Anti-obesity drug discovery and development Volume 1

293 Pages·2011·10.93 MB·English

by  Atta-ur- Rahman

Anti-Obesity Drug Discovery and
Development
(Volume 2)
Editor
Atta-ur-Rahman, FRS
Kings College
University of Cambridge
Cambridge
UK
&
M. Iqbal Choudhary
H.E.J. Research Institute of Chemistry
International Center for Chemical and Biological Sciences
University of Karachi
Karachi
Pakistan
Bentham Science Publishers Ltd.
Executive Suite Y - 2
PO Box 7917, Saif Zone
Sharjah, U.A.E.
[email protected]

All rights reserved-©2014 Bentham Science Publishers Ltd.

Please read this license agreement carefully before using this eBook. Your use of this eBook/chapter constitutes your agreement to the terms and conditions
set forth in this License Agreement. This work is protected under copyright by Bentham Science Publishers Ltd. to grant the user of this eBook/chapter, a
non-exclusive, nontransferable license to download and use this eBook/chapter under the following terms and conditions:

1. This eBook/chapter may be downloaded and used by one user on one computer. The user may make one back-up copy of this publication
to avoid losing it. The user may not give copies of this publication to others, or make it available for others to copy or download. For a multi-
user license contact [email protected]

2. All rights reserved: All content in this publication is copyrighted and Bentham Science Publishers Ltd. own the copyright. You may not
copy, reproduce, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit
any of this publication’s content, in any form by any means, in whole or in part, without the prior written permission from Bentham Science
Publishers Ltd..

3. The user may print one or more copies/pages of this eBook/chapter for their personal use. The user may not print pages from this
eBook/chapter or the entire printed eBook/chapter for general distribution, for promotion, for creating new works, or for resale. Specific
permission must be obtained from the publisher for such requirements. Requests must be sent to the permissions department at E-mail:
[email protected]

4. The unauthorized use or distribution of copyrighted or other proprietary content is illegal and could subject the purchaser to substantial
money damages. The purchaser will be liable for any damage resulting from misuse of this publication or any violation of this License
Agreement, including any infringement of copyrights or proprietary rights.

5. The following DRM (Digital Rights Management) policy is applicable on this eBook for the non-library / personal / single-user. Library /
institutional / multi-users will get a DRM free copy and they may implement their own institutional DRM policy.

• 25 ‘Copy’ commands can be executed every 7 days. The text selected for copying cannot extend to more than one single page.

• 25 pages can be printed every 7 days.

• eBook files are not transferable to multiple computer/devices. If you wish to use the eBook on another device, you must send a
request to [email protected] along with the original order number that you received when the order was placed.

Warranty Disclaimer: The publisher does not guarantee that the information in this publication is error-free, or warrants that it will meet the users’
requirements or that the operation of the publication will be uninterrupted or error-free. This publication is provided "as is" without warranty of any kind,
either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire
risk as to the results and performance of this publication is assumed by the user. In no event will the publisher be liable for any damages, including, without
limitation, incidental and consequential damages and damages for lost data or profits arising out of the use or inability to use the publication. The entire
liability of the publisher shall be limited to the amount actually paid by the user for the eBook or eBook license agreement.

Limitation of Liability: Under no circumstances shall Bentham Science Publishers Ltd., its staff, editors and authors, be liable for any special or
consequential damages that result from the use of, or the inability to use, the materials in this site.

eBook Product Disclaimer: No responsibility is assumed by Bentham Science Publishers Ltd., its staff or members of the editorial board for any injury
and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products
instruction, advertisements or ideas contained in the publication purchased or read by the user(s). Any dispute will be governed exclusively by the laws of
the U.A.E. and will be settled exclusively by the competent Court at the city of Dubai, U.A.E.

You (the user) acknowledge that you have read this Agreement, and agree to be bound by its terms and conditions.

Permission for Use of Material and Reproduction

Permission Information for Users Outside the USA: Bentham Science Publishers Ltd. grants authorization for individuals to photocopy copyright
material for private research use, on the sole basis that requests for such use are referred directly to the requestor's local Reproduction Rights Organization
(RRO). The copyright fee is US $25.00 per copy per article exclusive of any charge or fee levied. In order to contact your local RRO, please contact the
International Federation of Reproduction Rights Organisations (IFRRO), Rue Joseph II, 9-13 I000 Brussels, Belgium; Tel: [phone]; Fax: +32 2
234 62 69; E-mail: [email protected]; url: www.ifrro.org This authorization does not extend to any other kind of copying by any means, in any form,
and for any purpose other than private research use.

