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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 13, 2007
Contents
mTOR Inhibitors (Rapamycin and its Derivatives) and Nitrogen
Containing Bisphosphonates: Bi-Functional Compounds for the
Treatment of Bone Tumours Pp. 1381-1387
Benjamin Ory, Gatien Moriceau, Francoise Redini and Dominique
Heymann
[Abstract]
Apoptosis Remodeling in Immunosenescence: Implications
for Strategies to Delay Ageing Pp. 1389-1397
Massimo De Martinis, Claudio Franceschi, Daniela Monti
and Lia Ginaldi
[Abstract]
Pharmacologic Therapy in Growth Hormone Disorders
and the Heart Pp. 1399-1407
Vicente Climent, Francisco Marín and Antonio Picó
[Abstract]
Ethnicity and Inflammatory Pathways – Implications
for Vascular Disease, Vascular Risk and Therapeutic Intervention
Pp. 1409-1425
M.A. Miller and F.P. Cappuccio
[Abstract]
The Influence of Exercise Upon Cardiac Biomarkers:
A Practical Guide for Clinicians and Scientists Pp.
1427-1436
Rob Shave, Keith George and David Gaze
[Abstract]
Modulators of Small- and Intermediate-Conductance
Calcium- Activated Potassium Channels and their Therapeutic
Indications Pp. 1437-1457
Heike Wulff, Aaron Kolski-Andreaco, Ananthakrishnan Sankaranarayanan,
Jean-Marc Sabatier and Vikram Shakkottai
[Abstract]
Dual Action-Based Approaches to Antibacterial Agents
Pp. 1459-1477
John B. Bremner, Joseph I. Ambrus and Siritron Samosorn
[Abstract]
Relationship Between General Anesthesia and Memory
in Drosophila Involving the cAMP/PKA Pathways and
Adhesion Related Molecules Pp. 1479-1488
Yoshiharu Tanaka, Masaya Takase and Sumiko Gamo
[Abstract]
Abstracts
[Back to top]
mTOR Inhibitors (Rapamycin and its Derivatives) and Nitrogen
Containing Bisphosphonates: Bi-Functional Compounds for the
Treatment of Bone Tumours
Benjamin Ory, Gatien Moriceau, Francoise Redini and Dominique
Heymann
N-BP, rapamycin and its derivatives have been originally
developed respectively as anti-resorptive and anti-fungal
agents. In fact, in vitro and in vivo experiments
demonstrated that these compounds are multi-functional molecules
exerting their effects on tumour cell growth and bone remodelling.
The major challenge in treating cancer relates to mutations
in key genes such as p53, Rb or proteins affecting caspase
signalling carried by many tumour cells. Whether nitrogen
containing bisphosphonates (N-BP) are potent bone inhibitors,
they also inhibit tumour cell proliferation and increase atypical
apoptosis of bone tumour cells regardless of the p53 and Rb
status. N-BP may be then considered as effective therapeutic
agents in clinical trials of bone tumours. Rapamycin and its
derivatives inhibit mTOR dependent mRNA translation both in
osteoclasts and tumour cells. Cellular physiological mechanisms
regulated by mTOR integrate many environmental parameters
including growth factors, hormones, cytokines, amino acids,
energy availability and cellular stresses that are coupled
with cell cycle progression and cell growth. Rapamycin and
its derivatives as well as N-BP must be considered as bi-(multi)
functional molecules affecting simultaneously bone and tumour
metabolisms. The present survey describes these two molecular
families and discusses their therapeutic interests for primary
bone tumours and bone metastases.
[Back to top]
Apoptosis Remodeling in Immunosenescence: Implications
for Strategies to Delay Ageing
Massimo De Martinis, Claudio Franceschi, Daniela Monti
and Lia Ginaldi
Immunosenescence is characterized by a peculiar remodeling
of the immune system, mainly induced by lifelong antigenic
burden and oxidative stress. Apoptosis or programmed cell
death plays a central role in the ageing process. Both recurrent
antigenic stimulations and oxidative metabolism by-products,
impinging upon the immune system, modify the apoptotic capability
of lymphocytes, driving immunosenescence. The apoptosis remodeling,
in addition to inflamm-ageing, i.e. the upregulation of anti-stress
responses and inflammatory cytokines, represents one of the
major determinants of ageing rate and longevity, as well as
of the most common age-related diseases. The cells of the
immune system undergo two different kinds of apoptotic processes:
activation-induced cell death (AICD), geared towards the elimination
of unnecessary lymphocytes following clonal expansion, and
damage-induced cell death (DICD), particularly important for
preventing the onset of neoplastic proliferations. During
senescence these apoptotic pathways are differentially modulated,
with variable impacts on the ageing process. A correct modulation
of apoptosis may be useful for prolonging the lifespan or
at least reducing age-related degenerative, inflammatory and
neoplastic diseases whose incidence increases with age. This
review focuses on the role of AICD and DICD dysfunction in
the ageing process and highlights emerging anti-ageing therapeutical
strategies offered by apoptosis re-modulation. The challenge
for the future is to identify factors and signals that regulate
apoptotic processes and determine if selective apoptosis manipulation
in specific lymphocyte subsets could preserve immune function
in the elderly, contributing to successful ageing.
