Utility of VerifyNow to assess the immediate pharmacodynamic response of chewed and swallowed aspirin: comparison with aggregometry.

VerifyNow (VN) test is a less laborious method to assess pharmacodynamics (PD) compared to light transmittance aggregometry (LTA). VN assay has not been used to study the immediate PD effects of acetylsalicylic acid (ASA). Ten healthy volunteers were randomly assigned to a single 162 or 650 mg dose of chewed and swallowed ASA. Pharmacodynamic and pharmacokinetic measurements were performed at baseline and serially up to 60 min after ASA administration. Onset by VN was 20 ± 7 min with 162 mg and 13 ± 7 min with 650 mg ASA (p = .07). Onset by 1 mM AA-induced PA was 13 ± 12 min with 162 mg and 7 ± 3 min with 650 mg ASA (p=NS). VN correlated with AA-induced PA (r = 0.80, p < .001) and serum TxB2 levels (r = 0.76, p < .001). 95% inhibition of serum TxB2 was achieved at 38 ± 22 min and 22 ± 8 min with the 162 and 650 mg ASA, respectively (p = .08). The onset and extent of the antiplatelet effect of 650 mg ASA is numerically faster and greater than the 162 mg dose. VN identifies the onset, extent, and dose response to ASA therapy. The ease of using VN should facilitate multicenter PD investigations of ASA.

Aspirin (acetylsalicylic acid) is an important drug widely used to prevent adverse ischemic events in patients with cardiovascular disease. Platelet aggregation and thromboxane B₂ levels in blood samples by complex laboratory methods are used to assess platelet response to aspirin. VerifyNow assay is a simple laboratory test that has not been used to assess the immediate effect of aspirin. In this study, conducted in 10 healthy volunteers, we compared the immediate platelet response to aspirin by serially assessing platelet aggregation by aggregometry and VerifyNow assay, and thromboxane B₂ levels. We also measured plasma levels of acetylsalicylic acid and salicylic acid. Our study demonstrated that the VerifyNow Aspirin test identifies the onset, extent, and dose-response to aspirin therapy. The ease of using the VerifyNow test should facilitate multicenter pharmacodynamic investigations of aspirin.

A pharmacokinetics interaction study of antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide in rats by liquid chromatography-tandem mass spectrometry.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method has been developed to determine the pharmacokinetic interactions of the antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide. For the determination of aspirin metabolite salicylic acid, clopidogrel inactive metabolite SR26334 and NBP prototype drug in rat plasma, plasma samples were prepared by precipitation of proteins using methanol containing 0.1% formic acid, followed by centrifugation. Chromatography was performed on a C18 column, eluting with a gradient of acetonitrile (with 0.1% formic acid)-water (with 0.1% formic acid). The detection adopted electrospray ion source and positive ion multiple reaction monitoring modes. The linear detection response range of salicylic acid is 80-80,000 ng/ml, and the linear detection response range of SR26334 and dl-3-n-butylphthalide is 10-10,000 ng/ml. Our study revealed that dl-3-n-butylphthalide affected the pharmacokinetics of aspirin and clopidogrel when administered to rats.

Decreased plasma exposure of clopidogrel active metabolite in rats after long-term treatment with clopidogrel.

Clopidogrel (Clop) is oxidized by cytochrome P450s (CYPs) to an active thiol metabolite, Clop-AM, to inhibit platelet activation and aggregation. As an irreversible inhibitor of CYP2B6 and CYP2C19, clopidogrel may inhibit its own metabolism after long-term administration. The study compared the pharmacokinetic profiles of clopidogrel and its metabolites in rats receiving a single or a 2 week administration of Clop. The mRNA and protein levels of hepatic clopidogrel-metabolizing enzymes and their enzymatic activities were analyzed to explore their contribution to any altered plasma exposure of Clop and its metabolites. The results showed that long-term treatment with clopidogrel significantly decreased the AUC(0-t) and Cmax values of Clop-AM in rats, accompanied with markedly impaired catalytic activities of Clop-metabolizing CYPs including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. It suggests that consecutive administration of Clop to rats decreases hepatic CYPs activities, which may, in turn, inhibit clopidogrel metabolism and then reduce Clop-AM plasma exposure. Therefore, long-term treatment with clopidogrel has the potential to reduce its anti-platelet activity and to increase the risk of drug-drug interaction.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of Prasugrel in Healthy Male Volunteers.

