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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 14, 2007
Contents
Tumor Necrosis Factor-Alpha Monoclonal Antibodies for Crohn’s
Disease: Tipping the Balance Pp. 1489-1497
Silvio Danese, Nico Pagano, Erika Angelucci, Tommaso Stefanelli,
Alessandro Repici, Paolo Omodei, Marco Daperno and Alberto
Malesci
[Abstract]
Co-Treatment with Copper Compounds Dramatically Decreases
Toxicities Observed with Cisplatin Cancer Therapy and the
Anticancer Efficacy of Some Copper Chelates Supports the Conclusion
that Copper Chelate Therapy may be Markedly More Effective
and Less Toxic than Cisplatin Therapy Pp. 1499-1503
John R.J. Sorenson and Grant. W. Wangila
[Abstract]
Molecular Probes for P2X7
Receptor Studies Pp. 1505-1523
Hendra Gunosewoyo, Mark J. Coster and Michael Kassiou
[Abstract]
Microdialysis in the Human Brain and its Potential
Role in the Development and Clinical Assessment of Drugs
Pp. 1525-1537
Adel Helmy, Keri L.H. Carpenter and Peter J. Hutchinson
[Abstract]
Myocardial Ischemia-Reperfusion Injury, Antioxidant
Enzyme Systems, and Selenium: A Review Pp. 1539-1549
Kylie M. Venardos and David M. Kaye
[Abstract]
Hypokalemia: A Practical Approach to Diagnosis and
its Genetic Basis Pp. 1551-1565
Shih-Hua Lin and Mitchell L. Halperin
[Abstract]
Shear Stress, Protein Kinases and Atherosclerosis
Pp. 1567-1572
Gerasimos Siasos, Dimitris Tousoulis, Zoi Siasou, Christodoulos
Stefanadis and Athanasios G. Papavassiliou
[Abstract]
Pancreas Development and β-Cell
Differentiation of Embryonic Stem Cells Pp. 1573-1578
Jorge David Rivas-Carrillo, Teru Okitsu, Noriaki Tanaka
and Naoya Kobayashi
[Abstract]
Role of Topical Calcineurin Inhibitors on Atopic Dermatitis
of Children Pp. 1579-1591
G. Ricci, A. Dondi and A. Patrizi
[Abstract]
Abstracts
[Back to top]
Tumor Necrosis Factor-Alpha Monoclonal Antibodies for Crohn’s
Disease: Tipping the Balance
Silvio Danese, Nico Pagano, Erika Angelucci, Tommaso Stefanelli,
Alessandro Repici, Paolo Omodei, Marco Daperno and Alberto
Malesci
Crohn’s disease (CD) is a chronic inflammatory disorder
which may involve any part of gastrointestinal tract. Chronic
inflammation is primarily due to an immunological imbalance
between pro- and anti-inflammatory cytokines, and with a defective
apoptosis of lamina propria T cells. Amongst the pro-inflammatory
cytokines tumor necrosis factor-α
(TNF-α)
seems to play a central role in pathogenesis of CD.
Over the last years, increasing knowledge on the pathogenesis
of CD together with progresses in bio-technology have led
to the development of a number of biological agents targeting
specific molecules involved in gut inflammation, most importantly
TNF-? and its receptors.
The aim of this paper is to critically review the rationale
and state-of-the art for the use TNF- α
inhibitors in the treatment of CD.
[Back to top]
Co-Treatment with Copper Compounds Dramatically Decreases
Toxicities Observed with Cisplatin Cancer Therapy and the
Anticancer Efficacy of Some Copper Chelates Supports the Conclusion
that Copper Chelate Therapy may be Markedly More Effective
and Less Toxic than Cisplatin Therapy
John R.J. Sorenson and Grant. W. Wangila
Co-Administration of CuII
chelates are reported to decrease life threatening Cisplatin
[PtII(NH3)2(CL)2]-induced
acute degenerative renal, gastrointestinal, thymic, and bone
marrow states consistent with serious necrotizing and immune-mediated
inflammatory disease. Initially it was found that copper sulfate
treatment completely prevented lethality as well as gastric
and nephrotoxicity without compromising PtII(NH3)2(CL)2
antineoplastic activity, which led to suggestions that prior
CuII-treatment be used clinically
to prevent serious side effects of PtII(NH2)2(CL)2-treatment.