[Back to top]
Pharmacologic Therapy in Growth Hormone Disorders
and the Heart
Vicente Climent, Francisco Marín and Antonio Picó
Growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis
is not only involved in the regulation of somatic growth but
also has important physiological functions in adults. Several
studies have shown that GH deficiency in adults is associated
with abnormalities in body composition, metabolic derangements,
and suboptimal physical performance. Furthermore, GH/IGF-I
axis plays an important role in the maintenance of heart structure
and function. Until recently, GH therapy was only used to
treat short stature children, with or without established
GH deficiency, and it remains common practice to discontinue
GH replacement therapy when final height is achieved.
Acromegaly, entity characterized by GH hypersecretion, is
associated with an increased risk of premature death. Cardiac
complications are known to be major determinants of the shortened
life expectancy. Treatment of acromegaly accounts for a substantial
decrease in morbidity and mortality. Surgery, radiation therapy
and bromocriptine have only been able to reduce GH levels
to normal levels in 10-30% of patients. The synthesis of somatostatin
analogs has provided a new approach to acromegaly treatment.
These drugs reduce GH and IGF-I levels in 80% of cases and
normalize them in 40-60% of cases.
Finally, GH/IGF-I system improves left ventricular systolic
function and has also indirect effects on the cardiovascular
system, mainly as a consequence of the peripheral vasodilatation.
These effects are important in the understanding of the potential
role of GH on improving ventricular systolic dysfunction and
point to the use of GH as a potential therapy for chronic
heart failure.
The aim of the present review is to provide an update overview
describing the role of GH on acromegaly, adult GH deficiency
and heart failure, as well as the influence of GH-based therapy
on heart structure and function.
[Back to top]
Ethnicity and Inflammatory Pathways – Implications
for Vascular Disease, Vascular Risk and Therapeutic Intervention
M.A. Miller and F.P. Cappuccio
Cardiovascular disease remains the most common cause of death
worldwide, yet there is a wide variation in disease prevalence
between different ethnic groups. One’s individual risk
is not entirely explained by ‘traditional’ risk
factors and this, along with the observation that endogenous
and lifestyle risk factors appear to cluster in the same individuals
has led to the idea that there may be a common mechanism underlying
this disease. It has been postulated that inflammatory pathways
may be important. Results from our own and other studies have
demonstrated that there may be ethnic differences in the level
of circulating inflammatory markers which may be partially
related to demographic, lifestyle or genetic factors. Before
it is possible to add inflammatory markers to global risk
scores it is imperative that a clear understanding of their
function, normal range and major determinants in different
ethnic groups is established. To date the ethnic research
in this area has been very sparse and further work is urgently
required. The usefulness of these inflammatory markers in
the diagnosis and prognosis of disease in these different
populations also needs to be investigated before therapeutic
strategies can be fully developed.
[Back to top]
The Influence of Exercise Upon Cardiac Biomarkers:
A Practical Guide for Clinicians and Scientists
Rob Shave, Keith George and David Gaze
The field of diagnostic cardiac biomarkers has grown exponentially
since the development of an assay for aspartate transaminase
activity to diagnose myocardial infarction in 1954. The clinician
now has a vast array of clinical tools, which include biomarkers
of inflammation, ischaemia and necrosis as well as sensitive
imaging technology and coronary anatomy intervention at their
disposal when evaluating acute coronary syndromes. Previously
the World Health Organisation (1979) defined a myocardial
infarction (MI) in the presence of two of the following triad:
History of chest pain, electrocardiographic (ECG) changes
and a rise in cardiac enzymes to twice the upper limit of
normal. At this time, creatine kinase and its MB isoenzyme
were the preferred biochemical markers. The clinical requirements
of early diagnosis, risk stratification and effective treatment
have stimulated the development of numerous new and cardiac
specific biomarkers (e.g. cardiac troponins). Cardiac troponins
are now integral to the diagnosis of MI and have led to the
reclassification of MI into either ST elevated MI (STEMI)
or non-ST elevated MI (NSTEMI). Subsequent to the release
of each new cardiac specific assay there typically follows
an array of studies supporting or refuting its efficacy. Many
cardiac biomarkers originally proposed with high sensitivity
and specificity for ACS are now of questionable clinical value
or require the addition of significant caveats once they have
been fully evaluated. Indeed, acute exercise often stimulates
perturbations in cardiac biomarkers; such as elevations in
creatine kinase, cardiac troponins or reductions in Ischemia
Modified Albumin (IMA®).