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60 mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel.

Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective, randomized, crossover study.

Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p < 0.0001), with almost double the Cmax (720 vs. 368 ng/mL, p < 0.0001) and overall 44% higher exposure of acetylsalicylic acid (AUC0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values < 0.05). PL-ASA resulted in faster and more complete aspirin absorption paralleled by more prompt and potent platelet inhibition compared with EC-ASA after a single 81 mg dose. PL-ASA represents an attractive novel aspirin formulation for the secondary prevention of cardiovascular events.Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.

Interaction study of salvianolic acids for injection on pharmacokinetics of clopidogrel in rats using LC-MS/MS.

Salvianolic acids for injection (SAI) is developed from traditional Chinese medicine and approved for the treatment of cardiovascular and cerebrovascular diseases. Clopidogrel is an inhibitor of platelet aggregation, which is often prescribed for patients in combination with SAI. This present study aimed to assess the effects of SAI on the pharmacogenomics, pharmacokinetics, and pharmacodynamics of clopidogrel, thereby ensuring the safety and efficacy of coadministration. In vitro cytochrome P450 isoenzyme assays were performed in human liver microsomes using LC-MS/MS method to assess the metabolites of CYPs substrates. The effects of SAI on the pharmacokinetic and pharmacodynamic behaviors of clopidogrel were investigated in rats. The main pharmacokinetic parameters were analyzed using LC-MS/MS. Prothrombin time, activated partial thromboplastin time, bleeding time, and inhibition of platelet aggregation were measured to evaluate the effects of pharmacodynamics. Our study revealed that the clinical dose of SAI has no significant inhibitory effect on clopidogrel-related liver microsome metabolic CYP450 isoenzymes. Moreover, SAI did not affect the pharmacokinetics of clopidogrel when rats were administered both single and multiple doses. In pharmacodynamic study, SAI has no effect on platelet aggregation rate, prothrombin time, and activated partial thromboplastin time of clopidogrel but could significantly prevent the risk of bleeding caused by clopidogrel.

Ticagrelor.

Ticagrelor is one of the most recent antiplatelet agents used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It belongs to the non-thienopyridine class. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is usually used for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. This chapter include an overview on the physical properties, chemical properties, mode of action, pharmacokinetics and common uses of ticagrelor. In addition, the reported methods of ticagrelor assay will be discussed briefly in order to help analysts to find the most convenient method for its estimation in routine analysis. The methods of synthesis used for the preparation of ticagrelor will also be covered in this chapter. Moreover, the analytical and characterization techniques used to characterize ticagrelor row material are summarized herein.

Gut microbiota induces high platelet response in patients with ST segment elevation myocardial infarction after ticagrelor treatment.

Background: Ticagrelor is a first-line drug for the treatment of acute ST elevation myocardial infarction (STEMI). However, approximately 20% STEMI patients taking ticagrelor exhibited a delayed response and the mechanism was still unclear. Methods: To explore the mechanism of the poor response of ticagrelor in post-percutaneous coronary intervention (PCI) patients, we enrolled 65 high platelet reactivity (HPR) patients and 90 controls (normal platelet reactivity [NPR]). Pharmacokinetic assessment result showed that the plasma concentrations of ticagrelor and its metabolism production, AR-C124910XX, were lower in HPR patients than controls. Further single nucloetide polymorphism (SNP) analysis identified that there is no difference in ATP binding cassette subfamily B member 1 (ABCB1) gene expression between the NPR group and the HPR group. Metagenomic and metabolomic analyses of fecal samples showed that HPR patients had higher microbial richness and diversity. Transplantation of the gut microbiota from HPR donors to microbiota-depleted mice obviously decreased plasma concentration of ticagrelor. Results: Our findings highlight that gut microbiota dysbiosis may be an important mechanism for the ticagrelor of HPR in patients with STEMI and support that modify gut microbiota is a potential therapeutic option for STEMI. Conclusions: Our findings highlight that gut microbiota dysbiosis may be an important mechanism for the ticagrelor of HPR in patients with ST elevation myocardial infarction (STEMI) and support that modify gut microbiota is a potential therapeutic option for STEMI. Funding: NSFC 82170297 and 82070300 from the National Natural Science Foundation of China.

Dosage optimization of clopidogrel via a precision medicine approach: the way forward.

