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Biomedical subjects

P Ferrari

Publications and source records attributed to P Ferrari.

At least 145 records · Page 8Linked to original sources
PubMed1998

Pharmacogenomics: a new approach to individual therapy of hypertension?

The individual variation in the efficacy of and tolerability to antihypertensive drugs in human essential hypertension is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate a specific responsiveness to the therapy with some phenotypic traits of the patients, such as the renin-angiotensin profile or the characteristics of cell ion transports. More recently, a genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure in both animal models and patients. Also, individual variation to therapy can now be studied from the genetic point of view using pharmacogenomics, that is, the study of the genes or loci which are involved in determining the responsiveness to a given drug. Only a few examples of this approach are available to date. Our group has identified a polymorphism of the genes for the cytoskeletal protein, adducin, which is linked to both rat and human hypertension, sodium sensitivity and to the pressor responsiveness to diuretic therapy. These results, together with the indication that adducin can play a functional role by modulating the cellular sodium transport, have led to the identification of a new antihypertensive compound, which could be a candidate for the selective treatment of those patients in whom alterations of the renal sodium handling are associated with specific genetic traits such as the polymorphism for adducin.

Animals↗
PubMed1998

Complete androgen blockade versus chemical castration in advanced prostatic cancer: analysis of an Italian multicentre study. Italian Leuprorelin Group.

OBJECTIVES: In spite of a great amount of data, the hormonal treatment of advanced prostatic carcinoma (CaP) still remains controversial. As a relevant amount of dihydrotestosterone is present within the prostate tissue after castration, complete androgen blockade (CAB), with inhibition of the activity of both testicular and adrenal androgens, has been advocated as up-front treatment of advanced CaP. However, many controlled studies have failed to demonstrate a benefit for CAB in comparison with simple surgical or chemical castration. The present study was performed to bring additional data for a worldwide meta-analysis of all phase III trials comparing castration and CAB. METHODS: This is a centrally controlled phase III study in which chemical castration with leuprorelin acetate depot was compared with leuprorelin plus flutamide in stage C and D CaP. Two hundred and forty-one eligible and evaluable patients with histologically proven CaP were recruited for the study (120 treated with castration and 121 with CAB). The diagnostic and staging workup consisted of blood chemistry, general condition assessment, prostate-specific antigen (PSA), abdominal sonography and computed tomography scan, and whole-body isotopic bone scan. End points of the study were survival, time to treatment failure, and time to progression. The patients were followed every 6 months with PSA and sonography. RESULTS: At a cut-off analysis performed in December 1996, when the mean follow-up period was 43.7 +/- (SD) 24.1 months, no statistical differences in terms of time to treatment failure, time to progression, and death rate could be detected. Also considering the common risk factors, such as basal PSA, haemoglobin, alkaline phosphatase, and Gleason score, the outcome did not show any clear advantage for CAB. CONCLUSIONS: This study appears to confirm that the advantages of first-line CAB in CaP are at best marginal. The final analysis will be performed when the follow-up period has reached 5-years, but it seems unlikely that the present results will change.

Aged↗
PubMed1998

The codon 213 of the 11beta-hydroxysteroid dehydrogenase type 2 gene is a hot spot for mutations in apparent mineralocorticoid excess.

In the kidney, the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) inactivates glucocorticoids to their inactive ketoforms and thus prevents endogenous glucocorticoids from occupying the nonselective mineralocorticoid receptor in epithelial tissues. Several mutations have been described in the 11betaHSD2 gene in the congenital syndrome of apparent mineralocorticoid excess. These mutations generate partially or completely inactive 11betaHSD2 enzymes. In the present work, we describe an already known mutation in a new patient affected by apparent mineralocorticoid excess, which results in an arginine-to-cysteine mutation (R213C) in the 11betaHSD2 enzyme. This mutation has been found in two other independent families. In vitro expression studies of this mutant provide evidence that the mutant protein is normally expressed, but its activity is abolished. The CGC-to-TGC (C-toT) transition at codon 213 can be considered a typical CpG-consequence mutation. The present finding suggests that the codon R213 of 11betaHSD2 is a hot spot for mutations in this gene, as shown by the occurrence of an R213C point-mutation in several families unrelated to each other.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

A new polymorphic restriction site in the human 11 beta-hydroxysteroid dehydrogenase type 2 gene.

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) inactivates glucocorticoids in the kidney and thus prevents glucocorticoids from occupying the non-selective mineralocorticoid receptor in epithelial tissues. Mutations in the HSD11B2 gene have been found to cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disease characterized by severe hypertension. Thus, this locus could also be an ideal candidate involved in the etiology of primary hypertension. We identified a polymorphism in exon 3 characterized by a GAG to GAA transition at codon 178, with the loss of an Alu I restriction site and analysed it in an association study using end-stage renal disease patients, diabetic or essential hypertensive patients and control subjects. Two-hundred and eighty nine subjects and patients were analysed; the genotype was determined by amplification of genomic DNA and subsequent digestion with Alu I restriction enzyme. The prevalence of the Alu I allele was 8.6% in healthy control subjects (n = 116). This prevalence was lower (chi 2 P = 0.035 vs. controls) than the 18.0% in a group of renal transplant patients (n = 61). The corresponding values for patients with diabetes mellitus (n = 25), hypertension (n = 41) and patients on dialysis (n = 46) were 4.0%, 4.8% and 4.3%, respectively. There was no correlation between blood pressure and the marker in non-ESRD subjects. These data indicate the presence of a polymorphic marker in exon 3 of the HSD11B2 gene; this marker is associated with end-stage renal disease but not with essential hypertension in humans.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

A novel glycopeptide carrying a 3-oxazolin-5-one ring obtained by intra-molecular cyclization.

The structure of a product, isolated during the synthesis of the semisynthetic glycopeptide MDL 63,246, was elucidated on the basis of spectroscopic methods and proved to be a novel glycopeptide containing a 3-oxazolin-5-one ring between positions 36 and 38. Subjected to acid hydrolysis this compound gave the corresponding pseudo aglycone and aglycone derivatives which maintained the original oxazolinone structure. Tested for antibacterial activity, these compounds showed a moderate activity against Gram-positive and inactive against Gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed1998

Ecarin Clotting Time: a predictive coagulation assay for the antithrombotic activity of argatroban in the rat.

We studied the use of the Ecarin Clotting Time (ECT) as a predictive assay of the antithrombotic effects of argatroban in a new tissue factor-dependent model of venous thrombosis and a model of arterial thrombosis in the rat. Heparin was used as a reference anticoagulant. Infusions of argatroban dose-dependently increased the ECT across the range of doses required for antithrombotic activity in models of venous and arterial thrombosis (1.25-40 microg/kg/min). The TT was only useful as a marker in the case of venous thrombosis, since, in the arterial thrombosis model, the clotting times were >200 s in the majority of animals receiving antithrombotic doses. The aPTT is not sufficiently sensitive to be predictive of an antithrombotic effect in the venous model, and shows only modest increases in the arterial thrombosis model. Heparin did not significantly increase the ECT at antithrombotic doses in the venous thrombosis model, and only increased the ECT by 53% at 40 microg/kg/min in the arterial model, despite a marked antithrombotic effect. Both the TT and aPTT were dose-dependently increased by heparin at doses active in the venous model, whereas both parameters were >200 s at doses active in the arterial thrombosis model. Thus, the ECT provides a predictive marker for the antithrombotic activity of argatroban in both venous and arterial thrombosis, at least in the rat.

Animals↗
PubMed1998

PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain.

The inhibition of the long-term pressor effect of ouabain may be useful for the therapy of essential hypertension. Here, for the first time, a selective inhibitor of the ouabain pressor effect is described. In vitro, 17beta-(3-furyl)-5beta-androstane-3beta, 14beta, 17alpha-triol (PST 2238) displaced ouabain from its binding sites on purified sodium, potassium ATPase enzyme (Na-K ATPase) (IC50 1.7 x 10(-6) M) without interacting with other receptors involved in blood pressure regulation or hormonal control. In cultured renal cells, incubation with ouabain (10(-10) to 10(-8) M) for 5 days stimulated the Na-K pump at Vmax, whereas PST 2238 showed the same effect at micromolar concentration. The ouabain-dependent increase in the Na-K pump rate was abolished by PST 2238 at concentrations from 10(-14) to 10(-9) M. In rats made hypertensive by chronic infusion of 50 microg/kg/day of ouabain, PST 2238 given p.o at very low doses (0.1-1 microg/kg/day for 4 weeks) abolished the increase in blood pressure and renal Na-K ATPase activity caused by ouabain. PST 2238 did not affect either blood pressure or renal Na-K ATPase activity in normotensive rats. In conclusion, PST 2238 is a very potent compound that normalizes both blood pressure and alterations in the Na-K pump caused by ouabain. Thus it represents the prototype of a new class of antihypertensive drugs that could be effective in forms of hypertension sustained by the concomitant increase of endogenous ouabain levels and alterations in the Na-K pump.

Androstanols↗
PubMed1998

Plasma levels of endothelin-1 in patients with Crohn's disease and ulcerative colitis.

AIM: The purpose of this study was to investigate the behavior of circulating endothelin-1, a vasoconstrictor and mitogenic peptide, in patients with inflammatory bowel disease. PATIENTS: We investigated plasma endothelin-1 levels in 29 patients with Crohn's disease, 13 with ulcerative colitis and 26 healthy subjects as controls. METHODS: Erythrocyte sedimentation and C-reactive protein were also measured in all patients. Plasma endothelin-1 was measured by specific radioimmunoassay and expressed as pg/ml. RESULTS: Both Crohn's disease and ulcerative colitis patients showed a significant increase in plasma endothelin-1 concentration (22.3 +/- 8.2 pg/ml and 11.2 +/- 2.7 pg/ml, respectively) when compared to healthy subjects (6.2 +/- 1.5 pg/ml). Moreover, plasma endothelin-1 levels were significantly higher in Crohn's disease patients than those in ulcerative colitis patients (22.3 +/- 8.2 pg/ml vs 11.2 +/- 2.7 pg/ml; p < 0.001, respectively). A weak correlation (r = 0.645; p < 0.013) between erythrocyte sedimentation and endothelin-1 levels was observed in Crohn's disease patients. Age, sex, clinical activity of the disease, duration of history, anatomical localization of disease and therapy had no influence on plasma endothelin-1 levels. CONCLUSION: Our results show that plasma endothelin-1 levels increase in chronic inflammatory bowel disease and mainly in Crohn's disease. This observation leads us on to believe that endothelin-1 has a important role in inflammatory bowel disease.

Adult↗
PubMed1998

[Drug-induced gingival hyperplasia].

A case report is presented, which describes a kidney-transplant recipient medicated simultaneously with both cyclosporin A and nifedipine and who developed an extreme form of gingival hyperplasia. Repeated dental-surgical treatments provided only temporary regression of the gingival overgrowth, however, after discontinuation of the calcium channel blocker there was a significant improvement of the hyperplasia that no longer required specific dental treatment. The prevalence and mechanisms of this side effect in solid-organ transplant recipients on cyclosporin therapy is discussed. Treatment consists in the discontinuation of potentiating factors like calcium channel blockers and possibly also a dose reduction of cyclosporin, which together may support or reduce the need of dental-surgical procedures.

Adult↗
PubMed1997

Synthesis, cardiotonic activity, and structure-activity relationships of 17 beta-guanylhydrazone derivatives of 5 beta-androstane-3 beta, 14 beta-diol acting on the Na+,K(+)-ATPase receptor.

A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system.

Androstanes↗
PubMed1997

Truncation of the N- and C-terminal regions of the human 11beta-hydroxysteroid dehydrogenase type 2 enzyme and effects on solubility and bidirectional enzyme activity.

The 11beta-hydroxysteroid dehydrogenase type II enzyme (11betaHSD2) endows specificity on the mineralocorticoid receptor by metabolising glucocorticoids. Sequence comparisons with other microsomal proteins showed the strongly preferred topology of a lumenal pentapeptide followed by three transmembrane helices with residues beyond Ala73 on the cytoplasmic side of the membrane, suggesting that 11betaHSD2 is anchored to the endoplasmic reticulum by the N-terminal region. However, deletion of the N-terminus (11betaHSD2 deltaN) and expression of the construct in mammalian cells showed that the enzyme remained bound to the microsomal fraction, indicating that other regions are also involved in membrane anchoring. Crosslinking studies and nonreducing SDS-PAGE demonstrated that 11betaHSD2 is a non-covalently linked dimer. Deletion of the non-conserved C-terminal region (11betaHSD2 deltaC) resulted in an enzyme with a Km of 215 nM for cortisol in whole cell assays, while 11betaHSD2 and 11betaHSD2 deltaN displayed a Km of 62 and 74 nM, respectively. In homogenates 11betaHSD2 and 11betaHSD2 deltaC displayed maximal activity at 140 mM NaCl or KCl, but showed a marked decrease in enzyme activity with increasing salt. 11BetaHSD2 was more stable than 11betaHSD2 deltaC in the presence of NaSCN, suggesting that the C-terminal region plays a role in enzyme stability. There was no detectable activity in homogenates containing 11betaHSD2 deltaN, while 11betaHSD2 deltaC and 11betaHSD2 displayed a Km of 135 and 46 nM, respectively. Although 11betaHSD2 is conventionally considered a unidirectional dehydrogenase all constructs converted 11-dehydrodexamethasone to dexamethasone in whole cell assays, providing an explanation for the potency of the synthetic glucocorticoid in the face of a powerful inactivator of natural glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Vascular dementia Italian sulodexide study (VA.D.I.S.S.). Clinical and biological results.

In order to evaluate the biological effects on some haemostasis factors of antithrombotic-hemorheological treatments on patients with vascular dementia, a multicenter, randomized, double-blind, double-dummy, study comparing sulodexide (Sdx, 50 mg bid orally for 6 months) and pentoxifylline (Ptx, 400 mg tid orally for six months) was carried out. Eighty-six patients, 46 in Sdx group, 40 in Ptx group, fulfilling the NINDS-AIREN criteria for probable vascular dementia were evaluated. Plasma fibrinogen levels showed a significant reduction in both groups, in patients with high basal levels (> or = 350 mg/dl), the reduction being earlier in Sdx group (2nd month of therapy) than in Ptx group (4th month of therapy). In Sdx group a significant reduction in factor VII-Ag (baseline 102.8 U/dl; 6th month 90.1 U/dl) was also observed. Both drugs induced a slight reduction in activated factor VII levels as well. A parallel improvement of G.B.S. Rating Scale for dementia scores was observed in Sdx group. These results seem to indicate that sulodexide treatment can have positive effects in vascular dementia.

Administration, Oral↗
PubMed1997

Does p53 immunostaining improve diagnostic accuracy in urine cytology?

The frequent change of the transitional cell carcinoma of the urinary tract accounts for the fact that cytological abnormalities in urinary specimens are often not sufficient to enable a definitive diagnosis of malignancy. The purpose of this work was to evaluate the possible use of p53 protein in increasing the diagnostic accuracy of urinary cytology. The expression of p53 was investigated by immunocytochemistry in two groups of urinary specimens, one cytologically positive and the other cytologically negative for cancer. Immunostaining was carried out using a monoclonal antibody to p53. In the positive group, in which bladder cancer was confirmed by cystoscopy and biopsy (31 cases), positive reaction for p53 was found in 55% of the cases (17 cases). In the negative group (92 cases), presence of cancer was histologically ascertained in 64 cases and in this group 15 cases (23.4%) showed positive p53 staining. In the remaining 28 cases of this group, where TCC was not present, 7 cases showed p53 positivity in non-neoplastic urothelial cells. This result shows that, while immunocytochemical detection of p53 in urinary specimens may be used for prognostic evaluation of patients with bladder cancer, it does not contribute to the diagnostic accuracy in cases with morphologically inconclusive or negative cytology. The sensitivity and specificity of the method in detecting bladder carcinoma were 23.5 and 75%, respectively.

Biomarkers↗
PubMed1997

Fibronectin in bovine vitreous. An immunochemical study.

The vitreous body is a transparent gel essentially composed of hyaluronan, collagen and proteoglycans. These components are assembled in a three-dimensional structure that is maintained by self-aggregation of macromolecules and the interactions between these different macromolecules. We confirmed the presence of fibronectin in vitreous body using immunochemical methods and by indirect immunofluorescence on cryostat sections. We also determined its distribution in vitreous extracts as compared to those of collagen, proteoglycans and hyaluronan. Because of its high affinity to these macromolecules fibronectin in the vitreous appears to play an important role in strengthening and stabilizing the gel structure.

Animals↗
PubMed1997

Trends of liver cirrhosis mortality in Europe, 1970-1989: age-period-cohort analysis and changing alcohol consumption.

BACKGROUND: Since the mid 1970s, a striking reduction in alcohol-related problems has been observed in many Western countries. Liver cirrhosis mortality is considered to be a major indicator of alcohol-related problems in the general population. The aim of the present study is to describe liver cirrhosis mortality trends in European countries between 1970 and 1989. METHODS: This is a descriptive study on liver cirrhosis mortality in 25 European countries, and in four grouped European regions. A Poisson log-linear age-period-cohort model is used to clarify whether the recent trend in mortality represents a short-term fluctuation or an emerging long-term trend. In addition, a descriptive comparison between trends in per capital alcohol consumption and liver cirrhosis mortality is conducted. RESULTS: In the whole European population and in that of Western and Southern Europe increasing period effects were observed until the second half of the 1970s followed by a decline in the next periods. In Eastern Europe the decline in period effects started in the first half of the 1980s, whereas in Northern Europe an increasing period effect was observed until the second half of the 1970s, followed by a stabilization. Similar trends were observed for per capita alcohol consumption. The age effect analysis showed a continuously rising effect in Eastern Europe, whereas an attenuation of the effect at around age 65 years was observed in Western Europe. Intermediate patterns were observed in Southern and Northern Europe. The birth cohort effect suggested that in the Western and Southern populations mortality could continue to decrease over the next decade, while in Eastern and Northern mortality is still rising and this will probably continue for the next decade. CONCLUSIONS: The age-period-cohort analysis allows targeting of health care and prevention programmes based on future trends. Aetiological and prognostic factors act differently in Europe. A better understanding of the trends would require more detailed information on alcoholism treatment rates, alcohol habits, viral hepatitic infections and other factors involved in the aetiopathogenesis of the disease.

Adult↗