NIACIN-INDUCED PROSTACYCLIN (PGI2) GENERATION AND THE SEARCH FOR THE IDEAL DOSE OF ASPIRIN

1987 ◽  
Author(s):  
J A Jakubowski ◽  
D Deykin
Keyword(s):  
Plasma Levels ◽  
Chronic Administration ◽  
Normal Subjects ◽  
Enteric Coated Aspirin ◽  
Regular Aspirin ◽  
Thromboxane Production ◽  
Enteric Coated ◽  
Platelet Thromboxane

We have previously reported that chronic administration of 80 mg/day of enteric-coated aspirin (ECA) in three divided doses of 27 mg each day for 7 days produced over 90% inhibition of platelet thromboxane production. What we wanted to know was whether that dose of aspirin spared PGI2 production. We developed a sensitive plasma assay for PGI2 (measured as 6-keto-PGF1a). We confirmed the reports of others that normal plasma levels are very low, less than 2 pg/ml. We selected niacin as a provocative challenge to raise plasma levels of PGI2 to test the ability of a given aspirin regimen to spare or suppress PGI2 production in vivo. In 5 normal subjects an oral dose of 3 mg/kg of niacin produced a 3-fold rise in 6-keto-PGF1a from 0.86 to 2.64 pg/ml. A dose of 5 mg/kg produced a rise to 6.6 pg/ml. Administration of 323 mg of regular aspirin/day for 7 days completely abolished niacin-induced elevation of plasma PGI2. The lowest dose of ECA that we have found effective in suppressing platelet thromboxane production in vitro, 80 mg/day in divided doses of 27 mg three times a day for 7 days, also completely suppressed niacin-induced elevation of PGI2. Our data do not support the hyypothesis that a very low dose of ECA selectively suppress platelet thromboxane production but spares generation of PGI2

In Vitro Effects Of 5-Fluorouracil On Vascular Tissue Prostacyclin Release And Platelet Thromboxane Production

1981 ◽  
Author(s):  
L Caprino ◽  
F Antonetti ◽  
M Lagomarsino ◽  
L Morelli
Keyword(s):  
Platelet Aggregation ◽  
Vascular Tissue ◽  
Wet Weight ◽  
Thromboxane Production ◽  
In Vitro Effects ◽  
Dose Levels ◽  
Dose Dependent Increase ◽  
Platelet Thromboxane

Severe chest pain (angina attacks) and myocardial infarction has been recorded during 5-Fluorouracil (5-F.U.) tre atment. The present study was undertaken to evaluate the "in vitro" activity of 5-F.U. on vascular prostacyclin (PGI ) release and platelet thromboxane A2(TXA2) formation, which play a role in the onset of cardiovascular disorders. Rat aortic rings (about 20 mg wet/weight) were incubated at 30*C for 15 mins in 300 pi tris buffer containing 5-F.U. (250-500-1000 yg). The aortic rings were removed and the supernatant was kept 4 hrs at room temperature and the RIA of 6-keto PGF1α was thereafter performed.In 1 ml rabbit PRP containing 5-F.U. (50-100-500 yg) platelet aggregation was induced by Arachidonic acid (45 μg). Platelets were then removed by centrifugation and RIA of TXB2 was performed on supernatant.At the dose levels of 250, 500, 1000 μg, 5-F.U. yielded a dose-dependent increase (20, 44 and 68 percent, respectively) in the 6-keto PGF2 released by rat aortic rings. Coil versely, the TXB2 production by platelets during aggregation was reduced of 19, 27, 36 percent at 5-F.U. concentrations of 50, 100, 500 μg/ml, respectively. 5-F.U. had no effect on platelet aggregation.Considering the vasodilator and antithrombogenic effects of PGI2 and the vasoconstrictor effect of TXA2 the present results are not in agreement with the already described cardiotoxicity of 5-F.U. The “in vitro” results, however, if confirmed “in vivo”, show a new aspect of the mechanism of 5-F.U. cardiotoxicity.

Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan
Keyword(s):  
Soft Tissue ◽  
Room Temperature ◽  
Normal Subjects ◽  
Left Testis ◽  
Wide Range ◽  
Activity Ratios ◽  
The Right ◽  
Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

1988 ◽  
Vol 60 (02) ◽  
pp. 205-208 ◽  
Author(s):  
Paul A Kyrle ◽  
Felix Stockenhuber ◽  
Brigitte Brenner ◽  
Heinz Gössinger ◽  
Christian Korninger ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Blood Clotting ◽  
Normal Subjects ◽  
Chronic Uraemia ◽  
Wall Interaction ◽  
End Stage ◽  
Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

Rapeseed Oil and Sunflower Oil Diets Enhance Platelet In Vitro Aggregation and Thromboxane Production in Healthy Men when Compared with Milk Fat or Habitual Diets

1992 ◽  
Vol 67 (03) ◽  
pp. 352-356 ◽  
Author(s):  
Marja Mutanen ◽  
Riitta Freese ◽  
Liisa M Valsta ◽  
Irma Ahola ◽  
Antti Ahlström
Keyword(s):  
Sunflower Oil ◽  
Milk Fat ◽  
Rapeseed Oil ◽  
Controlled Trial ◽  
Collagen Concentration ◽  
Aggregation Pattern ◽  
Thromboxane Production ◽  
Low Erucic Acid ◽  
Platelet Thromboxane

SummaryIn this highly controlled trial, 26 normolipidemic men (average age 28 years, range 18 to 60) were fed a baseline diet high in milk fat (MF) (fat 36% of energy, saturates 19%, monounsaturates 11%, polyunsaturates 4%), followed by a diet high in sunflower oil (SO) (fat 38% of energy, saturates 13%, monounsaturates 10%, polyunsaturates 13%) and another diet high in low erucic-acid rapeseed oil (RO) (fat 38% of energy, saturates 12%, monounsaturates 16%, polyunsaturates 8%). All diets were mixed natural diets with the same cholesterol contents. The baseline milk fat diet was given for 14 days and the oil diets for 24 days in a blind cross-over design. The platelet in vitro aggregation (slope %/min) induced by 1, 2 and 3 pM ADP and collagen (25 pg/ml PRP) was highly significantly (p <0.001) increased after both oil diets when compared with the results from the milk fat diet. The aggregation pattern determined by threshold collagen concentration confirmed increased collagen sensitivity of the platelets after the rapeseed oil diet (p <0.001). The enhancement of platelet aggregation was associated with increased in vitro platelet thromboxane production after the oil diets vs. the milk fat diet (p <0.05 after the sunflower oil diet and p <0.001 after the rapeseed oil diet).

scholarly journals In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michele Dei Cas ◽  
Jessica Rizzo ◽  
Mariangela Scavone ◽  
Eti Femia ◽  
Gian Marco Podda ◽  
...  
Keyword(s):  
Oral Administration ◽  
Whole Blood ◽  
Serum Levels ◽  
Reversed Phase ◽  
Weekly Treatment ◽  
Low Dose Aspirin ◽  
Liquid Chromatography Tandem Mass ◽  
Enteric Coated

AbstractLow-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these “non-responders” patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC–MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37–63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8–1222) for EC-ASA, and 823.1(624–1196) ng h/mL (median, 25–75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.

