Analytical methodologies for the determination of ticagrelor

Bao B., Zheng C., Yu S., Shan C., Cheng F., Zhang L.

N1 N2 bond in molecules containing 1, 2, 3-triazoles framework is weakened and readily cleaved when N1 is attached to a strong electron-withdrawing group. However, ticagrelor, a pyrimidine-fused triazole without a strong electron-withdrawing group on N1 site still went through isomerization reaction via N1 N2 bond rupture in the presence of acid to produce an impurity T3. Its structure was precisely obtained via NMR spectral analysis, MS spectroscopy and X-ray crystallography. The optimal condition of the isomerization reaction was systematically studied. Moreover, the isomerization mechanism was investigated and it is likely that ticagrelor and its analogues go through isomerization reaction when the 4-NH group and electron-deficiency ring exist in their structures. Besides, the steric hindrance of the substituent on 4-NH has an effect on the reactivity of equilibrium. Under mimic in vivo condition, the isomerization reaction of ticagrelor also generated, indicating ticagrelor may be not stable in stomach.

Willeman T., Marlu R., Böhle H., Francony G., Jourdil J., Fonrose X., Stanke-Labesque F.

Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented.A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition.To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

Wingert N.R., Ellwanger J.B., Bueno L.M., Gobetti C., Garcia C.V., Steppe M., Schapoval E.E.

Simultaneous analysis of drug compounds and their impurities of degradation and synthesis became constant in the modern pharmaceutical analysis. Likewise, analytical techniques must improve sensitivity and selectivity for the monitoring of pharmaceutical products, allowing a full assessment of impurities in drug products and, therefore, ensure safety and efficacy of pharmacological treatments. The application of Quality by Design (QbD) principles has proved to be feasible on the elaboration of analytical methods, allowing the comprehensive evaluation and measurement of different analytical parameters and their effects on critical properties of the methodology in development. QbD approach was applied to the development of a fast and selective HPLC method for the analysis of the antiplatelet aggregation drug ticagrelor and its degradation products in presence of three impurities of synthesis. Fractional factorial resolution V was the screening experimental design applied to five method parameters. Response surface methodology was carried by central composite star face design on the two critical method parameters selected. Analytical design space, established after the application of Monte-Carlo simulations, verified whether predicted results were in accordance with critical quality attributes. The developed and validated HPLC method with DAD detection at 225 nm was able to resolve eight related compounds in less than three minutes.

Danielak D., Karaźniewicz-Łada M., Główka F.

Ticagrelor is a first drug of a new chemical class cyclopentyltriazolopyrimidines. It is an antiplatelet agent with a unique mechanism of action, allowing a direct and reversible competitive inhibition of P2Y12 receptor. According to newest guidelines, it is recommended for prevention of thrombotic events in patients with acute coronary syndromes. Moreover, it is preferred over clopidogrel, an older generation antiplatelet drug, and therefore gains more interest in modern cardiology and vascular medicine.This review is a comprehensive and thorough summary of the most important findings on ticagrelor. Pharmacokinetics, pharmacogenetics, drug-drug interactions, adverse effects, efficacy in specific patient populations and off-label properties of ticagrelor are discussed in this paper. Moreover, the results from pivotal clinical trials are presented.Introduction of ticagrelor, a first directly-acting and reversible P2Y12 inhibitor, gave some new possibilities as the efficacy of older drugs was often insufficient. Despite some drawbacks, such as a risk of bleeding events or dyspnea, a rapid onset of action, consistency in the antiplatelet effect and reports on pleiotropic properties make this drug a promising candidate for a first-choice antiplatelet agent in patients with acute coronary events.

Kakde R.B., Satone D.D., Dongare G., Chilbule R., Malkhede Y.

Sadou Yayé H., Rietveld I.B., Barrio M., Secrétan P., Faucheron A., Karoui M., Tilleul P., Yagoubi N., Do B.

