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Biomedical subjects

A Sala

Publications and source records attributed to A Sala.

At least 145 records · Page 8Linked to original sources
PubMed1995

Pharmacokinetic profile of ITF 296 in rats and dogs.

The pharmacokinetic profile of ITF 296 was studied after a single oral or i.v. dose administered to rats and dogs. ITF 296 and its first metabolite, ITF 1124, were measured in plasma and urine by a validated HPLC method with UV detection. Similar results were obtained in both animal species. After i.v. administration, the initial decline in plasma levels (distribution phase) was rapid, followed by a slower elimination phase. After oral administration, ITF 296 was rapidly and almost completely absorbed from the gastrointestinal tract, the maximal plasma levels being reached between 10 min and 1 h after administration in both species. Only traces of the parent compound were found in the urine of the two species, suggesting that ITF 296 was extensively metabolized. Preliminary data indicate that renal excretion is the major route of elimination of the biotransformed products. The denitrated metabolite was present in plasma from the earliest sampling time after either the i.v. or the oral route. After oral administration the drug was not significantly metabolized during passage through the liver, suggesting good bioavailability. The development of ITF 296 as a new orally active nitrate is supported by its pharmacokinetic profile in rats and dogs.

Administration, Oral↗
PubMed1994

Eosinophil 15-lipoxygenase is a leukotriene A4 synthase.

5-Lipoxygenase is the first committed enzyme in the leukotriene biosynthetic pathway and is known to catalyze not only the first oxygenation of arachidonate to form 5(S)-hydroperoxyeicosatetraenoic acid (5(S)-HPETE), but also dehydration of this intermediate into leukotriene A4 (LTA4) by an activity termed leukotriene A4 synthase. Inhibition of cytosolic 5-lipoxygenase prepared from human blood granulocytes with zileuton (100 microM) was virtually complete, but LTA4 synthase activity was only inhibited by 47%. Structural characterization of eicosanoids synthesized in these preparations revealed an abundance of 15-lipoxygenase metabolites including 15-HETE when arachidonate was used as substrate and 5(S),15(S)-dihydroxy-6,8,11,13(E,E,Z,Z)-eicosatetraenoic acid when 5(S)-HPETE was used as substrate. When neutrophils were prepared that contained less than 1% eosinophil contamination, zileuton was found to almost completely inhibit all 5-lipoxygenase, as well as LTA4 synthase products. Immunochemical analysis of the supernatants from purified neutrophils and eosinophils confirmed the previous observation that neutrophils do not express 15-lipoxygenase. Incubation of 5(S)-HPETE with recombinant mammalian 15-lipoxygenase resulted in the formation of 6-trans-LTB4 and 6-trans-12-epi-LTB4 as LTA4 products, as well as the 12-lipoxygenase product 5(S),12(S)-diHPETE. The mechanism of action of 15-lipoxygenase acting as an LTA4 synthase is proposed to involve removing the pro-R hydrogen atom at carbon-10 of 5(S)-HPETE, which is antarafacial to the hydroperoxy group to yield LTA4.

Arachidonate 15-Lipoxygenase↗
PubMed1994

Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest.

Overexpression of wild-type p53 protein has been shown to induce arrest in the G1 stage of the cell cycle and to transactivate expression of the gene that encodes the 21-kDa Waf1/Cip1 protein, a potent inhibitor of cyclin-dependent kinase activity. p53-dependent G1 arrest is accompanied by decreased expression of the B-myb gene, a relative of the c-myb cellular oncogene. In this study we show that B-myb expression is required for cells to progress from G1 into S phase and that high levels of ectopic B-myb expression uncoupled from cell cycle regulation rescues cells from p53-induced G1 arrest even in the presence of Waf1/Cip1 transactivation and inhibition of cyclin E/Cdk2 kinase activity. Cotransfection experiments with p53 expression plasmids and expression plasmids encoding in-frame deletion mutations in B-myb coding sequences indicate that the DNA-binding domain of the B-Myb protein is required for this activity. These results provide evidence of a bypass of p53-induced Waf1/Cip1-mediated cell cycle regulatory pathways by a member of the myb oncogene family.