In the course of these studies it was discovered that CuII-treatments
alone inhibited neoplastic growth and increased survival of
rat and mouse models of cancer. Subsequently it was discovered
that a stable non-toxic and non-polar lipophilic chelate,
CopperII2(3,5-diisopropylsalicylate)4,
caused redifferentiation of cultured neuroblastoma and mouse
muscle-implanted mammary adenocarcinoma without neoplastic
cell killing. Another stable non-toxic and non-polar lipophilic
chelate, CopperII2(3,5-ditertiarybutylsalicylate)4,
was found to prevent Bax-initiated and caspases-3-activation
mediated apoptosis. These remarkable observations are concluded
to be due to enzyme-mimetic or modulating reactivities of
CuII chelates and/or facilitation
of CuII or I-dependent
enzyme syntheses required to overcome inflammatory-neoplastic
disease states. Further, approaches to treating neoplastic
diseases by removal of Cu from tissues with ammonium tetrathiomolybdate
in an anticopper approach to therapy are not well founded
based upon existing scientific literature.
[Back to top]
Molecular Probes for P2X7
Receptor Studies
Hendra Gunosewoyo, Mark J. Coster and Michael Kassiou
The ionotropic P2X7 receptor
(P2X7R) has become the focus
of intense research interest for a number of reasons: i) it
is a cation selective ion channel that is modulated by extracellular
ATP. Upon stimulation by high concentrations of ATP it generates
a non-selective membrane pore which is permeable to hydrophilic
molecules with molecular weight up to 900 Da. ii) Though its
physiological function is yet to be fully understood, there
is high P2X7R expression
in microglia. Importantly, this implies a pivotal role for
the P2X7R in neuro-inflammatory
and -degenerative processes. In addition, P2X7R-stimulated
release of traditional neurotransmitters in the brain, such
as glutamate and GABA, further supports the involvement of
P2X7R in neuro-inflammatory
and -degenerative processes. P2X7-knockout
animals are also found to be resistant to inflammation and
neuropathic pain, which suggests that P2X7
antagonists could potentially serve as all-purpose analgesics.
Recent advances in the development of P2X7R
ligands have resulted in identification of several different
classes of P2X7R antagonists,
including ATP analogues (oxidized ATP), dyes (Brilliant Blue
G), tyrosine derivatives (KN-62 and KN-04), cyclic imides,
adamantane and benzamide derivatives. A KN-62 related radioligand
has also recently been reported for use in receptor binding
assays. A more extensive range of potent, selective P2X7R
ligands is required for a better understanding of the cascade
of cellular processes associated with the P2X7R.
This article will review P2X7R
ligands discovered to date, together with their biological
activity and therapeutic potential.
[Back to top]
Microdialysis in the Human Brain and its Potential
Role in the Development and Clinical Assessment of Drugs
Adel Helmy, Keri L.H. Carpenter and Peter J. Hutchinson
Neurological injury, as a result of stroke and traumatic brain
injury, causes significant morbidity and mortality. Despite
the importance of these conditions, the basis of current treatment
remains supportive. In recent years, our increasing understanding
of the pathophysiological mechanisms of secondary injury,
for example excitotoxity, has led to a search for specific
agents that can intercept these pathological pathways and
act as pharmaceutical neuroprotectants. While successful in
the laboratory, these agents have yet to demonstrate efficacy
in the clinical arena. The reasons for these failures are
varied and incompletely understood, but significant factors
include inconclusive pharmacokinetic data, particularly regarding
blood brain barrier penetration, and the heterogenous nature
of these pathologies in humans.
Microdialysis is an established, commercially available, clinical
and research tool that is used to sample brain extracellular
fluid. It provides the technology to determine the cerebral
penetration of drugs and it measures biological markers of
brain tissue injury. It can therefore be used to determine
the biochemical efficacy of therapeutic manoeuvres.
In this review we address the practical application of this
technology to the process of drug development.
[Back to top]
Myocardial Ischemia-Reperfusion Injury, Antioxidant
Enzyme Systems, and Selenium: A Review
Kylie M. Venardos and David M. Kaye
Coronary heart disease (CHD) remains the greatest killer in
the Western world, and although the death rate from CHD has
been falling, the current increased prevalence of major risk
factors including obesity and diabetes, suggests it is likely
that CHD incidence will increase over the next 20 years. In
conjunction with preventive strategies, major advances in
the treatment of acute coronary syndromes and myocardial infarction
have occurred over the past 20 years. In particular the ability
to rapidly restore blood flow to the myocardium during heart
attack, using interventional cardiologic or thrombolytic approaches
has been a major step forward. Nevertheless, while ‘reperfusion’
is a major therapeutic aim, the process of ischemia followed
by reperfusion is often followed by the activation of an injurious
cascade. While the pathogenesis of ischemia-reperfusion is
not completely understood, there is considerable evidence
implicating reactive oxygen species (ROS) as an initial cause
of the injury.