The mainstay treatment for patients with acute coronary syndrome is an oral route dual antiplatelet therapy with a P2Y12-receptor antagonist and Aspirin (ASA). To improve patient adherence to such treatments, combination therapies (polypill) are envisioned. Physicochemical solid-state studies have been carried out to develop a preformulation strategy of ASA with the P2Y12-receptor antagonist Ticagrelor (TIC). The investigations were carried out using differential scanning calorimetry, liquid chromatography-high resolution-multistage mass spectrometry (LC-HR-MSn) and as complementary techniques Fourier transform infrared measurements and thermogravimetric analysis. A simple eutectic transition at 98°C with a mole fraction for the eutectic liquid of 0.457 has been observed and the mixing of ASA and TIC molecules in each other's crystal structures appears to be limited. No cocrystals of TIC and ASA have been found. The appearance of the eutectic liquid was linked with a clear onset of chemical instability of the two pharmaceuticals. The decomposition mechanism in the liquid phase involves prior decomposition of ASA, whose residues react with well-identified TIC interaction sites. Seven interaction products were observed by LC-HR-MSn linked to corresponding degradation products. The most important degradation pathway is N-dealkylation. In conclusion, polypills of ASA and TIC are a viable approach, but the decomposition of ASA should be avoided by eliminating high temperatures and high humidity.

Tabassum K., Sarvesh R.

Objective: The present study was conducted to develop a simple and precise analytical method for the estimation of ticagrelor in tablet formulation.Methods: Reverse Phase HPLC was used for method development and validation studies of ticagrelor. The optimum chromatographic conditions comprised of C18 column (Kromasil, 250×4.6 mm, 5 µ) as the stationary phase and aqueous buffer (containing 0.5 ml formic acid and triethylamine each in water) and acetonitrile in the ratio of 50:50 v/v as the mobile phase. The flow rate was 1.3 ml/min with detection at 256 nm and a run time of 6 min. Forced degradation studies were conducted and the isocratic mode was modified to a gradient mode to make the method stability indicating in nature.Results: The retention time of ticagrelor was 3.372 min. The linearity studies indicated that the range of the developed method was 20-90 ppm with a correlation coefficient of 0.9956. The method was specific with a percent mean recovery was found to be 99.93%.. The % RSD in the precision studies was 0.069. The validated method was applied to conduct the assay of ticagrelor in tablets and the with a percent mean recovery of 99.82%. The modified method was capable of resolving 13 related substances from the ticagrelor peak in the forced degradation studies.Conclusion: The developed and validated RP-HPLC isocratic method was simple, accurate and precise as per the ICH guidelines. It was suitable for the analysis of ticagrelor in bulk and tablet formulation. The modified gradient method can be used to resolve the in-process impurities and related substances and can be directly applied to liquid chromatography hyphenated with mass spectroscopy (LC/MS) studies with minor modifications for identification of related substances.

Peng J., Wang Y., Li M., He C., Chen Y., Chen X., Ouyang D., Huang Y., Tan Z.

Bueno L.M., Manoel J.W., Giordani C.F., Mendez A.S., Volpato N.M., Schapoval E.E., Steppe M., Garcia C.V.

A simple, fast and sensitive analytical method by high-performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of ticagrelor and two synthesis impurities. The HPLC method was established using an Agilent 1200 Series equipment coupled to photodiode array detector (PDA) at 270nm with a Zorbax Plus C8 column (150×4.6mm, 5.0μm), injection volume of 20μL, and a constant temperature of 25°C. The mobile phase consisted of acetonitrile: ammonium acetate 50mM (57:43, v/v) and pH adjusted to 8.2 with ammonium hydroxide 6M, at a flow rate of 0.7mL/min. No interference peaks from excipients and diluent system indicated the specificity of the method. The calibration curves showed determination coefficients (r2)>0.99, calculated by linear regression. The limit of quantitation (LOQ) for impurities 1 and 2 were 2.0 and 0.2μg/mL, respectively. Intra and interday relative standard deviations (RSDs) were

Oliveira S.S., da Silva Bitencourt A., Gobetti C., Loureiro Mendez A.S., Garcia C.V.

Zhong W., Wang X., Tang L., Mai L., Chen X., He G., Zheng Z., Zhong S.