Clopidogrel is a prodrug chiefly metabolized by the hepatic isoenzyme CYP2C19 to its active metabolite that inhibits the platelet aggregation. It has been proven in many populations that the genetic polymorphism of CYP2C19 has influence on the pharmacokinetic and or pharmacodynamics of this drug and resulting in high inter-individual variability in the treatment outcomes. As CYP2C19 genetic polymorphism is highly prevalent among the Asian population, the influence of the same on the pharmacokinetics and; thereby, the pharmacodynamics of clopidogrel needs more attention. Using the pharmacogenetic information for drug therapy could help overcome these issues and to optimize the dosage regimen of clopidogrel, this review advocates the precision medicine approach for reducing the clopidogrel resistance and adverse cardiovascular events.

Effects of the CYP2C19 LoF allele on major adverse cardiovascular events associated with clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis.

The aggregated risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients inheriting CYP2C19 loss-of function (LoF) alleles who underwent percutaneous coronary intervention (PCI) and were treated with clopidogrel is controversial. In the current study, we searched the literature in different databases for eligible studies. The risk ratio (RR) was measured where p<0.05 was statistically significant. The ACS patients with either one or two CYP2C19 LoF alleles who underwent PCI, treated with clopidogrel were correlated with a significantly escalated risk of MACE compared with noncarriers (RR: 1.53, 95% CI: 1.39-1.69, p < 0.00001), driven by CV death (RR: 1.88, 95% CI: 1.18-3.01, p = 0.008), MI (RR: 1.67, 95% CI: 1.21-2.31, p = 0.002) and ST (RR: 1.90, 95% CI: 1.27-2.84, p = 0.002). Patients with two CYP2C19 LoF alleles were correlated with significantly greater risk of MACE compared with noncarriers (RR: 3.91, 95% CI: 2.78-5.50, p < 0.00001). Further analysis revealed that the risk of MACE was markedly significant in Asian patients (RR: 2.02, 95% CI: 1.67-2.44, p < 0.00001) and was comparatively low significance in western patients (RR: 1.35, 95% CI: 1.20-1.52, p < 0.00001). There was no significantly different bleeding events in patients with CYP2C19 LoF alleles compared with noncarriers (RR: 0.99, 95% CI: 0.85-1.15, p = 0.87). The ACS patients inheriting CYP2C19 LoF alleles, who underwent PCI and were treated with clopidogrel were correlated with significantly increased risk of MACE compared with noncarriers.

Solid self nano-emulsifying system for the enhancement of dissolution and bioavailability of Prasugrel HCl: in vitro and in vivo studies.

Prasugrel Hydrochloride (PHCl) is an antiplatelet drug. It is a class II drug with variable bioavailability. The objective of this work was to enhance the solubility and hence the bioavailability and efficacy of PHCl. A Self Nano-Emulsifying Drug Delivery System (SNEDDS) was prepared using Kolliphor El, Maisine 35-1, and Transcutol P as surfactant, oil, and co-surfactant, respectively in a ratio 10:72:18 v/v%. The SNEDDS was converted into solid by adsorption onto Neusilin. In vitro release of the drug from SNEDDS in (pH = 4) at 37 °C and 75 rpm for 45 min was studied. The results were compared to those from the unprocessed PHCl and Lexar® (the commercial drug). In-vivo studies (platelet Aggregation and bleeding time) were conducted using rats as animal models. It was found that the particle size of the SNEDDS ranged between 80 and 155 nm and EE% was in the range of 90.2% ± 0.4. The release from SNEDDS was about 84% compared to around 25% from unprocessed PHCl and 65% from Lexar® after 15 min. The platelet aggregation of the formula was lower than the PHCl, and Lexar® indicating higher bioavailability. In conclusion, SNEDDS with high EE% was prepared and was successful in enhancing the solubility, dissolution rate, and the bioavailability.

Ticagrelor and prasugrel in acute coronary syndrome: a single-arm crossover platelet reactivity study.

AIM: To compare the degree of platelet inhibition between ticagrelor and prasugrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. METHODS: Platelet function was assessed by impedance aggregometry after 30-90 days of therapy with acetylsalicylic acid and ticagrelor and over 15 days after switching to prasugrel. High-on-treatment platelet reactivity (HRPR) was defined for ADP test results above the upper limit of normal. RESULTS: A total of 105 patients were included, 81.9% males and 33.3% people with diabetes, with a mean age of 60.8 ±â€Š8.1 years. Mean platelet reactivity was not significantly different between the two antiplatelet strategies, as the prevalence of HRPR (8.6 vs 12.3%, P = 0.50). Switching between the two antiplatelet agents was safe and well tolerated, and effectively reduced platelet reactivity in over 95% of the patients (only 3.8% of the study population displaying ineffective response to both drugs). CONCLUSION: Ticagrelor and prasugrel have a similar effect on platelet reactivity. Switching between the two drugs can be safely done.

