Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 4, Number 1, January 2006
Contents
Cardiotoxicity of 5-Fluorouracil Pp.
1-5
P. Alter, M. Herzum, M. Soufi, J.R. Schaefer
and B. Maisch
[Abstract]
Pharmacogenomics of Essential Hypertension:
Are We Going the Right Way? Pp. 7-15
F. Filigheddu, C. Troffa and N. Glorioso
[Abstract]
Imidazoline Receptors, Novel Agents and Therapeutic
Potential Pp. 17-32
G.A. Head and D.N. Mayorov
[Abstract]
Treatment of Acute Leukaemias with Monoclonal
Antibodies: Current Status and Future Prospects
Pp.35-52
G. Leone, S. Sica, M.T. Voso, S. Rutella and L. Pagano
[Abstract]
Pathophysiological Basis for Anticoagulant and Antithrombotic
Therapy in Pulmonary Hypertension Pp. 53-59
A.A. Lopes
[Abstract]
A New Antihypertensive Agent that Antagonizes
the Prohypertensive Effect of Endogenous Ouabain and Adducin
Pp. 61-66
P. Manunta, M. Ferrandi, E. Messaggio and P. Ferrari
[Abstract]
Angiotensin Receptor Blockers in Hypertension and
Cardiovascular Diseases Pp. 67-73
A. de la Sierra
[Abstract]
Mineralocorticoid Receptor Blockade in the Protection
of Target Organ Damage Pp. 75-91
P. Mulatero, A. Milan, T.A. Williams and F. Veglio
[Abstract]
Abstracts
[Back to top]
Cardiotoxicity of 5-Fluorouracil
P. Alter, M. Herzum, M. Soufi, J.R. Schaefer
and B. Maisch
Cardiac side effects of the cytostatic agent 5-fluorouracil
(5-FU) have an incidence of 1.2 – 7.6%. Potentially,
arrhythmias, myocardial infarction and sudden cardiac death
could occur. Life-threatening cardiotoxicity is rarely observed
with a frequency <1%. Cardiotoxicity of 5-FU seems to differ
from well known effects of other cytostatics, e.g., anthracyclines.
Myocardial ischemia was suggested as potential mechanism due
to occasionally observed ECG alterations during 5-FU administration.
Experimental studies revealed potential mechanisms of cardiotoxicity
ranging from direct toxic effects on vascular endothelium
involving endothelial NO synthase leading to coronary spasms
and endothelium independent vasoconstriction via protein kinase
C. In addition, rheological side effects have to be considered.
Coronary artery disease is judged to increase the risk of
cardiac side effects. Despite lack of prospective trials,
verapamil type calcium antagonists as well as nitrates seem
to be useful for treatment of 5-FU induced coronary spasms.
In addition, modification of the cytostatic regimen has to
be considered in patients who had been symptomatic. It could
be assumed that 5-FU toxicity is reversible in the majority
of cases when acute complications, e.g., arrhythmias, are
resolved.
[Back to top]
Pharmacogenomics of Essential Hypertension: Are We
Going the Right Way?
F. Filigheddu, C. Troffa and N. Glorioso
Identifying the genetic predictors of the therapeutic response
to drugs is the role of pharmacogenomics. Although polymorphisms
in several genes have been associated with the blood pressure
response to diuretics, β-blockers
and ACE-inhibitors, the pharmacogenomics of essential hypertension
is still attempting to find satisfactory scientific evidence
to be translated into clinical practice. The main reasons
for this apparent failure are: the small sample sizes of the
cohorts of patients analyzed, the methodological variability,
the complexity of the biological organization, the context-dependency
and the genetic heterogeneity. This review will summarize
the available data on antihypertensive drugs and the criteria
used for study design and conduction, focusing on their strong
points and limitations.
[Back to top]
Imidazoline Receptors, Novel Agents and Therapeutic
Potential
G.A. Head and D.N. Mayorov
The initial realization that agents containing an imidazoline
structure may interact with a distinct class of receptors,
has led to a major class of cardiovascular agents, which now
has the potential to enter a third generation. There is now
general acceptance that there are three main imidazoline receptor
classes, the I1 imidazoline receptor which mediates
the sympatho-inhibitory actions to lower blood pressure, the
I2 receptor which is an important allosteric binding
site of monoamine oxidase and the I3 receptor which
regulates insulin secretion from pancreatic β cells.
