Human Pharmacology Studies in Volunteers with Indobufen (K 3920), Inhibitor of Platelet Aggregation

1979 ◽  
Author(s):  
L.M. Fuccella ◽  
G. Corvi ◽  
E. Pogliani ◽  
V. Tamassia ◽  
G. Tosolini ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Oral Administration ◽  
Healthy Volunteers ◽  
Kinetic Parameters ◽  
Plasma Levels ◽  
Half Life ◽  
Repeated Administration ◽  
Inhibitory Effect ◽  
Human Pharmacology ◽  
Unchanged Form

Given by the i.v. route to healthy volunteers, indobufen has an half-life of 7-9 h. After oral administration of tablets, the drug is completely absorbed. Excretion occurs through the kidney and the drug is present in the urine as glucoronide and in unchanged form. The maximum inhibitory effect on collagen-induced platelet aggregation was observed 1 to 4 h after i.v. and p.o. administration but activity at 8 h was more marked after p.o. administration in accordance with the higher plasma levels found at that time. During repeated administration at the dose of 100 mg b.i.d. for 7 days, no important changes in kinetic parameters and activity of indobufen was observed. Indobufen is rapidly absorbed also when given by the i.m. route, giving at 30 min peak levels comparable to those observed after oral administration. These data suggest that indobufen is active by the i.V., p.o. and i.m. routes, that its effect on platelets, unlike ASA, is reversible, and that its kinetics is linear.

The Effect of Collagen Mediated Platelet Release on Plasma Prekallikrein Activation

1984 ◽  
Vol 51 (01) ◽  
pp. 037-041 ◽  
Author(s):  
K M Weerasinghe ◽  
M F Scully ◽  
V V Kakkar
Keyword(s):  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Platelet Rich Plasma ◽  
Age Groups ◽  
Inhibitory Effect ◽  
Age Group ◽  
Platelet Factor ◽  
Activated Platelets ◽  
Platelet Release ◽  
Collagen Treatment

SummaryCollagen mediated platelet aggregation caused -5.6 ± 6.7% inhibition and +39.1 ± 15.2% potentiation of prekallikrein activation in plasma from normal healthy volunteers between 20–40 and 50–65 years of age, respectively (n = 15, p <0.01). The amouns of platelet factor-four (PF4) released in the two groups were not significantly different. Collagen treatment in the presence of indomethacin caused +11.5 ± 3.6% and +59.6 ± 19.5% potentiation in the 20–40 and 50–65 age groups respectively (p <0.02). Adrenaline mediated platelet aggregation caused -55.2 ± 7.1% and -35.2 ± 8.3% inhibition in the 20–40 and 50–65 age groups, respectively. Collagen treatment of platelet-deficient-plasma and platelet-rich-plasma in EDTA also caused potentiation of prekallikrein activation.The results indicate that the observed degree of prekallikrein activation after platelet aggregation is a net result of the inhibitory effect of PF4 and the potentiatory effect of activated platelets. The potentiatory effect was greater after collagen treatment as compared to adrenaline treatment, and in the 50–65 age group as compared to the 20–40 age group.

Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

1985 ◽  
Vol 54 (04) ◽  
pp. 808-812 ◽  
Author(s):  
Ulf Berglund ◽  
Henning von Schenck ◽  
Lars Wallentin
Keyword(s):  
Platelet Aggregation ◽  
Angina Pectoris ◽  
Platelet Function ◽  
Plasma Levels ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Controlled Study ◽  
Double Blind ◽  
Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

Randomized, Placebo-controlled, Blinded and Cross-matched Study on the Antiplatelet Effect of Inhaled Nitric Oxide in Healthy Volunteers

2000 ◽  
Vol 83 (02) ◽  
pp. 309-315 ◽  
Author(s):  
Axel Herr ◽  
Johann Motsch ◽  
Alexandra Holzmann ◽  
Jörg Weimann ◽  
Friedemann Taut ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Bleeding Time ◽  
Inhibitory Effect ◽  
Inhaled Nitric Oxide ◽  
Men And Women ◽  
Fibrinogen Binding ◽  
Matched Study

SummaryThe platelet inhibitory effect of 0-40 ppm inhaled nitric oxide (NO) was investigated in healthy men and women. In both groups, ADPand collagen-induced platelet aggregation was significantly inhibited 20 (T20) and 40 min (T40) after the beginning of inhalation of 5, 10, and 40 ppm. Moreover, in both men and women, the in vitro bleeding time was significantly prolonged at T20 and T40 during inhalation of 40 ppm. Inhalation of NO also inhibited P-selectin expression at 5, 10, and 40 ppm and fibrinogen binding to the GPIIb/IIIa-receptor at 40 ppm. In conclusion, in healthy volunteers, the platelet inhibitory effect of inhaled NO was not dose-related, since it was significant at 5 and 10 ppm but did not increase during the administration of higher NO concentrations. In addition, gender-related differences were only observed in ADP-induced platelet aggregation at 10 ppm and in bleeding time prolongation at 40 ppm.

