Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 5, Number 2, April 2007
Contents
Sclerosing Polidocanol Injections of Small Vessels
to Treat the Chronic Painful Tendon Pp. 97-100
H. Alfredson and R. Lorentzon
[Abstract]
Relaxin as a Cardiovascular Hormone: Physiology, Pathophysiology
and Therapeutic Promises Pp. 101-108
S. Nistri, M. Bigazzi and D. Bani
[Abstract]
Integrins: Novel Therapeutic Targets for Cardiovascular
Diseases Pp. 109-132
H. Lal, R.S. Guleria, D.M. Foster, G. Lu, L.E. Watson,
S. Sanghi, M. Smith and D.E. Dostal
[Abstract]
Emerging Therapeutic Approaches Multi-Targeting Receptor
Tyrosine Kinases and G Protein-Coupled Receptors in Cardiovascular
Disease Pp. 133-145
C. Flordellis, P. Papathanasopoulos, A. Lymperopoulos,
J. Matsoukas and H. Paris
[Abstract]
Current and Emerging Concepts in the Management of
Neovascular Age-Related Macular Degeneration Pp.
147-154
S.C. Maloney, K.D. Godeiro, A.N. Odashiro and M.N. Burnier,
Jr.
[Abstract]
Nitric Oxide, Malnutrition and Chronic Renal Failure
Pp. 155-161
T.M.C. Brunini, M.B. Moss, M.A.S. Siqueira, S.F.F. Santos,
J.R. Lugon and A.C. Mendes-Ribeiro
[Abstract]
Molecular Genetics of Quantitative Fibrinogen Disorders
Pp. 163-173
R. Asselta, S. Spena, S. Duga and M.L. Tenchini
[Abstract]
Abstracts
[Back to top]
Sclerosing Polidocanol Injections of
Small Vessels to Treat the Chronic Painful Tendon
H. Alfredson and R. Lorentzon
The chronic painful tendon (tendinopathy, tendinosis) is generally
considered difficult to treat, not seldom causing long-term
disability and sometimes ending the sports or work carreér.
Most common sites for tendinopathy are the Achilles-, patellar-,
extensor carpi radialis brevis (ERCB)-, and supraspinatus
tendons. The origin of pain has for many years been unknown,
but recently, by using ultrasound (US) + colour Doppler (CD),
immunohistochemical analyses of tendon biopsies, and diagnostic
injections of local anaestesia, we found a close relationship
between areas with vasculo-neural ingrowth and tendon pain.
Sensory nerves (Substance-P-SP and Calcitonin Gene Related
Peptide-CGRP) were found inside and outside the vascular wall.
In following clinical studies we have demonstrated good short-and
mid-term clinical results using treatment with US+CD-guided
sclerosing polidocanol injections, targeting the area with
neovessels outside the tendon. Two-year follow ups have showed
remaining good clinical results, and sonographically signs
of remodelling with a significantly thinner tendon with a
more normal structure. Whether the effects of polidocanol
are mediated through destruction of neovessels, activity on
nerves or a combination, is under evaluation.
[Back to top]
Relaxin as a Cardiovascular Hormone: Physiology, Pathophysiology
and Therapeutic Promises
S. Nistri, M. Bigazzi and D. Bani
Relaxin is a hormone belonging to the so-called relaxin superfamily,
which also includes insulin-like peptides. Relaxin is best
known for its effects on the female reproductive system, which
primarily include lengthening of the pubic symphysis and softening
of the tissues of the birth canal, stimulating mammary and
endometrial development, and maintenance of myometrial quiescence.
In recent years, evidence has been accumulating that relaxin
can have multiple and diverse effects on both reproductive
and nonreproductive organs, tissues and cells, thus acting
as a sort of ‘manager’ hormone to optimize the
many physiological changes taking place during pregnancy.
Among the specific relaxin targets, there are the blood vessels
and the heart. In fact, relaxin is a potent vasodilatator
of the systemic and coronary circulation, by a mechanism of
action involving nitric oxide, and can influence cardiac beating
rate. Identification of the numerous possible roles of relaxin
in the pathophysiology of cardiovascular diseases, not to
mention the possible therapeutical applications of relaxin,
remains a difficult task. Based on the known biological effects
of relaxin, it is becoming increasingly evident that the potential
fields of clinical investigation of human relaxin as a cardiovascular
drug could be in ischemic heart disease (acute and chronic
myocardial infarction), in cardiac fibrosis, in cell transplantation
for cardiac repair, and in obliterative peripheral arterial
disease. Availability of the homologous human peptide, knowledge
of its pharmacological, pharmacokinetic and pharmacodynamic
profiles, and increasing interest of clinicians and pharmaceutical
companies should synergistically act to transfer relaxin from
the laboratory bench to the bedside.
