Intake of aspirin prior to metamizole does not completely prevent high on treatment platelet reactivity.

PURPOSE: Metamizole can sterically inhibit aspirin (ASA) from binding to cyclooxygenase 1 (COX1). It is recommended that ASA should be taken 30 min prior to metamizole to maintain the irreversible inhibition of arachidonic acid (AA)-induced platelet aggregation. We aimed to analyse the inhibitory effect of ASA and metamizole on AA-induced platelet aggregation over the course of the day. METHODS: We analysed hospitalized patients who ingested ASA at least 30 min prior to metamizole (recommended dosing group, n = 15), metamizole prior or simultaneously with ASA (not recommended dosing group, n = 16) and patients with unknown or mixed intake (mixed dosing group, n = 5). AA-induced light transmission (LTA) and impedance aggregometry (IA) were measured before, 1-2 and 5-6 h after the intake of ASA ± metamizole. RESULTS: Maximum AA-induced LTA prior to the intake of ASA was significantly lower and the rate of high on treatment platelet reactivity (HTPR) higher in the recommended compared with the not recommended dosing group (19.6% vs. 46.9%, p = 0.011 and 4/15 vs. 12/16 patients, p = 0.017). There was no difference when IA was used. Maximum AA-induced LTA after the intake of ASA ± metamizole was lower in patients in the not recommended but not in the recommended dosing group. All patients with HTPR in the recommended dosing group had regular inhibition of AA-induced LTA after discontinuation of metamizole. CONCLUSION: Co-medication of ASA and metamizole significantly influences platelet inhibition with variations during the day and can cause HTPR in patients taking ASA prior to metamizole or simultaneously.

Hepatic dysfunction secondary to Kawasaki disease: characteristics, etiology and predictive role in coronary artery abnormalities.

Coronary artery abnormalities (CAAs) are prominent during the acute Kawasaki disease (KD) episode and represent the major contributors to the long-term prognosis. Several meta-analysis and published scoring systems have identified hepatic dysfunction as an independent predictor of CAA risks. The medical records of 210 KD children were reviewed. Blood samples were collected from all subjects at 24 h pre-therapy and 48 h post-therapy, respectively. Liver function test (LFT) and inflammatory mediators were detected. Multivariate logistic regression analysis was conducted to identify the reliable biomarkers predicting whether CAAs existed or not in KD patients. 90.95% of KD patients had at least 1 abnormal LFT. Hypoalbuminemia was the most prevalent type of hepatic dysfunction, followed by elevated aspartate aminotransferase, low TP, low A/G and hyperbilirubinemia, respectively. The elevated inflammatory mediators (procalcitonin and C-reactive protein) and moderate dose of aspirin played a synthetic role in hepatic dysfunction secondary to KD. However, LFT presented no significant differences between infectious and noninfectious conditions. By a multivariate analysis, a lower albumin/globulin ratio (A/G, OR 13.50, 95% CI 3.944-46.23) served as an independent predictor of CAAs and had a sensitivity of 56.25%, and a specificity of 61.11% at a cutoff value of < 1.48. In conclusion, hepatic dysfunction is a common complication during the acute KD episode, characterized by elevated serum liver enzymes, hypoalbuminemia and hyperbilirubinemia. Systemic inflammation and aspirin, rather than infectious agents, are both the major contributors of hepatic dysfunction secondary to KD. A lower A/G serves as an independent predictor of CAAs.

Hemorrhagic Complications of External Ventriculostomy in the Aspirin and P2Y12 Response Assay Era.

