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Potential Cardioprotective Effects of Orlistat for Treatment of Myocardial Infarction

  • Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil
  • Faculdade Pitágoras de Teixeira de Freitas


Background: Acute myocardial infarction (AMI) is characterized by ischemic lesions that severely compromise the cardiac structure/function, besides the survival of mammals. Although conventional therapy uses cardiac reperfusion, this procedure increases the cardiac damage caused by ischemia. Methods: Adult male Wistar rats (NWR) were anesthetized, placed on mechanical ventilation and underwent surgery to induce cardiac I/R by obstructing left descending coronary artery followed by reperfusion to evaluation of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) with pancreatic lipase inhibitor orlistat (ORL). At the end of reperfusion, blood samples were collected for determination of triglycerides (TG), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase-MB (CK-MB). Results: Treatment with ORL has been able to decrease the incidence of VA, AVB and LET. Besides that, the treatment with ORL reduced serum concentrations of CK and LDL, but did not alter the levels of serum concentration of TG, VLDL and HDL. Conclusion: The reduction of VA, AVB, and LET and serum levels of CK produced by 10 days of treatment with ORL indicate that ORL could be an important cardioprotective agent useful to attenuate myocardial damage caused by AMI in animal models. This result could be similar in humans, althoug similar studies will be necessary to confirm this effect.
Potential Cardioprotective Effects of Orlistat for Treatment of Myocardial
Francisco Sandro Menezes-Rodrigues1, José Gustavo Padrão Tavares1, Erisvaldo Amarante de Araújo1, Luciana de Paula2, Paolo Ruggero Errante1, Afonso
Caricati-Neto1 and Leandro Bueno Bergantin1*
1Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo-SP, Brazil
2Laborvisa–Laboratório de Análises Clínicas, São Paulo-SP, Brazil
*Corresponding author: Leandro Bueno Bergantin, Ph.D. Laboratory of Autonomic and Cardiovascular Pharmacology, Department of Pharmacology-Escola Paulista de
Medicina (EPM), Universida Federal de São Paulo (UNIFESP), Brazil, Tel: 55 11 5576-4973; E-mail:
Received date: July 13, 2017; Accepted date: July 21, 2017; Published date: July 28, 2017
Copyright: © 2017 Bergantin LB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Acute myocardial infarction (AMI) is characterized by ischemic
lesions that severely compromise cardiac structure and function, and
even the survival of mammals. e ischemic cardiac diseases (ICD) are
related to million deaths per year in the world [1,2]. Although
convencional therapy is based on the cardiac reperfusion (R), this
procedure increases cardiac damage caused by ischemia (I), and severe
arrhythmias (e.g. ventricular arrhythmias and atrio-ventricular
blockade) [2-5]. Several reports have demonstrated that cardiac
arrhythmias caused by myocardial ischemia and reperfusion (I/R)
could be originated from bioenergetic, and electrochemical, imbalance
triggered mainly by decrease of ATP synthesis by mitochondria, and
cytosolic Ca2+ overload in cardiomyocytes [2-5]. is Ca2+ overload is
massively worsed by the increase of Ca2+ inux through L-type
voltage-activated Ca2+ channels (VACC) caused by continuous
membrane depolarization of cardiomyocytes during cardiac I/R [2-5].
In addition, cytosolic Ca2+ overload promotes accumulated Ca2+ in the
mitochondrial matrix via increase of Ca2+ inux through
mitochondrial uniporter, leading to mitochondrial bioenergetic
collapse, and excessive production of free radical, which compromises
the structure and function of mitochondria, and other cytoplasmic
organelles [2-5]. ese cellular mechanisms importantly contribute for
developing arrhythmias, and death in AMI patients. Despite
continuous advances in AMI treatment, a high ratio of patients dies
suddenly in the early hours before arriving at the hospital [6-9]. Most
of these early deaths are due to complex ventricular arrhythmias (VA)
and atrio-ventricular blockade (AVB) [6-9]. Surprisingly, there is still
lack of knowledge about the exact events of these early malignant
arrhythmias, and their cellular and molecular mechanisms. Due to
involvement of intracellular Ca2+ overload in cardiac arrhythmias
caused by myocardial I/R, the use of pharmaceuticals that reduce this
Ca2+ overload represents an alternative pharmacological approach to
the treatment of ischemic cardiac diseases in humans, including AMI.
Nonetheless, the cardiac reperfusion (R) continues to be the therapy
more used to treat ICD [6-9]. Among the various risk factors for
persuing cardiac I/R, we can highlight obesity; this disease has
worldwide importance, and it is intrinsically related to cardiovascular
diseases (e.g. atherosclerosis and thrombosis). erefore, there is an
incessant and required worldwide research for drugs that eectively act
in the treatment of obesity. is is a metabolic disease that arises from
biochemical, hormonal and energetic disorders [10,11]. Several drugs
are used for the pharmacotherapy of obesity-FDA approved
pharmacological monotherapy options-including orlistat (ORL,
pancreatic lipase inhibitor) [12,13]. erefore, our group decided to
evaluate potential cardioprotective eects of the agents used in the
pharmacotherapy (such as ORL) of dyslipidemia in normotensive rats-
treated with ORL for ten days-and submitted to the model of in vivo
cardiac I/R developed by our group [14]. e cardioprotection was
analyzed by evaluation of the electrophysiological parameters through
the electrocardiogram analysis (arrhythmias), and serum
concentration biochemical markers of cardiac lesion produced in
response to the cardiac I/R protocol (creatine kinase (CK)), low-
density lipoprotein cholesterol (LDL-C) and lethality. We observed that
the treatment with ORL could decrease the lethality, the serum levels
of CK and LDL-C compared to control groups, indicating
cardioprotective eects of the ORL. ese results suggest that ORL
produced cardioprotective eects against cardiac damage caused by
cardiac I/R.
Research supported by CNPq, FAPESP and CAPES.
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DOI: 10.4172/2572-9462.1000e108
Editorial OMICS International
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Volume 3 • Issue 3 • 1000e108
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Citation: Menezes-Rodrigues FS, Padrão Tavares JG, Araújo EA, Paula LD, Errante PR, et al. (2017) Potential Cardioprotective Effects of
Orlistat for Treatment of Myocardial Infarction. J Thrombo Cir 3: e108. doi:10.4172/2572-9462.1000e108
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Volume 3 • Issue 3 • 1000e108
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The present study evaluated electrocardiographic alterations in rats with epilepsy submitted to an acute myocardial infarction (AMI) model induced by cardiac ischemia and reperfusion. Rats were randomly divided into two groups: control (n=12) and epilepsy (n=14). It was found that rats with epilepsy presented a significant reduction in atrioventricular block incidence following the ischemia and reperfusion procedure. In addition, significant alterations were observed in electrocardiogram intervals during the stabilization, ischemia, and reperfusion periods of rats with epilepsy compared to control rats. It was noted that rats with epilepsy presented a significant increase in the QRS interval during the stabilization period in relation to control rats (P<0.01). During the ischemia period, there was an increase in the QRS interval (P<0.05) and a reduction in the P wave and QT intervals (P<0.05 for both) in rats with epilepsy compared to control rats. During the reperfusion period, a significant reduction in the QT interval (P<0.01) was verified in the epilepsy group in relation to the control group. Our results indicate that rats submitted to an epilepsy model induced by pilocarpine presented electrical conductivity alterations of cardiac tissue, mainly during an AMI episode.
