Platelet Aggregation Inhibitory Effect Research Articles

Total Synthesis of (-)-Amovillosumin A and Structure Correction of (-)-Amovillosumin C Using Chemical Synthesis.

Norlignans are a rare class of natural products isolated from a diverse range of plant species, many of which have interesting biological activities including antibacterial, antioxidant, phytotoxic, platelet aggregation inhibitory effects, and more. Isolated from Amomum villosum (Amomi Fructus), amovillosumins A (1) and C (3) are norlignans which were of interest to synthesize, due to their interesting bioactivities, specifically their ability to increase stimulation of glucagon-like peptide-1 (GLP-1) secretion. In this research, key intermediate 15 was used to stereoselectively synthesize (7R,8R)-amovillosumins A (1) and C (3). The developed method includes a Mitsunobu coupling, a modified rhodium-catalyzed Miyaura arylation, and an acid-catalyzed cyclization in key bond-forming steps. After synthesis, the structure of 1 was confirmed, but it was revealed that the benzodioxane-containing structure of amovillosumin C (3) that had been proposed in the literature was incorrect. Thus, with further investigation a structure correction of 3 was achieved by synthesis, the correct structure being 8-O-4'-oxynorlignan.

Fluorescence quenching-based immunological probe for ticagrelor monitoring

Introduction: Ticagrelor is extensively utilized for the treatment of acute coronary syndromes (ACS), but its platelet aggregation inhibitory effects can potentially result in tissue bleeding, posing a serious risk to patients’ lives.Methods: In this study, we developed highly sensitive full length anti-ticagrelor Quenchbodies (Q-bodies) for fast monitoring of ticagrelor both in solution and serum for the first time. Ticagrelor coupled with N- hydroxysuccinimide (Ticagrelor-NHS) ester was also designed and synthesized for interaction and biological activity detection.Results: Both ATTO-labeled MEDI2452 (2452A) Q-body and TAMRA-labeled IgG 152 (152T) Q-body demonstrated efficient detection of ticagrelor and its active metabolite (TAM). The 2452A Q-body exhibited a broader detection range, while the 152T Q-body displayed a lower limit of detection (LOD). Under physiological conditions (Ticagrelor:TAM, 3:1), the concentration of ticagrelor was further measured, yielding LOD values of 4.65 pg/mL and 2.75 pg/mL for the two Q-bodies, with half-maximal effect concentrations of 8.15 ng/mL and 3.0 ng/mL, respectively.Discussion: Compared with traditional liquid chromatography-mass spectrometry (LC-MS) methods, anti-ticagrelor Q-bodies have higher sensitivity and detection speed. It enabled the completion of analysis within 3 min, facilitating rapid preoperative detection of blood drug concentration in ACS to determine the feasibility of surgery and mitigate the risk of intraoperative and postoperative hemorrhage. The swift detection of ticagrelor holds promise for enhancing individualized drug administration, preventing adverse reactions, and providing preoperative guidance.

Improving Chuanxiong Rhizoma quality standards using an effect-constituent index based bioassay

Chuanxiong Rhizoma is a traditional Chinese medicine (TCM) that is used to promote blood circulation. We set out to improve Chuanxiong Rhizoma quality standards using a bioassay-based Effect-constituent Index (ECI). We performed high performance liquid chromatography (HPLC) analysis to determine the chemical constituents of 10 Chuanxiong Rhizoma samples from different locations. We then constructed a direct bioassay method to investigate each sample’s antiplatelet aggregation effects. To screen for active ingredients that promote antiplatelet aggregation, we carried out Pearson correlation analyses between biopotency and compounds identified in the HPLC data. We developed an ECI of platelet aggregation inhibition using a multi-indicator synthetic evaluation method based on the integration of biopotency and active constituents. To further assess the biopotency-based Chuanxiong Rhizoma quality evaluation result accuracy, we compared the ECI with the chemical indicator’ method. Eight common chemical fingerprints peaks indicated notable content variation among samples. Biological evaluation showed that all 10 samples could inhibit platelet aggregation, although they had significantly different biological potencies. Using spectrum-effect relationships, we determined that Ligustilide was the significant active constituent responsible for antiplatelet aggregation. Using correlation analysis, we found that ECI correlated with the Chuanxiong Rhizoma extract’s platelet aggregation inhibitory effect. Additionally, ECI proved to be a good indicator of Chuanxiong Rhizoma quality, whereas chemical indicators failed to distinguish and predict the biopotency-based quality grade. This work indicates that ECI is a useful tool for associating sample quality with chemical markers linked to TCM clinical effects. ECI also provides a paradigm for improving the quality control of other TCMs that invigorate blood circulation.