OBJECTIVE: Hemorrhagic complications reported from external ventricular drain (EVD) placement range from 10% to 44%. There remains limited literature investigating the incidence, risk factors, and mechanisms to prevent its occurrence, especially in the setting of antiplatelet agent use. We investigated EVD-related hemorrhagic complications after the implementation of VerifyNow platelet inhibition assays at our institution. METHODS: Medical records from 445 patients requiring EVD placement during a 2-year period during which our institution used the assays were reviewed. In total 345 patients were included, and 208 of them underwent assay testing. Indications for EVD included complications of cerebrovascular disease (n = 215), traumatic brain injury (n = 74), primary hydrocephalus (n = 23), and tumor (n = 33). Hemorrhage was defined as any new area of hyperdensity adjacent to or immediately along the catheter trajectory on computed tomography. RESULTS: There was no significant decrease in catheter-induced hemorrhage (CIH) between patients who underwent the VerifyNow assay and those who did not. Platelet transfusion did not significantly decrease the risk of CIH. CIH occurred in 17.7% of patients, significantly decreased when compared with our previously published incidence of 33% before platelet inhibition assay use (P < 0.05). Patients with cerebrovascular disease complications exhibited a significant decrease in CIH, 20% versus 39%, before assay use (P < 0.01). CONCLUSIONS: The incidence of hemorrhage is lower in our new cohort when compared with that of our previously published cohort. Despite the overall decreased rate of hemorrhage, there was no significant difference in hemorrhage rates between patients who did or did not undergo the assay. Platelet transfusion did not decrease the incidence of hemorrhage in patients with inhibited platelet function.

Acetaminophen and Acetylsalicylic Acid Exposure in a Preterm Infant after Maternal Overdose.

Here, we review the case of a 26 1/7 weeks' gestation premature female infant born to a mother who intentionally ingested a large quantity of Tylenol, aspirin, quetiapine, and prenatal vitamins. The neonate subsequently had markedly elevated levels of both Tylenol and aspirin when checked on the first day of life. While overall clinically stable, the neonate did demonstrate coagulopathy as evidenced by abnormal coagulation studies. Both poison control and a pediatric gastroenterologist/hepatologist were consulted. She successfully tolerated a course of N-acetylcysteine; her subsequent Tylenol level was markedly decreased and the neonate exhibited no further effects of toxicity. The salicylate level decreased on its own accord. To our knowledge, this is the first report of a neonate at 26 weeks' gestation that has been successfully managed for supratherapeutic concentrations of acetaminophen and acetylsalicylic acid secondary to maternal ingestion. While rare, this case may serve as a reference for the effectiveness of N-acetylcysteine in premature infants in such instances.

Metamizole and Platelet Inhibition by Aspirin Following On-Pump Coronary Artery Bypass Grafting.

OBJECTIVE: The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease early after on-pump coronary artery bypass grafting (CABG). DESIGN: Prospective, single-blind, randomized trial. SETTING: Tertiary referal hospital. PARTICIPANTS: The study comprised 43 patients with multivessel coronary artery disease undergoing CABG. INTERVENTIONS: Patients were randomized to postoperative intravenous metamizole ± opioids (study group; n = 23) or opioids alone (control group; n = 20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multielectrode impedance aggregometry (acid-induced platelet activation [ASPI] and collagen-induced platelet activation [COL] test), P-selectin expression and urinary 11-dehydro-thromboxane B2 (11-DTXB2) level at baseline, postoperative day (POD) 0, POD 1, POD 2, and POD 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min. MEASUREMENTS AND MAIN RESULTS: In all study participants, postoperative ASPI test value moderately decreased (1058.2 v 966.6 AU*min, p = 0.047), urinary 11-DTXB2 level increased (923.4 v 4367.3 pg/mg, p < 0.001), and P-selectin expression and COL test value remained stable postprocedure. The decreases of ASPI (p = 0.146) and COL test (p = 0.642), and P-selectin expression (p = 0.318) did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB2 level (p = 0.001). The prevalence of RPR was high and comparable between study and control groups (day 1, 95.6% v 100%, p = 0.535; day 6, 100% v 90%, p = 0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and P-selectin expression, yet it independently predicted postoperative change of 11-DTXB2 level (b = -0.518, p = 0.001). CONCLUSIONS: Intravenous metamizole preceded by a loading dose of aspirin did not modify platelet response to aspirin in the postoperative period after CABG.

Impaired liver cytochrome P450 2C11 activity after dual antiplatelet therapy with aspirin and clopidogrel in rats.

