In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

scholarly journals Effect of host-mimicking medium and biofilm growth on the ability of colistin to kill Pseudomonas aeruginosa

Microbiology ◽  
2020 ◽  
Vol 166 (12) ◽  
pp. 1171-1180 ◽  
Author(s):  
Esther Sweeney ◽  
Akshay Sabnis ◽  
Andrew M. Edwards ◽  
Freya Harrison
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Ex Vivo ◽  
Clinical Success ◽  
Biofilm Growth ◽  
Content Type ◽  
The Matrix ◽  
Model Versus ◽  
High Doses

In vivo biofilms cause recalcitrant infections with extensive and unpredictable antibiotic tolerance. Here, we demonstrate increased tolerance of colistin by Pseudomonas aeruginosa when grown in medium that mimics cystic fibrosis (CF) sputum versus standard medium in in vitro biofilm assays, and drastically increased tolerance when grown in an ex vivo CF model versus the in vitro assay. We used colistin conjugated to the fluorescent dye BODIPY to assess the penetration of the antibiotic into ex vivo biofilms and showed that poor penetration partly explains the high doses of drug necessary to kill bacteria in these biofilms. The ability of antibiotics to penetrate the biofilm matrix is key to their clinical success, but hard to measure. Our results demonstrate both the importance of reduced entry into the matrix in in vivo-like biofilm, and the tractability of using a fluorescent tag and benchtop fluorimeter to assess antibiotic entry into biofilms. This method could be a relatively quick, cheap and useful addition to diagnostic and drug development pipelines, allowing the assessment of drug entry into biofilms, in in vivo-like conditions, prior to more detailed tests of biofilm killing.

Platelet Aggregation Induced In Vivo By Heparin And Heparin Fractions

1981 ◽  
Author(s):  
M Silane ◽  
J N Lindon ◽  
B J Ransil ◽  
R D Rosenberg ◽  
E W Salzman
Keyword(s):  
Molecular Weight ◽  
Platelet Aggregation ◽  
Reciprocal Relationship ◽  
Low Molecular Weight ◽  
Arterial Blood ◽  
Platelet Aggregate ◽  
Heparin Fractions ◽  
Platelet Aggregates

As we have reported, heparin-induced platelet aggregation in vitro varies among heparin subfractions, being generally less with lower molecular weights and having a reciprocal relationship with antithrombin affinity.We now have studied heparin-induced platelet aggregates in vivo by the technique of Wu and Hoak using arterial blood from unanesthetized rabbits. Porcine mucosal heparin was fractionated by gel filtration into high molecular weight (ave. 15,000 Daltons) or low molecular weight (ave. 6,000 Daltons) preparations. IV administration of commercial porcine mucosal heparin (spec. act. 150 u/mg) or high (spec. act. 183 u/mg) or low (spec. act. 208 u/mg) molecular weight fractions was followed by an increase in the platelet aggregate ratio compared with preinjection control values. The rise in platelet aggregate ratio with heparin was significantly different from the effect of a saline placebo (n=8) but was not significantly different among rabbits receiving the commercial heparin (n=9) or the high (n=8) or low (n=8) molecular weight preparations. Peak rise in circulating aggregate ratio occurred 2 minutes after the injection, and values returned to control levels within 15 to 30 minutes. There was no change in platelet count in blood collected in EDTA, suggesting that the aggregates were not removed from the circulation in vivo.Heparin fractions of low molecular weight were further separated according to antithrombin affinity by an antithrombin binding technique. In 8 rabbits low molecular weight/high antithrombin affinity heparin (spec. act. 480 u/mg) did not cause formation of platelet aggregates. The results were significantly different from those with commercial heparin (p=0.05) or with the other heparin fractions (p=0.06).Clinical use of low molecular weight heparin of high antithrombin affinity may lead to fewer heparin-induced platelet effects and to an improvement in anticoagulant therapy.

scholarly journals Prevention by Suloctidil of Spontaneous Platelet Aggregates in Rats

1977 ◽  
Author(s):  
R. N. Saunders ◽  
T. S. Burns ◽  
M. R. Stelzer
Keyword(s):  
Cerebrovascular Disease ◽  
Platelet Rich Plasma ◽  
Male Rats ◽  
Prevention Activity ◽  
Platelet Aggregate ◽  
Circulating Platelet Aggregates ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
Rat Platelets

Atherosclerosis and cerebrovascular disease have been reported by Wexler and True (Circ. Res. 12: 659,1963) to-occur in retired breeder rats but not in virgin rats of the same age. We have discovered that retired breeder (RB) male rats have spontaneous circulating platelet aggregates (CPA) as determined by the method of Wu and Hoak (Lancet 2: 924, 1974). These CPA respond to therapy with clinically proven antiplatelet drugs. Suloctidil (S) [l-(4-isopropyl-thiophenyl)-2-n-octylamino propanol, Continential Pharma, Brussels] administered for 8 days at 100 mg/kg i. g. showed a significant reduction in CPA from 0.76+0.05 (S.E.M.) to 0.92 + 0.03 (where 1.0 indicates no CPA). In these same rats, the endogenous platelet 5-HT level was significantly (P<0.01) lowered to 0.88+0.04 (S. E.M.) μg/10 9 platelets compared to control values of 1.66+0.08 μg/10 9platelets. Plasma 5-HT levels were not altered. In vitro rat platelet 5-HT uptake is inhibited 50% by S at 6.4 χ 10 -6M in platelet-rich plasma. In rat platelets with labeled 5-HT pools, 5 min incubation with S at 10 -5M resulted in significantly (P<0.01) greater release at 10, 20 and 30 sec after the addition of 2U/ml of thrombin. This suggests that S may decrease uptake as well as increase release of platelet 5-HT. The reduction of endogenous platelet 5-HT levels by S may be related to its observed platelet aggregate prevention activity.