The Inhibitory Effect of Triflusal (Disgren)on the Platelet Aggregation in Healthy Volunteers: Impedance Method with the Whole Blood

1998 ◽  
Vol 28 (5) ◽  
pp. 707 ◽  
Author(s):  
Seokmin Kang ◽  
Kwang Hoe Chung ◽  
Tae Yong Kim ◽  
Shinki Ahn ◽  
Jong Won Ha ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Whole Blood ◽  
Inhibitory Effect ◽  
Impedance Method

Absorption, Tissue Distribution and Elimination of 4-[3H]-Epigallocatechin Gallate in Beagle Dogs

2003 ◽  
Vol 22 (3) ◽  
pp. 187-193 ◽  
Author(s):  
Robert R. Swezey ◽  
Daphne E. Aldridge ◽  
Susanna E. Le Valley ◽  
James A. Crowell ◽  
Yukihiko Hara ◽  
...  
Keyword(s):  
Oral Administration ◽  
Tissue Distribution ◽  
Plasma Levels ◽  
Half Life ◽  
Peak Plasma ◽  
Parent Compound ◽  
Epigallocatechin Gallate ◽  
Total Radioactivity ◽  
Repeat Dose ◽  
Beagle Dogs

Polyphenols found in tea are potent antioxidants and have inhibitory activity against tumorigenicity. The purpose of the described study was to assess the absorption, tissue distribution, and elimination of epigallocatechin gallate (EGCG), the principal catechin found in green tea, in a nonrodent species. 4-[3H]-EGCG was administered to beagle dogs by intravenous (IV) and oral routes. Following IV administration of 25 mg/kg, radioactivity in the bloodstream resided predominantly in the plasma. Distribution occurred during the first hour, and the plasma levels of total radioactivity declined with a mean half-life of approximately 7 hours. The apparent volume of distribution (0.65 l/kg) indicated wide distribution, and the total body clearance (1.01 ml/min-kg) was low. A subsequent single oral dose (250 mg/kg) was rapidly absorbed, with peak plasma levels at about 1 hour after administration, followed by elimination with a mean half-life of 8.61 hours. The mean area under the curve (AUC) for total radioactivity was approximately 20% of the value following IV administration (corrected for dose administered). Excretion of radioactivity in the feces predominated over urinary excretion following both IV and oral administration of [3H]-EGCG. Tissue distribution was determined 1 hour after an IV dose (25 mg/kg) administered after 27 days of oral treatment with EGCG (250 mg/kg/day) to mimic chronic consumption of tea. Radioactivity was distributed to a variety of epithelial tissues; the highest concentrations were observed in the liver and gastrointestinal tract tissues. Repeat dose oral administration of EGCG resulted in significantly lower blood radioactivity compared to the concentration following a single dose. These results are generally in accord with previous studies in rodents and indicate that, after oral administration, EGCG (as parent compound and metabolites) is widely distributed to tissues where it can exert a chemopreventive effect.

Pharmacokinetics of the Bronchodilator Tulobuterol in Man after Repeated Oral Doses

1986 ◽  
Vol 14 (5) ◽  
pp. 223-227 ◽  
Author(s):  
L F Chasseaud ◽  
S G Wood
Keyword(s):  
Plasma Levels ◽  
Half Life ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Repeated Administration ◽  
Elimination Half Life ◽  
Time To Peak ◽  
Final Study ◽  
Elimination Half ◽  
Repeated Dosing

Plasma levels and elimination half-life of tulobuterol, a new beta-adrenergic agonist, were determined in ten healthy male volunteers after repeated dosing with 2mg, twice daily, for seven days. Peak plasma levels attained (2.8 ±0.8 ng/ml), the time to peak plasma concentration (1.0 ±0.3 hr) and the elimination half-life (2.4 ±0.4 hr) were generally unchanged from the first to the final study dose. This suggests that tulobuterol does not accumulate in plasma after repeated administration of a dose regimen known to be clinically effective.

FATE OF OESTRIOL-16,17 DIHEMISUCCINATE AFTER ORAL ADMINISTRATION TO RATS

1965 ◽  
Vol 48 (4) ◽  
pp. 630-644 ◽  
Author(s):  
J. van der Vies
Keyword(s):  
Portal Vein ◽  
Oral Administration ◽  
Half Life ◽  
Life Time ◽  
Clinical Effectiveness ◽  
Peripheral Circulation ◽  
The Body ◽  
Hydrolysis Of ◽  
Unchanged Form

ABSTRACT After oral administration to rats oestriol-16,17 dihemisuccinate is almost exclusively resorbed in the unchanged form and at a slower rate than oestriol itself. Via the portal vein it is transported to the liver and the peripheral circulation. In the liver, hydrolysis of the ester takes place rapidly and the free oestriol formed also enters the blood. In the blood the half life time of oestriol-16,17 dihemisuccinate is 7.6 minutes and that of oestriol 10.3 minutes. Elimination from the body occurs via the bile in which conjugates were found similar to those occurring after administration of oestriol. The ways in which oestriol dihemisuccinate is resorbed, distributed and eliminated differ from those of oestriol itself. This might well be a significant factor in its pharmacological and clinical effectiveness.

Phospholipase C from Clostridium Perfringens Induces Human Platelet Aggregation in Plasma

1988 ◽  
Vol 59 (02) ◽  
pp. 236-239 ◽  
Author(s):  
Giovanna Barzaghi ◽  
Chiara Cerletti ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Phospholipase C ◽  
Clostridium Perfringens ◽  
Human Platelet ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Platelet Activating Factor ◽  
Inhibitory Effect ◽  
Thromboxane Receptor Antagonist

SummaryWe studied the aggregating effect of different concentrations of phospholipase C (PLC) (extracted from Clostridium perfringens) on human platelet-rich plasma (PRP). PRP was preincubated with PLC for 3 min at 37° C and the platelet aggregation was followed for 10 min. The threshold aggregating concentration (TAG) of PLC was 3-4 U/ml.We also studied the potentiation of PLC with other stimuli on platelet aggregation. Potentiating stimuli, such as arachidonic acid (AA), ADP. Platelet Activating Factor (PAF) and U-46619 (a stable analogue of cyclic endoperoxides) were all used at subthreshold concentrations. We also studied the possible inhibitory effect of aspirin, apyrase, TMQ, a prostaglandin endoper- oxide/thromboxane receptor antagonist and BN-52021, a PAF receptor antagonist. Only aspirin and apyrase were able to reduce aggregation induced by PLC alone and PLC + AA and PLC + ADP respectively. TMQ and BN-52021 were inactive. In ex vivo experiments oral aspirin (500 mg) partially inhibited platelet aggregation induced by PLC alone, PLC + AA and PLC + ADP 2 and 24 h after administration. Aspirin 20 mg for 7 days also reduced aggregation induced by PLC + AA.

Plasma Thrombospondin as an Indicator of Intravascular Platelet Activation in Patients with Vasculitis

1987 ◽  
Vol 58 (03) ◽  
pp. 850-852 ◽  
Author(s):  
M B McCrohan ◽  
S W Huang ◽  
J W Sleasman ◽  
P A Klein ◽  
K J Kao
Keyword(s):  
Platelet Activation ◽  
Plasma Levels ◽  
Half Life ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
Primary Source ◽  
Positive Correlation ◽  
Activation Marker ◽  
Fibrin Degradation Products ◽  
The Mean

SummaryThe use of plasma thrombospondin (TSP) concentration was investigated as an indicator of intravascular platelet activation. Patients (n = 20) with diseases that have known vasculitis were included in the study. The range and the mean of plasma TSP concentrations of patients with vasculitis were 117 ng/ml to 6500 ng/ml and 791±1412 ng/ml (mean ± SD); the range and the mean of plasma TSP concentrations of control individuals (n = 33) were 13 ng/ml to 137 ng/ml and 59±29 ng/ml. When plasma TSP concentrations were correlated with plasma concentrations of another platelet activation marker, β-thromboglobulin (P-TG), it was found that the TSP concentration inei eased exponentially as the plasma β-TG level rose. A positive correlation between plasma levels of plasma TSP and serum fibrin degradation products was also observed. The results suggest that platelets are the primary source of plasma TSP in patients with various vasculitis and that plasma TSP can be a better indicator than β-TG to assess intravascular platelet activation due to its longer circulation half life.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

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