Such an influence of exercise upon commercially available
cardiac biomarkers may hamper or distort the viability of
such assays in the clinical arena. The purpose of this review
is to examine the influence of exercise upon a number of established
and novel cardiac biomarkers, including markers of necrosis,
inflammation, cardiac function and ischemia. We will also
address the clinical relevance of such exercise-induced perturbations.
[Back to top]
Modulators of Small- and Intermediate-Conductance
Calcium- Activated Potassium Channels and their Therapeutic
Indications
Heike Wulff, Aaron Kolski-Andreaco, Ananthakrishnan Sankaranarayanan,
Jean-Marc Sabatier and Vikram Shakkottai
Calcium-activated potassium channels modulate calcium signaling
cascades and membrane potential in both excitable and non-excitable
cells. In this article we will review the physiological properties,
the structure activity relationships of the existing peptide
and small molecule modulators and the therapeutic importance
of the three small-conductance channels KCa2.1-KCa2.3 (a.k.a.
SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a.
IKCa1).
The apamin-sensitive KCa2 channels contribute to the medium
afterhyperpolarization and are crucial regulators of neuronal
excitability. Based on behavioral studies with apamin and
on observations made in several transgenic mouse models, KCa2
channels have been proposed as targets for the treatment of
ataxia, epilepsy, memory disorders and possibly schizophrenia
and Parkinson’s disease. In contrast, KCa3.1 channels
are found in lymphocytes, erythrocytes, fibroblasts, proliferating
vascular smooth muscle cells, vascular endothelium and intestinal
and airway epithelia and are therefore regarded as targets
for various diseases involving these tissues. Since two classes
of potent and selective small molecule KCa3.1 blocker, triarylmethanes
and cyclohexadienes, have been identified, several of these
postulates have already been validated in animal models. The
triarylmethane ICA-17043 is currently in phase III clinical
trials for sickle cell anemia while another triarylmethane,
TRAM-34, has been shown to prevent vascular restenosis in
rats and experimental autoimmune encephalomyelitis in mice.
Experiments showing that a cyclohexadiene KCa3.1 blocker reduces
infarct volume in a rat subdural hematoma model further suggest
KCa3.1 as a target for the treatment of traumatic and possibly
ischemic brain injury. Taken together KCa2 and KCa3.1 channels
constitute attractive new targets for several diseases that
currently have no effective therapies.
[Back to top]
Dual Action-Based Approaches to Antibacterial Agents
John B. Bremner, Joseph I. Ambrus and Siritron Samosorn
This review collates and analyses recent work done on dual
action approaches to tackling the mounting health problem
of resistance by human pathogenic bacteria to antibacterial
agents. In particular the areas reviewed include the use of
two drugs in combination, dual action prodrugs, and dual action
drugs (or hybrid drugs).
[Back to top]
Relationship Between General Anesthesia and Memory
in Drosophila Involving the cAMP/PKA Pathways and
Adhesion Related Molecules
Yoshiharu Tanaka, Masaya Takase and Sumiko Gamo
On undergoing an operation under general anesthesia, we tend
to lose consciousness, and on recovering from the anesthetic
effect, we realize a memory loss during the operation, but
do remember the happenings before the operation. It implies
that the anesthesia deprivers us of short-term memory without
affecting long-term memory. Drosophila melanogaster
is known to be an excellent model for genetic studies related
to general anesthesia and memory. The various mutants in the
genes related to general anesthesia and memory have been found
to influence these mechanisms at the molecular level. In Drosophila,
learning and memory are classified into four distinct phases:
(1) short-term memory (STM), (2) middle-term memory (MTM),
(3) longer-lasting anesthesia-resistant memory (ARM), and
(4) long-term memory (LTM). On the other hand, based on the
genetic studies of the putative target molecules of general
anesthetics in model animals, the anesthetic action is classified
into five pathways: (1) presynaptic pathway including action
potential production, its transmission, and neurotransmitter
release; (2) postsynaptic pathway including inhibitory receptors
for sleep and pain; (3) memory pathway coupled with cAMP/PKA
signaling; (4) adhesion pathway in neuron; and (5) energy
production pathway. Memory and adhesion pathways of the anesthetic
action are developed in the Drosophila melanogaster
model. Many mutants of general anesthesia and those of memory
are overlapped suggesting that common molecules and signal
pathways are involved in both phenomena. In this review, we
will describe the relation between anesthesia and memory,
especially highlighting the interaction between the general
anesthetics and STM and MTM processes in Drosophila,
especially concentrating on the cAMP/PKA signaling and molecular
adhesion pathways.
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