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P Patrignani

Publications and source records attributed to P Patrignani.

At least 55 records · Page 3Linked to original sources
PubMed1989

Improvement of renal function with selective thromboxane antagonism in lupus nephritis.

To test the hypothesis that the vasoconstrictor thromboxane A2 may affect renal hemodynamics in lupus nephritis, we examined the short-term effects of a selective thromboxane-receptor antagonist, BM 13,177, and of low-dose aspirin. In a randomized, double-blind, crossover study, 10 patients with biopsy-proved lupus nephritis were given a 48-hour continuous infusion of BM 13,177 or placebo. At base line, seven patients had markedly elevated urinary levels of thromboxane B2, the breakdown product of thromboxane A2. During the infusion of BM 13,177, the inulin clearance rate, which was 68 ml per minute per 1.73 m2 of body-surface area at base line, increased by an average of 24 percent (range, 12 to 47 percent; P less than 0.01). Para-aminohippurate clearance was increased to the same extent, with no change in the filtration fraction. The bleeding time doubled, indicating an occupancy of platelet thromboxane receptors of more than 95 percent. The hemodynamic changes were associated with a significant increase in sodium excretion from 76 to 118 mmol per day (P less than 0.01) but with no change in arterial blood pressure. In another study, 10 additional patients with lupus nephritis were randomly assigned to receive either placebo or 20 mg of aspirin twice daily for four weeks. The aspirin regimen produced a selective, cumulative inhibition of platelet cyclooxygenase activity and a doubling of bleeding time. However, there was no change in the inulin clearance rate and no change in urinary levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha, which are indicators of renal synthesis of thromboxane A2 and prostacyclin, respectively. We conclude that in lupus nephritis, impairment of renal function is at least in part mediated hemodynamically and is reversible with a thromboxane antagonist. Platelets, however, are not a major source of thromboxane A2 synthesis and action within the kidney.

Adolescent↗
PubMed1989

The role of arachidonic acid metabolite PGE2 on T cell proliferative response.

We have examined the role of cyclooxygenase and lipooxygenase-derived metabolites of arachidonic acid (AA) during T cell activation. One of the major products of cyclooxygenase activity is prostaglandin E2 (PGE2). As is known, macrophages (Mo) are the main PGE2 producer cells among the peripheral blood mononuclear cells (PBL) and can be induced to release PGE2 during T cell activation. On culturing PBL with T cell mitogens such as phytohemagglutinin (PHA) or monoclonal antibody OKT3, the levels of PGE2 produced by Mo were positively correlated with the entity of the T cell mitogenic signal. During T cell activation, subcellular factors able to provide positive or negative signals on the Mo PGE2 production are released in culture. We observed that recombinant IL2 strongly enhanced PGE2 synthesis in lipopolysaccharide (LPS) stimulated Mo culture, while recombinant interferon gamma (IFN-gamma) partially inhibited its production. Moreover, purified IL1 induced PGE2 synthesis in resting Mo and increased its production when Mo were activated by LPS. The PGE2 released during T cell activation seems to have no effect on T cell mitogenesis, since the addition of cyclooxygenase inhibitors did not influence the proliferative response of mitogen stimulated T cells. However, the addition of PGE2 to OKT3 stimulated PBL at the beginning of the culture period inhibited the proliferative response in a dose-dependent manner. Its addition had no effect on PHA-stimulated PBL cultures. The PGE2-dependent inhibition of OKT3-induced T cell proliferation declined progressively from about 50-10% as the addition of PGE2 was delayed from 0 to 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Factors↗
PubMed1987

Platelet-activating factor (PAF) receptor antagonists inhibit mitogen-induced human peripheral blood T-cell proliferation.

