The Impact of Obesity on the Pharmacology of Medications Used for Cardiovascular Risk Factor Control

Sankaralingam, Sowndramalingam; Kim, Richard B.; Padwal, Raj

doi:10.1016/j.cjca.2014.10.025

Cited by 30 publications

(15 citation statements)

References 76 publications

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“…The organ and metabolic changes produced by obesity can particularly affect the pharmacokinetics of lipophilic drugs, such as aspirin. BW values up to 90 kg could predict a high level of residual thromboxane (TX) B 2 being released during collagen‐induced platelet aggregation ex vivo in patients with coronary artery diseases receiving standard low‐dose aspirin once daily .…”

Section: Introductionmentioning

confidence: 99%

Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

Petrucci

Zaccardi

Giaretta

et al. 2019

Journal of Thrombosis and Haemostasis

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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/m 2 ) 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) B 2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; agematched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB 2 data from obese subjects. At baseline, the major urinary TXA 2 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/m 2 ), residual serum TXB 2 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 TXB 2 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 TXA 2 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 lowdose aspirin may affect antithrombotic efficacy.

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Section: Introductionmentioning

confidence: 99%

Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

Petrucci

Zaccardi

Giaretta

et al. 2019

Journal of Thrombosis and Haemostasis

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“…In line with its important roles in metabolism, inflammation and cancer, WAT has emerged as a drug target with major therapeutic potential for a variety of diseases [17][18][19] . Additionally, storage metabolism by WAT can have a major impact on the efficacy of drug therapies, such as those for cardiovascular diseases and cancer 20,21 . For instance, adipocytes may metabolize and inactivate the chemotherapeutic Daunorubicin 21 , which strongly affects the efficacy of this anticancer therapeutic.…”

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confidence: 99%

WAT-on-a-chip integrating human mature white adipocytes for mechanistic research and pharmaceutical applications

Rogal

Binder

Kromidas

et al. 2020

Sci Rep

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Obesity and its numerous adverse health consequences have taken on global, pandemic proportions. White adipose tissue (WAt)-a key contributor in many metabolic diseases-contributes about one fourth of a healthy human's body mass. Despite its significance, many WAT-related pathophysiogical mechanisms in humans are still not understood, largely due to the reliance on non-human animal models. In recent years, Organ-on-a-chip (OoC) platforms have developed into promising alternatives for animal models; these systems integrate engineered human tissues into physiological microenvironment supplied by a vasculature-like microfluidic perfusion. Here, we report the development of a novel OoC that integrates functional mature human white adipocytes. The WAT-on-achip is a multilayer device that features tissue chambers tailored specifically for the maintenance of 3D tissues based on human primary adipocytes, with supporting nourishment provided through perfused media channels. The platform's capability to maintain long-term viability and functionality of white adipocytes was confirmed by real-time monitoring of fatty acid uptake, by quantification of metabolite release into the effluent media as well as by an intact responsiveness to a therapeutic compound. The novel system provides a promising tool for wide-ranging applications in mechanistic research of WAtrelated biology, in studying of pathophysiological mechanisms in obesity and diabetes, and in R&D of pharmaceutical industry. The global obesity pandemic poses one of today's biggest challenges to public health. Each year, 2.8 million people die from causes related to overweight or obesity 1. Since the 1970s, the worldwide prevalence of obesity has nearly tripled, also leading to an upsurge in associated comorbidities such as type 2 diabetes (Fig. 1a) 2. Future projections reveal the gravity of this public health crisis: the prevalence rates of childhood obesity are increasing at an alarming pace 3 , and by 2030, more than 50% of U.S. adults are predicted to be obese 4. White adipose tissue (WAT) is the principal organ in obesity. In healthy human adults, WAT comprises approximately 20-25% of the total body mass, thus constituting the second largest organ, after the skin. In obese individuals, WAT's contribution to the total body mass may become as high as 50% (Fig. 1b) 5. WAT is tightly involved in the two most important functions of an organism-energy homeostasis and reproduction 6. In energy homeostasis, not only does WAT act as the main storage site of excess dietary energy (Fig. 1c), it also performs crucial endocrine and metabolic functions (Fig. 1d) 7,8. WAT can sense the body's energy status, and respond appropriately, either by storing fuel, in the form of triacylglycerides, or by releasing it as glycerol and fatty acids, for ultimate delivery to organs in need. While this classically described role of WAT already entailed extensive crosstalk between WAT and other organs, its inter-organ communications extend beyond simple feedback loops activated by fed-or fast...

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“…(17-19) Additionally, storage metabolism by WAT can have a major impact on the efficacy of drug therapies, such as those for cardiovascular diseases and cancer. (20,21) For instance, adipocytes may metabolize and inactivate the chemotherapeutic, Daunorubicin, (21) which strongly affects the efficacy of this anticancer therapeutic. Furthermore, the capacity of WAT to sequester hydrophobic compounds, gives the tissue a prominent role in absorption, distribution, metabolism, and excretion (ADME) processes.…”

Section: Introductionmentioning

confidence: 99%

WAT’s up!? – Organ-on-a-chip integrating human mature white adipose tissues for mechanistic research and pharmaceutical applications

Rogal

Binder

Kromidas

et al. 2019

Preprint

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Obesity and its numerous adverse health consequences have taken on global, pandemic proportions. White adipose tissue (WAT) -a key contributor in many metabolic diseasescontributes about one fourth of a healthy human's body mass. Despite its significance, many WAT-related pathophysiogical mechanisms in humans are still not understood, largely due to the reliance on non-human animal models. In recent years, Organ-on-a-chip (OoC) platforms have developed into promising alternatives for animal models; these systems integrate engineered human tissues into physiological microenvironment supplied by a vasculature-like microfluidic perfusion. Here, we report the development of a novel OoC that integrates functional mature human WAT. The WAT-on-a-chip is a multilayer device that features tissue chambers tailored specifically for the maintenance of 3D tissues based on human primary adipocytes, with supporting nourishment provided through perfused media channels. The platform's capability to maintain long-term viability and functionality of WAT was confirmed by real-time monitoring of fatty acid uptake, by quantification of metabolite release into the effluent media as well as by an intact responsiveness to a therapeutic compound. The novel system provides a promising tool for wide-ranging applications in mechanistic research of WAT-related biology, in studying of pathophysiological mechanisms in obesity and diabetes, and in R&D of pharmaceutical industry.WAT's up!? -A human WAT-on-a-chip Rogal, Binder, Kromidas, Probst, Schneider, Schenke-Layland, and Loskill

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The Impact of Obesity on the Pharmacology of Medications Used for Cardiovascular Risk Factor Control

Cited by 30 publications

References 76 publications

Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

WAT-on-a-chip integrating human mature white adipocytes for mechanistic research and pharmaceutical applications

WAT’s up!? – Organ-on-a-chip integrating human mature white adipose tissues for mechanistic research and pharmaceutical applications

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