Synthesis, and docking studies of arylhydrazone compounds and evaluation of their platelet aggregation inhibitory effect and cytotoxicity

Synthesis, and docking studies of arylhydrazone compounds and evaluation of their platelet aggregation inhibitory effect and cytotoxicity

Functional and binding studies of gallic acid showing platelet aggregation inhibitory effect as a thrombin inhibitor

ObjectiveThis study was devoted to identifying natural thrombin inhibitors from traditional Chinese medicine (TCM) and evaluating its biological activity in vitro and binding characteristics. MethodsA combination strategy containing molecular docking, thrombin inhibition assay, surface plasmon resonance (SPR) and molecular dynamics simulation were applied to verify the study result. ResultsGallic acid was confirmed as a direct thrombin inhibitor with IC50 of 9.07 μmol/L and showed a significant inhibitory effect on thrombin induced platelet aggregation. SPR-based binding studies demonstrated that gallic acid interacted with thrombin with a KD value of 8.29 μmol/L. Molecular dynamics and binding free energy analysis revealed that thrombin-gallic acid system attained equilibrium rapidly with very low fluctuations, the calculated binding free energies was −14.61 kcal/mol. Ala230, Glu232, Ser235, Gly258 and Gly260 were the main amino acid residues responsible for thrombin inhibition by gallic acid, providing a mechanistic basis for further optimization. ConclusionThis study proved that gallic acid is a direct thrombin inhibitor with platelet aggregation inhibitory effect, which could provide a basis for the follow-up research and development for novel thrombin inhibitors.

Antithrombotic Potential of Red Allium cepa and Angelica gigas Nakai

Abstract: Introduction: Red Allium cepa and Angelica gigas Nakai is widely used in oriental medicine and also has various physiological activities. The main components of two substances will have potential benefits to blood flow improvement. Objectives: This study evaluated the cell viability and antioxidant effects of Red Allium cepa extract, Angelica gigas Nakai extract and their mixture and observed anticoagulation activity and antiplatelet aggregation activity. Methods: Red Allium cepa was bioconverted through the use of the Bacillus subtilis KJ-3 (BS3) strain after ethanol extraction (Red-BCQ). Angelica gigas Nakai extract (Agnex) contains a large amount of coumarins such as decursin and decursinol angelate (D/DA). Here, we observed antioxidant and antithrombotic effects after treatment with Red-BCQ, Agnex and mixture of these two compounds. Results: The quercetin content of Red-BCQ increased by about 7.4-fold after bioconversion. A 1 mg portion of Agnex contained 0.4146 mg of D and 0.3659 mg of DA. Red-BCQ and Agnex exerted strong antioxidant activities due to their high polyphenol and flavonoid content. In our study, Red-BCQ and Agnex exhibit beneficial effects to external coagulation pathways by significantly expanding aPTT. However, a combination of Red-BCQ and Agnex did not exert any synergistic effect on anti-coagulation activity. Additionally, our results concerning platelet aggregation inhibitory effects revealed that these effects increased by treatment with Agnex alone or in combination with Red-BCQ. Conclusion: Further research is required to clarify the underlying mechanism. However, Red-BCQ and Agnex are considered to possess antioxidant effects either alone or as a mixture and also exert antithrombotic effects. Key words: Red Allium cepa, Angelica gigas Nakai, Bacillus subtilis KJ-3, Bioconversion, Anti-coagulation.

Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Targeting Pathomechanisms with Bruton Tyrosine Kinase Inhibitors.