We have developed and validated a rapid, selective and sensitive method using high-performance liquid chromatography-tandem mass spectrometry (MS) for the quantification of ticagrelor and all of its as-yet-identified metabolites in human plasma and urine. For the analysis of ticagrelor, its metabolites and the internal standard (IS) plasma samples were processed by liquid-liquid extraction using ethyl acetate and urine was processed by protein precipitation. Separations were performed on an Ultimate XB-C18 column (2.1 mm × 150 mm, 3 μm), using aqueous ammonium acetate (0.025 mM)/acetonitrile (35 : 65, v:v) as the mobile phase. Ticagrelor and all 11 metabolites were eluted within 4.5 min. Quantification was performed using electrospray ionization, operating in negative ion mode. The ticagrelor and metabolite M8 (AR-C124910XX) responses were optimized at the m/z 521.2 → 361.2 and m/z 477.2 → 361.1 transitions, respectively. The assay was validated over the linear range of 0.5-2,000 ng/mL for ticagrelor and M8. The intra- and inter-assay precisions were ≤14.6% for ticagrelor and ≤14.7% for M8, respectively. The matrix effects of plasma and urine were in the range of 98.3-110.7% for ticagrelor and 102.1-112.3% for M8. The relative quantification of other metabolites was performed by assessing the ratio of metabolite to IS peaks. The newly developed method was successfully used in a pharmacokinetic study characterizing ticagrelor metabolism in human volunteers.

Kumar N., Devineni S.R., Gajjala P.R., Gupta D.K., Bhat S., Kumar R., Dubey S.K., Kumar P.

Five process-related impurities were detected in the range of 0.08-0.22% in ticagrelor laboratory batches by HPLC and LC-MS methods. These impurities were named as TIC Imp-I, -II, -III, -IV and -V. Four of these impurities, TIC Imp-I to -IV were unknown and have not been reported previously. Based on LC-ESI/MS(n) study, the chemical structures of new impurities were presumed as (1S,2S,3S,5S)-3-(2-hydroxyethoxy)-5-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)cyclopentane-1,2-diol (TIC Imp-I), (1S,2S,3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-II), (1S,2R,3S,4S)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (TIC Imp-III) and (3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-IV). The unknown impurities were isolated from enriched crude sample by column chromatography and preparative HPLC. The complete spectral analysis, MS, 1D NMR ((1)H, (13)C and DEPT), 2D NMR (HSQC and HMBC) and IR confirmed the proposed chemical structures of impurities. Identification, isolation, structural characterization, prospects for the formation of impurities and their synthesis were first reported in this paper.

Teng R.

Despite advancements in treatments for acute coronary syndromes over the last 10 years, they continue to be life-threatening disorders. Currently, the standard of treatment includes dual antiplatelet therapy consisting of aspirin plus a P2Y12 receptor antagonist. The thienopyridine class of P2Y12 receptor antagonists, clopidogrel and prasugrel, have demonstrated efficacy. However, their use is associated with several limitations, including the need for metabolic activation and irreversible P2Y12 receptor binding causing prolonged recovery of platelet function. In addition, response to clopidogrel is variable and efficacy is reduced in patients with certain genotypes. Although prasugrel is a more consistent inhibitor of platelet aggregation than clopidogrel, it is associated with an increased risk of life-threatening and fatal bleeding. Ticagrelor is an oral antiplatelet agent of the cyclopentyltriazolopyrimidine class and also acts through the P2Y12 receptor. In contrast to clopidogrel and prasugrel, ticagrelor does not require metabolic activation and binds rapidly and reversibly to the P2Y12 receptor. In light of new data, this review provides an update on the pharmacokinetic, pharmacodynamic and pharmacogenetic profiles of ticagrelor in different study populations. Recent studies report that no dose adjustment for ticagrelor is required on the basis of age, gender, ethnicity, severe renal impairment or mild hepatic impairment. The non-P2Y12 actions of ticagrelor are reviewed, showing indirect positive effects on cellular adenosine concentration and biological activity, by inhibition of equilibrative nucleoside transporter-1 independently of the P2Y12 receptor. CYP2C19 and ABCB1 genotypes do not appear to influence ticagrelor pharmacodynamics. A summary of drug interactions is also presented.

Jeon H., Kim M., Choi H., Kim Y., Kim E., Kim A., Park H., Bae K., Lim H.

A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers.Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 μmol/L of adenosine diphosphate.Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs.Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268.

Dhillon S.

Ticagrelor (Brilique™, Brilinta®), a cyclopentyl-triazolopyrimidine, is an orally active, reversible, and selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with acute coronary syndromes (ACS). Ticagrelor has a faster onset of action and provides greater inhibition of platelet aggregation than clopidogrel. In the large well-designed, PLATO study in adult patients with ACS, 12 months’ treatment with ticagrelor was more effective than clopidogrel in reducing the incidence of the primary composite endpoint of myocardial infarction, stroke, or cardiovascular (CV) death. Ticagrelor also reduced all-cause mortality relative to clopidogrel, although statistical significance of this was not confirmed in hierarchical testing. Benefit with ticagrelor was seen both in invasively and noninvasively managed patients. Ticagrelor was generally well tolerated and was not associated with an increased risk of major bleeding relative to clopidogrel. However, the incidences of non-coronary artery bypass grafting (CABG)-related bleeding, and major or minor bleeding, as well as some non-hemorrhagic adverse events, including dyspnea (usually of mild or moderate severity) and ventricular pauses (largely asymptomatic) were higher with ticagrelor. In addition, the ATLANTIC study showed that although pre-hospital administration of ticagrelor did not improve pre-percutaneous coronary intervention (PCI) coronary reperfusion in ACS patients relative to in-hospital administration, ticagrelor was safe in both instances, with no significant between-group differences in non-CABG-related major and minor bleeding events. Although further comparative studies with other antiplatelet agents, including prasugrel, are required to position it more definitively, current evidence indicates that ticagrelor is a useful option for the prevention of thrombotic CV events in ACS patients managed invasively or noninvasively.

Sarti C., Sforzi L., Martellini T., Cincinelli A.

The persistence of brominated flame retardants (BFRs) in the environment and the associated toxicological risks have made the development of efficient and rapid detection methods increasingly urgent. Despite regulatory mitigation action in many countries, BFRs such as polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBPA) continue to threaten ecosystems due to their resistance to degradation. BFRs persist in air, water, soil, and sediments, and bioaccumulate in the food chain, leading to prolonged exposure risks for both humans and wildlife. Additionally, in regions with less stringent regulations, products containing BFRs are still being manufactured, posing a challenge for customs agencies responsible for regulating imports. This scenario underscores the urgent need for rapid, sensitive, and cost-effective methods to monitor BFRs in commercial products and environmental matrices. Biosensors present a promising solution, offering rapid detection and screening of BFR contamination at trace levels. Their ability to provide accurate, real-time data makes them invaluable for environmental monitoring, product safety, and regulatory compliance. This review explores the recent advancements in biosensor technology for BFR detection, highlighting their potential for improving environmental and human health protection but also underlining the specific areas that require further research.

Wang J., Shi X., Chen L., Li T., Wu C., Hu M.

Aim/Background Acute coronary syndrome (ACS), a condition characterized by acute cardiac ischemia, is among the major causes of death from cardiovascular diseases (CVD). However, whether there is a correlation between platelet reactivity and major adverse cardiovascular events (MACE) remains debatable, and whether platelet function tests should be tailored for ACS patients after percutaneous coronary intervention (PCI) is still under discussion. This study aims to investigate the relationship between platelet reactivity and the occurrence of MACE in ACS patients post-PCI and to discuss the implications of these findings. Methods Clinical studies on ‘PCI, ACS, dual antiplatelet therapy (DAPT), platelet reactivity, major adverse cardiovascular events (MACE)’ up to 31 October 2023, were systematically collected from Embase, PubMed, and the Cochrane Library. Twelve articles meeting predefined criteria were selected. Meta-analysis was performed using Review Manager 5.4 (Cochrane, London, UK) and Stata 15.0 (StataCorp LLC, College Station, TX, USA) to compute pooled effect sizes, assess heterogeneity, explore sources of heterogeneity, and evaluate publication bias. Results Twelve articles consisting of 9297 patients were included. The meta-analysis showed that ACS patients with high platelet reactivity (HPR) who received PCI and used DAPT for 1–2 years had a greater risk of MACE (risk ratio (RR) = 1.79, 95% confidence interval (CI): 1.30–2.46) compared to those with low platelet reactivity. Moreover, greater platelet reactivity was associated independently with all-cause mortality (RR = 2.26, 95% CI: 1.63–3.12), cardiac mortality (RR = 2.87, 95% CI: 2.16–3.8), myocardial infarction (RR = 1.98, 95% CI: 1.53–2.5), in-stent restenosis (RR = 1.87, 95% CI: 1.22–2.87), as well as stroke (RR = 1.62, 95% CI: 1.02–2.57), but not with coronary revascularization events (RR = 0.99, p = 0.96, 95% CI: 0.80–1.24). On the other hand, meta-regression revealed that region (p = 0.99), type of ACS patient (p = 0.16), drug regimen (p = 0.48), testing method (p = 0.51), sampling time (p = 0.70), follow-up time (p = 0.45), and PCI protocol (p = 0.27) were not sources of heterogeneity in the study. Conclusion The meta-analysis outcomes indicate that in ACS patients receiving PCI and using dual antiplatelet therapy for 1–2 years, HPR was independently positively correlated with major adverse cardiovascular events, all-cause (or cardiac) mortality, recurrent myocardial infarction, in-stent restenosis, and stroke. This suggests that platelet reactivity testing has clinical and translational significance in predicting patients’ risk of adverse cardiovascular events.

Shaik M.A., Krishna Moorthy M., Devanna N., Gopireddy S.R.

Kachipande A., Temba B., Materu S., Kaonga C.

Abstract Introduction Endocrine-disrupting chemicals such as organochlorine pesticides (OCP) and some heavy metals disturb important life functions such as reproduction, metabolism, and growth by interfering with the normal functionality of the human hormonal system. These toxic and persistent chemicals used in agricultural and industrial processes, can enter the baby formula and remain effective for extended periods. These EDCs come from environmental contamination and the manufacturing process of the baby formula. Materials and method In this study, we examined the levels and risk of EDC contamination in a sample of 85 baby formula products available in the Malawian market. Extraction was done using the EU CEN 15662 QuEChERS method and then analyzed using gas-liquid chromatography with fluorescence to quantify OCP contamination. For heavy metals, samples were digested and analyzed using the Analytik Jena microwave digestion system (TOPwave_90_09) and an Atomic Absorption Spectrometer, respectively. The risk of exposure was computed using a hypothetical consumption of infant formula at 12 and 24 months, and weight ranges of 9.25–12.247 kg with corresponding average daily intakes of 0.057–0.2kg. Results EDC contamination ranged from not detected to 0.3 mg/kg. Common EDCs were Aldrin (23%), dieldrin (27%), and lindane (35%). The risk assessment showed a Hazard Index of 1.2. This suggests higher levels of exposure, are more likely to have lasting effects during human development. The detection levels were above the European Food Safety Authority (EFSA) recommended maximum residual limit of 0.01mg/kg. Conclusion Considering the health implications and susceptibility of the babies, it is pertinent to enforce and closely monitor the EDC content of baby formulas in the Malawi market.

Kachipande A., Temba B., Materu S., Kaonga C.

Abstract Background This cross-sectional study examines knowledge, practice, and attitudes regarding food safety among 100 people involved in manufacturing baby formula in Malawi regarding endocrine disruptors. The study received approval from the National Committee on Research and informed consent. Methods Data collected through face-to-face interviews were checked, cleaned and analyzed using R version 4.2.2. Logistic ordinal regression analysis was used to examine the correlation between socio-demographic variables against knowledge, attitudes, and practices. The p-value < 0.05 was considered statistically significant for the tests. Results and discussion There were more males (67%) than females (33%), at least half (51%) were below 35 years of age with 64% having at least 5 years of working experience. 92% trust in the safety of their product despite being unfamiliar with EDCs. Raw materials and packaging are suspected contamination sources. Only 42% of food handlers are aware of EDCs, slightly higher than Egypt and Ethiopia due to sociodemographic differences and study designs. Food safety knowledge correlated with sex (p = 0.016), ages 18-24 (p =0.069) and 45-54 (p = 0.036), and education level (p = 0.002). Food handlers who attained at least secondary education were better knowledgeable. The study reveals a significant knowledge gap and a higher likelihood of unsafe practices among food handlers regarding endocrine disruptors as they had positive attitudes. Conclusion The study identifies knowledge gaps and a lack of national strategies to deal with EDC contamination. It suggests the need for strengthening food safety knowledge, practices, and attitudes through legal instruments, awareness, training, and collaboration.

Zhang S., Cheng Y., Gao Y., Zou Y., Xiao W., Li T., Li M., Yu B., Dong J.

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.

Zheng S., Jie Q., Chen N., Chen X., Zhu Y.

Platelets play a pivotal role in thrombotic events associated with acute coronary syndrome (ACS), making oral antiplatelet therapy a cornerstone in antithrombotic strategies. The dosing regimen for the oral antiplatelet drug ticagrelor warrants evaluation to ensure its appropriateness in clinical practice. Therefore, this study aimed to investigate the real-world clinical application of ticagrelor by determining the optimal therapeutic concentration of ticagrelor in Chinese patients undergoing percutaneous coronary intervention (PCI). We enrolled a cohort of 912 patients who underwent PCI with drug-eluting stent implantation for the treatment of ACS. We measured steady-state plasma drug concentrations using high-performance liquid chromatography–tandem mass spectrometry. The therapeutic drug concentration range at steady state was established on the basis of clinical pharmacodynamic indices, with verification of reliability through concentration-effect analysis and receiver operating characteristic curve assessment. Analysis of plasma samples from the 912 patients revealed significant variations in the steady-state trough concentration of ticagrelor associated with factors such as gender, age, hypertension, and hyperlipidemia. On the basis of this analysis, the optimal therapeutic range for steady-state trough concentration was determined to be 240.65–335.83 ng/mL. Furthermore, the upper limit values for steady-state concentration were established at 439.97 ng/mL for male patients and 347.06 ng/mL for female patients. This study provides robust and reliable insights into the optimal therapeutic steady-state trough concentrations of ticagrelor in Chinese patients with post-percutaneous coronary intervention. These findings have significant implications for guiding the rational use of antiplatelet drugs and facilitating precise drug administration in Chinese patients undergoing percutaneous coronary intervention.

Sunarić S., Mladenov K., Nikolić V., Pavlović M.

AbstractA simple HPLC method was developed for the determination of antiplatelet drug ticagrelor (TCG) in blood. Sample preparation and extraction conditions were investigated and optimized. The preparation of blood plasma was investigated by protein precipitation using perchloric acid, methanol, acetonitrile (ACN), and trifluoroacetic acid. Protein precipitation using ACN was found to be the most suitable. Chromatographic separation of TCG was performed on a C18 column with a mobile phase consisting of ACN and 15 mM ammonium acetate buffered at pH 8.0. The method was applied to determine TCG in blood plasma of patients who had a heart attack. Blood samples were collected 1.5 h after the administration of the initial loading dose of the antiplatelet drug. The average concentration of TCG was found to be 0.97 ± 0.53 μg/ml. The developed method proved to be very selective, without interferences from other endogenous substances and the influences of possible coadministered drugs. The limits of detection and quantification estimated by the signal‐to‐noise ratio in real samples were 0.24 and 0.4 μg/ml, respectively. The developed method is simple and can be easily applied in clinics and emergency cardiac situations after the initial loading dose of TCG in the first few hours of a heart attack.

Al-Nami S.Y., Hameed A., Azher O.A., Alamrani N.A., Aljuhani E., Abumelha H.M., El-Metwaly N.M.

Herein, the construction and the electroanalytical applications of novel ticagrelor (TIC) voltammetric sensors were described. Integration of the working carbon paste electrodes with zeolite nanostructures showed a proper electrocatalytic activity toward oxidation of the TIC molecule. At the optimum measuring conditions, TIC showed an irreversible oxidation peak at 0.954 V with an assumed diffusion–reaction mechanism. Based on the electrochemical behavior at different pH and the scan rate values, the electrode reaction takes place through oxidation of the N Enamine of the ticagrelor moiety with the participation of one electron and one proton in agreement with the molecular orbital calculations. Calibration curves showed improved linearity (r = 0.9998) within the TIC concentration ranging from 8.8 to 1665 ng mL−1 with LOD and LOQ values of 2.5 and 7.5 ng mL−1, respectively. The introduced TIC voltammetric sensor exhibited improved performance with high measurement reproducibility and prolonged operational lifetime. The cited ZY/CPEs sensors were capable of simultaneous voltammetric determination of TIC in the existence of its degradation outcomes and expected interferents. The proposed voltammetric approach was suggested for the sensitive determination of ticagrelor in biological fluids and pharmaceutical samples with good recovery values in agreement with the spectrophotometric measurements.

Lović J.

Moorthy M.K., Ali S.M., Reddy G.V.

The foremost objective of the present study was to develop and validate a new LC–QTOF–MS/MS method for the identification and quantitative determination of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (DPP) genotoxic impurity through the derivatization process in ticagrelor active pharmaceutical ingredient (API). Owing to the low response of DPP at the specification level, DPP was converted to 4,6-dibenzylamino-5-nitro-2-(propylthio)pyrimidine (DPP derivative) by addition of benzyl amine, then analyzed using mass spectrometry with a time-of-flight analyzer, and good separation was accomplished under the experimental conditions described. The effective separation of DPP derivative was achieved using an Acquity UPLC BEH C18 reverse-phase column (100 × 4.6 mm × 1.7 μm) with an isocratic program with mobile phase A as 0.1% formic acid in milli Q water and mobile phase B as acetonitrile in the ratio of 20:80 v/v. The flow rate was maintained as 0.4 ml/min, the injection volume was 2 μl, the autosampler temperature was 5°C, the column oven temperature was ambient and the run time was 6.0 min. The diluent used was 0.2% benzyl amine in water and acetonitrile in the ratio of 30:70 v/v. The retention time of the DPP derivative was 2.87 min. The limit of detection and limit of quantification were 0.03 and 0.08 ppm, respectively. The DPP derivative was linear from 1.68 to 12.78 ppm with R2 of 0.9958. Thus, the developed method is valid for the identification and quantitative determination of DPP derivative in ticagrelor API.

Zhang W., Liu L., Liu Y., Wang Z.

Pradhan R., Hejmady S., Taliyan R., Singhvi G., Khadgawat R., Kachhawa G., Dubey S.K.

Endocrine-disrupting chemicals (EDCs) are xenobiotics that disrupt the endocrine system in humans at ecologically significant concentrations. Various substances are exposed to human health via routes including food, water, air and skin that result in disastrous maladies at low doses as well. Therefore EDCs need a meticulous strategy of analysis for dependable and consistent monitoring in humans. The management and risk assessment necessitate advancements in the detection methodologies of EDCs. Hyphenated MS-based chromatograph and other validated laboratory analysis methods are widely available and employed. Besides, in vitro bioassay techniques and biosensors are also used to conduct accurate toxicological tests. This article provides a revision of various bioanalytical detection methods and technologies for the clinical estimation of EDCs.

Zhang Y., Xue Z., Chen K., Xu L., Wang W., Tao H., Liu T., Che J., Wang X., Rha S., Wang J., Wang P.

Background: Periprocedural myocardial infarction is a common complication following percutaneous coronary intervention. The present study was conducted with an aim to compare the safety and efficacy of loading doses of ticagrelor versus clopidogrel in preventing periprocedural myocardial infarction in Asian patients with acute coronary syndrome undergoing elective percutaneous coronary intervention. Methods: A total of 114 patients with acute coronary syndrome undergoing elective percutaneous coronary intervention were assigned to clopidogrel group (n = 57, the loading and maintenance doses were 300 and 75 mg qd for clopidogrel, and 300 and 100 mg qd for aspirin), or ticagrelor group (n = 57, the loading and maintenance doses were 180 and 90 mg bid for ticagrelor, and 300 and 100 mg qd for aspirin). Cardiac biomarkers were measured before, 8 hours, and 24 hours after percutaneous coronary intervention. The percutaneous coronary intervention–related periprocedural myocardial infarction was defined according to the fourth universal definition of myocardial infarction (2018). Results: The overall incidence of percutaneous coronary intervention–related periprocedural myocardial infarction was 21.1%. The ticagrelor group showed a significantly lower incidence of periprocedural myocardial infarction (12.3% vs 29.8%, p = 0.022) and numerically lower bleeding events (3.5% vs 8.8%, p = 0.242) as compared with clopidogrel group. No patient had major adverse cardiovascular events during the 1-month follow-up. The levels of high-sensitivity C-reactive protein did not differ significantly between the two groups (p > 0.05), indicating that the benefits of ticagrelor were not from its anti-inflammatory effects. Multivariable analysis showed that the use of ticagrelor (odds ratio: 0.50; 95% confidence interval: 0.29-0.87; p = 0.014) and number of stents (odds ratio: 2.75; 95% confidence interval: 1.25-6.06; p = 0.012) were independent predictors of periprocedural myocardial infarction. Conclusion: Pretreatment with a loading dose of ticagrelor seems to be superior in reducing the incidence of percutaneous coronary intervention–related periprocedural myocardial infarction in Asian patients with acute coronary syndrome as compared with clopidogrel.