The addition of L-652,731 and L-653,150, two synthetic PAF-specific receptor antagonists, to 72 hour cultures of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear leukocytes (PBML) caused a dose-dependent inhibition of (3H)-thymidine incorporation into T-cells (IC50: 25 microM and 3.2 microM, respectively). This inhibition was not reversed by exogenous interleukin (IL)-1 and IL-2. PAF receptor antagonists did not affect the expression of IL-2 receptors (TAC-antigen) on T-cells. Exogenous PAF which by itself had no significant effect on PHA-stimulated PBML proliferation, only partially reversed the inhibition of proliferation caused by PAF receptor antagonists. These results may suggest the involvement of endogenously produced PAF in the regulation of immune reactions.

Cells, Cultured↗
PubMed1987

Biosynthesis, characterization and inhibition of leukotriene B4 in human whole blood.

We have evaluated the biosynthesis, characterization and inhibition of Leukotriene (LT) B4 in unstimulated and in A23187-stimulated human whole blood. LTB4 was assayed by radioimmunoassay (RIA) both in unextracted serum and after extraction and thin-layer chromatography (TLC). Unstimulated human whole blood allowed to clot at 37 degrees C for 60 min produced only trace amounts of LTB4 (0.16 +/- 0.05 ng/ml, mean +/- SD, n = 3). LTB4-like immunoreactivity (ir-LTB4) detectable in unstimulated serum samples was largely overestimated by direct RIA, most likely because of interfering substance(s) unrelated to cyclooxygenase or lipoxygenase activity. Incubation of human whole blood with A23187 (2-10 microM) resulted in a concentration-dependent stimulation of LTB4 production. At 10 microM A23187, ir-LTB4 was 18 +/- 2.4 ng/ml (mean +/- SEM, n = 28). In A23187-stimulated serum samples, LTB4 concentrations measured by direct RIA correlated in a statistically significant fashion with those measured after extraction and TLC. Nafazatrom added in vitro caused a dose-dependent inhibition of A23187-stimulated ir-LTB4 production with an IC50 of 17 microM.

Aspirin↗
PubMed1987

Effects of sulindac on renal and extrarenal eicosanoid synthesis.

We measured the renal and extrarenal synthesis of prostacyclin and thromboxane A2, as reflected by the urinary excretion of the stable hydration products 6-keto-prostaglandin F 1 alpha and thromboxane B2 and the corresponding 2,3-dinor-derivatives, during chronic administration of sulindac (200, 400, 600, and 800 mg/day, each dose given for 7 days in successive weeks) in seven healthy subjects. Urinary eicosanoids were measured by negative ion, chemical ionization-GC/MS-validated RIA techniques. Both 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F 1 alpha showed a dose-dependent reduction, ranging between 45% and 85%. In contrast, the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 did not change significantly throughout the study. These results extend previous observations of a selective sparing of renal cyclooxygenase activity by sulindac in humans and demonstrate that this selectivity is not related to an overall weaker enzyme inhibition.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Altered renal and platelet arachidonic acid metabolism in cirrhosis.

Urinary excretion rates of prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2 were evaluated in three groups of cirrhotic patients [without ascites (group 1, 13 cases), with ascites and normal renal function (group 2, 15 cases), and with ascites and renal failure (group 3, 5 cases)] and in 14 healthy controls. All urinary arachidonate metabolites were significantly increased in group 2 patients. Patients with renal failure showed lower PGE2, PGF2 alpha, and TXB2 values than those from group 2; PGF2 alpha values were also lower than controls. Platelet TXA2 production during whole blood clotting was significantly reduced in all groups of patients. Administration of low-dose aspirin and sulindac, two cyclooxygenase inhibitors selectively sparing renal cyclooxygenase activity, effectively inhibited platelet TXA2 production without affecting urinary TXB2 excretion, thus ruling out platelets as a possible source of urinary TXB2. We conclude that patients with ascites and normal renal function show an overall activation of the renal PG system. Renal production of vasodilating PGE2 and PGI2 may be involved in supporting renal function in these patients. A reduced platelet synthesis of proaggregatory TXA2 also occurs in cirrhotic patients. This may play a role in the bleeding tendency of cirrhosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effects of prostaglandin synthesis inhibition on sympathetic-and parasympathetic-mediated coronary hemodynamic responses.