A series of cases with rare thromboembolic incidents including cerebral sinus vein thrombosis (some of them fatal) and concomitant thrombocytopenia occurring shortly after vaccination with the coronavirus disease 2019 (COVID-19) vaccine AZD1222 (Vaxzevria) have caused significant concern and led to its temporary suspension in many countries. Immediate laboratory efforts in four of these patients have identified a tentative pathomechanism underlying this syndrome termed initially vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and renamed recently vaccine-induced immune thrombotic thrombocytopenia (VITT). It encompasses the presence of platelet-activating antibodies to platelet factor-4/heparin complexes, possibly emulated by polyanionic constituents of AZD1222, and thus resembles heparin-induced thrombocytopenia (HIT). Because these immune complexes bind and activate platelets via Fcγ receptor IIA (FcγRIIA), high-dose intravenous immunoglobulin G has been suggested for treatment of VITT in addition to non-heparin anticoagulants. Here we propose inhibitors of Bruton tyrosine kinase (Btk) approved for B cell malignancies (e.g., ibrutinib) as another therapeutic option in VITT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, for example, as demonstrated for the effective inhibition of platelet aggregation, dense granule secretion, P-selectin expression and platelet-neutrophil aggregate formation stimulated by FcγRIIA cross-linking. Moreover, C-type lectin-like receptor CLEC-2- and GPIb-mediated platelet activation, the interactions and activation of monocytes and the release of neutrophil extracellular traps, as encountered in HIT, could be attenuated by Btk inhibitors. As a paradigm for emergency repurposing of approved drugs in COVID-19, off-label use of Btk inhibitors in a low-dose range not affecting haemostatic functions could thus be considered a sufficiently safe option to treat VITT.

Efficacy of Monitoring for Multiple Antiplatelet Therapy during Intracranial Stent Placement: A Preliminary Study.

During cerebral aneurysm embolization using intracranial stents, platelet aggregation increases owing to increased wall shear stress and a loss of vascular endothelial function at the stent implantation site. Preoperative multiple antiplatelet therapy was introduced to prevent severe thromboembolic complications due to increased platelet aggregation. However, specific guidelines for the administration and pharmacological evaluation of this therapy do not exist currently. We examined the benefits of perioperative platelet aggregation monitoring in a cohort of patients. We had 377 patients with unruptured intracranial aneurysms who underwent stent-assisted embolization at our hospital between December 2012 and November 2019. We ultimately included 181 patients in our final analysis. These patients were continuously administered aspirin (100 mg/day) and clopidogrel (75 mg/day) for more than 5 days before the procedure to the post-procedural period. Of these patients, 30 patients who underwent light transmission aggregometry (LTA) before procedure, post-procedure (3 days after procedure), and at first post-discharge clinic visit were included as the subjects. The following characteristics were studied: age; sex; presence/absence of hypertension, dyslipidemia, and/or diabetes mellitus; location of aneurysm; type/number of stent; technique for stent placement; duration of preoperative multiple antiplatelet therapy; perioperative platelet aggregation test results; and postoperative ischemic or hemorrhagic complications. Among these 30 patients, the median duration of antiplatelet therapy prior to the preoperative platelet aggregation measurements was 7 (interquartile range [IQR]: 6-8) days, and post-discharge measurement of LTA was performed at a median period of 27 (IQR: 22-35.5) days after procedure. The preoperative, postoperative, and first post-discharge clinic visit LTA values for adenosine diphosphate (ADP)-induced platelet aggregation were 50% (IQR: 44-54%), 42.5% (IQR: 36-48%), and 36% (IQR: 32-40%), respectively. These results represented gradual decrease in LTA values and a significant difference between the preoperative and post-discharge values. The LTA values for collagen aggregation showed a significant difference evident between the preoperative and post-discharge values; preoperative 38% (IQR: 27-60%), postoperative 42% (IQR: 30-58%), post-discharge 28% (IQR: 20-42%), respectively. We had one thromboembolic complication and one hemorrhagic complication. The results indicated that appropriate platelet aggregation monitoring during multiple antiplatelet therapy prevents thromboembolic complications such as stent thrombosis. However, we also found that many patients demonstrated increased postoperative platelet aggregation inhibitory effects due to the postoperative continuation of the same multiple antiplatelet therapy that was used preoperatively. This study demonstrates that postoperative, continuous, oral antiplatelet therapy induces increased platelet aggregation inhibition effects, which may lead to hemorrhagic complications. Therefore, continued platelet aggregation monitoring after surgery may be important to allow for any necessary alterations to the therapeutic dose and regimen.

