Search PubMed⌕ Search

Biomedical subjects

R Paoletti

Publications and source records attributed to R Paoletti.

At least 91 records · Page 5Linked to original sources
PubMed1994

Hormonal agents used in lowering lipoprotein(a).

Lipoprotein(a) (Lp(a)) plasma concentrations in Caucasian populations are classified as a quantitative genetic trait. Although the prevailing view has been that Lp(a) levels are affected by age and gender, recent data are beginning to indicate otherwise. Lp(a) levels change throughout life especially in females after menopause. Lp(a) levels decrease in women treated with anabolic steroids such as stanozolol and danazol. The Lp(a) plasma concentration is also profoundly affected by sex hormone variations during pregnancy. In men with prostatic cancer Lp(a) levels are reduced about 50% by estrogen therapy, and increased 20% by orchidectomy. We have evaluated the changes in Lp(a) and lipid levels in postmenopausal women following estrogen/progestogen replacement therapy. The mean level of Lp(a) in treated women was about 50% lower after 6 and 12 months of replacement therapy. A significant correlation between basal Lp(a) levels and the changes at either 6 or 12 months was observed, suggesting that therapy was particularly efficacious in those women with high basal Lp(a) levels. One year after therapy cessation, Lp(a) concentrations tended to return to pre-therapy values. In addition estrogen-progestogen treatment significantly lowered total-cholesterol (12%) and LDL-cholesterol (28%), and increased HDL-cholesterol (18%). From these studies it appears that sex hormones are actively involved in the modulation of plasma Lp(a) levels and that both female and male sex hormones possess a lowering effect. The results confirm a direct effect of sex hormones on Lp(a) metabolism and suggest that estrogen-progestogen treatment of postmenopausal women can improve the lipid profile not only by lowering total- and LDL-cholesterol and raising HDL cholesterol, but also by lowering plasma Lp(a).

Estrogen Replacement Therapy↗
PubMed1994

Endothelial dysfunction and dyslipidemia: possible effects of lipid lowering and lipid modifying therapy.

Hypercholesterolemic and atherosclerotic coronary endothelial dysfunction consist of a progressive, not irreversible, impairment in reactions to various endothelium dependent relaxing substances in both the epicardial coronary artery and in the resistance vessel. Paradoxical vasoconstriction, dynamic stenoses and dysregulation of the coronary blood flow make this endothelial dysfunction contribute to the pathogenesis of myocardial ischemia. The selectivity of the impairment makes the concept of specific receptor operated signal transductions in hypercholesterolemia and low doses of oxidized LDL likely. In progressive atherosclerosis and high levels of oxidized LDL the dysfunction may spread to other receptors, the availability of L-arginine may decrease and the metabolism of EDRF change. Cholesterol-lowering therapy may restore this endothelial dysfunction. This paper will discuss the recent pathophysiological insights in dyslipidemic endothelial dysfunction and exposes the mode of action of various therapeutic drugs.

Animals↗
PubMed1994

Experimental and clinical effects of isradipine relevant to atherosclerosis.

A number of studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. This class of compounds can influence several processes that are involved in the development of atherosclerotic lesions. This action is independent of either blood pressure reduction or hypercholesterolemia. A major problem encountered from the experimental data are the high doses used, which are several times higher than those used in the treatment of humans. One notable exception to this problem is the second-generation calcium antagonist isradipine, which exerts a direct antiatherosclerotic effect in rabbits at doses similar to those used in the clinic. Thus, this review is a summary of the effects and mechanisms of the antiatherosclerotic activity of isradipine.

Animals↗
PubMed1994

Effect of lacidipine on the carotid intimal hyperplasia induced by cuff injury.