Oral aspirin or low dose of intravenous lysine acetylsalicylate in ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

AIM: To compare the pharmacodynamic effect of an oral loading dose of 'noncoated' ASA 300 mg vs. an intravenous bolus injection of lysine acetylsalicylate 150 mg in patients with STEMI undergoing pPCI. METHODS: This was a prospective single-center, open label, pharmacodynamic study, including nonconsecutive patients presenting at our catheterization laboratory with STEMI undergoing pPCI and not receiving ASA within the previous 7 days. Pharmacodynamic analyses were performed at five time points: baseline, and 1, 2, 4 and 12 h after the loading dose, and measured as ASA reaction units (ARU) by the Verify Now System. An ARU more than 550 was considered as nonresponsiveness to study drugs. The primary end point was the different rate of patients with ARU more than 550 at 2 h after the loading dose of oral vs. intravenous ASA. Secondary end points included the comparison of ARU more than 550 at the other time points and the comparison of continuous ARU at each time point. RESULTS: The study was planned with a sample size of 68 patients, but it was prematurely stopped due to slow enrollment after the inclusion of 23 patients, 12 randomized to oral ASA and 11 to intravenous lysine acetylsalicylate. At 2 h the rate of patients with ARU more than 550 was numerically but not significantly higher in patients receiving oral ASA as compared with intravenous lysine acetylsalicylate (33 vs. 14.2%; Δ -0.19, 95% confidence interval -0.59-0.21, P = 0.58). The difference over time was NS (P = 0.98), though the prevalence of ARU more than 550 was higher at the other time points. Both routes of administration reduced ARU values over time, though with no overall significant difference between profiles (P overall = 0.48). CONCLUSION: In patients with STEMI undergoing pPCI the rate of nonresponsiveness to ASA was not different comparing an oral 'noncoated' loading dose of ASA with an intravenous bolus injection of lysine acetylsalicylate. However, as patient enrollment was prematurely terminated, this study is underpowered to draw a definite conclusion.

Safety and Functional Pharmacokinetic Profile of APAC, a Novel Intravascular Antiplatelet and Anticoagulant.

ABSTRACT: Vascular intervention-induced platelet and coagulation activation is often managed with a combination of antiplatelets and anticoagulants, with evident benefits, but with a risk of systemic bleeding. Antiplatelet and anticoagulant (APAC) is a dual antiplatelet and anticoagulant heparin bioconjugate, which targets vascular injury sites to act as a local antithrombotic. We assessed the nonclinical safety and exposure of intravenously infused APAC in rats and cynomolgus monkeys by using single-day and 14-day repeat dose toxicology and pharmacodynamic markers. Activated partial thromboplastin time (APTT) was used as a functional surrogate of anticoagulant exposure of APAC. Routine clinical in-life observations were followed by clinical pathology and necropsy. The no-observed-adverse-effect level (NOAEL) in rats for the single APAC dose was 20 mg/kg and for the repeated administration was 10 mg/kg/d. Monkeys tolerated a single APAC dose of 10 mg/kg, although the red blood cell count reduced 16%-19% correlating with tissue hemorrhage at vein puncture and affected muscle sites during handling of the animals. However, after 2-week recovery, all clinical signs were normal. The single dose NOAEL exceeded 3 mg/kg. The repeat administration of 3-6 mg/kg/d of APAC was tolerated, but some clinical signs were observed. The NOAEL for repeated dosing was 0.5 mg/kg/d. APAC prolonged APTT dose-dependently in both species, returning to baseline after 1.5 (<10 mg/kg) or essentially by 6 hours also under repetitive dosing. The toxicology profile supports the safety of an intravenous APAC dose of 0.5 mg/kg/d for possible clinical applications. APTT is an acceptable indicator of the immediate systemic anticoagulation effect of APAC.

Systematic Review and Meta-analysis: The Effects of Prophylactic Proton Pump Inhibitor Treatment in Patients With Coronary Heart Disease Receiving Dual Antiplatelet Therapy.