Thus all three represent important targets for cardiovascular
research. Interestingly, an I1- receptor candidate
has been cloned (IRAS, imidazoline receptor antisera selected)
which is a homologue of the mouse cell adhesion integrin binding
protein Nischarin. There has been range of new agonists and
antagonists with very high selectivity for I1,
I2 and I3 receptors developed. Three
different endogenous ligands have been characterized including
agmatine (decarboxylated arginine), a range of β-carbolines
including harman and harmane, and more recently imidazoleacetic
acid-ribotide. The imidazoline field has recently seen an
enormous diversification with discoveries that I1 and I2
receptors also play a role in cell proliferation, regulation
of body fat, neuroprotection, inflammation and some psychiatric
disorders such as depression. This diversification has continued
with the addition of effective agents with imidazoline affinity
in the fields of cancer, pain and opioid addiction, stress,
cell adhesion, epilepsy and appetite. The imidazoline field
has maturated considerably with a range of highly selective
leader molecules, candidate receptors and endogenous ligands.
We are therefore only at the threshold of an exciting new
era as we begin to understand the diverse and complex nature
of their function.
[Back to top]
Treatment of Acute Leukaemias with Monoclonal Antibodies:
Current Status and Future Prospects
G. Leone, S. Sica, M.T. Voso, S. Rutella and L. Pagano
Monoclonal antibodies are a new class of agents targeted
at specific receptors on cancer cells. In addition to direct
cellular effects, antibodies can carry substances to the targeted
cells, such as radioactive isotopes, toxins, and antineoplastic
agents. At present monoclonal antibodies, directed against
both lymphoid antigens (CD 20 and CD 52) and a myeloid antigen
(CD33) are available for clinical use. In ALL, rituximab,
a humanised anti CD20 antibody, has been combined to chemotherapy
mainly in mature B-ALL and Burkitt’s lymphoma and preliminary
results are promising. Alemtuzumab is an anti-CD52 humanised
antibody, which showed anti-tumour activity in CLL; clinical
effects were observed in some patients with relapsed adult
ALL. Monoclonal antibodies against myeloid antigens have been
prevalently used in acute myeloid leukaemias (AML), where
the most utilised immunological target is CD33. The CD33 molecule
is expressed by approximately 90% of AMLs but not on CD34+
bone marrow-resident hematopoietic stem cells. The humanised
anti-CD33 monoclonal antibody HuM195 has only modest activity
against overt AML, but it can eliminate minimal residual disease.
Radioimmunotherapy with β-particle-emitting isotopes targeting
CD33 shows a major efficacy. Targeted chemotherapy with the
anti-CD33-calicheamicin construct gemtuzumab ozogamicin (GO)
has produced remissions as a single agent in patients with
relapsed AML and appears promising when used in combination
with standard chemotherapy. GO is composed of a humanised
immunoglobulin G4 (IgG4) monoclonal antibody (mAb), targeting
the CD33 antigen and linked to a calicheamicin derivative,
a cytotoxic anthracycline antibiotic. GO has been approved
by FDA as second-line therapy in older patients with AML.
The most common adverse effects of monoclonal antibodies are
myelosuppression, infusion-related reactions, and hypersensitivity
reactions. Rituximab may cause tumour lysis syndrome. Alemtuzumab
causes immunosuppression, increasing the risk of infection.
GO may cause hepatotoxicity.
[Back to top]
Pathophysiological Basis for Anticoagulant and Antithrombotic
Therapy in Pulmonary Hypertension
A.A. Lopes
In pulmonary hypertension (PH), thrombosis and thromboembolism
may occur as primary events associated with inherited or acquired
thrombophilia. Alternatively, in situ thrombosis
may develop as a complication of pre-existing vasculopathy
as in the case of idiopathic PH and related disorders (so
called pulmonary arterial hypertension). In these disorders,
a number of abnormalities has been described involving endothelial
cells, platelets and other circulating cellular and soluble
elements. These abnormalities are suggestive of a shift of
pulmonary vascular microenvironment toward a procoagulant,
prothrombotic and antifibrinolytic pattern. The abnormalities
described so far include circulating antiphospholipid antibodies,
increased plasma levels of platelet aggregating agents (serotonin,
thromboxane), adhesion molecules (P-selectin, von Willebrand
factor), antifibrinolytic enzymes (plasminogen activator inhibitor
1) and cytokines. Also, decreased endothelial production of
natural anticoagulants (thrombomodulin) and platelet antiaggregating
substances (nitric oxide, prostacyclin) have been demonstrated.