Semi-Mechanistic Modeling of HY-021068 Based on Irreversible Inhibition of Thromboxane Synthetase.

Background: HY-021068 [4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate], developed by Hefei Industrial Pharmaceutical Institute Co., Ltd. (Anhui, China), is a potential thromboxane synthetase inhibitor under development as an anti-platelet agent for the treatment of stroke. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the PK of HY-021068 and its platelet aggregation inhibitory effect in beagle dogs. Method: Beagle dogs received single oral administration of 2.5 mg/kg HY-021068 or consecutively oral administration of 5 mg/kg HY-021068 once daily for 7 days. The plasma concentration of HY-021068 and the platelet aggregation rate (PAR) were determined by liquid chromatography tandem-mass spectrometry (LC‐MS/MS) assay and a photometric method, respectively. The PK/PD data was sequentially fitted by Phoenix NLME. The PK/PD parameters of HY-021068 in beagle dogs were estimated by 2.5 and 5 mg/kg dosing on the 1st day, and then used to simulate the PAR of HY-021068 on the 7th day after 5 mg/kg dosing daily. Result: A one-compartment model with saturable Michaelis-Menten elimination was best fitted to the PK of HY-021068. A mechanistic PD model based on irreversible inhibition of thromboxane synthetase was constructed to describe the relationship between plasma concentration of HY-021068 and PAR. Diagnostic plots showed no obvious bias. Visual predictive check confirmed the stability and reliability of the model. Most of PK/PD observed data on the 7th day after 5 mg/kg dosing fell in the 90% prediction interval. Conclusion: We established a semi-mechanistic PK/PD model for characterizing the PK of HY-021068 and its anti-platelet effect in beagle dogs. The model can be used to predict the concentration and PAR under different dosage regimen of HY-021068, and might be served as a reference for dose design in the future clinical studies.

Evaluation of treatment adaptation for low response to ASA in vascular surgery

HintergrundEine verminderte antithrombozytäre Prophylaxe („Low-Response [LR]“/„high on-treatment platelet reactivity [HPR]“) mit Acetylsalicylsäure (ASS) ist mit einem erhöhten Risiko für thrombembolische Ereignisse assoziiert. Die Prävalenz einer Low-Response ist mit ca. 20 % häufig und ein Therapieregime wurde bisher noch nicht etabliert. Das Ziel dieser prospektiven Studie war es, die Effektivität eines Therapieschemas zur Therapieanpassung bei detektierter LR/HPR bei gefäßchirurgischen Patienten zu evaluieren.MethodikInsgesamt wurden 36 gefäßchirurgischen Patienten mit einer antithrombozytären Dauermedikation mit ASS 100 mg/Tag und einer nachgewiesenen ASS-Low-Response (ALR) in die Studie eingeschlossen. Entsprechend dem festgelegten Therapieplan wurde bei diesen Patienten eine Therapieanpassung durchgeführt und eine Kontrollaggregometrie zur Erfolgskontrolle durchgeführt. Das verwendete Therapieschema folgte dem Test-and-treat-Prinzip. Zur Beurteilung der Wirkung von ASS diente die Impedanzaggregometrie mittels Mehrelektrodenaggregometer (Multiplate).ErgebnisseInsgesamt konnten alle 36 Patienten erfolgreich in eine Response überführt werden. Bei 32 (88,89 %) Patienten erfolgte eine Dosiserhöhung auf 300 mg ASS, 2 (5,56 %) Patienten wurden von ASS auf Clopidogrel umgestellt. Bei weiteren 2 (5,56 %) Patienten wurde auf eine orale Antikoagulation mit Phenprocoumon aufgrund anderer Indikationen umgestellt. Blutungskomplikationen oder Nebenwirkungen traten nicht auf.SchlussfolgerungDas gewählte Therapieschema zur Behandlung einer Low-Response erwies sich als effektiv und sicher bei gefäßchirurgischen Patienten. Überwiegend führte eine leitliniengerechte Dosiserhöhung der Prophylaxe von 100 mg auf 300 mg ASS zu einer effektiven Thrombozytenaggregationshemmung in der Aggregometrie.

Effect of acetylsalicylic acid intake on platelet derived microvesicles in healthy subjects

Platelet-derived microvesicles (pMVs) are released from platelets in physiological and pathological conditions and exhibit a wide range of prothrombotic, antithrombotic, proatherogenic, and pro-inflammatory properties. Antiplatelet agents, such as acetylsalicylic acid (ASA), are widely used for the prevention and treatment of vascular diseases, but their impact on pMV release remains poorly understood and contradictory mainly because of discrepancies in the methodology and lack of well-standardized MV assessment protocols. The present study investigated the effects of ASA not only on total pMV release but also on their phenotypes defined using the surface expression of pro-inflammatory (CD40L, CD62P, CD31) and procoagulant (PS, PAC-1) markers in healthy subjects. Fifty healthy volunteers were enrolled in the study and received a daily dose of 150 mg ASA for 3 consecutive days. Circulating pMVs were characterized and quantified before and after the intervention period using flow cytometry. Serum levels of thromboxane B2 (TXB2) and whole blood impedance platelet aggregation under arachidonic acid (AA) stimulation were also investigated to assess ASA compliance. In general, ASA did not effect pMV numbers in healthy subjects despite its effective inhibition of platelet aggregation Moreover, in premenopausal women, we noticed an increase in the number of pMVs. Further studies are needed to assess whether dose modification of ASA or combinations or changes in antiplatelet therapy would reduce pMV formation, especially in patients with cardiovascular risk factors.

Pharmacological Studies Pertaining to Smooth Muscle Relaxant, Platelet Aggregation Inhibitory and Hypotensive Effects of Ailanthus altissima.

Objective This in vitro and in vivo study was conducted to rationalize some of traditional medicinal uses of Ailanthus altissima in gastrointestinal, respiratory, and cardiovascular systems. Materials Crude extract of Ailanthus altissima (Aa.Cr) and its fractions were prepared and utilized in in vitro and in vivo studies. For in vitro studies, Aa.Cr was investigated on isolated rabbit jejunum, isolated tracheal strip, and isolated aorta of rat suspended in tissue organ bath. Platelet rich and platelet poor plasma were used to study platelet aggregation inhibitory activity. In vivo antidiarrheal effect of Aa.Cr was investigated on balb/c mice pretreated with castor oil to induce diarrhea and SD rats were used to study hypotensive activity. Results Concentration dependent spasmolytic effects of Aa.Cr and its DCM fraction (Aa.DCM) were observed on spontaneous and spasmogen induced contractions in jejunum isolated from rabbit, but effect against high potassium (high-K+) induced contractions was more potent. Moreover Aa.Cr showed parallel shifting of calcium response curve to the right side. While its aqueous fraction (Aa.aq) caused spasmogenesis of isolated rabbit jejunum, this effect was blocked partially with prior administration of atropine (1μM). Concentration dependent protection against castor oil induced diarrhea was also observed. Relaxant effect was observed by the application of Aa.Cr and Aa.DCM against high-K+ and carbachol (CCh) induced contractions in tracheal strips isolated from SD rats, while Aa.Aq caused partial relaxation of high-K+ induced contractions, but no effect was observed against CCh induced contractions. Relaxation of rat aorta by the application of Aa.Cr and its fractions was also observed. Inhibition of force of contraction in rabbit atrium was also observed. Inhibition of platelet aggregation was observed against epinephrine and ADP induced aggregation. Conclusion Keeping in view the observed results, it is concluded that smooth muscle relaxant, platelet aggregation inhibitory and hypotensive effect may be due to the blockage of calcium channels.

Rational Design and Synthesis of 1-(Arylideneamino)-4-aryl-1H-imidazole-2-amine Derivatives as Antiplatelet Agents.

Based on previous studies indicating the pharmacophoric role of a hydrazone group and azole rings for antiplatelet aggregation activity, a few series of compounds with both hydrazone and an azole (imidazole) ring in their structures were synthesized, and their platelet aggregation inhibitory effects were evaluated. Two of these 1-(arylideneamino)-4-aryl-1H-imidazole-2-amine derivatives, compounds 4 a [(E)-1-(benzylideneamino)-4-phenyl-1H-imidazol-2-amine] and 4 p [(E)-4-phenyl-1-((thiophen-2-ylmethylene)amino)-1H-imidazol-2-amine], exhibited IC50 values similar to that of acetylsalicylic acid against collagen as a platelet aggregation inducer. Structural comparison of the synthesized compounds revealed that those with a para-substituted phenyl ring on the imidazole were among the most active compounds against platelet aggregation induced by arachidonic acid (AA), and the presence of a thiophene ring in these compounds maximized their antiplatelet activity.