Dual antiplatelet therapy (DAPT) and proton pump inhibitors (PPIs) are widely used in clinical treatment. However, the pharmacokinetic interaction between PPIs and DAPT is still unclear in patients with cardiovascular disease. This systematic review and meta-analysis aimed to evaluate the risks and benefits of the combination of PPI and DAPT in patients with coronary heart disease. The PubMed, EMBASE, Cochrane, and Web of Science databases were systematically searched from inception to April 1, 2020, for eligible studies. The outcomes investigated in this study included major adverse cardiovascular events, myocardial infarction, all-cause death, gastrointestinal complications, and platelet function testing. Studies were excluded from the review if other gastrointestinal medication or aspirin or P2Y12 receptor inhibitor monotherapy was administered. The review included 52 studies, and data from 40 studies were extracted for meta-analysis. No association was found between the risk of adverse clinical outcomes and the combination of PPI and DAPT based on the randomized controlled trial data (risk ratio: 0.98; 95% confidence interval: 0.87-1.09; P = 0.877; I2 = 0%). However, an increased risk of adverse clinical outcomes due to the use of PPIs was observed in patients treated with DAPT based on the data from observational studies (risk ratio: 1.259; 95% confidence interval: 1.079-1.468; P = 0.003; I2 = 67.8%), although the heterogeneity of these studies was high. In conclusion, this systematic review and meta-analysis demonstrated that pharmacokinetic interactions between PPI and DAPT do not lead to adverse clinical outcomes.

Multidrug Resistance Protein 4 (MRP4/ABCC4): A Suspected Efflux Transporter for Human's Platelet Activation.

The main role of platelets is to contribute to hemostasis. However, under pathophysiological conditions, platelet activation may lead to thrombotic events of cardiovascular diseases. Thus, anti-thrombotic treatment is important in patients with cardiovascular disease. This review focuses on a platelet receptor, a transmembrane protein, the Multidrug Resistance Protein 4, MRP4, which contributes to platelet activation, by extruding endogenous molecules responsible for their activation and accumulation. The regulation of the intracellular concentration levels of these molecules by MRP4 turned to make the protein suspicious and at the same time an interesting regulatory factor of platelet normal function. Especially, the possible role of MRP4 in the excretion of xenobiotic and antiplatelet drugs such as aspirin is discussed, thus imparting platelet aspirin tolerance and correlating the protein with the ineffectiveness of aspirin antiplatelet therapy. Based on the above, this review finally underlines that the development of a highly selective and targeted strategy for platelet MRP4 inhibition will also lead to inhibition of platelet activation and accumulation.

Development of an LC-MS/MS method for simultaneous quantitative analysis of macromolecular pharmaceutical adjuvant 2-hydroxypropyl-ß-cyclodextrin and active pharmaceutical ingredients butylphthalide in rat plasma.

Hydroxypropyl-ß-cyclodextrin, which possesses a high water solubility and low hemolycity, is widely used as a solubilizer and an excipient. It had also been reported that hydroxypropyl-ß-cyclodextrin has the activity of regulating lipid homeostasis. In order to further understand the metabolism, the primary focus was to establish a quantitative method for hydroxypropyl-ß-cyclodextrin. The analytes were extracted from plasma by protein precipitation with methanol and then carried out on a Waters CORTECS T3 column in the gradient elution of pure water and methanol. Finally, liquid chromatography-tandem mass spectrometry was applied in multiple reaction monitoring mode to complete the quantitative analysis of hydroxypropyl-ß-cyclodextrin. This validated method had been successfully applied to investigate the interaction between hydroxypropyl-ß-cyclodextrin and butylphthalide in vivo by optimizing the extraction reagent, simplifying the experimental procedure, and improving the sensitivity while considering the difference of drug chemical properties. Results showed that the inclusion of hydroxypropyl-ß-cyclodextrin with butylphthalide significantly improved the pharmacokinetic behavior of free body hydroxypropyl-ß-cyclodextrin and 3-n-butylphthalide in vivo. It had been implied that the metabolism of hydroxypropyl-ß-cyclodextrin and the drug active ingredients could impact each other. It will help better application of hydroxypropyl-ß-cyclodextrin and the developed method might lay the foundation for development of hydroxypropyl-ß-cyclodextrin as a treatment drug for brain diseases.

Pharmacokinetics and safety of ticagrelor in infants and toddlers with sickle cell disease aged <24 months.

Inhibition of platelet activation may reduce vaso-occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR-C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD.