Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 5, Number 3, July 2007
Contents
Advances in Antithrombotic Agents Pp.
175-185
R. Chakrabarti and S.K. Das
[Abstract]
Carbohydrates in Therapeutics Pp. 186-197
M. Kilcoyne and L. Joshi
[Abstract]
JAK2 as a Molecular Marker in Myeloproliferative Diseases
Pp. 198-203
R. Mata, D. Subirá, A. García-Raso and P.
Llamas
[Abstract]
Development of Nitric Oxide Donors for the Treatment
of Cardiovascular Diseases Pp. 204-208
H. Katsumi, M. Nishikawa and M. Hashida
[Abstract]
Management of Cardiovascular Risk Factors in Patients
with Metabolic Syndrome Pp. 209-214
A. de la Sierra and L.M. Ruilope
[Abstract]
Statins and Metabolism of High Density Lipoprotein
Pp. 215-221
D. Sviridov, P. Nestel and G. Watts
[Abstract]
Natural Products to Anti-trypanosomal Drugs: An Overview
of New Drug Prototypes for American Trypanosomiasis
Pp. 222-235
A.G. Tempone, P. Sartorelli, C. Mady and F. Fernandes
[Abstract]
Advanced Glycation End Products (AGEs) and Cardiovascular
Disease (CVD) in Diabetes Pp. 236-240
S.-I. Yamagishi, T. Matsui, S.-I. Ueda, K. Nakamura and
T. Imaizumi
[Abstract]
Regulation of Blood Pressure by D5
Dopamine Receptors Pp. 241-248
C. Zeng, Z. Yang, L.D. Asico and P.A. Jose
[Abstract]
Abstracts
[Back to top]
Advances in Antithrombotic Agents
R. Chakrabarti and S.K. Das
Thrombosis is the condition where an imbalance in the homeostatic
mechanism results in unwanted intravascular thrombus formation.
Imbalances in this highly regulated process of coagulation
and anticoagulation can lead to a variety of pathophysiological
conditions leading to stroke, pulmonary heart attack and other
serious conditions. In the western world, thromboembolic diseases
are the leading cause of morbidity and mortality. Remarkable
progress has occurred over the last decade in the development
of antithrombotic drugs, which can be classified into 3 major
categories – Anticoagulants, Antiplatelets and thrombolytics.
Increased understanding of the pathobiology of thrombotic
and vascular disorders has helped researchers to target novel
pathways involving the coagulation, thrombolytic, fibrinolytic
and integrin systems. Traditionally aspirin and unfractionated
heparin was used for myocardial infarction. Newer antiplatelet
agents such as, clopidogrel, GP IIb/IIIa inhibitors, low molecular
weight heparin, direct thrombin inhibitors and several improved
thrombolytic agents have been introduced for clinical use.
This review will discuss different important drugs, which
have been launched in recent years and also some new targets
pursued by different companies.
[Back to top]
Carbohydrates in Therapeutics
M. Kilcoyne and L. Joshi
Awareness of the importance of carbohydrates in living systems
and medicine is growing due to the increasing understanding
of their biological and pharmacological relevance. Carbohydrates
are ubiquitous and perform a wide array of biological roles.
Carbohydrate-based or -modified therapeutics are used extensively
in cardiovascular and hematological treatments ranging from
inflammatory diseases and anti-thrombotic treatments to wound
healing. Heparin is a well-known and widely used example of
a carbohydrate-based drug but will not be discussed as it
has been extensively reviewed. We will detail carbohydrate-based
and –modified therapeutics, both those that are currently
marketed or in various stages of clinical trials and those
that are potential therapeutics based on promising preclinical
investigations. Carbohydrate-based therapeutics include polysaccharide
and oligosaccharide anti-inflammatory, anti-coagulant and
anti-thrombotic agents from natural and synthetic sources,
some as an alternative to heparin and others which were designed
based on known structure-functional relationships. Some of
these compounds have multiple biological effects, showing
anti-adhesive, anti-HIV and anti-arthrithic activities. Small
molecules, derivatives or mimetics of complement inhibitors,
are detailed for use in limiting ischemia/ reperfusion injuries.
Monosaccharides, both natural and synthetic, have been investigated
for their in vivo anti-inflammatory and cardioprotective
properties. Modification by glycosylation of natural products,
or glycosylation-mimicking modification, has a significant
effect on the parent molecule including increased plasma half-life
and refining or increasing desired functions. It is hoped
that this review will highlight the vast therapeutic potential
of these natural bioactive molecules.
[Back to top]
JAK2 as a Molecular Marker in Myeloproliferative Diseases
R. Mata, D. Subirá, A. García-Raso and P.
Llamas
The molecular pathogenesis of the myeloproliferative disorders
(MPD) is poorly understood, except for chronic myeloid leukemia
(CML). Recently, several groups have discovered a novel recurrent
unique acquired clonal mutation in a tyrosine-kinase JAK2
in patients with Philadelphia-negative MPD and other myeloid
disorders. It consists in a guanine-to-thymine change encoding
a valine to phenylalanine at codon 617 (JAK2 V617F). JAK2
and the other members of the Janus kinase family are tyrosine
kinases that function as intermediates between membrane receptors
and intracellular signalling molecules. The mutation occurs
within the enzymatically inactive JH2 pseudo-kinase domain
that regulates the active JH1 kinase domain. The JAK2 activation
leads to constitutive JAK and STAT (activators of transcription)
hyperactivation with induction of growth factor hypersensitivity
and cell transformation. Some authors have found a higher
risk of vascular thrombosis and higher platelet activation
when the mutation is present. Therefore, the JAK2 mutation
offers a molecular target for new drugs investigation in a
similar way to bcr/abl rearrangement in CML. For all these
reasons, several studies related to JAK2 have arisen in the
last year. In this report, we will review the literature and
discuss its possible clinical and prognostic significance.
[Back to top]
Development of Nitric Oxide Donors for the Treatment
of Cardiovascular Diseases
H. Katsumi, M. Nishikawa and M. Hashida
Nitric oxide (NO) is a molecule that dynamically modulates
the physiological functions of the cardiovascular system,
which include relaxation of vascular smooth muscle, inhibition
of platelet aggregation, and regulation of immune responses.
Because a reduced NO level has been implicated in the onset
and progression of various disease states, NO is expected
to provide therapeutic benefits in the treatment of cardiovascular
diseases, such as essential hypertension, stroke, coronary
artery disease, atherosclerosis, platelet aggregation after
percutaneous transluminal coronary angioplasty, and ischemia/reperfusion
injury. To date, pharmacologically active compounds that can
release NO within the body, such as organic nitrates and sodium
nitroprusside, have been used as therapeutic agents, but their
efficacy is significantly limited by their rapid NO release,
poor distribution to the target site, toxicity, and induction
of tolerance. Therefore, new NO donors with better pharmacological
and pharmacokinetic properties would be highly desirable.
In this review, recent challenges in the development of new
NO donors and NO delivery systems are summarized. Then, future
developments of novel NO donors are also discussed in order
to optimize NO delivery in the treatment of cardiovascular
diseases.
[Back to top]
Management of Cardiovascular Risk Factors in Patients
with Metabolic Syndrome
A. de la Sierra and L.M. Ruilope
Metabolic syndrome is defined as the combination of abdominal
obesity, insulin resistance, atherogenic dyslipidemia, and
prothrombotic and proinflammatory states. Due to the epidemic
proportion of overweight and obesity worldwide and the development
of useful clinical tools to identify these patients more easily,
metabolic syndrome is increasingly recognized in adults and
represents a clear risk factor for the development of both
type 2 diabetes and cardiovascular disease. Management of
patients with metabolic syndrome is a clinical challenge and
requires a multifactorial, multidisciplinary approach. Changes
in lifestyle are obviously the first therapeutic step and
include both dietary modifications and increased daily exercise.
Several questions remain to be elucidated with respect to
pharmacological treatment. The blood pressure levels required
to initiate antihypertensive treatment, the blood pressure
goal to be achieved and the possibility of including a renin-angiotensin
system blocker as a part of the pharmacological treatment
are still under discussion. The management of atherogenic
dyslipidemia is focused on LDL-cholesterol levels, although
most patients with metabolic syndrome have normal LDL-cholesterol.
There is lack or poor evidence on the need for specific drugs
to reduce triglycerides, to increase HDL-cholesterol, to improve
insulin sensitivity or to decrease abdominal obesity. There
is an urgent need for consensus in the treatment of subjects
with metabolic syndrome in order to prevent very high future
rates of type 2 diabetes and cardiovascular disease.
[Back to top]
Statins and Metabolism of High Density Lipoprotein
D. Sviridov, P. Nestel and G. Watts
Statins are competitive inhibitors of HMG-CoA reductase, the
rate-limiting enzyme of cholesterol biosynthesis. Statins
are widely and successfully used for lowering plasma cholesterol
levels causing up to 45% reduction of plasma cholesterol and
considerable reduction in risk of cardiovascular diseases.
The main atheroprotective action of statins is reduction of
plasma low density lipoprotein levels due to improved clearance
of this lipoprotein by the liver. In addition, statins cause
mild elevation of high density lipoprotein (HDL) concentration,
but the mechanism responsible for this effect of statins on
HDL metabolism is not well understood. It has been hypothesized
that statins affect the HDL level through inhibition of cholesteryl
ester transfer protein activity or by stimulating apolipoprotein
A-I synthesis. Increased cholesterol efflux from liver due
to raised expression of the ABCA1 transporter may also elevate
HDL levels. Whereas raising the plasma HDL-C concentration
may contribute to the atheroprotective effect of statins,
its magnitude is uncertain and additional mechanisms that
improve the functionality of HDL may be equally or more important.