In-vitro and in-vivo evaluation of enteric-coated starch-based pellets prepared via extrusion/spheronisation

2008 ◽  
Vol 70 (1) ◽  
pp. 302-312 ◽  
Author(s):  
A DUKICOTT ◽  
T DEBEER ◽  
J REMON ◽  
W BAEYENS ◽  
P FOREMAN ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Enteric Coated

Measurements of the jejunal unstirred layer in normal subjects and patients with celiac disease

1996 ◽  
Vol 270 (3) ◽  
pp. G487-G491 ◽  
Author(s):  
A. Strocchi ◽  
G. Corazza ◽  
J. Furne ◽  
C. Fine ◽  
A. Di Sario ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Layer Thickness ◽  
Villous Atrophy ◽  
Normal Subjects ◽  
Unstirred Layer ◽  
Maximal Velocity ◽  
Normal Rat ◽  
Kinetics Of

Normal intestinal absorption of nutrients requires efficient luminal mixing to deliver solute to the brush border. Lacking such mixing, the buildup of thick unstirred layers over the mucosa markedly retards absorption of rapidly transported compounds. Using a technique based on the kinetics of maltose hydrolysis, we measured the unstirred layer thickness of the jejunum of normal subjects and patients with celiac disease, as well as that of the normal rat. The jejunum of humans and rats was perfused with varying maltose concentrations, and the apparent Michaelis constant (Km) and maximal velocity (Vmax) of maltose hydrolysis were determined from double-reciprocal plots. The true Km of intestinal maltase was determined on mucosal biopsies. Unstirred layer thickness was calculated from the in vivo Vmax and apparent Km and the in vitro Km of maltase. The average unstirred layer thickness of 11 celiac patients (170 micron) was seven times greater than that of 3 controls (25 micron). The unstirred layer of each celiac exceeded that of the controls. A variety of factors could account for the less efficient luminal stirring observed in celiacs. Although speculative, villous contractility could be an important stirring mechanism that would be absent in celiacs with villous atrophy. This speculation was supported by the finding of a relatively thick unstirred layer (mean: 106 micron) in rats, an animal that lacks villous contractility. Because any increase in unstirred layer slows transport of rapidly absorbed compounds, poor stirring appears to represent a previously unrecognized defect that could contribute to malabsorption in celiac disease and, perhaps, in other intestinal disorders.

scholarly journals Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 161-167 ◽  
Author(s):  
Nicholas T. Funderburg ◽  
Elizabeth Mayne ◽  
Scott F. Sieg ◽  
Robert Asaad ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Tissue Factor ◽  
Immune Activation ◽  
Interleukin 6 ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Hiv Replication ◽  
Increased Risk

Abstract HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

scholarly journals Granulocyte aggregometry: a sensitive technique for the detection of C5a and complement activation

Blood ◽  
1980 ◽  
Vol 55 (6) ◽  
pp. 898-902 ◽  
Author(s):  
DE Hammerschmidt ◽  
TK Bowers ◽  
CJ Lammi-Keefe ◽  
HS Jacob ◽  
PR Craddock
Keyword(s):  
Lupus Erythematosus ◽  
Cytochalasin B ◽  
Normal Subjects ◽  
Standard Methods ◽  
Sensitive Technique ◽  
Fresh Serum ◽  
Induced Aggregation ◽  
Transfusion Reactions

Abstract We have previously shown that complement (C) activated plasma causes granulocyte (PMN) aggregation in vitro and that C5a is responsible. The C-induced aggregation of PMNs treated with cytochalasin-B (CB) is markedly enhanced and irreversible, and the magnitude of the response is proportional to the log (concentration of activated plasma), allowing use of this technique to detect C5a and hence C-activation. To compare the sensitivity of granulocyte aggregometry to that of more standard methods of detecting C-activation, we produced graded C- activation in vitro by treating fresh serum with varying amounts of zymosan. Aggregometry was the most sensitive index of C-activation, detecting C-activation, produced by 0.02 mg zymosan/ml of serum--1/10 that required to produce C-activation detectable by C3 immunoelectrophoresis (the next most sensitive technique). Granulocyte aggregometry may also be used to detect in vivo C-activation. We have found aggregating activity in plasmas from patients with systemic lupus erythematosus, immune vasculitis, transfusion reactions, and other conditions associated with in vivo C-activation, but not in the plasmas of normal subjects.

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