Permission Information for Users in the USA: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific
clients, is granted by Bentham Science Publishers Ltd. for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional
Reporting Services, provided that the appropriate fee of US $25.00 per copy per chapter is paid directly to Copyright Clearance Center, 222 Rosewood
Drive, Danvers MA 01923, USA. Refer also to www.copyright.com
CONTENTS
Preface i
List of Contributors iv
CHAPTERS
1. An Approach to Obesity as a Cardiometabolic Disease: Potential
Implications for Clinical Practice 3
José Sabán-Ruíz, Martin Fabregate-Fuente, Rosa Fabregate-Fuente,
Ana Alonso-Pacho, Cristina de la Puerta González-Quevedo,
Susana Tello Blasco, Asunción Guerri, Alcira Andrés and Delia
Barrio
2. Estrogen is Protective Against Obesity and Obesity Related Co-
Morbidities; Cardiovascular Diseases and Malignancies 86
Zsuzsanna Suba
3. Herbal and Microbial Products for the Management of Obesity 130
Essam Abdel-Sattar, Soheir M. El Zalabani and Maha M. Salama
4. Natural Compounds – Anti-Obesity Properties 211
Sara M. Reyna and Jameela Banu
5. Sphingolipid Turnover Inhibitors as Modulators of Cellular
Metabolism and Obesity 242
Nataliya A. Babenko
Index 264
i
PREFACE
Obesity is a disease which leads to several chronic illnesses and reduces the life
expectancy. It is a complex health problem, caused by a number of factors, such
as excessive food intake, lack of physical activity, genetic predisposition,
endocrine disorders, use of certain medications, and psychiatric illnesses. More
recently a linkage between infection with Adenovirus 36 and obesity has also
been investigated. Obesity has been identified as the leading preventable cause of
mortality and morbidity, and substantial research has been conducted to identify
the molecular targets for pharmacological interventions. Extensive studies on
nutritional aspects and life style changes have also been carried out to prevent the
on-set of obesity. Prevalence of obesity in both developing and developed world
has reached to an epidemic proportion. In response to this, efforts to control and
treat obesity have also been vigorously pursued, ranging from raising awareness
about lifestyle modifications to the discovery and development of safe and
effective anti-obesity drugs.
“Anti-Obesity Drug Discovery and Development” focuses on this important area
of healthcare research. The second volume of this eBook series is a compilation of
five well written reviews on the state-of-the-art developments in obesity research.
This volume begins with a review of Sabán-Ruíz et al., explaining the relationship
between obesity and cardiometabolic syndrome. This comprehensive review
covers basic research and epidemiology about obesity, metabolic syndrome and
cardiac diseases, as well as old and new drugs used to treat obesity and
hypertension. The problem with such drugs that were approved for prescription,
was they are effective in the short-term but that they often exhibit several adverse
side effects. These include newer drugs, such as sibutramine, rimonabant and
orlistart. This has been an ongoing concern in anti-obesity drug development. The
researchers have also mentioned progress in the new drug development and
combined therapies in clinical trials. The chapter concludes with a discussion of
anti-obesity therapy using Topiramate, a drug used to treat psychological
disorders and the implications of such drugs for the treatment of cardiovascular
disorders.
ii
Obesity is also be regarded as a consequence of homeostatic imbalance within the
body. Homeostatic balance is influenced by hormone levels, food intake,
epigenetics, immunological factors, and others. Suba, in chapter 2, explores the
hypothesis of estrogen as an anti-obesity agent. The author suggests that estrogen
has positive regulatory effects on the lipid distribution in the body as well as
resistance to insulin. Research also suggests that insulin helps to promote
pancreatic insulin secretion and controls the inflammatory response of adipocytes.
Hormonal therapy, such as estrogen administration to patients - postmenopausal
women in particular - has shown positive outcomes with respect to curbing fat
deposition in the body.
In chapter 3, Essam Abdel-Sattar and colleagues have reviewed the scientific
works on herbal and microbial remedies of obesity. This review presents the
mechanisms of action of active ingredients and contains a comprehensive list of
herbs that can be used to treat obesity and associated disorders. The authors have
also included illustrations of some of these herbs, many of which could be used to
develop effective nutritional supplements.
Reyna and Banu have reviewed the work conducted on the capacity of natural
extracts which can be used to interface with lipid metabolism. Natural products
can provide a safe and cost effective OTC solution for the treatment of obesity.
This review focuses on several types of plant extracts and also discusses some
benefits of common dietary herbs, such as tea, lotus and certain oriental and
eastern spices. The review also provides information about the anti-obesity
mechanism of action of selected natural products.
Babenko has contributed a lucidly written review on the possibility of targeting
sphingolipids metabolism in the quest for controlling obesity. Specifically, this
can be achieved by targeting sphingomyelin hydrolysis and nucleotide synthesis
pathways to limit the ceramide production in cells. Since an increased ceramide
