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1.
Application of the GastroDuo to study the interplay of drug release and gastric emptying in case of immediate release Aspirin formulations.
Schick, P, Sager, M, Voelker, M, Weitschies, W, Koziolek, M
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2020;:9-17
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Abstract
The process of gastric emptying is of major importance for the in vivo performance of immediate release dosage forms. In the fed state, this process consists of two phases: the rapid emptying of water along the "Magenstrasse" and the continuous emptying of the chyme. The relevance of these phases for the pharmacokinetic (PK) profile of a drug depends on the release behavior from its dosage form. It was the aim of this study to investigate the role of gastric emptying for the pharmacokinetics of a fast disintegrating and dissolving Aspirin® tablet (FDDT). For this purpose, a three way pharmacokinetic study with 30 healthy volunteers was performed to investigate the performance of the FDDT under fasted and fed conditions and compare it to a regular Aspirin® tablet (RT) administered in the fed state. Plasma samples were taken at predetermined time points and analyzed by LC MS/MS. In the second part of this work, both products were tested in a biorelevant dissolution test device - the GastroDuo. To simulate the occurrence of the Magenstrasse at different time points, two test programs have been applied. The results of the PK study clearly demonstrated the superiority of the FDDT over the RT. We observed an earlier tmax (0.39 h vs. 2.00 h) and a higher Cmax (6.33 ± 2.37 μg/mL vs. 3.23 ± 1.28 μg/mL), whereas the AUC was only slightly different between both formulations. The administration of the FDDT together with food had no marked effect on tmax (0.34 h vs. 0.39 h), but caused a decrease in Cmax compared to fasted intake (14.76 ± 4.81 μg/mL vs. 6.33 ± 2.37 μg/mL). This effect could be explained by the in vitro data collected with the GastroDuo. The FDDT showed a faster drug release and improved emptying kinetics in the GastroDuo. In contrast, the RT showed incomplete emptying in both test programs. Thus, the early tmax observed for the FDDT under fed conditions could be related to the presence of the Magenstrasse. In contrast, drug release from the RT was insufficient to allow gastric emptying via the Magenstrasse, which resulted in later tmax. This study highlighted the importance of gastric emptying for immediate release dosage forms and illustrated that the application of suitable formulation techniques provides a strategy to generate a fast and reliable onset of drug plasma concentrations even in the fed state.
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Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial.
Kim, BJ, Kwon, SU, Park, JH, Kim, YJ, Hong, KS, Wong, LKS, Yu, S, Hwang, YH, Lee, JS, Lee, J, et al
Stroke. 2020;(3):931-937
Abstract
Background and Purpose- Although cilostazol has shown less hemorrhagic events than aspirin, only marginal difference was observed in hemorrhagic stroke events among patients at high risk for cerebral hemorrhage. To identify patients who would most benefit from cilostazol, this study analyzed interactions between treatment and subgroups of the PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage). Methods- Ischemic stroke patients with a previous intracerebral hemorrhage or multiple microbleeds were randomized to treatment with cilostazol or aspirin and followed up for a mean 1.8 years. Efficacy, defined as the composite of any stroke, myocardial infarction, and vascular death, and safety, defined as the incidence of hemorrhagic stroke, were analyzed in the 2 groups. Interactions between treatment and age, sex, presence of hypertension and diabetes mellitus, index of high-risk cerebral hemorrhage, and white matter lesion burden were analyzed for primary and key secondary outcomes. Changes in vital signs and laboratory results were compared in the 2 groups. Results- Among all 1534 patients enrolled, a significant interaction between treatment group and index of high risk for cerebral hemorrhage on hemorrhagic stroke (P for interaction, 0.03) was observed. Hemorrhagic stroke was less frequent in the cilostazol than in the aspirin group in patients with multiple microbleeds (1 versus 13 events; hazard ratio, 0.08 [95% CI, 0.01-0.61]; P=0.01). A marginal interaction between treatment group and white matter change on any stroke (P for interaction, 0.08) was observed. Cilostazol reduced any stroke significantly in patients with mild (5 versus 16 events; hazard ratio, 0.36 [95% CI, 0.13-0.97]; P=0.04)-to-moderate (16 versus 32 events; hazard ratio, 0.50 [95% CI, 0.29-0.92]; P=0.03) white matter changes. Heart rate and HDL (high-density lipoprotein) cholesterol level were significantly higher in the cilostazol group than in the aspirin group at follow-up. Conclusions- Cilostazol may be more beneficial for ischemic stroke patients with multiple cerebral microbleeds and before white matter changes are extensive. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01013532.
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Treatment of thrombotic antiphospholipid syndrome in adults and children.
Madison, JA, Duarte-García, A, Zuo, Y, Knight, JS
Current opinion in rheumatology. 2020;(3):215-227
Abstract
PURPOSE OF REVIEW Antiphospholipid syndrome (APS), more common than once believed, is an autoimmune disease best known for its high risk of incident and recurrent thrombotic events. The approach to treatment potentially differs from treatment of thrombosis in the general population, and this article endeavors to review the latest updates on this topic. RECENT FINDINGS The epidemiology of APS is being increasingly elucidated by large population-based studies, with APS perhaps affecting as many as 1 in 2000 individuals. Vitamin K antagonists, aspirin, and heparinoids continue to have obvious roles in the management of patients with APS. There has recently been intensive study of direct oral anticoagulants in APS, with the most recent randomized studies raising concerns about their inferiority to vitamin K antagonists, at least in some subgroups. Other approaches to treating APS beyond anticoagulants and antiaggregants are also receiving increased attention in mechanistic and preclinical studies with an eye toward future roles in patients with refractory and/or microvascular disease. Pediatric APS is identified as an area in desperate need of additional prospective research. SUMMARY Progress continues to be made in pursuit of improving the lives of individuals afflicted with APS. The most important future directions would seem to involve leveraging modern molecular technologies in order to improve subphenotyping of antiphospholipid antibody-positive individuals. This will help personalize risk profiles and ideally define the optimal approach to therapy based on future risk, rather than past morbid events.
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Metabolomics Analysis of Aspirin's Effects in Human Colon Tissue and Associations with Adenoma Risk.
Barry, EL, Fedirko, V, Uppal, K, Ma, C, Liu, K, Mott, LA, Peacock, JL, Passarelli, MN, Baron, JA, Jones, DP
Cancer prevention research (Philadelphia, Pa.). 2020;(10):863-876
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Abstract
Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.
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Platelet function in stroke/transient ischemic attack patients treated with tocotrienol.
Slivka, A, Rink, C, Paoletto, D, Sen, CK
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;(9):11838-11843
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Abstract
The purpose of this study was to characterize the effects of tocotrienol form of vitamin E (TCT) on platelet function in patients with stroke or transient ischemic attack (TIA). A double blind, randomized, single center phase II clinical trial was conducted comparing placebo (PBO) and 400 and 800 mg TCT daily for a year in 150 patients with a sentinel ischemic stroke or TIA event in the prior 6 months. Platelet function was measured at baseline and then, at 3 month intervals for a year, using light transmission aggregometry. The incidence of aspirin resistance in aspirin-treated patients or platelet inhibition in patients on clopidogrel alone was compared between the three treatment groups. Results showed that in patients taking aspirin and clopidogrel, the incidence of aspirin resistance was significantly decreased from 40% in PBO-treated patients to 9% in the 400 mg TCT group and 25% in the TCT 800 mg group (P = .03). In conclusion, patients on aspirin and clopidogrel had a higher incidence of aspirin resistance than all patients treated with aspirin alone and TCT decreased the frequency of aspirin resistance in this group.
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Platelet Apoptotic Response May Be Associated With the Capacity of Aspirin to Inhibit Platelets.
Zamorano-León, JJ, Gascón, M, Martínez, CH, Freixer, G, Guerra, R, Zekri-Nechar, K, Bernardo, E, Serna-Soto, M, Segura, A, Giner, M, et al
Journal of cardiovascular pharmacology. 2020;(5):584-591
Abstract
An inadequate platelet response to aspirin (ASA) has been identified in some patients under chronic ASA treatment. The aim of this study was to analyze if ASA-sensitive and ASA-resistant platelets have differences in their apoptotic capability. Clinically stable ischemic coronary patients who had been taking ASA (100 mg/d) for at least 9 months before inclusion were divided into ASA-resistant (n = 11) and ASA-sensitive (n = 13) groups as defined by the PFA-100 test. Platelets from ASA-sensitive patients showed higher expression of the proapoptotic proteins Bak and Bax than those from ASA-resistant patients, although only Bak protein remained different when the results were adjusted by age. In resting platelets, neither caspase-3 activity nor cytosolic cytochrome C levels were different between both experimental groups. Stimulation of platelets with calcium ionophore (10 nmol/L, A23187) increased caspase-3 activity (1.91-fold higher; P < 0.05) and cytosolic cytochrome C levels (1.84-fold higher; P < 0.05) to a higher degree in ASA-sensitive than in ASA-resistant platelets. In conclusion, ASA-sensitive platelets seem to be better prepared to undergo apoptosis during robust platelet activation.
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Indications and Evidence for Dual Antiplatelet Therapy After Acute Ischemic Stroke.
Ringler, J, Steck, M, Shah, SP, Chester, KW
Critical care nursing quarterly. 2020;(2):122-137
Abstract
The antiplatelet landscape for the secondary prevention of ischemic stroke has changed significantly over the past decade. Poststroke dual antiplatelet regimens are becoming increasingly routine as supported by recent literature and guideline recommendations. Dual antiplatelet therapy after stroke generally consists of aspirin and clopidogrel and is considered in the short term after stroke in select populations including those with mild stroke or transient ischemic attack and in patients with severe intracranial atherosclerosis. When initiating dual antiplatelet therapy, factors that may increase a patient's risk of bleeding must be weighed against the patient's risk of future ischemic events. This review focuses on antiplatelet medications available in the United States with the aim to provide a summary of the available literature on poststroke dual antiplatelet therapy, pharmacological nuances of the agents, and reversal of antiplatelets in the setting of intracerebral hemorrhage.
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[Treatment of coronary artery disease in renal insufficiency].
Lopau, K, Wanner, C
Der Internist. 2020;(4):362-367
Abstract
The treatment of chronic but stable coronary artery disease is based on the stages of chronic kidney disease (CKD) stages G1-2 and stages G3-G5, distinguishing between advanced kidney disease (stages G3-G5) and end-stage kidney disease (G5D) treated by dialysis. In Germany, national guidelines are followed for patients with normal kidney function in addition to the recommendations of Kidney Disease - Improving Global Outcomes (KDIGO) for CKD patients. These guidelines focus on standard of care and include treatment with aspirin, statins, beta-blockers, inhibitors of the renin-angiotensin system, and sodium glucose cotransporters for patients with cardiovascular disease. Revascularization strategies follow a more pragmatic approach for the fragile, comorbid, and aging patient population. Younger patients appear to benefit from surgical interventions. Treatment of acute events is currently administered independent of the patient's kidney function, but there is no consensus yet on the best strategy. The focus of our efforts should be, via more controlled studies, to avoid "navigating through the darkness" to reach the end of the tunnel.
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Adherence to Triple-Free-Drug Combination Therapies Among Patients With Cardiovascular Disease.
Lombardi, N, Crescioli, G, Simonetti, M, Marconi, E, Vannacci, A, Bettiol, A, Parretti, D, Cricelli, C, Lapi, F
The American journal of cardiology. 2020;(9):1429-1435
Abstract
Combination therapies are often needed to modify the concomitant risk factors for cardiovascular disease. Nonadherence to cardiovascular medications is a relevant concern, especially in polytherapy. We conducted a population-based, cohort study with the aim of quantifying the level of adherence and its related determinants in patients exposed to free 3-drug combination therapies, namely concurrent use of angiotensin-converting-enzyme inhibitor (ACEi), calcium channel blocker (CCB), and statin or of ACEi, statin, and low-dose aspirin. Within Health Search Database, we selected a cohort of adult patients concurrently prescribed with ACEi, CCB, and statin, as well as those prescribed with ACEi, statin and low-dose aspirin, from the January 1, 2002 to the December 31, 2014. Adherent patients were concurrent users of triple free pill regimen with a proportion of days covered ≥80% during 1-year follow-up; demographics and clinical determinants of 1-year adherence were identified by multivariate logistic regression. We found that more than half of patients prescribed with triple free drug combination therapy with ACEi plus CCB plus statin or ACEi plus statin plus low-dose aspirin, were found to be nonadherent to these treatments. Males and patients at high/very-high cardiovascular risk were more likely to be adherent, whereas depression and atrial fibrillation were associated with nonadherence. Our findings indicate that sex, cardiovascular risk, presence of atrial fibrillation, and depression can influence adherence to polytherapy. In conclusion, given that patients suffering from multiple cardiovascular risk factors are at higher risk of fatal events, strategies are needed to improve medication adherence to combination therapies.
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Firefighting Induces Acute Inflammatory Responses that are not Relieved by Aspirin in Older Firefighters.
Smith, DL, Friedman, NMG, Bloom, SI, Armero, WL, Pence, BD, Cook, MD, Fernhall, B, Horn, GP, Woods, J
Journal of occupational and environmental medicine. 2019;(7):617-622
Abstract
OBJECTIVE Sudden cardiac events account for 40% to 50% of firefighter line-of-duty deaths. Inflammatory proteins are strong biomarkers of cardiovascular inflammation. The present study investigated the effects of aspirin supplementation on inflammatory biomarkers following firefighting. METHODS Using a randomized, placebo-controlled, double-blind crossover design, 24 male firefighters (48.2 ± 5.9 years) were allocated into four conditions: acute (81 mg; single-dose) aspirin and placebo supplementation, and chronic (81 mg; 14 days) aspirin and placebo supplementation. Inflammatory proteins [interleukin (IL)-6, C-reactive protein (CRP), intracellular adhesion molecule (ICAM)-1, P-selectin, matrix metalloproteinase-9 (MMP-9)] and antioxidant potential [total antioxidant capacity (TAC)] were measured pre- and post-structural firefighting drills. RESULTS Firefighting activities significantly increased IL-6, MMP-9, and P-Selectin; however, no changes in TAC and ICAM-1 were detected. Neither acute nor chronic aspirin supplementation attenuated this inflammatory response. CONCLUSION Firefighting significantly increases inflammatory biomarkers and neither acute nor chronic low-dose aspirin mitigates this response.