Base Sequence↗
PubMed1994

Correlation between E2F-1 requirement in the S phase and E2F-1 transactivation of cell cycle-related genes in human cells.

The mammalian nuclear protein E2F-1 has recently been cloned based on its ability to bind the retinoblastoma protein. To determine whether E2F-1 plays a role in the control of the cell proliferation, we introduced an inducible construct expressing an E2F-1 antisense RNA into the human glioblastoma T98G cell line and assessed DNA synthesis during the cell cycle. Expression of the antisense transcripts during the G1-S transition resulted in a marked delay in the completion of DNA synthesis. Band-shift analysis of bacterially produced E2F-1 showed that this protein bound to the promoters of human DNA polymerase-alpha, cyclin D1, and c-myb but not to the cdc2 gene promoter. E2F-1 also transactivated the bound promoters in transient transfection assays. These results suggest a major role for E2F-1 in the control of cell cycle progression via transcriptional regulation of proliferation-associated genes.

Base Sequence↗
PubMed1994

Effects of loratadine on cytosolic Ca2+ levels and leukotriene release: novel mechanisms of action independent of the anti-histamine activity.

Loratadine, a non-sedating anti-histamine drug, displays in vitro potential anti-allergic properties not related to its interaction with the histamine H1 receptor. In a search for the mechanisms of these actions, we have found that loratadine induces an elevation of cytosolic calcium ion, [Ca2+]i, in rat peritoneal macrophages or human platelets. The mechanism of this elevation resides in the ability of loratadine to discharge intracellular Ca2+ stores, similarly to thapsigargin. This in turn brings about the inhibition of [Ca2+]i rise induced by physiological activators (platelet activating factor and ADP), as well as by thapsigargin. One of the active metabolites of loratadine, descarbo-ethoxy-loratadine, and another anti-histamine, namely terfenadine, exhibit the same effects. In addition, loratadine partially inhibits antigen-induced leukotriene release from human bronchi, but is unable to inhibit the concomitant contraction. We conclude that loratadine can interfere with the mechanisms controlling Ca2+ release, thus inhibiting the cell activation elicited by various agonists through [Ca2+]i elevation. This might be the mechanism underlying its anti-allergic actions in vitro. Furthermore, loratadine might represent an interesting tool in the study of Ca2+ homeostasis.

Animals↗
PubMed1994

Prostacyclin production by different human grafts employed in coronary operations.

Segments of human saphenous vein, internal mammary artery, right gastroepiploic artery, and inferior epigastric artery were incubated in vitro in Krebs-Henseleit solution and compared in terms of their capacity to generate and release into the medium 6-keto-prostaglandin F1 alpha (PGF1 alpha), the stable metabolite of prostacyclin. The four vascular conduits were also challenged with endothelin-1 (40 ng/mL), and accumulation of the lipidic material in the bathing fluid was also studied. The results obtained show clearly that under both normal and endothelin-1-stimulated conditions, the four vascular segments generate a substantial amount of 6-keto-PGF1 alpha. Multiple-comparisons analysis of the results indicates that the rank order in producing 6-keto-PGF1 alpha is as follows: inferior epigastric artery > internal mammary artery > right gastroepiploic artery > saphenous vein (p < 0.01). A similar order of potency was obtained in vascular conduits stimulated with endothelin-1. The rate of formation of immunoreactive 6-keto-PGF1 alpha under both normal and stimulated conditions by the inferior epigastric artery (normal, 301 +/- 8 pg/mg of tissue; stimulated, 519 +/- 15 pg/mg of tissue) was at 10 minutes more than 2 times (p < 0.01) that of the saphenous vein and about 1.5 times (p < 0.01) that of the right gastroepiploic artery.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

An improved assay for urinary LTE4.

An improved method for the measurement of urinary LTE4 is described, based on the combined use of solid phase extraction (SPE)-HPLC-enzyme-immunoassay (EIA). This allows the use of homologous radioactive tracer in easily measurable amount for HPLC retention time evaluation and recovery estimation. Recovery linearly correlated with the total amount of LTE4 present in the extracted sample, indicating the existence of a carrier effect. Identification of immunoreactivity in HPLC fractions as LTE4 was based on parallel dilution assay and confirmed by the observable isotopic separation between tritium labeled LTE4 and immunoreactive LTE4. Critical selection of urine sample size, on the basis of creatinine content, together with efficient purification by SPE, resulted in total absence of aspecific immunoreactivity in fractions surrounding those associated with LTE4. Urinary LTE4 was measured in normal subjects and in cirrhotic patients, where an increased LTE4 excretion has been reported. The method described fulfils the criteria of specificity, sensitivity and accuracy necessary for a potential successful use in the study of sulfidopeptide leukotrienes formation in normal and pathological conditions.

Adult↗
PubMed1994

Site-specific water relations and stomatal response of Quercus ilex in a Mediterranean watershed.

Intraspecific variations in the water relations and stomatal response of Quercus ilex L. were analyzed under field conditions by comparing trees at two locations within a Mediterranean watershed (l'Avic, Catalonia, NE Spain). Distinct environmental gradients exist between the two sites (referred to as ridge top at 975 m and valley bottom at 700 m) with greater soil depth for water storage, reduced radiation, reduced wind and higher water vapor pressure deficits at the valley bottom than at the ridge top. Osmotic adjustment and changes in tissue elasticiity did not significantly increase drought resistance in the trees studied. The leaf-to-air vapor pressure difference (Deltaw) threshold for inducing stomatal closure was higher at the ridge top (15.6 kPa MPa(-1) +/- 0.5 SE) than at the valley bottom (9.8 kPa MPa(-1) +/- 1.0 SE). However, increases in Deltaw beyond the threshold were followed by greater reductions in leaf conductance of trees at the ridge top than at the valley bottom. At both sites, maximum leaf conductance was related to predawn shoot water potential which, in turn, was related to watershed stream flow. The effects of water deficits during the dry summer of 1989 were more severe in trees at the valley bottom than at the ridge top. During periods of high evaporative demand, site-specific differences in the control of water loss led to more conservative water use by trees at the ridge top and, thus, to even greater drought avoidance (higher predawn water potentials) in late summer.

Journal Article↗
PubMed1994

Effects of nedocromil sodium on bronchospasm and HS-NCA release induced by allergen inhalation in asthmatic patients.

The aim of this study was to assess the ability of nedocromil sodium (NS) to prevent the immediate asthmatic reaction and the increase in the serum level of heat stable neutrophil chemotactic activity (HS-NCA) induced by antigen inhalation. In a double-blind, cross-over study, 13 atopic subjects affected with seasonal asthma underwent a bronchial provocation test with a preselected dose of grass pollen allergen (enough to cause a decrease of > or = 20% in FEV1:FEV1 PD20) after pre-treatment with 4 mg NS or placebo. Serum samples were withdrawn from 11 subjects for HS-NCA determination. After NS administration the decrease in FEV1 was significantly less than after placebo administration at all time points after challenge (2 min P = 0.0004; 7 min, P = 0.0005; 17 min P = 0.0002 and 27 min P = 0.0005). The percentage increase in HS-NCA was significantly higher after placebo than after NS inhalation, both 10 (P = 0.0048) and 20 (P = 0.0068) min after challenge. Our study confirms previous investigations, showing that NS inhibits the immediate asthmatic response to allergen inhalation in atopic, asthmatic subjects and moreover it shows that this drug prevents in vivo the increase of the serum HS-NCA. This last finding has not been previously reported.

Adolescent↗
PubMed1994

[The "arrhythmic pattern": a new method with prognostic significance in myocardial infarct].

