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Biomedical subjects

A Lippi

Publications and source records attributed to A Lippi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Alteration of cytochrome P-450 isozymes by captopril and idrapril in hepatic and renal microsomes of normotensive and spontaneously hypertensive rats.

To examine the effects of angiotensin-converting enzyme (ACE)inhibitors such as captopril and idrapril on the P-450 system, these compounds were administered 100 mg/kg i.p. for 4 days to spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats; thereafter, the principal hepatic and renal microsomal monooxygenase activities were determined. In all the rat strains used, both captopril and idrapril decreased only the P-450 2C11, (as determined by immunoblotting) and its linked activities such as 16alpha-, 2alpha- and 17-testosterone hydroxylases. These changes were accompanied by a significant decrease of blood testosterone levels both in normotensive and, more markedly, in hypertensive rats and by a reduction of systolic blood pressure, but only in SHRs. Only in SHRs as well, the renal immunodetectable P-450 4A content and the P-450 4A-dependent activities, such as the (omega)-lauric acid hydroxylase, diminished after captopril or idrapril treatment. These data suggest that the decrease of increased blood pressure in hypertensive SHRs by the ACE inhibitors may be linked to the downregulation of the circulating testosterone level, the renal P-450 4A expression, and the related formation of the potent vasoconstrictor (omega)-hydroxy arachidonic acid.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Tachykinin receptors and intestinal motility.

Substance P (SP) and neurokinin A (NKA) are synthesized by enteric cholinergic motorneurons that project to the longitudinal and circular muscle of the mammalian intestine. Thus, acetylcholine, SP, and NKA are the excitatory neuromuscular transmitters in the intestine. Tachykinin NK1 and NK2 receptors are expressed by smooth muscle cells in most regions of the intestine: the corelease of SP and NKA from nerves thus realizes paradigms of tachykininergic cotransmission. Examples have been found in which a cooperative model can be applied to account for the action of SP-NKA acting at NK1 and NK2 receptors (e.g., circular muscle of guinea-pig duodenum), as well as examples in which the message produced by activation of the two receptors diverges sharply in producing responses that have a markedly different time course and use different effector systems (e.g., circular muscle of guinea-pig colon). NK3 receptors are expressed on both excitatory and inhibitory motor neurons: indirect contractions (via release of acetylcholine and tachykinins) and relaxations (via release of nitric oxide) can be evoked in the gut by selective stimulation of NK3 receptors. Although a role of NK3 receptors in certain enteric reflexes has been evidenced, the importance of this system in mediating hexamethonium-resistant enteric transmission appears less important than previously speculated.

Animals↗
PubMed1996

Kinetics of human thrombin inhibition by two novel peptide inhibitors (Hirunorm IV and Hirunorm V).

A study on the kinetics of human thrombin inhibition by two novel synthetic peptides (Hirunorm IV and Hirunorm V) and a comparison with recombinant hirudin and a commonly used thrombin inhibitor, Hirulog-1, are reported. The dissociation constants for Hirunorm IV and Hirunorm V were determined by varying the concentration of inhibitors at fixed concentrations of the chromogenic substrate Chromozym-TH (N-tosylglycyl-L-prolyl-L-arginine 4-nitroanilide acetate). Both inhibitors behaved as reversible tight-binding inhibitors of amidolytic thrombin activity. The apparent dissociation constants determined showed a linear dependence on the concentration of substrate; this finding, which indicates that the inhibition was competitive, made possible the estimation of the dissociation constants (KI) for Hirunorm IV and Hirunorm V, which were 0.134 +/- 0.014 nM and 0.245 +/- 0.016 nM, respectively. Similar dissociation constants were also obtained for the two inhibitors when thrombin activity was measured with fibrinogen in the clotting assay. When tested for resistance to thrombin proteolytic activity, both inhibitors were inviolate to cleavage by thrombin. The data obtained demonstrate that both Hirunorm IV and Hirunorm V are potent and stable inhibitors of human thrombin activity.

Amino Acid Sequence↗
PubMed1996

Reductive metabolism and its role in the disposition of the hydroxamic angiotensin-converting enzyme inhibitor idrapril calcium in rat.

1. The metabolism of 14C-idrapril calcium, the prototype of a new class of angiotensin-converting enzyme inhibitors, was studied in rat after a single intravenous administration. Plasma, urine, faeces, and bile were assayed for total and hplc-fractionated radioactivity. 2. Only one major metabolite (M1, 2-sarcosinamide-cis-1,2-cyclohexanedicarboxylamide) was observed, along with idrapril, in plasma. Three metabolites (M1, M2, cis-1,2-cyclohexanedicarboxylic acid, and M3, a glucuronate derivative of M1) were present in 0-8-h urine, unchanged idrapril being the most abundant product. In bile, two metabolites (M1, M3), but not the parent compound, were found. 3. In conclusion intravenous idrapril undergoes hepatic reduction to M1 and hydrolysis to M2. M1 can be glucuronated to M3 and both are partially excreted in the bile and further processed in the gut to reabsorbable radioactive species.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor.

Enhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking alpha-thrombin amidolytic activity (IC50 = 10 +/- 2, 15 +/- 1 and 0.3 +/- 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 microM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 microM for aPTT and 0.8 to 17 microM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against alpha-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (< or = 0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i.v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

Animals↗
PubMed1996

Autologous bone marrow transplantation for extramedullary relapse in childhood leukemia. The AIEOP Group and the FONOP. Italian Association of Pediatric Hemato/Oncology.

The role of autologous bone marrow transplantation (ABMT) in childhood ALL after an isolated extramedullary (IE) relapse is controversial. Between December 1984 and November 1995, 52 children underwent ABMT because of an IE relapse. The data were stored in the AIEOP-BMT Registry. Thirty four children were transplanted in 2nd CR; eighteen > 2nd CR. The median duration of 1st CR was 24 (range 3-69) and 18 (range 3-59) months, respectively. The median interval from last CR to ABMT was 6 (range 1-28) and 3 (range 1-81) months, respectively. The 5 year EFS for patients transplanted in 2nd CR was 67.7%, while the 3 year EFS for patients in > 2nd CR was 16.7%. In conclusion, ABMT was an effective treatment in early IE relapse only if performed in 2nd CR.

Adolescent↗
PubMed1995

Recombinant human erythropoietin and high flux haemodiafiltration.

Since 1982, 32 uraemic patients were treated in our institution by high flux haemodiafiltration (H-HDF) in order to shorten significantly the dialytic treatment session. H-HDF used a high surface area filter (1.4-1.9 m2) with high hydraulic permeability (polyacrylonitrile and polysulfone), at high blood flow (450 ml/min) and high rates of reinfusion of substitution fluid (22 l/session). In this way the dialytic session was shortened to 140 +/- 19 min, maintaining a good cardiovascular stability and high dialytic efficiency (Kt/V > 1.1). Human recombinant erythropoietin rHuEpo introduced in the therapy of this group in 1987 has resulted in an improvement of renal anaemia, but also a prolongation of the time of dialytic treatment due to a decrease in the efficiency of filters. During the period of the study, the treatment time increased from 140 +/- 19 min to 168 +/- 25 min with a concomitant increase of haematocrit and haemoglobin (from 24% to 36% and from 7.9 to 10.5 g/dl, respectively). H-HDF maintains a noticeable increase in dialytic efficacy with good cardiovascular stability, but the goal of a significant reduction in the time of treatment can no longer be obtained.

Adult↗
PubMed1995

Education and occupation as risk factors for dementia: a population-based case-control study.

To further investigate the putative associations between education and dementia and between occupation and dementia, we conducted a population-based case-control study. Cases were all subjects affected by dementia ascertained through a prevalence survey conducted in the municipality of Appignano, Macerata Province, Italy. For each case (n = 48), we randomly selected 2 population controls residing in the same municipality and matched for age and sex (n = 96). Information regarding exposures was collected by nonmedical personnel during the first contact for the prevalence survey. Although we found a striking trend toward decreasing prevalence with increasing education, this association was suggestive but not significant after age and sex adjustment at case-control analyses (odds ratio for illiterates = 1.4; 95% CI 0.6-3.1). In contrast, we found a significant association between manual principal lifetime occupation and dementia using both unadjusted and adjusted analyses (odds ratio = 2.9; 95% CI 1.2-7.4). Our findings suggest that, although education and occupation are related, occupation is a stronger indicator of risk than education.

Aged↗
PubMed1995

Effects of idrapril calcium on tissue angiotensin-converting enzyme in rats.

Tissue angiotensin-converting enzyme (ACE) inhibition was measured in rats after single intravenous (i.v.) and oral (p.o.) doses of idrapril calcium, and the correlation between peak inhibition and tissue concentration of the drug was investigated. Five minutes after idrapril calcium (3 mg/kg i.v. as free acid), ACE in the examined tissues (serum, lungs, kidneys, heart, aorta, adrenals, testes, and brain) showed > 50% inhibition, always associated with measurable amounts of idrapril. After 90 min, ACE activity was still inhibited only in serum, lungs, kidneys, and aorta, recovering to basal values by 8 h in all samples but serum. Oral idrapril calcium (30 mg/kg) produced > 50% peak ACE inhibition in serum, lungs, and kidneys, in which measurable levels of the drug were detected, and in the aorta, where idrapril was not detected. Other tissues showed neither marked inhibition nor measurable drug levels. Kinetics of ACE inhibition in affected tissue mirrored those observed after intravenous administration. Idrapril, despite its hydrophilic nature, is able to reach extravascular tissues and to inhibit local ACE. However, in no tissue did the effect on ACE last longer than in serum and the hypothesis of a peculiar role of tissue RAS in determining the hypotensive activity of idrapril calcium is not supported in rats.

