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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 9, 2006
Contents
Pharmaceutical Interventions to Influence Arteriogenesis:
New Concepts to Treat Ischemic Heart Disease
Pp. 979-987
Imo E. Hoefer, Jan J. Piek and Gerard Pasterkamp
[Abstract]
Vascular Dysfunction in Aging: Potential Effects of Resveratrol,
an Anti-Inflammatory Phytoestrogen Pp. 989-996
Nazar Labinskyy, Anna Csiszar, Gabor Veress, Gyorgyi Stef,
Pal Pacher, Gabor Oroszi, Joseph Wu and Zoltan Ungvari
[Abstract]
Bile Acid Reabsorption Inhibitors (BARI): Novel Hypolipidemic
Drugs Pp. 997-1016
Werner Kramer and Heiner Glombik
[Abstract]
Glycine Transporter Type-1 and its Inhibitors Pp.
1017-1044
L.G. Harsing Jr., Z. Juranyi, I. Gacsalyi, P. Tapolcsanyi,
A. Czompa and P. Matyus
[Abstract]
Carboxylesterases – Detoxifying Enzymes and
Targets for Drug Therapy Pp. 1045-1054
Philip M. Potter and Randy M. Wadkins
[Abstract]
Silymarin as a New Hepatoprotective Agent in Experimental
Cholestasis: New Possibilities for an Ancient Medication Pp.
1055-1074
Fernando A. Crocenzi and Marcelo G. Roma
[Abstract]
Oxidative Stress in Alzheimer Patients in Different
Stages of the Disease Pp. 1075-1083
P. Zafrilla, J. Mulero, J.M. Xandri, E. Santo, G. Caravaca
and J.M. Morillas
[Abstract]
Ruthenium Complexes as Anticancer Agents Pp.
1085-1107
Irena Kostova
[Abstract]
Abstracts
[Back to top]
Pharmaceutical Interventions to
Influence Arteriogenesis: New Concepts to Treat Ischemic Heart
Disease
Imo E. Hoefer, Jan J. Piek and Gerard Pasterkamp
Despite the technical progress in interventional techniques
to overcome the harmful effects of ischemic heart disease
there is still an urgent need for alternative, pharmaceutical
treatment modalities. Exogenous stimulation of vessel growth,
i.e. vasculogenesis, angiogenesis or arteriogenesis serves
as a promising strategy to restore blood flow to the jeopardized
tissue regions downstream of arterial stenosis or occlusion.
While vasculogenesis is defined as the arrangement of angioblasts
during prenatal development creating the first vascular network,
angiogenesis and arteriogenesis refer to important adaptive
mechanisms in the adult organism. Angiogenesis, neo-formation
of capillaries, is a key process in many different physiological
and pathophysiological events where improvement of microvascular
function and tissue nutrition is needed (e.g. wound healing,
tumor growth). In contrast to this capillary sprouting, the
term arteriogenesis refers to the development of large caliber
collateral arteries. Under conditions of increasing shear
stress, anastomoses between interconnected perfusion territories
can undergo adaptive enlargement, developing into a functional
network of collateral arteries, natural bypasses able to maintain
sufficient blood flow and compensating for the gradual occlusion
of a large artery (e.g. in the coronary circulation). However,
in most cases arteriogenesis does not proceed as fast as the
stenosis progresses and infarction and tissue necrosis results.
A well-developed collateral network is an important protective
factor for the occurrence of ischemic events and therefore
pharmaceutical acceleration and stimulation of arteriogenesis
in patients represents an eminent aim for the future. This
review focuses on the basic mechanisms of arteriogenesis,
the recent progresses in translating these insights into the
clinical situation and the problems yet to be solved.
[Back to top]
Vascular Dysfunction in Aging: Potential Effects of
Resveratrol, an Anti-Inflammatory Phytoestrogen
Nazar Labinskyy, Anna Csiszar, Gabor Veress, Gyorgyi Stef,
Pal Pacher, Gabor Oroszi, Joseph Wu and Zoltan Ungvari
Epidemiological studies demonstrated that even in the absence
of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia,
hypercholesterolemia), advanced age itself significantly increases
cardiovascular morbidity by enhancing vascular oxidative stress
and inflammation. Because the population in the Western world
is rapidly aging, there is a substantial need for pharmacological
interventions that delay the functional decline of the cardiovascular
system. Resveratrol is an atoxic phytoestrogen found in more
than 70 plants including grapevine and berries. Recent data
suggest that nutritional intake of resveratrol and other polyphenol
compounds may contribute to the “French paradox”,
the unexpectedly low cardiovascular morbidity in the Mediterranean
population. There is increasing evidence that resveratrol
exerts multifaceted anti-oxidant and/or anti-inflammatory
effects in various disease models. Importantly, resveratrol
was reported to slow aging and increase lifespan in simple
organisms and has been suggested as a potential calorie restriction
mimetic. Resveratrol has also been reported to activate NAD-dependent
histone deacetylases (sirtuins), which may contribute to its
anti-aging effects. This review focuses on the role of oxidative
stress and inflammation in cardiovascular dysfunction in aging,
and on emerging anti-aging therapeutic strategies offered
by resveratrol and other polyphenol compounds.