The present review is focused on the procoagulant, prothrombotic
and antifibrinolytic mechanisms so far identified in PH, in
both clinical setting and animal models. Understanding of
these mechanisms is crucial for a proper selection of anticoagulant
and antithrombotic therapies and provides the rationale for
development of novel therapeutic options.
[Back to top]
A New Antihypertensive Agent that Antagonizes the
Prohypertensive Effect of Endogenous Ouabain and Adducin
P. Manunta, M. Ferrandi, E. Messaggio and P. Ferrari
Endogenous Ouabain (EO) and Adducin enhance the Na-K pump
function and play an important role in sodium homeostasis
and blood pressure (BP) regulation. In the general population,
plasma EO modulates BP either by inhibiting the prohypertensive
effect of an excessive salt intake or counteracting the depressor
action of normal-moderate salt intake. Almost 50% of hypertensive
patients have increased circulating plasma levels of EO. EO
has been associated both to left ventricular dysfunction and
hypertrophy. A new antihypertensive agent, PST2238, (17β-(3-furyl)-5β-androstan-3β,
14β,
17α-triol
a digitoxigenin derivative) able to selectively antagonize
both the EO and adducin prohypertensive and molecular effects,
has been developed. In hypertensive rats (MHS strain) carrying
both adducin mutations and increased plasma EO and in ouabain-infused
rats (OS), PST2238 lowers BP by normalizing the renal Na-K
pump function. In OS rats, PST antagonized the cardiac and
renal pro-hypertrophic ouabain effect associated to the activation
of the Src-EGFr-ERK1/2 signaling cascade. Phase 1 clinical
studies demonstrated a high tolerability of PST2238. In a
preliminary phase 2 study on 42 mild never-treated hypertensive
patients, PST2238 given for 3 months at 0.5 mg/day, significantly
reduced BP in subjects with moderate salt intake, implying
that it may be selectively effective in conditions where EO
plays a prohypertensive role. In conclusion, PST2238, because
of its peculiar action mechanism, represents a new tool to
disentangle the complex relationship between salt intake,
genetic control of renal sodium handling and EO effect.
[Back to top]
Angiotensin Receptor Blockers in Hypertension and
Cardiovascular Diseases
A. de la Sierra
Angiotensin receptor blockers are the newest class of antihypertensive
agents marketed for the treatment of hypertension. There is
now an important amount of evidence indicating that this class
of drugs exerts beneficial effects in patients with a variety
of cardiovascular disorders. Evidence-based medicine includes
well controlled studies with mortality and morbidity endpoints
in patients with left ventricular dysfunction after a myocardial
infarction, congestive heart failure, cerebrovascular disease,
type-2 diabetic subjects with renal dysfunction and high-risk
hypertensive patients. In addition to these hard endpoints,
treatment with angiotensin receptor blockers prevents the
development of type-2 diabetes, promotes a more pronounced
regression of left ventricular hypertrophy, decreases microalbuminuria
and proteinuria in renal patients, ameliorates coronary and
peripheral vascular endothelial dysfunction and decreases
plasma levels of several markers of vascular inflammation.
In summary, angiotensin receptor blockers are antihypertensive
drugs with a very good profile in terms of efficacy, tolerability
and cardiovascular protection. They represent an important
step in the search for the ideal antihypertensive agent.
[Back to top]
Mineralocorticoid Receptor Blockade in the Protection
of Target Organ Damage
P. Mulatero, A. Milan, T.A. Williams and F. Veglio
Over the last decade a wealth of studies have shed new light
on the role of aldosterone in the pathogenesis of cardiovascular
diseases. It is now evident that in addition to its classical
role in increasing sodium reabsorbtion in the kidney , aldosterone
also exhibits several nonepithelial effects such as the induction
of inflammation, fibrosis and necrosis in various organs.
Herein we review the experimental evidences for the protective
effects of mineralocorticoid receptor blockade in the prevention
and treatment of target organ damage, both in animals and
in humans. We also discuss the pharmacological and clinical
differences between the two available mineralocorticoid receptor
blockers, spironolactone and eplerenone.
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