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C Patrono

Publications and source records attributed to C Patrono.

At least 127 records · Page 7Linked to original sources
PubMed1989

Fractional conversion of thromboxane A2 and B2 to urinary 2,3-dinor-thromboxane B2 and 11-dehydrothromboxane B2 in the cynomolgus monkey.

Following the intravenous administration of thromboxane (TX) B2, the stable hydration product of TXA2, to human and nonhuman primates the most abundant urinary metabolites are 2,3-dinor-TXB2 and 11-dehydro-TXB2. However, it is not known whether fractional conversion of TXB2 to its enzymatic metabolites is an accurate representation of TXA2 metabolism. Thus, we have compared the metabolic disposition of synthetic TXA2 and TXB2 via the beta-oxidation and 11-OH-dehydrogenase pathways in vivo in the monkey. TXA2 or TXB2 (20 ng/kg) was intravenously administered to four cynomolgus monkeys pretreated with aspirin in order to suppress endogenous TXA2 production. Urinary TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 were measured before, during and up to 24 h after thromboxane administration by means of reversed-phase high-performance liquid chromatography radioimmunoassay. Aspirin treatment suppressed urinary 2,3-dinor-TXB2 and 11-dehydro-TXB2 by approx. 75%. A similar fractional conversion of TXA2 and TXB2 into 2,3-dinor-TXB2 and 11-dehydro-TXB2 was found. These results suggest that TXA2 is hydrolyzed to TXB2 prior to enzymatic degradation and that metabolites of the latter represent reliable indices of TXA2 biosynthesis. Due to the variability in the conversion of thromboxanes into 2,3-dinor-TXB2 and 11-dehydro-TXB2, the measurement of both metabolites seems to represent a more reliable index of acute changes in TXA2 production.

Animals↗
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

Aspirin and human platelets: from clinical trials to acetylation of cyclooxygenase and back.

Aspirin has been convincingly shown to reduce the incidence of vascular occlusive events in a wide range of patients at risk of thrombotic complications. These beneficial effects are currently linked to suppression of thromboxane A2-dependent platelet aggregation. This in turn reflects permanent loss of the cyclooxygenase activity of platelet prostaglandin G/H synthase, through acetylation of Ser530. Progress in our understanding of the molecular mechanism of action of aspirin and definition of the clinical pharmacology of its platelet effects has been associated with a downward trend in its daily dosage. This has been reduced by a factor of ten over the last decade, substantially reducing gastrointestinal toxicity, while leaving antithrombotic efficacy virtually unchanged. Carlo Patrono reviews the biochemical, pharmacological and clinical data that form the basis of the present consensus and provide a rationale for clinical trials of low-dose aspirin.

Acetylation↗
PubMed1989

Eicosanoid biosynthesis and action: novel opportunities for pharmacological intervention.

Novel eicosanoid biosynthetic pathways and receptors are reviewed as potential targets for pharmacological intervention. In addition to the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism, a cytochrome P450-dependent monooxygenase has been identified in corneal and renal epithelial cells. Elucidation of the enzymatic pathways of thromboxane (TX) disposition and development of analytical techniques for measuring urinary metabolites have allowed a reliable assessment of TXA2 biosynthesis in health and disease, and provide a rationale for the combined use of TX-synthase inhibitors and TXA2-receptor antagonists in the setting of platelet activation. Recent evidence for a transcellular metabolism of neutrophil-derived leukotriene (LT) A4 by other human blood cells might link platelet and neutrophil activation to the occurrence of vasospastic phenomena. Prostacyclin (PG1(2)), PGE2, PGD2, TXA2/PGH2, and sulfidopeptide-LT receptors are being characterized in terms of distribution, signal-transduction mechanisms, and agonist-mediated regulation. Development of relatively selective agonists and antagonists of these receptors is providing novel therapeutic strategies for several human diseases.

Animals↗
PubMed1989

Renal metabolism and urinary excretion of thromboxane B2 in the rat.

We wanted to evaluate whether the kidney tissue can metabolize thromboxane (Tx) B2 and, specifically, whether the 2,3-dinor metabolite might be formed in the kidney and excreted in the urine. For this purpose, we used an isolated perfused kidney preparation exposed to vehicle or TxB2 at different infusion rates. Approximately 96% of the total TxB2 infused was recovered in the venous effluent, whereas approximately 1% was found in urine. Isolated perfused kidneys exposed to [3H]TxB2 eliminated in the urine 1.2% of the [3H]TxB2 infused, measured by thin-layer chromatographic analysis, and actively metabolized [3H]TxB2 to 2,3-dinor-TxB2, 11-dehydro-TxB2, and possibly 2,3,4,5-tetranor-TxB1. No metabolites of TxB2 were recovered in the venous effluent. As a marker of renal TxB2 metabolic activity, urinary 2,3-dinor-TxB2 was quantified by high-resolution gas chromatography-negative-ion chemical ionization mass spectrometry. The 2,3-dinor-TxB2 was detected both before and during TxB2 infusion in urinary samples but not in the venous effluent. The ratio of 2,3-dinor-TxB2-TxB2 increased during the infusion reaching a peak value immediately after stopping the TxB2 infusion. These results indicate that, in the rat, the kidney tissue metabolizes TxB2 to 2,3-dinor-TxB2, and both TxB2 and 2,3-dinor-TxB2 are excreted in the urine.

Animals↗
PubMed1989

Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials.

Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.

Animals↗
PubMed1987

Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine.

Because of the discrepancy between the capacity of platelets to synthesize thromboxane B2 ex vivo and the actual synthetic rate in vivo, measurement of thromboxane B2 in plasma is highly influenced by sampling-related artifacts. We have developed and validated a radioimmunoassay for a major enzymatic derivative of thromboxane B2 with an extended plasma half-life, i.e., 11-dehydrothromboxane B2. The binding of the tracer is displaced by as low as 1 pg/ml of the homologous ligand, with a high degree of specificity for the open ring structure as well as for the omega side-chain. This method can detect changes in the plasma concentration and urinary excretion of 11-dehydrothromboxane B2 associated with stimulated short-term increases of thromboxane B2 secretion in the human circulation.

Adult↗
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↗
PubMed1987

Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis.

Release of acetyl glyceryl ether phosphorylcholine, platelet-activating factor (PAF), has been demonstrated to be associated with glomerular inflammatory damage in acute serum sickness. Moreover, PAF can increase glomerular permeability to proteins and induce mesangial contraction. Thus PAF might be a good candidate as a mediator of glomerular damage. However the in vivo evidence that PAF might cause glomerular injury is lacking. To evaluate if PAF has a major role in promoting glomerular inflammatory reaction and fibrin deposition, we studied the effect of a molecule, L-652,731, which blocks the PAF receptor, on the evolution of an experimental model of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN). GN was initiated by sheep-anti-rabbit nephrotoxic serum. A proliferative GN regularly occurred in which heavy proteinuria, intra and extracapillary proliferation of resident and inflammatory cells and fibrin deposition in Bowman's capsule were the prominent findings. Our results showed that the PAF receptor antagonist reduces the glomerular damage in anti-GBM GN, supporting the hypothesis that PAF is indeed a mediator of glomerular inflammatory reaction. PAF receptor blocking prevented renal function deterioration in the early phase of the disease, probably preserving glomerular hemodynamics. In the delayed phase of the disease the PAF receptor antagonist reduced proteinuria and prevented renal function deterioration and fibrin deposition. These effects appear to be mediated by an inhibitory action of PAF receptor blocking on macrophage accumulation and activation.

Animals↗
PubMed1987

Role of platelet and vascular eicosanoids in the pathophysiology of ischemic heart disease.

The role of platelet and vascular arachidonate metabolism in ischemic heart disease can be derived from direct measurements and/or inhibitor trials. Direct measurements have yielded somewhat conflicting results, largely related to analytical problems and ex vivo platelet activation during blood sampling. On the other hand, inhibitor trials have clearly established the following: 1) thromboxane (TX) A2-dependent platelet activation plays an important role in the dynamic process of coronary thrombosis in unstable angina, 2) TXA2 does not appear to mediate coronary vasospasm, as seen in variant angina, 3) endogenous prostacyclin (PGI2) is not released in response to myocardial ischemia and is unlikely to regulate coronary blood flow, and 4) exogenous PGI2 is of limited therapeutic benefit. The demonstration that low-dose aspirin (0.5-1.0 mg/(kg X day] is a selective inhibitor of TXA2-dependent platelet function provides a conceptual and practical framework for the rational design of future trials. Moreover, the identification of major enzymatic metabolites of TXB2 in plasma (11-dehydro-TXB2) and urine (2,3-dinor-TXB2) and development of appropriate analytical techniques offer the opportunity for better defining the pathophysiological role of TXA2 in humans.

Blood Platelets↗
PubMed1986

Renal effects of nonsteroidal anti-inflammatory drugs in chronic glomerular disease.

In contrast to a variety of clinical conditions characterized by ineffective circulatory volume, chronic glomerular disease is not usually associated with increased circulating levels of vasoconstrictor hormones. However, a reduction in glomerular prostacyclin production can possibly account for the prostaglandin dependence of renal function in these patients by virtue of the enhanced constrictor effects of angiotensin II on glomerular arterioles and mesangium. The reduction of renal function induced by a nonselective cyclo-oxygenase inhibitor is inversely related to the basal prostacyclin production. Increased renal synthesis of vasoconstrictor thromboxane A2, as noted in patients with systemic lupus erythematosus, might contribute to the cyclo-oxygenase dependence of renal function. Aspirin as well as a variety of structurally unrelated nonsteroidal anti-inflammatory drugs reduce renal function in systemic lupus erythematosus patients. However, the functional consequences of renal cyclo-oxygenase inhibition are partially attenuated in patients with lupus nephritis vis-à-vis other forms of chronic glomerular disease because of concomitant suppression of enhanced glomerular thromboxane A2 production. Animal data consistent with a prevailing functional significance of vasodilator prostaglandins have also been reported. Short-term administration of sulindac at the recommended dosage is relatively safe in patients with chronic glomerular disease because of selective sparing of glomerular cyclo-oxygenase activity. The long-term consequences of selective versus nonselective cyclo-oxygenase inhibition remain to be established in humans. The beneficial effects of a combination of aspirin and dipyridamole in slowing the deterioration of renal function in patients with membranoproliferative glomerulonephritis does provide a rationale for exploring the effects of low-dose aspirin (i.e., 0.5 to 1.0 mg/kg per day), which most effectively suppresses platelet thromboxane A2 production without interfering with renal prostacyclin synthesis.

Animals↗