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single‐administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple‐administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2–5. In both studies, the plasma concentration of the active metabolite of prasugrel, R‐138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single‐administration study, the inhibitory effect on adenosine diphosphate–induced platelet aggregation was significantly higher in the prasugrel 20‐ and 30‐mg groups than in the placebo group at all times (1–144 hours) after administration. In the multiple‐administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3–6 days after the last administration. There were study drug‐related adverse events; however, all were mild, and none was clinically significant.

Anti-platelet and anti-thrombogenic effects of shikimic acid in sedentary population.

This ex vivo study was performed to evaluate the anti-platelet and anti-thrombogenic potential of shikimic acid (SA), a plant phenolic metabolite. Fasting blood samples were collected from 22 sedentary participants to analyse the effect of varying concentrations of SA (0.1 mM, 0.2 mM, 0.5 mM, 1 mM and 2 mM) on platelet surface-marker expression, platelet aggregation and biomarkers of thrombogenesis. Monocyte-platelet aggregates (CD14/CD42b) and platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31), effective indicators of thrombus formation were evaluated. Procaspase-activating compound 1 (PAC-1) and P-selectin or CD62P were used to assess platelet activation-related thrombogenesis. Adenosine diphosphate (ADP) was used to stimulate the P2Y1/P2Y12 pathway of platelet activation to mimic the in vivo thrombogenic pathway. Platelet aggregation studies utilised both ADP and collagen as exogenous platelet agonists to target both P2Y1/P2Y12 and GPVI pathways of thrombus formation. It was observed with flow cytometry that SA produced a significant antiplatelet effect on PAC-1 (p = 0.03 at 2 mM) and CD62P (p = 0.017, p = 0.036 at 1 mM and 2 mM respectively) expression in addition to lowering monocyte-platelet aggregate formation (p = 0.013, p < 0.01 and p < 0.01 at 0.5 mM, 1 mM and 2 mM respectively). SA at 1 mM concentration reduced PECAM-1 expression (p = 0.035), signifying a reduction to endothelial leucocyte migration during thrombus growth. SA did not demonstrate a platelet aggregation inhibitory effect by targeting the GPVI collagen pathway but reduced ADP induced platelet aggregation at 2 mM concentration (p < 0.01 at 2 mM). The results suggest that SA, an active metabolite of polyphenol-rich food intake, could play an important role in reducing platelet activation, aggregation related thrombus formation and biomarkers of thrombogenesis in sedentary individuals.

Semi‐Mechanistic Modelling and Simulation of Inhibition of Platelet Aggregation by Antiplatelet Agents

Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi-mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent-metabolite pharmacokinetic model, based on a two-compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: Ks , the active-form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active-form platelets; Kel-PRP , the apparent rate constant of platelets; and ε, an intrinsic activity parameter. This semi-mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half-life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi-mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.

Influence of antiplatelet therapy on postoperative recurrence of chronic subdural hematoma: A multicenter retrospective study in 719 patients

ObjectiveThe present study tested the hypothesis of whether antiplatelet agents (APA) induce chronic subdural hematoma (CSDH) recurrence via a platelet aggregation inhibitory effect. MethodWe examined risk factors for CSDH recurrence, focusing on APA, in 719 consecutive patients who admitted to three tertiary hospitals and underwent burr-hole craniostomy and irrigation for CSDH. This was a multicenter, retrospective, observational study. ResultsAge, sex, history of diabetes mellitus, hypertension, chronic renal failure, alcohol consumption habits, consciousness disturbance on admission, or preoperative CT density was not associated with recurrence. Subdural drainage was significantly associated with less recurrence. Preoperative oral APA administration was significantly associated with more recurrence. The recurrence rate of CSDH in non-APA group was 11% if surgery was performed on admission. However, if surgery was performed immediately after discontinuation of oral APA administration, the recurrence rate in APA group significantly increased to 32% (p value<0.0001; odds ratio, 3.77; 95% confidence interval, 1.72–8.28). The effect of APA on CSDH recurrence gradually diminished as the number of days until initial surgery, after stopping APA, increased. ConclusionAntiplatelet therapy significantly influences the recurrence of CSDH.

