PEEP required to maintain an adequate gas exchange. The 10 most severe patients (group A) underwent continuous positive pressure ventilation (CPPV) (I/E 3:1) with the mean airway pressure maintained at 21 +/- 6.2 cmH2O. The PEEP values were 12.6 +/- 4.3 cmH2O during CPPV and 6.5 +/- 3.7 cmH2O during IRV (p less than 0.01). Eleven less severe ARDS patients (group B) underwent CPPV and positive pressure spontaneous breathing (CPAP) at constant mean airway pressure of 14.3 +/- 3.8 cmH2O. The PEEP was 7 +/- 2.5 cmH2O during CPPV and 14.9 +/- 4.3 cmH2O during CPAP (p less than 0.001). In five patients of each group, the SF6 shunt was measured as representative of true shunt. The results showed that gas exchange, including true shunt, and haemodynamics did not change between CPPV and IRV and between CPPV and CPAP tests. Taken with previous work on mean airway pressure, our results further support the concept that the main determinant of oxygenation and haemodynamics is the mean airway pressure, irrespective of the PEEP level and of the mode of ventilation.

Adolescent↗