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Biomedical subjects

A Colella

Publications and source records attributed to A Colella.

At least 19 recordsLinked to original sources
PubMed1998

The role of TRP84 in catalytic power and the specificity of AChE.

The structure-function relationship between the alkaloids physostigmine, physovenine and the three structurally related compounds were investigated by employing kinetic studies and molecular modeling. Crystallographic data from the X-ray conformation of the Torpedo californica acetylcholinesterase complex together with the transition state analog inhibitor m-(N,N,N,-Trimethylammonio) trifluoroacetophenone (TMTFA) was used as template onto which inhibitors were superimposed. Among the structural elements of the active site, TRP84 residue shows a versatile role. In fact, its aromatic electrons not only can be employed in pi-cation interactions, as is the case for ACh, but they can also provide a polarizable surface for van der Waals and London interactions.

Acetylcholinesterase↗
PubMed1998

Evaluation of clotting and fibrinolytic activation after protracted physical exercise.

The behavior of hemostatic system activation during protracted physical exercise is well known, but the duration of its modification is not yet defined. In order to evaluate the time of hemostatic system activation after prolonged strenuous endurance physical exercise (typical marathon race: 42.195 km, v=15.35 km/h; mean length of time run 2.45+/-0.15 hours) 12 well-trained long-distance male runners (mean age: 35+/-7, range 25-47 years) were investigated. Blood samples were drawn in the morning on the day before the performance, immediately after the race, and 24 hours and 48 hours after the end of run. With respect of baseline, immediately after the race, a significant decrease of fibrinogen (-25%) and significant increases of prothrombin fragment 1+2 (+633%) and thrombin-antithrombin complex (+848%) were observed. A significant acceleration of euglobulin lysis time (-41%), and rises of plasma levels of tissue plasminogen activator antigen (+361%), plasminogen activator inhibitor type 1 antigen (+235%), d-dimer (+215%), and plasma fibrinogen degradation products (+1200%) were also found. Only a slight, yet not significant, decrease in plasminogen activator inhibitor type 1 activity was observed. One day after the end of marathon different parameters were still unchanged. Forty-eight hours after the competition all parameters investigated returned to baseline values. These results indicate a persistence of clotting as well as fibrinolysis activation up to 24 hours after the end of the race.

Adult↗
PubMed1998

The impact of ratee's disability on performance judgments and choice as partner: the role of disability-job fit stereotypes and interdependence of rewards.

An experiment assessed the impact of disability-job fit stereotypes and reward interdependence on personnel judgments about persons with disabilities. Students (N = 87) evaluated 3 confederates. The experiment varied disability of the target confederate (dyslexia vs. nondisabled), task, and dependence of rater rewards on partner performance. Two disability-task combinations represented stereotypical poor fit and good fit. Dependent variables were performance evaluations, performance expectations, and ranking of target as a partner. There was negative bias against the confederate with dyslexia in poor-fit conditions. In the interdependent reward condition, there was a negative main effect for disability, regardless of fit. No effects for disability were found on performance ratings or expectations. Results indicate the need to consider disability-job fit stereotypes and consequences to raters when assessing the impact of disability on personnel judgments.

Adult↗
PubMed1998

Classical risk factors and emerging elements in the risk profile for coronary artery disease.