OBJECTIVES: To establish a score or arrhythmic pattern for the prediction of long-term cardiac deaths on patients who have survived to the first acute myocardial infarction. PATIENTS AND METHODS: We studied prospectively 200 patients that survived at a first myocardial infarction and in whom ambulatory ECG monitoring during 24 hours between days 7th and 18th (mean 12th) from the infarction was performed. The mean follow-up time was 51 +/- 18 months. The number and type of ventricular arrhythmias were analyzed and a score was measured, accordingly with Castellanos and Lown's classifications. An "arrhythmic pattern" or "total punctuation" was defined and compared among two groups: group 1 > 65 points and group 2 < 65 points. RESULTS: The differential characteristics of both groups were: age (60 +/- 9 versus 56 +/- 10 years old; p = 0.004); hypertension (63% versus 29%; p < 0.001); clinic stage II-III (23% versus 11%; p = 0.02); echocardiographic ejection fraction (45 +/- 11% versus 50 +/- 10%; p = 0.04); positive exercise testing (73% versus 56%; p = 0.01); arrhythmias on the exercise test (15% versus 25%; p = 0.006). The long-term cardiac mortality was 25% versus 6% (p = 0.01), with an incidence of sudden death of 11% versus 3% (p < 0.05). Specificity, sensibility, positive predictive value and negative predictive value (reference cut point of 100) were 94, 65, 71 and 91%, respectively. CONCLUSIONS: The use of a score of arrhythmic pattern may identify 2 groups of patients with different clinic profiles that probably justify a different long-term prognosis after a first acute myocardial infarction.

Cardiac Complexes, Premature↗
PubMed1994

Stereochemical analysis and biological activity of 3-hydroxy-leukotriene B4: a metabolite from ethanol-treated rat hepatocytes.

Leukotriene B4 (LTB4), a biologically active metabolite derived from arachidonic acid by the 5-lipoxygenase cascade, is inactivated by cytochrome P-450-dependent omega-hydroxylation followed by second oxidation into a omega-carboxyl group. In many tissues, this second step is mediated by alcohol dehydrogenase. Isolated rat hepatocytes metabolized LTB4 in the presence of ethanol and ethoxyresorufin into substantial quantities of 3-hydroxy-LTB4 as determined by mass spectrometry. The absolute configuration of this metabolite was found to be greater than 98% 3(S)-hydroxy-LTB4 by comparison to synthetic standards. Investigation of the pharmacologic properties of the 3(S)- and 3(R)-hydroxy-LTB4 revealed that both caused a significant increase in intracellular free calcium in human neutrophils at 1 microM. Both enantiomers also induced thromboxane A2 release from the isolated guinea pig lung in a dose-dependent manner. This activity was fully blocked by a specific LTB4 receptor antagonist, LY223982, with an IC50 of 0.21 microM for LTB4. These results suggested that activation of the LTB4 receptor does not involve significant recognition of the carbon atoms close to the carboxyl moiety of LTB4. The failure of the hepatocyte to metabolically inactivate LTB4 in the presence of ethanol may be of importance to humans, particularly because the bioactive metabolite 3(S)-hydroxy-LTB4 was further metabolized by human neutrophils significantly more slowly than LTB4.

Animals↗
PubMed1994

Reoperative cardiac valve surgery: a multivariable analysis of risk factors.

From December 1983 to March 1992, of 1650 patients who underwent a cardiac valve procedure 41 (2.5%) underwent reoperation on prosthetic heart valves. The indications for reoperation were: structural degeneration (13 patients, 32%), non-structural dysfunction (nine patients, 22%), prosthetic valve endocarditis (seven patients, 17%), valve thrombosis (four patients, 10%), native valve pathology (three patients, 7%), aortic ascending pathology (five patients, 12%). The hospital mortality rate for mitral valve reoperation was 12% (two of 17) and for reoperation on the aortic prosthesis 26% (five of 19). No deaths occurred for associated mitral and aortic replacement (zero of five). The mortality rate for associated procedures was 24% (four of 17) versus 12% (three of 24) for isolated procedures. Preoperative and operative variables were analysed to determine risk factors for hospital mortality. New York Heart Association functional class, ascites, endocarditis and surgical timing had a univariate influence on operative mortality. The pulmonary capillary wedge pressure and preoperative creatinine level were also higher in non-survivors. Elective reoperation had a mortality rate of 7%, while that for emergency procedures was 38%. Multivariable analysis indicated a longer extracorporeal circulation time and the urgent-emergency status as predictors of mortality. Reoperation before severe haemodynamic impairment occurs is recommended.

Aortic Valve↗