levels in obesity patients has been observed, it is believed that reducing the
concentration of ceramides, by inhibiting the enzymes involve in its biosynthesis,
can help in tackling the disease. The author discusses the results of inhibition of
sphingolipids in mice as a first step towards drug development.
iii
At the end we would like to express our deep gratitude to all the contributors for
making this volume an excellent compilation of state-of-the-art knowledge on the
molecular basis of obesity and its effective treatment. We also wish to express our
thanks to Ms. Maria Baig (Manager Publications) and other members of the
Bentham Science Publishers for their efforts in the timely completion of this
volume. We are also most grateful to Mr. Mahmood Alam (Director Publications)
for efficiently leading the Bentham team in this project.
Atta-ur-Rahman, FRS
Kings College
University of Cambridge
Cambridge
UK
&
M. Iqbal Choudhary
H.E.J. Research Institute of Chemistry
International Center for Chemical and Biological Sciences
University of Karachi
Karachi
Pakistan
iv
List of Contributors
Alcira Andrés
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Ana Alonso-Pacho
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Asunción Guerri
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Cristina de la Puerta González-Quevedo
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Delia Barrio
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Essam Abdel-Sattar
Pharmacognosy Department, College of Pharmacy, Cairo University, 11562,
Cairo, Egypt
Jameela Banu
Coordinated Program in Dietetics and Department of Biology, University of
Texas-Pan American, 1201, W. University Dr., Edinburg, TX 78539-2999, USA
José Sabán-Ruíz
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Maha M. Salama
Pharmacognosy Department, College of Pharmacy, Cairo University, 11562,
Cairo, Egypt
v
Martin Fabregate-Fuente
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Nataliya A. Babenko
Department of Physiology of Ontogenesis, Institute of Biology, Kharkov Karazin
National University, 4 Svobody pl., 61077 Kharkov, Ukraine
Rosa Fabregate-Fuente
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Sara M. Reyna
Department of Medicine and Medical Research Division, Edinburg Regional
Academic Health Center, University of Texas Health Science Center at San
Antonio, 1214, W Schunior, Edinburg, TX 78541, USA
Soheir M. El Zalabani
Pharmacognosy Department, College of Pharmacy, Cairo University, 11562,
Cairo, Egypt
Susana Tello Blasco
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Zsuzsanna Suba
National Institute of Oncology, Department of Surgical and Molecular Pathology,
Budapest, Hungary
Send Orders for Reprints to [email protected]
Anti-Obesity Drug Discovery and Development, Vol. 2, 2014, 3-85 3
CHAPTER 1
An Approach to Obesity as a Cardiometabolic Disease: Potential
Implications for Clinical Practice
José Sabán-Ruíz*, Martin Fabregate-Fuente, Rosa Fabregate-Fuente, Ana
Alonso-Pacho, Cristina de la Puerta González-Quevedo, Susana Tello Blasco,
Asunción Guerri, Alcira Andrés and Delia Barrio
Endothelium and Cardiometabolic Medicine Unit, Internal Medicine Service,
Ramón y Cajal Hospital, Madrid, Spain
Abstract: Obesity is a multifactorial disease that is currently developing a threatening
tendency towards becoming the main cause of chronic disease in the world. Obesity can
induce type 2 diabetes mellitus, dyslipidemia, cardiovascular disease and other chronic
disorders with high social and health costs. Obesity was firstly described in 2000 as a
cardiometabolic disease, even before Metabolic Syndrome, type 2 diabetes mellitus and
coronary disease were considered as such. In this chapter we recover this approach to
obesity, which has remained almost forgotten for the last decade. In obese subjects,
adipokines and miokines interact to promote reticulum stress, insulin resistance,
metabolic inflexibility and endothelial dysfunction. These pathological processes are
amplified when hyperglycemia is present, leading to an increased risk for
atherosclerosis. A number of potential implications for clinical practice are derived
from the cardiometabolic state underlying obesity and its comorbidities. The first step in
the therapeutic strategy against obesity should be the correct diagnosis of its causes and
the promotion of lifestyle changes including physical exercise and a healthy diet. In the
usual case of failing to achieve results, we can still resort to the pharmacological
therapy. While awaiting the release of new drugs, topiramate, alone or combined with
phentermine, has been proposed as a novel anti-obesity drug, showing relevant effects
not only on weight loss but also on cardiometabolic alterations and biomarkers, even
though new studies should clarify the mechanisms of these findings. Finally, our own
experience with topiramate is described, focusing on its effects upon weight loss and
inflammatory markers.
Keywords: Adipokine, adiposity, adiposopathy endoplasmic reticulum stress,
anti-obesity drugs, atherosclerosis, cardiometabolic disease, coronary heart
disease, diet, endothelial dysfunction, inflammation, insulin resistance, lifestyle
changes, metabolic inflexibility, miokine, obesity, physical activity, topiramate,
weight loss.
*Address correspondence to José Sabán-Ruiz: Endothelium and Cardiometabolic Medicine Unit, Internal
Medicine Service, Ramón y Cajal Hospital, Madrid, Spain; E-mail: [email protected]
Atta-ur-Rahman and M. Iqbal Choudhary (Eds)
All rights reserved-© 2014 Bentham Science Publishers