The prevention of coronary artery disease is based on the control of several factors associated with a disease or clinical condition and suspected to play a pathogenetic role, defined as 'risk factors'. Smoking is a powerful risk factor for coronary artery disease, with risk of events increasing in relation to the number of cigarettes smoked daily. Smoking cessation is associated within 3-4 years, with a significant reduction in cardiovascular risk. Hyperlipidaemia is a powerful predictor of coronary disease with a strong, independent, continuous and graded positive association between cholesterol levels and risk of coronary events. Several large studies have shown the benefit of cholesterol reduction, and there is clear evidence of the efficacy of statins in the reduction of events in primary and secondary prevention. Hypertension is a significant, strong and independent risk factor for coronary artery disease morbidity and mortality and the reduction of events and mortality by antihypertensive treatment is well documented. Obesity is associated with an increase in all-cause mortality and cardiovascular mortality, with a particularly high risk for subjects with central obesity. Central obesity is also part of the so-called 'metabolic X syndrome' including insulin resistance, which appears to be associated with a particularly high risk of coronary artery disease. Type 1 and type 2 diabetes mellitus are associated with an increased risk of cardiovascular disease, especially in women. Several studies have shown that good metabolic control and multifactorial risk factor reduction significantly lower the coronary risk in these patients. Recent evidence is accumulating that some clotting factors (fibrinogen, factor VII, von Willebrand factor) and fibrinolytic factors (t-PA and PAI-1) are associated with an increased risk of coronary artery disease. The European Concerted Action on Thrombosis (ECAT) showed that the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent coronary syndromes in patients with angina pectoris, and that low fibrinogen is associated with a low risk of events despite high cholesterol levels. Post-menopausal status is associated with increased risk of coronary artery disease, particularly when menopause is premature (before the age of 45) or abrupt (surgical). There is strong, thought not yet completely definite evidence that post-menopausal hormone replacement therapy may significantly reduce the risk of events and improve survival. Hyperhomocysteinaemia is an emerging risk factor independently associated with an increased risk of coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The administration of vitamin B6, B12 or folate seems to be useful and is currently under further evaluation. Recently, attention has been focused on the correlation between coronary artery disease and genetic factors, such as ACE gene polymorphism or the gene polymorphism for the IIIa-moiety of the platelet fibrinogen receptor IIb-IIIa. In primary prevention, control of the major risk factors mainly in patients with clustered factors will substantially reduce the risk of ischaemic events. Secondary prevention of CHD is based on: aggressive behavioural advice, blood pressure reduction in hypertensives, good metabolic control of diabetes, and cholesterol reduction. Aspirin, beta-blockers, ACE inhibitors, and oral anticoagulants, may be useful in selected patients.

Coronary Disease↗
PubMed1997

Studies on a new series of THA analogues: effects of the aromatic residues that line the gorge of AChE.

A series of N-monoalkylsubstituted 1,2,3,4-tetrahydro-9-aminoacridines have been prepared after modelling simulation of the AChE-inhibitor complex. Molecular modelling has predicted a number of hydrophobic residues to be involved in the catalytic mechanism of this interaction between the binding sites of AChE and this series of aminoacridines. In these compounds the acridine moiety becomes sandwiched between the rings of PHE330 and TRP84. In particular, the alkyl chain shows the important role of aromatic groups as binding sites. Their in vitro inhibitory properties (enzyme from Electrophorus electricus) confirm the aromatic groups as a general and significant characteristic of the mechanism of AChE inhibition.

Acetylcholinesterase↗
PubMed1997

Identification of candidates for prevention of venous thromboembolism.

The rationale for prophylaxis of venous thromboembolism (VTE) is based on the frequently clinically silent nature of the disease. A number of risk factors for VTE have been known for a long time, even if some of them are still controversial. Many studies have been performed in the surgical field, and have established different risk classes for VTE. Such risk stratification is especially determined by type of surgery and to some extent by personal characteristics of patients, and it defines operations at high, intermediate, and low risk for VTE. According to this classification, prophylaxis of VTE is mandatory in some cases, less useful in others. Less information is available on medical diseases, in which the clinical conditions and the intrinsic characteristics of patients determine the class of risk for VTE. Different strategies for identifying patients who should undergo prophylaxis have been proposed based on risk factor evaluation in the individual patient. However, even if such an approach may be of help for the physician, its validity is still impaired by the difficulty of taking into account all of the variables possibly involved in VTE occurrence.

Humans↗
PubMed1996

[Oxygen therapy and pulmonary hypertension in chronic obstructive bronchopneumopathies].