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Background Cardiovascular diseases (CVDs) are the number one cause of death globally and are the leading cause of death in India also. Several surveys conducted across the country over the past few decades have shown a rising prevalence of major risk factors for CVD in Asian Indian population. The problem of increasing risk factors for CVD in India is because of lack of surveillance system and lack of proper diagnosis. This study will help to point out the need of research so that some advanced diagnosis system may be developed for proper diagnosis of CVDs and to reduce the growing burden of CVDs in the country. Methods We did a literature search for the period from 1968 to 2012 using PUBMED search to identify all relevant studies of cardiovascular diseases. Besides PUBMED searching, manual searching has also been done. This article provides a review of current understanding of the epidemiology of cardiovascular disease, particularly, coronary heart disease (CHD), stroke and related risk factors in Asian Indian population. Results Hypertension and diabetes are highly prevalent among Asian Indian population, which may explain their high rate of stroke and heart attack in India. The increasing rate of CVD may be explained by the high rates of other risk factors including adverse lipid profile. The etiology of cardiovascular diseases (CVD) is multifactorial and no single factor is an absolute cause. Conclusion The cardiovascular diseases and its risk factors are increasing with a rapid pace in Asian Indian population. Though the prevalence of CVD risk factors is found higher in urban population, yet it is increasing at an alarming rate in rural population also, which is a serious threatening to the nation. Since majority of the Indians live in rural area, CVD may lead to epidemic proportions. We need health promotion programs and reorientation of primary health care to improve CVD detection in earlier stage and its management.
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Ventricular fibrillation is the main cause of sudden cardiac death among patients with acute myocardial infarction (AMI). Substantial benefits could be obtained by both researchers and practitioners if an AMI reperfusion-ventricular fibrillation-cardiac arrest model were established. Twenty swine were anesthetized and underwent occlusion of the left anterior descending branch for 90 minutes prior to blood reperfusion. Throughout this process, continuous 12-lead electrocardiography (ECG) was used to monitor heart rate, rhythm, and electrocardiogram alteration. Thereafter, AMI was confirmed by ECG and left ventricular angiography. Heart tissue was collected for pathological analysis, and for evaluation of the establishment of a model of AMI reperfusion. Seven swine died during the model establishment, and the 13 surviving swine were proven to have myocardial infarction; nine of those survivors had ventricular fibrillation-cardiac arrest after reperfusion based on the electrocardiograph and pathological examination. Blocking the left anterior descending branch by inflation of an over-the-wire coronary balloon catheter in swine can result in successful establishment of a swine model of AMI and reperfusion-ventricular fibrillation-cardiac arrest, with good reproducibility and a high survival rate.
Full-text available
Myocardial ischemia reperfusion injury contributes to adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. Primarily, no blood flow to the heart causes an imbalance between oxygen demand and supply, named ischemia (from the Greek isch, restriction; and haema, blood), resulting in damage or dysfunction of the cardiac tissue. Instinctively, early and fast restoration of blood flow has been established to be the treatment of choice to prevent further tissue injury. Indeed, the use of thrombolytic therapy or primary percutaneous coronary intervention is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. Unfortunately, restoring blood flow to the ischemic myocardium, named reperfusion, can also induce injury. This phenomenon was therefore termed myocardial ischemia reperfusion injury. Subsequent studies in animal models of acute myocardial infarction suggest that myocardial ischemia reperfusion injury accounts for up to 50% of the final size of a myocardial infarct. Consequently, many researchers aim to understand the underlying molecular mechanism of myocardial ischemia reperfusion injury to find therapeutic strategies ultimately reducing the final infarct size. Despite the identification of numerous therapeutic strategies at the bench, many of them are just in the process of being translated to bedside. The current review discusses the most striking basic science findings made during the past decades that are currently under clinical evaluation, with the ultimate goal to treat patients who are suffering from myocardial ischemia reperfusion-associated tissue injury.
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.
Obesity is a disease that has historically eluded effective medical therapy. Prior to 2012, phentermine and orlistat were the only medications available to treat obesity in the USA, with phentermine approved only for short-term use. However, as of 2015, the repertoire of pharmacological agents available to treat obesity has greatly expanded to include four new drugs: lorcaserin, phentermine/topiramate extended release (ER), naltrexone ER/wellbutrin ER and liraglutide. Each has a unique mechanism of action and all are intended for long-term use. These newer medications share a common strategy to promote weight loss in that they are designed to manipulate the control of hunger and satiety in the central nervous system. Interestingly, the majority of these new agents are combinations of older medications that have been used for conditions other than obesity. The amount of weight loss seen with these agents beyond placebo varies but generally falls in the range of 3-10% of starting weight and requires continual use of the drug in order for weight loss to be sustained. In addition, each drug has a unique side effect profile that should be carefully considered when selecting the best agent for a given individual. This article provides a review of these recently approved medications focusing on efficacy, side effect profiles and appropriate application to the individual patient.