In chloralose-anesthetized dogs with the left circumflex coronary artery perfused at constant flow, the effects of indomethacin or naproxen on coronary and systemic responses to sympathetic and parasympathetic stimulation were evaluated. Sympathetic stimulation was evoked either by 1-min carotid artery occlusion or by epinephrine (5 micrograms) or norepinephrine (5 micrograms) intracoronary administration. Reflex or direct parasympathetic stimulation was produced by ouabain (40 micrograms) or acetylcholine (2.5 micrograms) injection, respectively, in the perfused coronary artery. The administration of indomethacin or naproxen reduced the integrated areas of coronary vasodilatation induced by epinephrine and norepinephrine. The extent of this reduction was dose-dependent with both indomethacin (epinephrine: r = 0.774, n = 35, P less than .001; norepinephrine: r = 0.766, n = 35, P less than .001; norepinephrine: r = 0.799, n = 35, P less than .001) up to 1.5 and 7 mg/kg, respectively. Further increase in dosage of both prostaglandin synthesis inhibitors failed to induce further reduction of integrated areas of coronary vasodilatation. In contrast, the maximum fall in coronary perfusion pressure, induced by both catecholamines, remained unmodified after inhibition of prostaglandin synthesis, whereas a faster return of the perfusion pressure to base line was observed. The extent of cyclooxygenase activity inhibition induced by indomethacin or naproxen, assessed through the radioimmunoassay of thromboxane B2, showed a consistent dose-dependent increase until complete inhibition was attained with 1.5 mg/kg of indomethacin and 7 mg/kg of naproxen. No significant change in the coronary and systemic hemodynamic response induced by carotid occlusion and by ouabain or acetylcholine intracoronary administration was observed. Furthermore, complete cyclooxygenase inhibition, induced by either indomethacin or naproxen, was able to reduce the coronary vasodilatation induced by isoproterenol (5 micrograms) intracoronary injection but failed to modify the coronary vasoconstriction elicited by both epinephrine and norepinephrine in propranolol-treated dogs. These data indicate that the prostaglandin system is involved in the coronary vasodilatation induced by humoral sympathetic stimulation, whereas coronary hemodynamic responses to both neural sympathetic or parasympathetic stimulation are not influenced by the administration of prostaglandin synthesis inhibitors.

Acetylcholine↗
PubMed1985

Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction.

This study explores the effects on some hematological parameters of a low-dose aspirin regimen (50 mg/day) versus a conventional aspirin treatment with reported antithrombotic efficacy (324 mg/day), in patients with acute myocardial infarction. Fifteen patients were randomized into 3 equal groups receiving 50 mg or 324 mg aspirin or placebo, daily for 21 days. Compared with placebo, bleeding time was significantly and similarly prolonged with both aspirin doses (+ 71 +/- 22% and + 69 +/- 20%, mean +/- S.D.). Aspirin 50 mg/day suppressed arachidonate-induced platelet aggregation and secondary phase aggregation after ADP and adrenaline. Collagen aggregation was inhibited by 44 +/- 15%. In no case were differences in the antiplatelet effects of the two doses observed. The effects of 50 mg/day persisted without attenuation during the observation period. Platelet thromboxane B2 generation during arachidonate-induced aggregation was inhibited by 95 +/- 2 and 99 +/- 1% compared to placebo group after 50 and 324 mg/day, respectively (P between doses less than 0.05). No change was observed with any treatment in coagulation time, prothrombin time or plasma thromboplastin time. Thus, in patients with acute myocardial infarction, the antiplatelet effects of aspirin 50 mg/day are stable over time and superimposable on those of 324 mg/day. The antithrombotic efficacy of aspirin 50 mg/day remains to be tested clinically.

Administration, Oral↗
PubMed1985

Role of prostaglandins in the renal handling of a salt load in essential hypertension.

