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C Patrono

Publications and source records attributed to C Patrono.

At least 145 records · Page 8Linked to original sources
PubMed1986

Long-lived enzymatic metabolites of thromboxane B2 in the human circulation.

Thromboxane A2, a potent vasoconstrictor and platelet agonist, is an evanescent cyclooxygenase product of arachidonic acid. Assessment of thromboxane biosynthesis commonly relies upon analysis of the stable but biologically inactive hydration product, thromboxane B2. However, measurement of this compound in plasma is readily confounded by platelet activation ex vivo. We have identified 11-dehydro-thromboxane B2, 11-dehydro-13,14-dihydro-15-keto-thromboxane B2, and 2,3-dinor-thromboxane B2 as enzymatic products of infused thromboxane B2 in the human circulation. Biosynthesis of deuterated standards permitted the development of quantitative analyses for these compounds, employing capillary gas chromatography-negative ion chemical ionization-mass spectrometry. We thus established that the postinfusion half-lives of 11-dehydro-thromboxane B2 and the keto-dihydro metabolite approximated 1 hour, while that of the dinor metabolite ranged from 15 to 17 min. Combined analysis of short- and long-lived enzymatic metabolites of thromboxane B2 promises to bypass the problem of ex vivo platelet activation and enhance the likelihood of relating a discreet clinical event to an alteration in the biosynthesis of thromboxane A2 in the human circulation.

Adult↗
PubMed1986

Estimated rate of thromboxane secretion into the circulation of normal humans.

We have measured the excretion of a major urinary metabolite of thromboxane B2 (TxB2), i.e., 2,3-dinor-TxB2, during the infusion of exogenous TxB2 over a 50-fold dose range to enable estimation of the rate entry of endogenous TxB2 into the bloodstream. Four healthy male volunteers received 6-h i.v. infusions of venhicle alone and TxB2 at 0.1, 1.0, and 5.0 ng/kg X min in random order. They were pretreated with aspirin at a dose of 325 mg/d in order to suppress endogenous TxB2 production. Urinary 2,3-dinor-TxB2 was measured before, during, and up to 24 h after the infusions and in aspirin-free periods, by means of radioimmunoassay. The nature of the extracted immunoreactivity was characterized by thin-layer chromatography and confirmed by negative ion-chemical ionization gas chromatography/mass spectrometry. Aspirin treatment suppressed urinary 2,3-dinor-TxB2 excretion by 80%. The fractional elimination of 2,3-dinor-TxB2 was independent of the rate of TxB2 infusion and averaged 5.3 +/- 0.8%. Interpolation of metabolite values obtained in aspirin-free periods onto the linear relationship between the quantities of infused TxB2 and the amount of metabolite excreted in excess of control values (y = 0.0066x, r = 0.975, P less than 0.001) permitted calculation of the mean rate of entry of endogenous TxB2 into the circulation as 0.11 ng/kg X min. The rate of disappearance of immunoreactive TxB2 from the circulation was monoexponential over the first 10 min with an apparent half-life of 7 min. This corresponded to a maximal estimate of the plasma concentration of endogenous TxB2 of 2.0 pg/ml. These results suggest that ex vivo platelet activation and/or analytical problems confound estimates of endogenous thromboxane release based on plasma TxB2 and provide a rationale for seeking longer-lived enzymatic metabolites of TxB2 in plasma.

Adult↗
PubMed1986

Inhibition of renal prostaglandin synthesis in man: methodological and clinical implications.

Integrity of renal prostaglandin synthesis is necessary to maintain renal cortical and medullary function in patients with kidney, heart and liver disease. A comparison of the biochemical effects of various non-steroidal anti-inflammatory drugs (NSAIDs) necessitates that renal prostaglandin synthesis, as reflected by urinary immunoreactive prostaglandin excretion, be assessed with proper attention to problems created by seminal fluid contamination, inadequate chromatographic separation of samples, and largely unknown cross reactivities of systemic eicosanoid metabolites with antibodies raised against primary prostaglandins. Most, but not all, clinical studies support the observation that conventional doses of sulindac, administered orally, do not inhibit renal prostaglandin synthesis or alter renal function. Caution is in order, however, about the use of any NSAID, including sulindac at conventional dosage, in patients with severe liver disease as the plasma levels of sulindac sulfide are increased and prolonged compared to patients with normal hepatic function. Furosemide-induced natriuresis is probably not prostaglandin-mediated, in contrast to increased in renal blood flow and renin release. Some NSAIDs can attenuate the efficacy of antihypertensive therapy. Inasmuch as sulindac does inhibit systemic vascular prostacyclin production, its lack of hypertensive effect vis-a-vis other NSAIDs argues in favor of the importance of intrarenal prostaglandin-dependent mechanisms in mediating the hemodynamic effects of non-selective cyclooxygenase inhibitors.

Animals↗
PubMed1986

The role of prostaglandin synthesis inhibition in the renal syndromes associated with non-narcotic analgesics.

Prostaglandin (PG) synthesis in the kidney is localised to specific sites and is not uniformly present throughout the nephron. It is generally accepted that the regional heterogeneity of PGs, as well as the lack of vascular communications between the medulla and cortex, dictate that PGs [primarily prostacyclin (PGI2)] synthesised in the cortex (glomeruli and vasculature) regulate cortical function, while PGs (primarily PGE2) synthesised in the medulla (collecting tubule and medullary interstitial cells) regulate medullary function. Measurement of urinary unmetabolised PGs, or their stable hydration products, provides the best clinical assessment of the state of renal PG production. Under physiological circumstances, renal function is not critically dependent upon the integrity of PG synthesis, possibly because other regulatory mechanisms can compensate for PG synthesis inhibition. However, when renal PG synthesis is activated in response to altered haemodynamics (e.g. cirrhosis with ascites) or is pathologically reduced (e.g. chronic glomerular disease) then the consequences of pharmacological inhibition can become clinically apparent and measurable. In these circumstances, drugs that inhibit renal cyclo-oxygenase activity can acutely reduce glomerular filtration rate and renal blood flow by 30 to 50%. These functional changes are usually reversible upon discontinuing the drug. The long term consequences of renal PG synthesis inhibition are more difficult to assess. Theoretically, chronic inhibition of renal PG synthesis might be responsible for medullary ischaemia, possibly contributing to the picture of so-called analgesic nephropathy. Selective sparing of renal cyclo-oxygenase activity can be obtained by at least 3 mechanisms: differential 'sensitivity' of the glomerular cyclo-oxygenase; selective intra-renal inactivation of an active metabolite of the drug; differential rate of recovery of glomerular cyclo-oxygenase following irreversible acetylation by aspirin. The recent demonstration of a functional correlate of such biochemical selectivity suggests novel strategies for reducing the chronic renal toxicity of cyclo-oxygenase inhibitors.

Analgesics↗
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

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

Leukotriene C4 as a mediator of luteinizing hormone release from rat anterior pituitary cells.

This study demonstrates that leukotriene C4, at concentrations in the picomolar range, released luteinizing hormone (LH) but not growth hormone (GH) from dispersed rat anterior pituitary cells. Leukotriene B4, another lipoxygenase pathway product of arachidonic acid, had no effect on LH or GH release. The stimulatory effect of leukotriene C4 could be seen after 0.5 but not after 3 hr of incubation. This was in contrast to the dose-dependent LH-releasing hormone (LHRH)-induced LH release that was not measurable after 0.5 hr but was fully established after incubation for 3 hr. Furthermore, the LH-releasing ability of leukotriene C4 was blocked in the presence of high doses of LHRH. The immunohistochemical analysis revealed leukotriene C4-immunoreactive fibers at all levels of the median eminence, mainly in the lateral parts. These fibers exhibited a marked overlap distribution with LHRH-immunoreactive fibers and elution-restaining experiments revealed identity of at least a large proportion of the leukotriene C4- and LHRH-immunoreactive fibers. Furthermore, cell bodies in the preoptic area contained both leukotriene C4- and LHRH-like immunoreactivities, suggesting localization of these two compounds in the same neurons.

Animals↗
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

Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation.

The present investigation was undertaken to study cardiac release of adenosine and prostacyclin (prostaglandin [PG] I2) in patients with ischemic heart disease (IHD), and to assess coronary vascular resistance before and after inhibition of synthesis in such patients. In 48 patients with IHD, arterial and coronary sinus blood samples were taken at rest, during atrial pacing to angina, and after pacing. Levels of purines were determined by high-performance liquid chromatography and the PGI2 metabolite 6-keto-PGF1 alpha was measured with radioimmunoassay. Coronary sinus blood flow was determined with retrograde continuous thermodilution before and after oral administration of indomethacin, aspirin, naproxen, or ibuprofen. Atrial pacing induced myocardial ischemia, as evidenced by typical chest pain and arrested lactate extraction. Adenosine was extracted at rest, but during ischemia there was a significant release of its metabolite hypoxanthine, indicating increased myocardial breakdown of high-energy adenine nucleotides. Arterial and coronary sinus concentrations of 6-keto-PGF1 alpha were low and no significant differences between them were found. After administration of the PG-synthesis inhibitor indomethacin, coronary vascular resistance was elevated, as was the cardiac oxygen extraction. The three other PG-synthesis inhibitors (aspirin, naproxen, and ibuprofen) did not, however, induce any change in coronary vascular resistance or in the cardiac extraction of oxygen. On the basis of these data we suggest that in patients with IHD cardiac ischemia results in increased myocardial production and release of purines, cardiac ischemia does not elicit any detectable increase in coronary production of prostacyclin, and the increased coronary resistance induced by indomethacin does not reflect the involvement of locally formed PG in the maintenance of coronary flow, but is rather a direct effect of the drug.

Adenosine↗
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

Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus.

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.

Adolescent↗