[Back to top]
Integrins: Novel Therapeutic Targets for Cardiovascular
Diseases
H. Lal, R.S. Guleria, D.M. Foster, G. Lu, L.E. Watson,
S. Sanghi, M. Smith and D.E. Dostal
Integrins are the principle mediators of molecular dialog
between a cell and its extracellular matrix environment. The
unique combinations of integrin subunits determine which extracellular
matrix molecules are recognized by a cell. Recent studies
have demonstrated that remodeling in heart and vasculature
is linked to alterations in extracellular matrix and integrin
expression. The roles of integrins in controlling cellular
behavior have made these molecules highly attractive drug
targets. New insights into mechanisms whereby the extracellular
matrix takes part in the control of smooth muscle cell proliferation
and cardiac growth suggest a number of putative targets for
future therapies that can be applied to increase plaque stability,
prevent the clinical consequences of atherosclerosis and improve
outcomes after interventional procedures such as cardiac transplantation.
Therapeutic candidates include antibodies, cyclic peptides,
peptidomimetics and small molecules. The integrin inhibitors
Integrilin and ReoPro have been approved as blood thinners
in cardiovascular disease, and newer agents are undergoing
testing. Although integrin function is important in the cardiovascular
system, there are wide gaps in knowledge. In this review,
we discuss the primary mechanisms of action and signaling
of integrins in the cardiac and vascular system in normal
and pathological states, as well as therapeutic strategies
for targeting these molecules in the cardiovascular system.
[Back to top]
Emerging Therapeutic Approaches Multi-Targeting Receptor
Tyrosine Kinases and G Protein-Coupled Receptors in Cardiovascular
Disease
C. Flordellis, P. Papathanasopoulos, A. Lymperopoulos,
J. Matsoukas and H. Paris
Advances in molecular biology and functional genomics have
demonstrated that the “one gene-one phenotypeone drug”
paradigm, that has dominated pharmaceutical industry and clinical
pharmacology thinking, is too simplistic for management of
complex polygenic traits. The traditional highly specific
drugs with unique target have proven their clinical usefulness.
However, they do not always display the required efficacy
versus side-effect profile, in major part because polygenic
traits are determined by redundant mechanisms. Simultaneously
modulating multiple targets may enhance therapeutic efficacy
in the treatment of a range of disorders. Multi-targeting
can be achieved by the combination of different drugs having
specific single target activity. This approach introduces
potential problems with pharmacokinetic interactions, toxicity
and patient compliance. High efficacy can be achieved, alternatively,
by administering selectively non-selective drugs with complex
pharmacological profiles directed towards various molecular
targets and affording pleiotropic actions. Dual- or multiple-ligands
can be discovered accidentally, but can also be rationally
designed according to validated medicinal chemical approaches.
The merits of multiple-target versus single-target approaches
for cardiovascular disease traits are assessed in the present
review. The main aim is to make evident the molecular biological
basis of the possibility for targeting multiple sites and
the subsequently emerging strategies for interventions with
superior clinical value by harnessing receptor tyrosine kinases
(RTKs) such as VEGFR, PDGFR, bFGFR, as well as G protein-coupled
receptors (GPCRs). The premises for lead discovery in this
new area and the challenges of medicinal chemistry behind
the rational design of multitasked ligands are also discussed.
[Back to top]
Current and Emerging Concepts in the Management of
Neovascular Age-Related Macular Degeneration
S.C. Maloney, K.D. Godeiro, A.N. Odashiro and M.N. Burnier,
Jr.
Age-related macular degeneration (AMD) is the leading cause
of blindness in the elderly worldwide. The more severe form
of the disease, known as neovascular AMD, is characterized
by aberrant growth of blood vessels from the choroid into
the subretinal space. This pathologic choroidal neovascularization
can have drastic consequences, often seriously impairing vision
in affected individuals. Current treatment approaches focus
on combination therapies that include photodynamic therapy
in conjunction with numerous forms of antiangiogenic or anti-inflammatory
drug intervention. To date, however, no adequate treatment
is available for the majority of affected individuals. The
threat of a rapidly aging population provides the impetus
for aggressive efforts to control the prevalence and progression
of this disease. This review will outline the currently available
pharmacotherapies, discussing the justification for their
use as well as their short-comings. Furthermore, drugs that
are currently under investigation as monotherapies and adjuncts
will be highlighted. The potential for alternate targets will
also be examined, with a focus on the most promising candidates.