In this review we analyze what is currently known about effect
of statins on HDL metabolism and on reverse cholesterol transport
in particular.
[Back to top]
Natural Products to Anti-trypanosomal Drugs: An Overview
of New Drug Prototypes for American Trypanosomiasis
A.G. Tempone, P. Sartorelli, C. Mady and F. Fernandes
Protozoan tropical diseases cause great suffering throughout
developing countries, with high rates of morbidity and mortality.
American Trypanosomiasis affects 16-18 million people in Latin
America, representing a dramatic disease among symptomatic
patients. Old, toxic and ineffective chemotherapeutic agents
continue to be used for the treatment of Chagas´ disease.
Since the early days of medicine, chemical substances derived
from plants and animals have been used to treat human diseases.
In the marine ecosystem ecological pressures, such as competition
for space and predation, may have favored several invertebrate
organisms to select unique metabolites with an assortment
of astonishing biological activities. In terrestrial ecosystems,
amphibians present a unique efficient skin secretion system
with a variety of glands which produce a myriad of potent
bioactive compounds such as peptides, alkaloids, biogenic
amines and lipids. Plants contribute with several antitrypanosomal
compounds derived mainly from their secondary metabolism.
Proteins and peptides from snake venoms have also been considered
as novel drug candidates, showing effective activities. In
this review, we broadly discuss the epidemiology, pathology,
and current treatment of Chagas’ disease as well as
the contributions of pharmacologically tested marine invertebrate,
amphibian, snake and plant compounds which have shown promising
antitrypanosomal activities. We also explore these possibilities
for developing new chemotherapeutics against Chagas’
disease.
[Back to top]
Advanced Glycation End Products (AGEs) and Cardiovascular
Disease (CVD) in Diabetes
S.-I. Yamagishi, T. Matsui, S.-I. Ueda, K. Nakamura and
T. Imaizumi
Accelerated atherosclerosis and microvascular complications
are perhaps the leading cause of coronary heart disease, blindness
and renal failure, which could account for disabilities and
high mortality rates in patients with diabetes. Several mechanisms
including endothelial cell damage, platelet activation and
aggregation, hypercoagulability, and impaired fibrinolysis
are involved in the pathogenesis of thrombogenic diathesis
in diabetes. However, the underlying molecular mechanism is
not fully elucidated. A recent clinical study, the Diabetes
Control and Complications Trial-Epidemiology of Diabetes Interventions
and Complications (DCCT-EDIC) Research, has revealed that
the reduction in the risk of progressive retinopathy and nephropathy
resulting from intensive therapy in patients with type 1 diabetes
persist for at least several years, despite increasing hyperglycemia.
In addition, intensive therapy during the DCCT also reduced
the risk of cardiovascular events by about 50 % in type 1
diabetic patients 11 years after the end of the trial. These
clinical studies strongly suggest that so-called ‘hyperglycemic
memory’ causes chronic abnormalities in diabetic vessels
that are not easily reversed, even by subsequent, relatively
good control of blood glucose. Among various biochemical pathways
implicated in diabetic vascular complications, the process
of formation and accumulation of advanced glycation end products
(AGEs) and their mode of action are most compatible with the
theory ‘hyperglycemic memory’. In this review,
we discuss the role of AGEs in thrombogenic abnormalities
in diabetes, especially focusing on the deleterious effects
of these macroproteins on endothelial cell function, platelet
activation and aggregation, coagulation and fibrinolytic systems.
[Back to top]
Regulation of Blood Pressure by D5
Dopamine Receptors
C. Zeng, Z. Yang, L.D. Asico and P.A. Jose
Dopamine receptors have been identified in a number of organs
and tissues, which include the central and peripheral nervous
systems, various vascular beds, the heart, the gastrointestinal
tract, and the kidney. Dopamine receptors are classified into
D1- and D2-like
subtypes based on their structure and pharmacology; during
conditions of moderate sodium balance, more than 50% of renal
sodium excretion is regulated by D1-like
receptors. Most of the knowledge on the actions of dopamine
has been focused on the D1
dopamine receptor. The D5
dopamine receptor also belongs to the D1-like
receptor subfamily. Disruption of the D5
receptor results in hypertension. However, unlike the D1
receptor, the hypertension in D5
receptor null mice is caused by the increased activity of
the sympathetic nervous system, apparently due to activation
of oxytocin, V1 vasopressin,
and non-NMDA receptors in the central nervous system. In this
paper, we review the physiological action of D5
receptor on the central and peripheral nervous systems, and
discuss the possible mechanisms by which hypertension develops
when the D5 receptor function
is perturbed.
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