The in vivo antiatherogenic activity of the calcium antagonist lacidipine was investigated in arterial hyperplasia induced by perivascular manipulation of hypercholesterolemic carotid rabbits. This was accomplished by positioning a hollow silastic collar around one carotid, which within a few days induces an atherosclerotic lesion (proliferative lesion) showing biochemical and morphologic changes similar to those of early human atherosclerosis: the contralateral carotid, with no collar, served as control in the same animal. The effect of lacidipine was also investigated in aortic atherosclerotic lesions (fatty lesions) induced by hypercholesterolemia mixed with either cholesterol (1%) and lacidipine (3 mg/kg/day) or cholesterol (1%) alone for 8 weeks. Hypercholesterolemic New Zealand White rabbits were fed daily a standard diet. Intimal hyperplasia was mechanically induced in one carotid artery of each rabbit 6 weeks after dietary and drug treatment started. Neointimal formation was followed by measuring by light microscopy the cross-sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In positive control animals receiving dietary cholesterol only (n = 10), by 14 d after collar positioning the process of intimal hyperplasia was significantly pronounced. The control arteries showed an I:M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.56 +/- 0.11. In the animals receiving lacidipine, neointimal formation was significantly lower [I:M tissue ratio 0.32 +/- 0.1 (n = 10), about 60% of positive controls]. Measurement of the percent area of the aortic intima covered by plaques did not show significant differences between control and lacidipine-treated animals. These results suggest a direct antiatherosclerotic effect of lacidipine on proliferative lesions.

Animals↗
PubMed1994

[The use of gemeprost in diagnostic hysteroscopy].

The authors base their argument on the concept that difficulties sometimes arise in performing hysteroscopy above all due to impediments to the introduction of the diagnostic instrument. They therefore report their experience of the pharmacological preparation of the cervix using the local application of prostaglandin vaginal bougie, gemeprost, for short intervals, between 15 and at most 30 minutes, above all when diagnostic hysteroscopy is performed in an out-patients setting. A total of 224 cases of hysteroscopy are analysed which are divided into two distinct groups: the first, a control group without preparation and the second which included 101 patients who underwent pharmacological preparation for 15 (29 women, group B) or 30 minutes (62 women, group C). Having described the method of examination, an analysis of the results confirms that the use of gemeprost facilitates the cervical stage of hysteroscopy, allowing the examination to be performed even in more complex conditions, such as post-menopause or during the secretive phase of the cycle.

Alprostadil↗
PubMed1994

[Dihydrogesterone vs. medroxyprogesterone acetate in association with transdermal estradiol in postmenopausal substitution treatment].

The authors consider postmenopausal replacement oestrogen therapy to be appropriate provided that in non-hysterectomised women it is associated with a progestin compound. For this purpose they studied the endometrial changes in women treated randomly with dihydrogesterone and medroxyprogesterone acetate. Having performed a pre-treatment biopsy, in order to include only those cases with hypotrophic endometrium or with residual proliferative activity, cyclical treatment was commenced with transdermic estradiol and dihydrogesterone or medroxyprogesterone acetate. An endometrial follow-up was performed after 6 months to control the maturation of the endometrium which was free from atypical transformations although medroxyprogesterone acetate was preferable due to its effects on the metabolism in general and because it allowed a higher percentage of conversion into secreting endometrium without evolving towards hyperplasia.

Administration, Cutaneous↗
PubMed1993

The lowering of lipoprotein[a] induced by estrogen plus progesterone replacement therapy in postmenopausal women.

OBJECTIVE: To evaluate whether estrogen plus progesterone replacement therapy influences the plasma lipoprotein[a] (Lp[a]) levels in postmenopausal women. DESIGN: Fifty-five women who had been menopausal for at least 1 year were followed up for 12 months. Twenty-four subjects served as the control group and 31 subjects served as the therapy group. The therapy consisted of conjugated estrogen (1.25 mg/d) and medroxyprogesterone acetate (10 mg/d for 10 days a month). Blood samples were obtained before the start of therapy and at 6 months and 12 months after therapy. Nine subjects in the therapy group were followed up for an additional year after the treatment was suspended (washout group). SETTINGS: All subjects were healthy women (mean age, 52 years) who had natural menopause at least 1 year before the beginning of recruitment. None of the women had received exogenous sex steroids or drugs known to influence lipid and lipoprotein metabolism in the previous 12 months. MAIN RESULTS: In the control group, no change was noted in the plasma Lp[a] concentrations during the study. In the treatment group, the mean plasma Lp[a] concentrations decreased 50% after 6 months (P < .01) and remained at this level 12 months after treatment was started. In the washout group, mean plasma Lp[a] levels tended to return to pretherapy values. In addition, estrogen plus progesterone treatment significantly lowered total cholesterol levels by 15% and low-density lipoprotein cholesterol levels by 30%; it increased high-density lipoprotein cholesterol levels by 19%. CONCLUSION: The results suggest that in estrogen plus progesterone-treated postmenopausal women, the lipid profile is improved not only by lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein levels, but also by lowering plasma Lp[a] concentrations.

Adult↗
PubMed1993

Pharmacological control of hypertriglyceridemia.

Hypertriglyceridemia has been recently recognized as a vascular risk factor, based on both clinical and experimental findings. Epidemiological studies clearly showed that elevated plasma triglycerides in subjects with low high-density lipoprotein (HDL) cholesterol (<35 mg/dl) and/or a low-density lipoprotein (LDL)/HDL cholesterol ratio > 5 are associated with an elevated risk for coronary heart disease (CHD), while intervention studies indicate that triglyceride lowering with drugs may lead to a significant CHD reduction. Elevated blood triglycerides are associated with major alterations in the structure/function of plasma lipoproteins, which become more atherogenic, and with abnormalities in the clotting system, which may predispose to coronary thrombosis. New criteria for the classification of hypertriglyceridemias and a stepwise approach to the management of patients with elevated plasma triglycerides have been recently developed. Nonpharmacological interventions, i.e., weight reduction, alcohol and smoking cessation, and physical exercise, are the first-line actions to control hypertriglyceridemia. Drug therapy should be considered when the nonpharmacological approaches are ineffective or inadequate. Fibric acid derivatives and nicotinic acid (and its derivatives) are the drugs of choice when treating hypertriglyceridemic patients; n-3 fatty acids (fish oil) and metformin (especially in diabetic patients) represent additional therapeutic agents.

Body Weight↗
PubMed1993

Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase.

The role of mevalonate and its products (isoprenoids) in the control of cellular proliferation was examined by investigating the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (vastatins) on growth and on cholesterol biosynthesis of cultured arterial myocytes (SMC). Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. The inhibition, evaluated as cell number, was dose-dependent with IC50 values of 2.8 and 2.2 microM for S and F, respectively; P (1-500 microM) was inactive. The inhibition of cell growth induced by 3.5 microM S (70% decrease) was prevented completely by the addition of 100 microM mevalonate, partially (70-85%) by the addition of 10 microM geraniol, 10 microM farnesol and 5 microM geranylgeraniol, but not by the addition of squalene, confirming the specific role of isoprenoid metabolites in regulating cell proliferation. All the tested vastatins inhibited the incorporation of [14C]acetate into cholesterol but P had 800 times lower potency than S and F. Similar results were obtained in SMC from human femoral artery. At least 80% inhibition of cholesterol synthesis was necessary to induce a decrease in SMC proliferation. To further investigate the relationship between cholesterol synthesis and cell growth, two enantiomers of F were investigated. The enantiomer more active on HMG-CoA reductase was 70- and 1.6-fold more potent on arterial myocyte proliferation than its antipode and the racemic mixture, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclic Monoterpenes↗
PubMed1993

Effects of lacidipine on experimental models of atherosclerosis.

AIM: To evaluate the effect of lacidipine on the major processes of atherogenesis. METHODS: Cell-culture methods were used to study the effect of lacidipine. Low-density lipoprotein (LDL) receptor expression and cholesterol esterification were evaluated in human skin fibroblasts and in mouse peritoneal macrophages, respectively. The effect of lacidipine on cellular proliferation was tested on aortic myocytes cultured from rat aorta. RESULTS: Lacidipine did not affect LDL receptor expression, but it inhibited the ability of acetyl LDL to stimulate cholesterol esterification in macrophages by more than 95%. The drug inhibited cellular proliferation in a dose-dependent manner. This antiproliferative effect was confirmed in human femoral artery myocytes. In accord with the inhibitory effect on cellular growth, preliminary in vivo studies suggest that lacidipine may reduce neointimal formation induced by perivascular manipulation of the carotid artery in hypercholesterolemic rabbit. CONCLUSIONS: Our results indicate that lacidipine may be antiatherosclerotic through an effect on the major processes involved in atheroma formation.

Animals↗
PubMed1993

HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexible collar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 mg/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36 +/- 0.04 versus 0.03 +/- 0.02). Animals treated with lovastatin (n = 12), simvastatin (n = 12), and fluvastatin (n = 12) showed significantly less neointimal formation; I/M tissue ratios were 0.24 +/- 0.03, 0.20 +/- 0.03, and 0.17 +/- 0.03, respectively. The inhibition elicited by pravastatin (n = 12, 0.32 +/- 0.03) did not reach statistical significance. alpha-Actin antibody immunofluorescence analysis of serial sections revealed that cells present in the hyperplastic intima were mostly myocytes. Rates of intimal myocyte proliferation were also measured by incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into replicating DNA. Immunofluorescence analysis showed that 5-bromo-2'-deoxyuridine was actively incorporated into intimal myocytes after ++reinsertion of the collar, with a labeling index (percent of labeled myocytes) of 2.15 after 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of trapidil derivative AR 12456 on intracellular cholesterol homeostasis in human hepatoma cell line Hep G2.

The effect of trapidil derivative AR12456 on intracellular cholesterol metabolism was investigated in human hepatoma cell line HepG2. AR12456 enhanced the uptake and degradation of 125I-LDL in a dose-dependent manner. The drug inhibited cholesterol synthesis and esterification without affecting cellular cholesterol content and bile acid synthesis; cholesterol efflux was slightly increased. These results show that the inhibition of cholesterol synthesis together with the enhanced expression of LDL receptors may partially explain the hypocholesterolemic activity of compound AR12456.

Anticholesteremic Agents↗
PubMed1992

Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells.

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.

Anticholesteremic Agents↗
PubMed1992

Classification of calcium channels and calcium antagonists: progress report.

The molecular biology and electrophysiology of calcium channels is proceeding apace, partially driven by the clinical success of the drugs classed as "calcium antagonists." Indeed, there are now more than 70 drugs in development that have been claimed to be "calcium antagonists" of one type or another. In order to ensure that there is a logical nomenclature for the channels and the drugs acting at the channels, an international committee has met over the last 2 years to classify the channels and the drugs. This report consists of an overview of current thinking, which will be finalized in a document submitted to the IUPHAR (International Union of Pharmacologists) nomenclature committee.

Calcium Channel Blockers↗
PubMed1992

Focus on anti-atherosclerotic therapy.

Calcium antagonists (CA) exert an anti-atherosclerotic effect in cholesterol-fed rabbits through reduction of cholesterol accumulation in the arterial wall. Further studies in our Institute indicate that verapamil-like compounds and diltiazem stimulate receptor-mediated LDL uptake by human fibroblasts in culture, while nifedipine-like compounds and flunarizine are inactive. Verapamil and diltiazem stimulated LDL-receptor activity also in cells from a heterozygous FH patient, while they were inactive in a receptor defective homozygous FH patient. A basic group needs to be present on the CA molecule to modulate the LDL receptor expression. Preliminary data in our laboratory suggest that some CA can achieve concentrations in the aortic wall likely to exert effects on LDL receptors. This stimulatory activity may improve lipid metabolism in the arterial wall.

Animals↗