ROS formed during oxidative stress can initiate lipid peroxidation,
oxidize proteins to inactive states and cause DNA strand breaks,
all potentially damaging to normal cellular function. ROS
have been shown to be generated following routine clinical
procedures such as coronary bypass surgery and thrombolysis,
due to the unavoidable episode of ischemia-reperfusion. Furthermore,
they have been associated with poor cardiac recovery post-ischemia,
with recent studies supporting a role for them in infarction,
necrosis, apoptosis, arrhythmogenesis and endothelial dysfunction
following ischemia-reperfusion. In normal physiological condition,
ROS production is usually homeostatically controlled by endogenous
free radical scavengers such as superoxide dismutase, catalase,
and the glutathione peroxidase and thioredoxin reductase systems.
Accordingly, targeting the generation of ROS with various
antioxidants has been shown to reduce injury following oxidative
stress, and improve recovery from ischemia-reperfusion injury.
This review summarises the role of myocardial antioxidant
enzymes in ischemia-reperfusion injury, particularly the glutathione
peroxidase (GPX) and the thioredoxin reductase (TxnRed) systems.
GPX and TxnRed are selenocysteine dependent enzymes, and their
activity is known to be dependent upon an adequate supply
of dietary selenium. Moreover, various studies suggest that
the supply of selenium as a cofactor also regulates gene expression
of these selenoproteins. As such, dietary selenium supplementation
may provide a safe and convenient method for increasing antioxidant
protection in aged individuals, particularly those at risk
of ischemic heart disease, or in those undergoing clinical
procedures involving transient periods of myocardial hypoxia.
[Back to top]
Hypokalemia: A Practical Approach to Diagnosis and
its Genetic Basis
Shih-Hua Lin and Mitchell L. Halperin
Hypokalemia is a common and important finding in hospitalized
patients because it may provoke cardiac arrhythmias and/or
respiratory arrest. Our aim is to suggest better diagnostic
tools and therapeutic principles, and summarize new molecular
advances that are linked to hypokalemia. Measurements in freshly-voided
urine to evaluate potassium (K+)
excretion and an assessment of the acid-base status in blood
can help differentiate between the various causes of hypokalemia.
In patients with a low rate of K+ excretion, hypokalemia
can be explained by an acute shift of K+ into cells,
intestinal K+ loss, or prior renal K+
excretion. Patients with a high rate of K+ excretion
usually have metabolic acid-base disorders. In patients with
hyperchloremic metabolic acidosis, an assessment of the rate
of excretion of ammonium (NH4+)
in the urine separates those with renal tubular acidosis (RTA)
(low NH4+ excretion)
from those with causes other than RTA. In patients with metabolic
alkalosis, a high blood pressure helps to distinguish between
a state with high mineralocorticoid activity from others with
extracellular fluid (ECF) volume contraction. Measurement
of renin activity, aldosterone, and cortisol levels in plasma
help to differentiate between the causes with mineralocorticoid
excess whereas the urine chloride (Cl-) concentration
may reveal the basis for renal Na+ wasting and
distinguish it from non-renal Na+ loss. The treatment
of hypokalemia is guided by the risk imposed by hypokalemia,
magnitude of the K+ deficit, route of the K+
administration, available K+ preparations, adjuncts
to therapy, and special associated conditions. Recent molecular
advances in inherited hypokalemic disorders affecting transcellular
K+ shift, gastrointestinal and renal K+
excretion are also discussed.
[Back to top]
Shear Stress, Protein Kinases and Atherosclerosis
Gerasimos Siasos, Dimitris Tousoulis, Zoi Siasou, Christodoulos
Stefanadis and Athanasios G. Papavassiliou
Shear stress represents the frictional force that the flow
of blood exerts at the endothelial surface of the vessel wall
and plays a central role in cell function and structure via
managing several processes and contributes to the progress
of atherosclerosis. It is a fact that interaction of blood
flow and the endothelial surface is the critical interface
for shear stress-dependent mechanotransduction. Vascular endothelial
cells are equipped with numerous receptors in order to “sense”
and react to mechanical forces elicited by shear stress. The
intracellular signal transduction pathways and specifically
the activation of protein kinases, is the second important
molecular event underpinning cellular reactions to extracellular
stimuli. MAPKs, comprising ERK1/2, JNKs/stress-activated protein
kinases (SAPKs), and p38s, are serine/threonine protein kinases
with a prominent role in cell differentiation, growth, and
apoptosis, by modulating the activity of downstream target
proteins and various transcription factors, hence gene expression
programs. Shear stress (nonlaminar or disturbed blood flow)
plays an important role in atherosclerosis, where flow conditions
are characterized by low or oscillatory shear stress. Atherosclerosis
is promoted by decreased shear stress, as it is associated
with a suppression of functions taking place on the vascular
wall, such as eNOs production and endothelial cell repair.
In the presence of systemic risk factors, there is an increased
tendency for atherosclerotic plaque formation, which, once
formed, further disrupt flow and forward growth of the fibroinflammatory
lipid plaque. Targeted inhibition of many kinase types and
subtypes is an immense research field as this may lead to
novel therapeutic approaches to prevent atherogenesis.
[Back to top]
Pancreas Development and β-Cell
Differentiation of Embryonic Stem Cells
Jorge David Rivas-Carrillo, Teru Okitsu, Noriaki Tanaka
and Naoya Kobayashi
Embryonic stem (ES) cells may offer an unlimited cell source
for the treatment of diabetes. However, a successful derivation
of ES cells into islet-cells has proven to be more difficult
than it was initially expected. Considering that the pancreas
coordinates the global use of energy in the organism by secreting
digestive enzymes and hormones, it is understandable that
a sophisticated and tight regulation that lies on the pancreas
itself to orchestrate its own tissue development and maturation.
The complex process of endocrine cell differentiation can
be better understood by analyzing the normal development of
the pancreas. The proper detection of the signals provided
in the pancreatic environment gives us a clue as to how the
stem cells give rise to the whole pancreas. Careful and extensive
screening of the natural or synthetic cytokines and growth
factors and biochemical compounds that are essential in pancreatic
development is required to properly mimic the process in
vitro. Such a study would allow the researchers to achieve
selective control of the differentiation and proliferation
of the stem cells.
The development and identification of the key molecules can
provide us new insights into the pancreatic differentiation
of the stem cells. We herein discuss the role of the microenvironment
and transcriptional factors and cytokines, which have been
recognized as important molecules during the major steps of
the development of the pancreas. Finally, a more complete
comprehension of the mechanisms that drive the pancreatic
regeneration will provide us with new perspectives for future
prophylactic and therapeutic interventions.
[Back to top]
Role of Topical Calcineurin Inhibitors on Atopic Dermatitis
of Children
G. Ricci, A. Dondi and A. Patrizi
Besides the traditional topical treatment of mild
and moderate forms of atopic dermatitis (AD), which includes
the daily use of emollients and the intermittent use of topical
corticosteroids (TCSs) as anti-inflammatory drugs, a new group
of drugs has recently been introduced to control the inflammatory
phase of the disease: topical calcineurin inhibitors (TCIs).
Although the efficacy of TCSs is evident, prolonged unrestricted
use is limited by local and systemic side effects. The major
risk in children is the hypothalamic-pituitary-adrenal gland
suppression, due to the higher percutaneous absorption of
the TCSs.
TCIs selectively block the activity of calcineurin, a serin/threonine
protein phosphatase regulated by cellular calcium first detected
in skeletal muscle and brain. Within the past few years, calcineurin
has been implicated in a wide range of biological responses
including lymphocyte activation, neuronal and muscle development,
and morphogenesis of heart valves. TCIs disrupt the intracellular
signalling towards NF-AT by forming a complex with macrophilin-12.
This complex inhibits the activity of calcineurin, thereby
preventing the dephosphorylation of NF-AT and so interfering
with the transcription of several genes. The nuclear component
of NF-AT, binding to its nuclear counterpart, is essential
for the transcription of various genes, including interleukin
(IL)-2 and other proinflammatory cytokines.
Recent findings about the therapeutic efficacy of TCIs have
provided a possible alternative to TCSs in the treatments
of mild to severe forms of AD.
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