Renal function and systemic hemodynamics were assessed in 10 hypertensive patients and in 10 age-matched normotensive subjects during control conditions (80 mEq of sodium/day) and after a salt load, either alone (480 mEq/day) or combined with indomethacin or sulindac. Indomethacin was used to induce ubiquitous inhibition of prostaglandin synthesis and sulindac to inhibit prostaglandin synthesis in all tissues except the kidney. Under control conditions there was no significant difference between the 2 groups in any measurement except blood pressure and total peripheral resistance. Also, the changes induced by salt load in the 2 groups were comparable. However, after indomethacin administration, only hypertensive patients showed a significant reduction in the 24-hour sodium excretion (from 417 +/- 61 to 317 +/- 49 mEq, p less than 0.05), so that the difference between this value and the corresponding value of normotensive subjects (453 +/- 79 mEq) became significant (p less than 0.05). The changes in sodium excretion in hypertensive patients were significantly correlated with the changes in renal plasma flow (r = 0.803, p less than 0.01). However, cardiac output and renal blood flow showed a similar pattern in normal and hypertensive persons. Finally, after the addition of sulindac to salt load, the differences in the 24-hour sodium excretion vanished. These results were also confirmed in an ancillary study performed, using the same protocol, in 10 other hypertensive patients using ibuprofen rather than indomethacin. Our data suggest that renal prostaglandins participate in renal disposal of chronic salt load in hypertensive patients but not in normal persons.

Adolescent↗
PubMed1985

Physiologic variables affecting thromboxane B2 production in human whole blood.

Thrombin-induced thromboxane (TX) A2 production in whole blood, as reflected by serum TXB2 measurements, has proven to be a simple and reproducible capacity-related index of platelet TXA2 production ex vivo. In the present study we have determined the influence of a number of physiologic variables on serum TXB2 measurements performed by radioimmunoassay in a group of 177 subjects undergoing evaluation for atherosclerosis risk factors. Serum TXB2 averaged 300 +/- 108 ng/ml in the whole group, with a normal distribution. No statistically significant correlation was found between serum TXB2 and the continuous variables examined (age, BMI, blood pressure, cigarettes, serum cholesterol, triglyceride, glucose and wine consumption) except for the number of platelets. Platelet TXB2 production did not differ between men and women (296 +/- 119 vs 302 +/- 100 ng/ml). We conclude that, within the limits of the examined variables, serum TXB2 is an easily measurable and highly reproducible capacity index primarily related to platelet cyclooxygenase and TX-synthase activity, which can be used for monitoring drug- or disease-induced changes of these enzyme activities.

Adolescent↗
PubMed1985

Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function.

The adequacy, selectivity and long-term persistence of inhibition in cyclooxygenase-dependent platelet function by a daily low-dose (0.45 mg kg-1 day-1) aspirin treatment have been evaluated in 15 patients after a recent (less than 17 days) acute myocardial infarction. Serum thromboxane (TX) B2, an index of platelet TXA2 production, was decreased by 94-98% (P less than 0.001) by aspirin, while urinary excretion of 6-keto-prostaglandin F1 alpha, as an index of extraplatelet cyclooxygenase activity, remained unchanged. Compared to placebo, aspirin induced a persistent increase in bleeding time (% difference 45.6 +/- 21.4, mean +/- SD) and a decrease in platelet aggregation by ADP, epinephrine, collagen and arachidonic acid. No tendency towards an attenuation of the effects was apparent for the period of aspirin administration (4 weeks). Aspirin 0.45 mg kg-1 day-1 is adequate and selective in the long-term inhibition of TX-related platelet function in patients after acute myocardial infarction. The clinical effectiveness of such a regimen remains to be proven in clinical trials.

Adult↗
PubMed1985

Clinical pharmacology of platelet cyclooxygenase inhibition.

Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0.1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGF1 alpha or 2,3-dinor-6-keto-PGF1 alpha, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials.

Aspirin↗
PubMed1985

Dose-related prolongation of the bleeding time by intravenous nitroglycerin.