Pulmonary hypertension has a negative prognostic value in the progression of chronic obstructive lung disease. The hypoxic vasoconstriction and subsequent morphological alterations that occur in the small arteries and in the pre-capillary arterioles may contribute to the reduction of the pulmonary vascular bed. The evolution of pulmonary hypertension in patients with chronic obstructive lung disease is not rapid except during relapses of the disease. Oxygen therapy reduces pulmonary arterial pressure values not only via a reduction in the functional abnormalities of the vessels but also via a regression in the anatomic changes induced by hypoxemia. Thus, long-term oxygen therapy may slow the progression of pulmonary hypertension in the course of chronic obstructive lung disease and the longer is oxygen administration the better haemodynamic results are obtained. The Medical Research Council (MRC) Study and the Nocturnal Oxygen Therapy Trial (NOTT) have clearly demonstrated that mortality among hypoxiemic patients treated with low-flow oxygen therapy is reduced; the NOTT also reported a reduction of about 10% in the levels of pulmonary vascular resistances in patients treated with long-term oxygen therapy, while an increase of about 7% has been observed in patients treated with oxygen therapy only during the night. Nevertheless, the reduction of mortality observed during long-term oxygen therapy not always is accompanied by an haemodynamic improvement; in particular a reduction in the pulmonary arterial pressure seems not to reduce mortality. In conclusion long term oxygen therapy may slow the progression of pulmonary hypertension during chronic obstructive lung disease while the improvement in pulmonary haemodynamic due to oxygen therapy is not strictly correlated with a reduction of mortality.

Hemodynamics↗
PubMed1995

Increased number of thromboxane A2-prostaglandin H2 platelet receptors in active unstable angina and causative role of enhanced thrombin formation.

The current study was designed to investigate the number and affinity of platelet thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptors in patients with unstable angina and, if any, the role played by the increased thrombin formation that is a common finding in these patients. Measurements taken during active unstable angina but not those taken during inactive angina showed an increase number (p < 0.001), without changes in affinity, of platelet TxA2/PGH2 receptors, evaluated as the binding capacity of iodine 125-PTA-OH, a stable TxA2 analogue. Moreover patients with active angina had higher plasma concentrations of fibrinopeptide A (FPA) (p < 0.0001), which were significantly related to the number of platelet TxA2/PGH2 receptors (r = 0.76; p < 0.01). Heparin infusion but not aspirin treatment promptly normalized the number of TxA2/PGH2 receptors and significantly reduced plasma FPA concentrations. In an in-vitro study thrombin in a concentration similar to that found in vivo significantly increased the number of platelet TxA2/PGH2 receptors (p < 0.01), whereas heparin did not affect TxA2/PGH2 receptors. These results have important therapeutic implications and indicate the preferential use of heparin rather than aspirin during the acute phase of unstable angina.

Aged↗
PubMed1995

Plasma endothelin and renal endothelin are two distinct systems involved in volume homeostasis.

This study of seven healthy young subjects was designed both to establish whether endothelin-1 (ET-1) is involved in the homeostasis of blood volume and to clarify the relationship between plasma and urinary ET-1. Acute volume expansion (+17%) caused increases in venous blood pressure (+4.4 mmHg) and the plasma concentration of ET-1 (+129%) and a decrease (-99%) in the urinary excretion of ET-1. Volume depletion (-8.5%) provoked an increase in the plasma concentration of ET-1 without altering the urinary excretion of ET-1. Passive elevation of an arm resulting in a local decrease of venous blood pressure (-17 mmHg) elicited an increase of the local formation of ET-1, with a 10-fold increase in the venous-arterial gradient compared with the opposite arm, which lay at the level of the heart. The increased local formation of ET-1 was blunted by volume expansion. The results indicate that 1) plasma ET-1 and urinary ET-1 represent two different endothelin-generating systems, both of which are involved in the regulation of blood volume, and 2) plasma ET-1 appears to be an important mechanism for the long-lasting adaptations of venous wall tension to changes in blood volume.

Adult↗
PubMed1994

Binding kinetics and antiplatelet activities of picotamide, a thromboxane A2 receptor antagonist.

1. Picotamide was shown to inhibit platelet binding of thromboxane A2 (TxA2)-mimetics and to cause a reduction of TxA2 platelet receptors after in vivo administration. The present study aimed to investigate directly [3H]-picotamide binding to human platelets and in particular the relationship between binding kinetics and antiaggregating properties. 2. [3H]-picotamide time-dependently bound to a single class of platelet TxA2 receptors with a KD of 325 nmol l-1 at equilibrium. The binding was displaceable by TxA2 analogues U46619 and ONO11120 (Ki 19 and 28 nmol l-1 respectively) but not by prostacyclin (PGI2), prostaglandin E2 (PGE2) and TxB2. Antiaggregating activity and TxA2 formation inhibition paralleled with binding kinetics. 3. By prolonging the incubation time from 30 to 120 min, picotamide showed a progressively increasing non-displaceable binding, whereas specific displaceable binding decreased in comparison to the values reached at 30 min. Non displaceable binding was specific, temperature-dependent saturable and followed a Michaelis-Menten kinetic (Vmaxapp = 130 fmol per 10(8) platelets h-1, KMapp = 330 nmol l-1). Picotamide progressively underwent a specific stable interaction with its platelet receptor. 4. In conclusion, after an initial reversible binding, a progressive stabilization of picotamide binding takes place resulting in a progressively more stable interaction with platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Predictive value for thrombotic disease of plasminogen activator inhibitor-1 plasma levels.