The Thrombostat System A Useful Method to Test Antiplatelet Drugs and Diets

1995 ◽  
Vol 21 (S 02) ◽  
pp. 25-31 ◽  
Author(s):  
Michael Kratzer ◽  
Emil Negrescu ◽  
Azan Hirai ◽  
Young Yeo ◽  
Franke Petra ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Synergistic Effects ◽  
Antiplatelet Drugs ◽  
Small Samples ◽  
Fish Diet ◽  
Heart Attacks ◽  
Primary Hemostasis ◽  
High Doses

The use of platelet inhibitory drugs, like aspirin, has resulted in a significant reduction of thrombotic complications in primary and secondary prevention of heart attacks. To find more effective substances or better drug combinations, inhibition of primary hemostasis in vitro (Thrombostat system) was investigated, with different drugs and fish diet, using small samples (1 ml) of anticoagulated (Na- citrate 3.8%, 1/9) human blood. Results: 1. In the presence of 1mM aspirin, which had no effect on bleeding volume, only 0.6 nM iloprost were necessary to show a 50% inhibition, in contrast to 2.5 μM without aspirin. 2. At aspirin concentrations of 1 mM, 50% inhibition of primary hemostasis could be achieved with 20 μM SIN-I, or with 7 μM SIN-l together with iloprost (500 pM). The same effect was seen only with very high doses of SIN-l (1000 μM) alone. 3. For 50% inhibition of primary hemostasis in vitro, RGDS concentrations were reduced from 250 μM to 160 μM when blood was pretreated with 1 mM aspirin and to 75 μM when 500 pM i1oprost were added additionally. 4. Japanese fishermen (eating 270 g fish/day) demonstrated significantly longer in-vivo bleeding times and in-vitro bleeding volumes (6.49 min/224 μI), respectively, as compared to Japanese farmers (90g fish/day, 4.85 min/137 μI). 5. In Japanese subjects in-vivo bleeding times correlated with in-vitro bleeding volumes (0.69). The Thrombostat system proved to be a sensitive method to detect synergistic effects of various antiplatelet drugs in vitro and of a platelet inhibitory diet ex vivo.

scholarly journals Effect of host-mimicking medium and biofilm growth on the ability of colistin to kill Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Esther Sweeney ◽  
Akshay Sabnis ◽  
Andrew M. Edwards ◽  
Freya Harrison
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Ex Vivo ◽  
Clinical Success ◽  
Biofilm Growth ◽  
The Matrix ◽  
Model Versus ◽  
High Doses ◽  
Fluorescent Tag

AbstractIn vivo biofilms cause recalcitrant infections with extensive and unpredictable antibiotic tolerance. Here, we demonstrate increased tolerance of colistin by Pseudomonas aeruginosa when grown in cystic fibrosis-mimicking medium versus standard medium in in vitro biofilm assays, and drastically increased tolerance when grown in an ex vivo CF model versus the in vitro assay. We used colistin conjugated to the fluorescent dye BODIPY to assess the penetration of the antibiotic into ex vivo biofilms and showed that poor penetration partly explains the high doses of drug necessary to kill bacteria in these biofilms. The ability of antibiotics to penetrate the biofilm matrix is key to their clinical success, but hard to measure. Our results demonstrate both the importance of reduced entry into the matrix in in vivo-like biofilm, and the tractability of using a fluorescent tag and benchtop fluorimeter to assess antibiotic entry into biofilms. This method could be a relatively quick, cheap and useful addition to diagnostic and R&D pipelines, allowing the assessment of drug entry into biofilms, in in vivo-like conditions, prior to more detailed tests of biofilm killing.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

Accumulation of Macromolecular Particles in the Reticuloendothelial System (RES) Mediated by Platelet Aggregation and Disaggregation

1969 ◽  
Vol 22 (03) ◽  
pp. 496-507 ◽  
Author(s):  
W.G van Aken ◽  
J Vreeken
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Reticuloendothelial System ◽  
Caproic Acid ◽  
Carbon Particles ◽  
Carbon Clearance ◽  
Aggregation And Disaggregation ◽  
Platelet Aggregates

SummaryCarbon particles cause platelet aggregation in vitro and in vivo. Prior studies established that substances which modify thrombocyte aggregation also influence the rate at which carbon is cleared from the blood.This study was performed in order to elucidate the mechanism by which the carbon-platelet aggregates specifically accumulate in the RES.Activation of fibrinolysis by urokinase or streptokinase reduced the carbon clearance rate, probably due to generated fibrinogen degradation products (FDP). Isolated FDP decreased the carbon clearance and caused disaggregation of platelets and particles in vitro. Inhibition of fibrinolysis by epsilon-amino-caproic acid (EACA), initially accelerated the disappearance of carbon and caused particle accumulation outside the RES, predominantly in the lungs. It is supposed that platelet aggregation and locally activated fibrinolysis act together in the clearance of particles. In the normal situation the RES with its well known low fibrinolytic activity, becomes the receptor of the particles.

Studies on the Haemostatic Defect in a Complicated Syndrome

1995 ◽  
Vol 74 (05) ◽  
pp. 1244-1251 ◽  
Author(s):  
H Stormorken ◽  
H Holmsen ◽  
R Sund ◽  
K S Sakariassen ◽  
T Hovig ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Abnormal Finding ◽  
Shear Rates ◽  
Perfusion Chamber ◽  
Coagulant Activity ◽  
5 Ht Uptake ◽  
And Storage

SummaryThe Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. Survival time was half normal. Clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP’s were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway.

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