[Back to top]
Nitric Oxide, Malnutrition and Chronic Renal Failure
T.M.C. Brunini, M.B. Moss, M.A.S. Siqueira, S.F.F. Santos,
J.R. Lugon and A.C. Mendes-Ribeiro
The conditionally essential amino acid L-arginine is the substrate
for nitric oxide (NO) synthesis, a key second messenger involved
in physiological functions including endothelium-dependent
vascular relaxation and inhibition of platelet adhesion and
aggregation. Extracellular L-arginine transport seems to be
essential for the production of NO by the action of NO synthases
(NOS), even when the intracellular levels of L-arginine are
available in excess (L-arginine paradox). Chronic renal failure
(CRF) is a complex clinical condition associated with accelerated
atherosclerosis and thrombosis leading to cardiovascular events.
Various studies document that markers of malnutrition and
inflammation, such as low body mass index (BMI), C-reactive
protein (CRP) and interleukin-6 (IL-6), are strong independent
predictors of cardio-vascular mortality in patients with end-stage
renal disease (ESRD). There is considerable literature demonstrating
that a disturbance in the nitric oxide control mechanism plays
a role in mediating the haemodynamic and haemostatic disorders
present in CRF. Endogenous analogues of L-arginine, ADMA and
L-NMMA, which can inhibit NO synthesis and L-arginine transport,
are increased whilst L-arginine is reduced in plasma from
all stages of CRF patients. In this context, the uptake of
L-arginine in blood cells is increased in undialysed CRF patients
and in patients treated by CAPD and haemodialysis. In platelets
obtained from haemodialysis patients, the activation of L-arginine
transport and NO production was limited to well-nourished
patients.Impairment in nitric oxide bioactivity, coupled with
malnutrition and inflammation, may contribute to increased
incidence of atherothrombotic events in CRF. This article
summarizes the current knowledge of L-arginine-nitric oxide
pathway and malnutrition in CRF and briefly describes possible
therapeutic interventions.
[Back to top]
Molecular Genetics of Quantitative Fibrinogen Disorders
R. Asselta, S. Spena, S. Duga and M.L. Tenchini
Fibrinogen is a complex glycoprotein involved in
the final step of the coagulation cascade as the precursor
of fibrin monomers that participate in the formation of the
haemostatic plug. Three genes (FGA, FGB, and FGG)
clustered on chromosome 4q31.3–4q32.1 encode the three
polypeptide chains (Aα,
Bβ,
and γ),
which in a pairwise fashion form the hexameric circulating
molecule. Among congenital fibrinogen deficiencies, quantitative
defects (also called type I deficiencies; i.e. congenital
afibrino-genemia [CAF] and hypofibrinogenemia) are characterized
by the concomitant absence or reduction of coagulant activity
and immunoreactive protein, while qualitative defects (type
II deficiencies; i.e. dysfibrinogenemia and hypodysfibrino-genemia)
show low clotting protein in contrast with normal or moderately
reduced antigen. Patients affected by CAF (Mendelian Inheritance
in Man, [MIM] #202400) or severe hypofibrinogenemia (MIM+134820,
*134830, and *134850) may experience bleeding manifestations
varying from mild to catastrophic. Although many cases of
fibrinogen deficiencies have been described from a clinical
point of view, only in a minority of cases the causal mutation
was identified. The genetic defects so far described, most
unique for any analyzed family, are invariantly located in
the fibrinogen cluster; for only few of them the pathogenic
role either at the protein or at the mRNA level has been investigated.
This review, besides providing a concise description of the
main structural and functional properties of fibrinogen and
giving an overview of the clinical manifestations, the laboratory
diagnosis and therapeutic approches, will be focused on the
present knowledge on the genetic basis of quantitative fibrinogen
deficiencies. Our systematic analysis of the available clinical
and genetic data on these disorders evidences their high allelic
heterogeneity, the existence of different pathogenic mechanisms,
and the absence of strong genotype/phenotype correlations.
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