Administration, Oral↗
PubMed1994

High-performance liquid chromatographic method with electrochemical detection for the determination of idrapril, a novel angiotensin-converting enzyme inhibitor, in biological matrices.

A reversed-phase high-performance liquid chromatographic method for the determination of idrapril in human and rat plasma and urine and in rat tissue homogenates is described. The method is based on the electrochemical detection of idrapril without prior derivatization. Sample preparation simply consists in deproteinization with acetonitrile for plasma and tissue homogenates and in passage through a Sep-Pak C18 cartridge for urine. The limit of quantification is 12.5 ng/ml for plasma, 125 ng/g for tissues and 2.5 micrograms/ml for urine. The method is suitable for monitoring idrapril plasma pharmacokinetics in humans and its tissue distribution and urinary excretion in rats.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Factors affecting course and survival in Alzheimer's disease. A 9-year longitudinal study.

OBJECTIVE: To evaluate mean survival and to identify prognostic factors in a cohort of patients with Alzheimer's disease (AD). DESIGN: Multicentric 9-year cohort analytic study. SETTING: Seven neurology departments throughout Italy between April 1982 and January 1984. PATIENTS: We recruited a consecutive sample of 145 patients affected by probable AD (Multicenter Italian Study on Dementia protocol, National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria). Five were misdiagnosed, and 21 could not participate in the longitudinal study. The clinicodemographic characteristics of the 119 enrolled patients (49 men, 70 women; mean age, 64.7 years; SD, 4.1 years; mean duration of disease, 3.1 years; SD, 1.8 years) did not differ from those of the 26 excluded patients. All underwent extensive cliniconeuropsychological testing every 6 months for at least 2 years until the patient died or our survey ended (April 30, 1991). Mean follow-up was 5.1 years (SD, 2.5 years). MAIN OUTCOME MEASURES: Death, severe functional impairment (a score > or = 17 on the Blessed Dementia Scale), and severe cognitive impairment (a score of < or = 7 on the Information-Memory-Concentration Test). RESULTS: Survival curves obtained by the Kaplan-Meier method indicated that (1) patients with early- and late-onset disease (ie, before or after age 65 years) showed no difference either in relative survival or in time to reach predetermined functional and cognitive end points; (2) severely aphasic patients became profoundly demented significantly sooner than those with mild to moderate aphasia (P < .0001). Among clinicodemographic variables analyzed by a Cox model, severe language disability and functional loss proved to be the best predictors of death independent of age at onset or degree of dementia. CONCLUSIONS: Age at onset did not influence course and survival in AD. Severe aphasia appears to be the best predictor of death and unfavorable course.

Aged↗
PubMed1994

Pharmacokinetics and biochemical efficacy of idrapril calcium, a novel ACE inhibitor, after multiple oral administration in humans.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Cross-national interrater agreement on the clinical diagnostic criteria for dementia. WHO-PRA Age-Associated Dementia Working Group, WHO-Program for Research on Aging, Health of Elderly Program.

We assessed the interobserver agreement on the clinical diagnosis of dementia syndrome and dementia subtypes as part of a cross-national project on the prevalence of dementia. Fourteen clinicians from the participating countries (Canada, Chile, Malta, Nigeria, Spain, and the United States) independently assessed the diagnosis of 51 patients whose clinical information was in standard records written in English. We used the DSM-III-R and ICD-10 criteria for dementia syndrome, the NINCDS-ADRDA criteria for Alzheimer's disease (AD), and the ICD-10 criteria for other dementing diseases, and measured interobserver agreement. We found comparable levels of agreement on the diagnosis of dementia using the DSM-III-R (kappa = 0.67) as well as the ICD-10 criteria (kappa = 0.69). Cognitive impairment without dementia was a major source of disagreement (kappa = 0.10). The kappa values were 0.58 for probable AD, 0.12 for possible AD, and rose to 0.72 when the two categories were merged. The interrater reproducibility of the diagnosis of vascular dementia was 0.66 in terms of kappa index; the diagnoses of other dementing disorders as a whole reached a kappa value of 0.40. This study suggests that clinicians from different cultures and medical traditions can use the DSM-III-R and the ICD-10 criteria for dementia effectively and thus reliably identify dementia cases in cross-national research. The interrater agreement on the diagnosis of dementia might be improved if clear-cut guidelines in the definition of cognitive impairment are provided. To improve the reliability of AD diagnosis in epidemiologic studies, we suggest that the NINCDS-ADRDA "probable" and "possible" categories be merged.

Aged↗
PubMed1993

Relation between MRI features and dementia in cerebrovascular disease patients with leukoaraiosis: a longitudinal study.

We examined selective MRI features (localization and degree of white matter abnormalities, cortical and subcortical atrophy) in relation to cognitive decline in patients with cerebrovascular disease (CVD) and leukoaraiosis (LA). We enrolled 6 female and 18 male CVD patients (mean age 66.2 +/- 6.6 years) whose Magnetic Resonance Images (MRI) revealed LA and who displayed a history of stroke or TIA; none showed signs of cortical infarcts or normal pressure hydrocephalus. Two blind raters independently scored MRI scans with a high level of agreement. All patients underwent extensive clinico-neuropsychological assessment upon admission to the study and 19 were followed for an average of 48 +/- 7.6 months. Twelve patients were initially classified as non-demented and 12 as demented. Three years later, one in the former group had become demented and mental impairment had worsened for 6 patients in the latter group; these 7 subjects were labeled as "decliners". Ventricular indexes were significantly higher in the demented group and correlated with severity of mental impairment, while the degree of LA was similar in demented and non-demented subjects. Neither white matter lesions nor sulcal and ventricular enlargement differed statistically between decliners and non-decliners.

Aged↗
PubMed1993

Inhibition of rabbit lung angiotensin converting enzyme by idrapril.

Idrapril, the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors, competitively inhibited, with nanomolar apparent Ki, the hydrolysis of hippuryl-glycyl-glycine by rabbit lung ACE. The pre-steady-state analysis of this tight-binding inhibition showed it to be characterized by slow kinetics, but at variance with what was found for enalaprilat in the same conditions, idrapril appeared to act through a simple, single step mechanism. Kinetic Ki and k(on) and k(off) values were 470 pM, 3.0 +/- 1.5 x 10(6) M-1 sec-1 and 1.4 +/- 0.3 x 10(-3) sec-1, respectively.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Effect of rociverine on P450-dependent monooxygenases and its N-deethylation metabolism in rat liver microsomes.

Rociverine [2-(diethylamino)-1-methylethyl cis-1-hydroxy [bicyclohexyl]-2-carboxylate] citrate (ROC) is an antispasmodic agent therapeutically active in humans at doses of 0.5-1 mg/kg. This study investigated the effect of acute administration of the drug on hepatic microsomal cytochrome P450 (P450)-catalysed drug metabolism. Only high doses (> or = 100 mg/kg) of ROC were able to induce in rats the hepatic microsomal pentoxyresorufin O-depenthylase (PROD) and 16 beta-testosterone hydroxylase activities both associated with P4502B1/2 and the erythromycin N-dimethylase (ErD) and 2 beta-testosterone hydroxylase activities both dependent on P4503A1/2. However, at 100 and 200 mg/kg of ROC, the 16 beta-testosterone hydroxylase and PROD were the most induced activities, suggesting that P4502B1/2 are the isoforms most sensitive to ROC induction. Accordingly, ROC treatment enhanced, in a dose-dependent manner, the amount of P4502B1/2 and 3A1/2 in microsomes as assayed by western blotting. The northern blot analysis of ROC-treated rat liver showed that the P4502B1/2 induction appears to be regulated at the mRNA level as in the induction by phenobarbital (PB). The oxidative metabolism of ROC with hepatic microsomes from control or PB- and ROC-induced rats resulted in a N-deethyl ROC derivative (major metabolite) and an unknown minor ROC derivative. The kinetic parameters for the N-deethylation of ROC were studied with purified P4502B1 and with microsomes from control or rats treated with various inducers (phenobarbital, ethanol, beta-naphthoflavone, dexamethasone and rociverine). It was found that phenobarbital-, dexamethasone- and rociverine-induced microsomes deethylated ROC with a Vmax about five times higher than that (0.9 nmol/min/mg protein) of control microsomes, although with a similar affinity (Km approximately 0.3 mM). In a reconstituted system, the purified P4502B1 metabolized ROC with a high deethylation rate (22 nmol/min/nmol P450). Moreover, the ROC deethylation was inhibited by compounds such as hexobarbital, metyrapone and triacetyloleandomicin, selective inhibitors for P4502B and/or P4503A enzymes. On the other hand ROC, when added in vitro, inhibited the 16 beta- and 2 beta-testosterone hydroxylases and the PROD and ErD activities. Taken together, these results indicate that the ROC-inducible P4502B and P4503A are involved in ROC deethylation. In conclusion, it has been demonstrated that ROC is a weak phenobarbital-like inducer of P450, probably able at high and reiterated doses to alter its own metabolism, at least in the rat liver.

Acetaldehyde↗