Introduction: Ischemia-reperfusion injury (IRI) involves a complex sequence of events and limits the outcome of various surgical interventions. Clinical trials, based on the data of experimental models, aim to prove whether a pharmacological or technical approach could be suitable to provide a beneficial effect in humans. Due to the complexity of IRI, few pharmacological treatments have been investigated in clinical Phase III. Areas covered: In this review we report clinical trials that test specific drugs in clinical trials of organ transplantation. These studies form part of Phase II trials and examine the administration of caspase inhibitors, P-selectin antagonist or an antioxidant component in order to attenuate cold IRI during transplantation. Moreover, we provide a brief description of drugs tested on trials of different clinical situations associated to IRI, such as the coronary artery bypass graft surgery and percutaneous coronary intervention. Expert opinion: Future clinical trials could be centered on the application of techniques suitable for organs with increased vulnerability toward IRI. Furthermore, the standardization of reliable biomarkers and a careful estimation of the impact of high risk factors may be the key in order to achieve a more critical evaluation of the obtained results.
An implantable-cardioverter defibrillator (ICD) can terminate ventricular arrhythmias by delivering a shock or by antitachycardia pacing (ATP). The ATP works by capturing the excitable gap and disrupting re-entrant ventricular arrhythmias. Multiple studies have demonstrated that ATP is successful at terminating ventricular tachycardia (VT). Shocks from the ICD are associated with higher mortality. The data are conflicting about whether appropriate ATP is associated with higher mortality. In a patient with VT that is treated by ATP, the patient's guideline-based heart failure medications should be maximized. The use of VT ablation after appropriate and successful ATP requires additional studies. Copyright © 2015 Elsevier Inc. All rights reserved.
Introduction: Options for treating obesity remain limited despite it being a chronic, recurrent and morbid condition. New drugs that are proposed for its treatment encounter strong reluctance by regulatory agencies and many doctors. Areas covered: This review will focus on the safety of an older drug, orlistat (the only one still approved in the European Union) and a newer recently FDA-approved one, lorcaserin. Both are approved as long-term monotherapy for obesity in the United States of America and they have demonstrated median weight loss of nearly 3% over placebo. Expert opinion: Research, development and approval of new anti-obesity drugs are necessary for improved management of this chronic condition. Orlistat and lorcaserin are two FDA-approved drugs with limited overall efficacy. Nevertheless they are useful weapons for at least some obese individuals. Orlistat has a long and solid safety profile, whereas the safety of lorcaserin is still a matter of debate, mainly due to a lack of long-term data. However, lorcaserin's selective agonism on 5HT2c serotonin receptors diminishes concerns about valvulopathy associated with other serotonin agonists, such as fenfluramine.
Fatty acid synthase (FASN), the sole protein capable of de novo synthesis of free fatty acids, is overexpressed in a wide variety of human cancers and is associated with poor prognosis and aggressiveness of these cancers. Orlistat, an FDA-approved drug for obesity treatment that inhibits pancreatic lipases in the GI tract, also inhibits the thioesterase (TE) of human FASN. The cocrystal structure of TE with orlistat shows a pseudo TE dimer containing two different forms of orlistat in the active site, an intermediate that is covalently bound to a serine residue (Ser(2308)) and a hydrolyzed and inactivated product. In this study, we attempted to understand the mechanism of TE-catalyzed orlistat hydrolysis by examining the role of the hexyl tail of the covalently bound orlistat in water activation for hydrolysis using molecular dynamics simulations. We found that the hexyl tail of the covalently bound orlistat undergoes a conformational transition, which is accompanied by destabilization of a hydrogen bond between a hydroxyl moiety of orlistat and the catalytic His(2481) of TE that in turn leads to an increased hydrogen bonding between water molecules and His(2481) and increased chance for water activation to hydrolyze the covalent bond between orlistat and Ser(2308). Thus, the conformation of the hexyl tail of orlistat plays an important role in orlistat hydrolysis. Strategies that stabilize the hexyl tail may lead to the design of more potent irreversible inhibitors that target FASN and block TE activity with greater endurance.