The effects of intravenous nitroglycerin (NTG) upon the bleeding time, platelet aggregation response, and plasma 6-keto-PGF1 alpha concentration were measured in 17 patients about to undergo coronary bypass grafting. NTG produced a dose-related prolongation of the bleeding time that correlated with the accompanying decrease in systolic blood pressure. Platelet aggregation was not affected and measurements of 6-keto-PGF1 alpha failed to reveal detectable levels (less than 10 pg/ml) either before or after NTG infusion. This suggests that the prolonged bleeding time associated with NTG infusion may be due to vasodilation and increased venous capacitance, rather than altered vascular-platelet interaction.

Adult↗
PubMed1984

Differential effects of dazoxiben, a selective thromboxane-synthase inhibitor, on platelet and renal prostaglandin-endoperoxide metabolism.

Pharmacologic inhibition of thromboxane (TX) synthase can result in redirection of prostaglandin (PG) endoperoxide metabolism, possibly affecting platelet, vascular and renal function. This study explores the in vitro, ex vivo and in vivo effects of dazoxiben, an orally active TX-synthase inhibitor, on platelet and renal TXB2 production and associated changes in PG-endoperoxide metabolism. Dazoxiben inhibits TXB2 production in clotting human whole blood with an IC50 of 0.3 micrograms/ml and causes parallel enhancement of PGE2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha production. Similar redirection of PG-endoperoxide metabolism is observed ex vivo, after the oral administration of 1.5 and 3.0 mg/kg to six healthy volunteers. Plasma 6-keto-PGF1 alpha ranges between less than 4 and 8 pg/ml during the first 3 h. Urinary TXB2 excretion, a reflection of renal TXA2 production, is significantly reduced by 30% with no evidence of redirection of renal PG-endoperoxide metabolism. In vitro inhibition of TXB2 production in rat kidney glomeruli requires significantly higher dazoxiben concentration (IC50 = 1.60 micrograms/ml) than in rat whole blood (IC50 = 0.32 micrograms/ml) and is not associated with changes in PGE2, PGF2 alpha and 6-keto-PGF1 alpha production. These results demonstrate quantitatively and qualitatively diverse effects of dazoxiben in different TXA2-producing cells and suggest the possibility of developing tissue-selective TX-synthase inhibitors.

Adult↗
PubMed1983

Release of two vasodilators, adenosine and prostacyclin, from isolated rabbit hearts during controlled hypoxia.

The release of two locally formed vasodilators, adenosine and prostacyclin (PGI2), from hearts subjected to different degrees of hypoxia was investigated. Isolated rabbit hearts were perfused according to Langendorff with Tyrode solution, saturated with gas mixtures containing 8-95% O2 and 5% CO2 in N2. Coronary flow rate, O2 extraction and uptake, and cardiac production of lactate, purines and 6-keto-PGF1 alpha (the stable metabolite of PGI2) were determined. During perfusion of the hearts with a solution saturated with 95% O2, release of lactate, 6-keto-PGF1 alpha and purines was very low: lactate was liberated at a rate of about 5 mumol/100 g . min, purine release corresponded to 2% of the total adenosine nucleotide content of the heart per hour and the release of 6-keto-PGF1 alpha was about 150 mumol/100 g . min. During hypoxia there was a graded release of lactate and purines from the heart, as well as a liberation of 6-keto-PGF1 alpha. Mild hypoxia (60% O2 in the gas mixture) elicited a 160% increase in the formation of lactate and a 40% increase in the release of purines. During severe hypoxia (8% O2 in the gas mixture) the release of lactate and purines increased by more than 2000%. In contrast, the release of 6-keto-PGF1 alpha never increased more than 80% at any degree of hypoxia, neither did it correlate to the severity of the hypoxia. From these data we conclude that of the two vasodilating agents formed in the heart, adenosine and prostacyclin, the former is probably more important in the regulation of coronary flow.

6-Ketoprostaglandin F1 alpha↗