Plasminogen activator inhibitor-1 plays a major role in the fibrinolytic system as the main physiological inhibitor of both tissue-type and urinary-type plasminogen activators. The inhibitor is present in plasma in small amounts and derives mainly from endothelial cells. Positive correlations have been reported between plasma levels and different parameters, such as serum triglycerides, insulin plasma levels and body mass index. Moreover, high plasma inhibitor concentrations have been observed in different disease states, but it must be stressed that plasminogen activator inhibitor-1 behaves as an acute-phase reactant and measurement of plasma levels is not significant in the acute phase of the disease. A possible predictive value of inhibitor levels for thrombotic events such as deep vein thrombosis and ischemic heart disease has been studied. On the basis of available studies, the predictive value is not clear for venous thrombosis, whereas plasminogen activator inhibitor-1 levels can predict some coronary events, at least in subgroups of young patients with a first myocardial infarction. It remains to be established if treatments able to reduce plasma inhibitor levels lead to a decrease in the risk of thromboembolic events.

Female↗
PubMed1991

Platelet thromboxane A2 receptors in type I diabetes.

1. Human platelet thromboxane A2 receptor expression on the membrane surface is possibly dynamically regulated by changes either in the ligand concentration or in membrane fluidity. An increased thromboxane A2 production and a decreased membrane fluidity has been reported in diabetic patients. 2. In the present study the binding characteristics of platelet thromboxane A2 receptors have been investigated in nine diabetic patients (type I) and in 15 healthy control subjects by a radioligand-binding method using 9,11-dimethylmethane-11,12-methane-16-[3-125I-4-hydroxyphenyl]-13, 14- dihydro-13-aza-15-tetranor-thromboxane A2 as the radiolabelled ligand. 3. The maximum concentration of binding sites was 163 (SD 35) fmol/10(8) platelets (n = 15) with 987 (SD 209) receptors/platelet in controls, whereas in diabetic patients the maximum concentration of binding sites was 74.2 (SD 28) fmol/10(8) (n = 9) with 447 (SD 172) receptors/platelet (P less than 0.001). The dissociation constants were 18 (SD 4) nmol/l and 21 (SD 6) nmol/l (not significant) in control subjects and in diabetic patients, respectively. Glycated haemoglobin, which is reported to reduce membrane fluidity, was found to be negatively correlated (r = 0.60, P less than 0.05) with thromboxane A2 receptor number in the diabetic patient group. On the contrary, a positive linear correlation between the equilibrium dissociation constant and glycated haemoglobin was found in diabetic patients (r = 0.75, P less than 0.01).

Binding Sites↗
PubMed1991

Acute reduction of TxA2 platelet binding sites after in vivo administration of a TxA2 receptor inhibitor.

1. Picotamide has been shown to interfere competitively with the thromboxane A2 (TxA2) platelet receptor. In the present study the effect of in vivo administration of picotamide on TxA2 human platelet receptors was investigated in 10 healthy subjects. 2. Picotamide (300 mg x 3 daily) or placebo were administered in a double-blind, cross-over, placebo controlled study, each treatment lasting 1 week with a 2 week interval period. TxA2 receptors were investigated by a direct radioligand binding assay method employing [125I]-PTA-OH as labelled ligand. Platelet studies were performed on the first day of treatment immediately before and 2, 4 and 8 h after the ingestion of the drug. The effects of chronic administration were assessed on the seventh day. 3. Two and 4 h after the administration of picotamide 300 mg orally platelet TxA2 receptors were significantly reduced from 1366 +/- 237 to 957 +/- 221 (P less than 0.05) and 753 +/- 119 receptors/platelet (mean +/- s.d.) (P less than 0.03). After 8 h platelet receptor population was restored (1362 +/- 324, NS). The same pattern was observed after 7 days of treatment. Thus picotamide seems to induce a short lasting down regulation of platelet TxA2 receptors.

Adult↗
PubMed1990

Heparin, monocytes, and procoagulant activity.

Monocytes are able to specifically bind heparin rapidly, reversibly, and saturably with 5.5 +/- 2.6 x 10(6) binding sites per monocyte and a dissociation constant of 330 +/- 221 nmol/l. Moreover, at least 40-50% of the cell-bound heparin can be internalized. Heparin binding by monocytes is affected by cell stimulation with an increase of the availability of binding sites after challenge with calcium ionophore, lipopolysaccharide, and interleukin 2. The interaction of heparin with monocytes reversibly decreases the expression of tissue factor on the cellular surface, so hampering the cellular procoagulant potential.

Blood Coagulation↗
PubMed1990

Kinetic analysis of a TxA2 receptor antagonist. Evidence for the existence of an uptake system.

The kinetics of the binding of TxA2 and the characteristics of its putative uptake by platelets (plt) were investigated with a radiolabelled structural TxA2 analogue, 125I-PTA-OH, in platelets from 6 male healthy volunteers. The kinetic constants (Kobs, K1 and K-1) were calculated by time-course experiments according to Weiland and Molinoff. The affinity constant (Km) and maximal uptake velocity (Vmax) values for each subject were determined by the double-reciprocal plot of Lineweaver-Burk. The kinetically determined dissociation constant Kd was 10 nmol/l. In the uptake experiments a saturability of the association rate of the non-displaceable binding was observed at increased ligand concentration. Michaelis-Menten type kinetics were obtained and the Vmax was 32.44 fmol/10(8) plt x hour with a Km of 6.39 nmol/l. These observations suggest that the uptake was a carrier-mediated active transport.

Adult↗
PubMed1989

Competitive inhibition of platelet thromboxane A2 receptor binding by picotamide.

On the basis of indirect pharmacological evidence, picotamide, a methoxy derivative of 4-hydroxy-isophthalic acid (N,N'bis(3-picolyl)-4-methoxy-isophthalamide) has been postulated to inhibit platelet aggregation by competitively interfering with the thromboxane A2 (TxA2) platelet receptor. In the present study the interaction between picotamide and TxA2 receptors on human platelets was investigated by a direct radioligand assay method with [125I]PTA-OH and [3H]U46619 as labelled radioligands. The ONO11120 and U46619 inhibitory constants (Ki) for [125I]PTA-OH binding were 19 +/- 4 and 17 +/- 3 nM, respectively. Picotamide displaced [125I]PTA-OH binding with a Ki of 1472 +/- 321 nM. The Ki for ONO 11120 and U46619 on [3H]U46619 binding were 42 +/- 12 and 16 +/- 5 nM, respectively, whereas the Ki for picotamide was 1648 +/- 431 nM. These data provide evidence that picotamide can directly inhibit the TxA2 platelet receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Platelet thromboxane A2 receptors in habitual smokers.

Cigarette smoking is a major risk factor for cardiovascular disease but its effect on platelet aggregability and particularly on TxA2 platelet metabolism is controversial. In present study TxA2 platelet receptors of 8 male clinically healthy habitual smokers (more than 20 cig./day) aged 30-55 (44 +/- 6 years) and of 9 age matched healthy controls were evaluated. Platelet TxA2 receptors were investigated by a radioligand binding method employing 125I-PTA-OH, a radio-iodinated hydroxy derivative of the 13-azapinane thromboxane antagonist (ONO 11120). Binding studies evidentiated a single class of specific high affinity receptors for the TxA2 analogue. In non smokers 990 + 220 receptors/platelet (rec/plt) with a dissociation constant (kd) of 22 +/- 11 nM were found. Smokers had a significantly larger number of TxA2 platelet receptors (1268 +/- 190 rec/plt p less than 0.01). No differences in the receptor affinity was found (23 +/- 6 nM, ns). Those changes could contribute to the high responsiveness of platelet from smokers to external aggregating stimuli.

Adult↗