[Back to top]
Bile Acid Reabsorption Inhibitors (BARI):
Novel Hypolipidemic Drugs
Werner Kramer and Heiner Glombik
The enterohepatic circulation of bile acids is a major regulator
of serum cholesterol homeostasis. After biosynthesis from
cholesterol in the liver, bile acids are secreted with bile
into the lumen of the small intestine to aid in the digestion
and absorption of fat and fat-soluble vitamins. The bile acids
are nearly quantitatively reabsorbed in the terminal ileum
by a Na+-dependent transport system (IBAT) and
are transported with portal blood to the liver and taken up
by a second Na+-/bile acid cotransporter (LBAT)
to be resecreted into bile. In the liver bile acids inhibit
the rate-limiting enzyme for the conversion of cholesterol
into bile acid: cholesterol-7α-hydroxylase;
interruption of the enterohepatic circulation of bile acids
withdraws this feedback inhibition and leads to an upregulation
of hepatic LDL-receptors with a concomitant decrease of serum
LDL-levels. Specific inhibitors of the ileal bile acid transporter
belonging to different chemotypes have been developed in recent
years for this purpose, some now entering clinical stage.
To exert a profound systemic effect these compounds do not
need to be available systemically but can act from the luminal
side of the small intestine, which offers the advantage to
avoid the well-known adverse side effects of other hypolipidemic
drugs like statins due to metabolism and drug-drug interactions
in the liver. This implies several aspects in compound optimization
and drug development quite different from standard procedures,
for example the concept of low absorption drugs was established
to avoid systemic side effects. The review article covers
the mechanistic and therapeutic principles of the approach
and presents an overview on the molecular target, the discovery
of specific inhibitors and respective optimization strategies.
[Back to top]
Glycine Transporter Type-1 and its Inhibitors
L.G. Harsing Jr., Z. Juranyi, I. Gacsalyi, P. Tapolcsanyi,
A. Czompa and P. Matyus
The ionotropic glutamate receptor NMDA is allosterically
modulated by glycine, a coagonist, its presence is an absolute
requirement for receptor activation. The transport of glycine
in glutamatergic synapse is carried out by glycine transporter-1
(GlyT1), a Na+/Cl--dependent carrier molecule.
The primary role of GlyT1 is to maintain glycine concentrations
below saturation level at postsynaptic NMDA receptors. Several
isoforms of GlyT1 (a-e) have been identified, which are expressed
both in glial and neuronal cell membranes. GlyT1 operates
bidirectionally: it decreases synaptic glycine concentration
when operates in normal mode and releases glycine from glial
cells as operates in a reverse mode. It is expected that non-transportable,
non-competitive inhibitors of GlyT1 may have therapeutic value
in CNS disorders characterized by hypofunctional NMDA receptor-mediated
glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors
exhibited antipsychotic profile in a number of animal tests.
The first promising in vitro and in vivo
experiments with glycine itself, and its N-methyl analogue,
sarcosine, had initiated the syntheses of potential GlyT1
inhibitors with more complex structures, in which, however,
the glycine or sarcosine moiety had always been incorporated.
Those attempts led to the development of two compounds, ALX-5407
and Org-24461 with high inhibitory potency; however, none
of which is now considered as a drug candidate due, most probably,
to safety and/or pharmacokinetic issues. More recently, several
structurally new series of highly potent inhibitors with no
aminomethylcarboxy group have also been discovered. Some of
them might be expected to fulfill all requirements for clinical
development. The new generation of GlyT1 inhibitors may represent
a novel treatment of patients suffering from schizophrenia
and/or other neuropathological conditions.
[Back to top]
Carboxylesterases – Detoxifying Enzymes and
Targets for Drug Therapy
Philip M. Potter and Randy M. Wadkins
Carboxylesterases (CE) are ubiquitous enzymes responsible
for the detoxification of xenobiotics. Many therapeutically
useful drugs are metabolized by these proteins which impacts
upon the efficiency of drug treatment. In some instances,
CEs convert inactive prodrugs to active metabolites, a process
that is essential for biological activity. Such compounds
include the anticancer agents CPT-11 (3) and capecitabine
(4), the antibiotics Ceftin (9) and Vantin, as well as the
illicit street drug heroin (6). However, more commonly, CEs
hydrolyze many esterified drugs to inactive products that
are then excreted. Agents such as flestolol (11), meperidine
(5), lidocaine (8) and cocaine (7), are all hydrolyzed and
inactivated by these enzymes. Therefore the efficacy of esterified
drugs will be dependent upon the distribution and catalytic
activity of different CEs. In this review, we examine the
structural aspects of CEs and their roles in drug detoxification
and propose that modulation of CE activity may allow for improvements
in, and potentiation of, drug efficacy.
[Back to top]
Silymarin as a New Hepatoprotective Agent in Experimental
Cholestasis: New Possibilities for an Ancient Medication
Fernando A. Crocenzi and Marcelo G. Roma
Silymarin is a purified extract from milk thistle (Silybum
marianun (L.) Gaertn), composed of a mixture of four
isomeric flavonolignans: silibinin (its main, active component),
isosilibinin, silydianin and silychristin. This extract has
been empirically used as a remedy for almost 2000 years, and
remains being used as a medicine for many types of acute and
chronic liver diseases. Despite its routinely clinical use
as hepatoprotectant, the mechanisms underlying its beneficial
effects remain largely unknown. This review addresses in detail
a number of recent studies showing a novel feature of silymarin
as a hepatoprotective drug, namely: its anticholestatic properties
in experimental models of hepatocellular cholestasis with
clinical correlate. For this purpose, this review will cover
the following aspects:
1. The chemistry of silymarin, including chemical composition
and properties.
2. The current clinical applications of silymarin as a hepatoprotective
agent, including the mechanisms by which silymarin is thought
to exert its hepatoprotective properties, when known.
3. The physiological events involved in bile formation, and
the mechanisms of hepatocellular cholestasis, focusing on
cellular targets and mechanisms of action of drugs used to
reproduce experimentally cholestatic diseases of clinical
interest, in particular estrogens and monohydroxylated bile
salts, where anticholestatic properties of silymarin have
been tested so far.
4. The recent findings describing the impact of silymarin
on normal bile secretion and its novel, anticholestatic properties
in experimental models of cholestasis, with particular emphasis
on the cellular/molecular mechanisms involved, including modulation
of bile salt synthesis, biotransformation/depuration of cholestatic
compounds, changes in transporter expression/activity, and
evocation of signaling pathways.
[Back to top]
Oxidative Stress in Alzheimer Patients in Different
Stages of the Disease
P. Zafrilla, J. Mulero, J.M. Xandri, E. Santo, G. Caravaca
and J.M. Morillas
Increasing evidence demonstrates that oxidative stress causes
damage to cell function with aging and is involved in a number
of age-related disorders including atherosclerosis, arthritis,
and neurodegenerative disorders. Cellular changes show that
oxidative stress is a condition that precedes the appearance
of the hallmark pathologies of the disease, neurofibrillary
tangles and senile plaques.
The aim of this article is to analyze the different biomarkers
of oxidative stress in Alzheimer patients, in different stages
of the illness, and compare the results with a control group.
A nutritional evaluation was carried out, including anthropometric
and biological measures and a 3 day dietary record. The concentration
of substances which react to thiobarbituric acid (TBARS) was
measured as a marker of the degree of peroxidation using the
HPLC method. The oxidation of proteins was analyzed by measuring
the carbonyl groups in plasma. In addition, measurements were
made of the total antioxidant activity in plasma and the activity
of endogenous antioxidant enzymes such as gluthatione peroxidase,
gluthatione reductase and superoxide dismutase.
The total antioxidant plasmatic status of the patients with
Alzheimer both in light-moderate phase and in advanced phase
was lower than in the control. No significant differences
were observed between the different stages of the disease
in protein oxidation levels.
Peroxidation was higher in patients in the advanced stage
of the disease than in the control group. However, no significant
differences were observed between the different stages of
the disease.
In this preliminary study, it was observed that Alzheimer
patients in the light-moderate stage already present oxidative
stress levels above those of the control group.
[Back to top]
Ruthenium Complexes as Anticancer Agents
Irena Kostova
Cancer is one of the major cases of death in the world. Current
treatment of cancer is limited to surgery, radiotherapy, and
the use of cytotoxic agents, despite their well known side
effects and problems associated with the development of resistance.
For most forms of disseminated cancer, however, no curative
therapy is available, and the discovery and development of
novel active chemotherapeutic agents is largely needed. Since
the development of cisplatin, an inorganic platinum
complex, numerous platinum and non-platinum metal complexes
were synthesized and tested for anticancer activity. Very
few match the clinical efficacy of cisplatin. Ruthenium
complexes were prepared to ameliorate cisplatin activity,
particularly on resistant tumours, or to reduce host toxicity
at active doses. Since many years a lot of scientific groups
have actively worked in the field of inorganic antitumor drugs
and have developed a number of Ru(II) and Ru(III) complexes,
which were shown to possess good antitumor and, above all,
antimetastatic properties against animal models. Ruthenium
complexes are presently an object of great attention in the
field of medicinal chemistry, as antitumor agents with selective
antimetastatic properties and low systemic toxicity. Ruthenium
compounds appear to penetrate reasonably well the tumor cells
and bind effectively to DNA. In this review, the achievements
in the field of medicinal chemistry, DNA binding modes, and
the development status of Ru(II) and Ru(III) complexes as
anticancer agents are discussed. The aim of this review is
therefore that of critically examining the past and the actual
work on ruthenium compounds with emphasis on their proposed
role in cancer therapy.
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