1. Aspirin (ASA) and clopidogrel (CLP) are used in combination as dual antiplatelet therapy (DAPT) for acute coronary syndrome based on their complementary mechanisms for platelet aggregation inhibition. However, the pharmacokinetics of such drug combination usage has not been thoroughly investigated. 2. In the current study, an LC-MS/MS method was developed to simultaneously determine the plasma concentrations of ASA and its metabolite salicylic acid (SA) with CLP and its metabolites, clopidogrel carboxylic acid (CLPM) and clopidogrel active metabolite derivative (CAMD). The pharmacokinetics of ASA, SA, CLP, CLPM and CAMD in rats receiving two-week DAPT with ASA and CLP were then determined. 3. After two-week DAPT with ASA and CLP in rats, the activities of aspirin esterase and rCyp2c11, enzymes mediating rat metabolism of ASA and CLP, respectively, in prepared rat liver microsomes were measured followed by further determination of rCyp2c11 mRNA expressions. The results demonstrated that DAPT led to minimal impact on aspirin esterase activity but significant decrease in rCyp2c11 activity and mRNA expression. 4. In conclusion, our findings on impairment in rCyp2C11 activity and mRNA expression by DAPT in rats could provide guidance on its safe clinical use with other CYP 2C19 substrates.

Hansen solubility parameters for assay method optimization of simvastatin, ramipril, atenolol, hydrochlorothiazide and aspirin in human plasma using liquid chromatography with tandem mass spectrometry.

A simple, specific, sensitive, validated method was developed using liquid chromatography with tandem mass spectrometry with electrospray ionization of human plasma for the simultaneous estimation of drugs (simvastatin, ramipril, atenolol, hydrochlorothiazide, and aspirin) of PolycapTM capsule used in cardiovascular therapy. The interaction of these actives including internal standards between the stationary and mobile phase were investigated using Hansen solubility parameters. Chromatographic separation was performed on Phenomenex Synergi Polar-RP (30 × 2 mm, 4 µm) column with a gradient mobile phase composition of acetonitrile and 5 mM ammonium formate for positive mode and 0.1% formic acid in both water and acetonitrile for negative mode. The flow rate and runtime were 1.0 mL/min and 3.5 min, respectively. Sample extraction was done by protein precipitation using acetonitrile, enabling a fast analysis. The calibration ranges from 0.1 to 100, 0.1 to 100, and 1 to 1000 ng/mL for simvastatin, ramipril, and atenolol using internal standard carbamazepine in positive mode, respectively, whereas it was 0.3-300 and 2-2000 ng/mL for hydrochlorothiazide and aspirin using internal standard 7-hydroxy coumarin in negative mode, respectively. Hansen solubility parameters can be used as a high-throughput optimizing tool for column and mobile phase selection in bioanalysis. This validated bioanalytical method has the potential for future fixed dose combination based preclinical and clinical studies that can save analysis time.

Proton Pump Inhibitors in Cardiovascular Disease: Drug Interactions with Antiplatelet Drugs.

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.

Bioavailability of aspirin in rats comparing the drug's uptake into gastrointestinal tissue and vascular and lymphatic systems: implications on aspirin's chemopreventive action.

Aspirin is an effective analgesic and antiplatelet drug that in addition to its ability to reduce pain, inflammation and fever, appears to have efficacy in the prevention/treatment of a range of diseases including heart disease, numerous cancers and Alzheimer's. It is important to understand the bioavailability of aspirin and its major metabolite, salicylic acid, since dosage and route of administration can vary for treating differing diseases, and the major side-effects of aspirin, upper gastrointestinal ulceration and bleeding, are dose-dependent. We examined the time course for gastroduodenal uptake of aspirin and the appearance of its major metabolite salicylic acid in blood and lymph after intragastric (to simulate oral) and intraduodenal (to simulate enteric-coating) dosing in rats. Results show that after intragastric dosing, intact aspirin is absorbed primarily by the gastric mucosa and to a lesser extent by the duodenal mucosa. When aspirin is dosed intragastrically or intraduodenally, a much greater concentration of aspirin enters the lymph than the blood. In contrast, the concentration of salicylic acid was higher in blood than in lymph. Lymph levels of both aspirin and salicylic acid were sufficiently high so as to perform a pharmacologic function there, possibly as a chemopreventive agent against colon cancer and potentially the metastatic spread of non-gastrointestinal cancers.

Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

UNLABELLED: ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor. BACKGROUND: The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged ≥ 70 years. RESULTS: Among 494 patients on DAPT, 224 (45.3%) were ≥ 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 ± 148.6 vs. 319.6 ± 171.1 vs. 347.3 ± 190.1 vs. 345.7 ± 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29-3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]). CONCLUSION: In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor.