Giovanna Petrucci1,2, Francesco Zaccardi3, Alberto Giaretta4, Viviana Cavalca5, Esmeralda Capristo2,6, Carmine Cardillo2,7, Dario Pitocco2,8, Benedetta Porro5, Francesca Schinzari7, Gianna Toffolo4, Elena Tremoli5, Bianca Rocca1,2. 1. Istituto di Farmacologia, Università Cattolica, Rome, Italy. 2. Fondazione Policlinico Universitario IRCCS, A. Gemelli, Rome, Italy. 3. Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK. 4. Department of Information Engineering, University of Padova, Padova, Italy. 5. Centro Cardiologico Monzino, IRCCS, Milano, Italy. 6. Internal Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 7. Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, Rome, Italy. 8. Diabetology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Abstract
BACKGROUND: The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. OBJECTIVES: To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. PATIENTS/ METHODS: Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. RESULTS: In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. CONCLUSIONS: Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.
BACKGROUND: The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. OBJECTIVES: To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. PATIENTS/ METHODS: Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. RESULTS: In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. CONCLUSIONS:Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.
Authors: David A Drew; Madeline M Schuck; Marina V Magicheva-Gupta; Kathleen O Stewart; Katherine K Gilpin; Patrick Miller; Melanie P Parziale; Emily N Pond; Oliver Takacsi-Nagy; Dylan C Zerjav; Samantha M Chin; Jennifer Mackinnon Krems; Dana Meixell; Amit D Joshi; Wenjie Ma; Francis P Colizzo; Peter J Carolan; Norman S Nishioka; Kyle Staller; James M Richter; Hamed Khalili; Manish K Gala; John J Garber; Daniel C Chung; Joseph C Yarze; Lawrence Zukerberg; Giovanna Petrucci; Bianca Rocca; Carlo Patrono; Ginger L Milne; Molin Wang; Andrew T Chan Journal: Cancer Prev Res (Phila) Date: 2020-07-27
Authors: Robert A Ariëns; Beverley J Hunt; Ejaife O Agbani; Josefin Ahnström; Robert Ahrends; Raza Alikhan; Alice Assinger; Zsuzsa Bagoly; Alessandra Balduini; Elena Barbon; Christopher D Barrett; Paul Batty; Jorge David Aivazoglou Carneiro; Wee Shian Chan; Moniek de Maat; Kerstin de Wit; Cécile Denis; Martin H Ellis; Renee Eslick; Hongxia Fu; Catherine P M Hayward; Benoit Ho-Tin-Noé; Frederikus A Klok; Riten Kumar; Karin Leiderman; Rustem I Litvinov; Nigel Mackman; Zoe McQuilten; Matthew D Neal; William A E Parker; Roger J S Preston; Julie Rayes; Alireza R Rezaie; Lara N Roberts; Bianca Rocca; Susan Shapiro; Deborah M Siegal; Lirlândia P Sousa; Katsue Suzuki-Inoue; Tahira Zafar; Jiaxi Zhou Journal: Res Pract Thromb Haemost Date: 2022-07-06
Authors: Matthew A M Devall; David A Drew; Christopher H Dampier; Sarah J Plummer; Stephen Eaton; Jennifer Bryant; Virginia Díez-Obrero; Jiancheng Mo; Dmitriy Kedrin; Dylan C Zerjav; Oliver Takacsi-Nagy; Lucas T Jennelle; Mourad W Ali; Ömer H Yilmaz; Victor Moreno; Steven M Powell; Andrew T Chan; Ulrike Peters; Graham Casey Journal: Cancer Prev Res (Phila) Date: 2021-08-13