Acetylsalicylsäure-Nonresponder nach ischämischem Insult bei geriatrischen Patienten

The cardiovascular and cerebral ischemic risk is defined as the risk of suffering a thromboembolic event. The common secondary prophylaxis is still the use of acetylsalicylic acid (ASA). The usual daily dose is 100 mg. Efficacy concerning platelet aggregation is not routinely checked. In this study, patients taking 100 mg aspirin daily (orally) were examined after admittance to the stroke unit due to a stroke or stroke recurrence. Platelet aggregation was performed using a Platelet Function Analyser (PFA 100). A total of 71 patients were examined, 53(73%) had experienced a primary ischemic insult, and 18(25.4%) stroke recurrence. Patients with prolonged closure time in the collagen/epinephrine cell (normal range 85-165 s) were classified as responders to ASA, while 14 (19.7%) were classified as non-responders. It remains open whether the secondary prophylaxis or a more effective inhibition of platelet aggregation results in the improved protection against a future event.

Hemolytic activity and platelet aggregation inhibitory effect of vipoxin’s basic sPLA2 subunit

In the present study we evaluated the effect of secreted phospholipase A2 (sPLA2) (the toxic subunit of the heterodimeric neurotoxin vipoxin, isolated from the Bulgarian long-nosed viper Vipera ammodytes meridionalis) on hemolysis, erythrocyte morphology and platelet aggregation. Hemolytic activity of sPLA2 was examined in the presence of saturated (palmitic) and unsaturated (oleic) fatty acids and it was found that oleic acid increased the hemolytic activity of sPLA2 in a concentration-dependent manner, compared to the effect of palmitic acid and controls. The addition of heparin to red blood cells (RBC) suspension containing sPLA2 or mixture of sPLA2 and the corresponding fatty acid led to an inhibition of hemolytic activity. The effect of sPLA2 on RBC morphology resulted in formation of echinocytes (spherocyte subtype), suggesting that RBC could be the possible targets attacked by sPLA2. Vipoxin sPLA2 inhibited (in a dose-dependent manner) platelet aggregation when arachidonic acid and collagen were used as inducers, while in the case of ADP its inhibitory effect was inappreciable.

Oral antiplatelet therapy in acute coronary syndromes: recent developments.

The purpose of this article is to summarize the current knowledge about treatment with oral platelet inhibitors in patients with acute coronary syndrome (ACS). Antiplatelet therapy has been shown to improve the prognosis of patients with ACS with ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation ACS (NSTE-ACS). Aspirin should be given with a loading dose of 250–500 mg, followed by 75–100 mg/day. Dual antiplatelet therapy is recommended for all patients with ACS for 12 months regardless of the initial revascularization strategy. Clopidogrel should be administered at first medical contact in STEMI with a loading dose of 600 mg. In patients with ACS and percutaneous coronary intervention (PCI) 2 × 75 mg clopidogrel should be given daily over 7 days, while in all other patients 75 mg per day appears to be sufficient. The two newer adenosine diphosphate-receptor antagonists prasugrel and ticagrelor lead to a more rapid and effective inhibition of platelet aggregation compared with clopidogrel, which was associated with an improved clinical outcome in two large randomized studies. Prasugrel is indicated in patients with ACS undergoing PCI and was most effective in diabetics and in patients with STEMI. In the recent TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial in medically treated patients with NSTE-ACS, prasugrel did not significantly reduce ischemic events compared with clopidogrel. Ticagrelor has been studied in the whole spectrum of ACS patients and reduced cardiovascular and total mortality in comparison with clopidogrel. The greatest benefit has been observed in patients with planned conservative treatment and in patients with impaired renal function. Expanding antiplatelet therapy from dual to triple therapy including a platelet thrombin receptor antagonist in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial was not associated with a significant reduction in the primary combined endpoint but an increase in bleeding complications. However, in the Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events study in patients with prior myocardial infarction, vorapaxar on top of standard antiplatelet therapy was effective.