The Role of Interferon-Alpha in the Treatment of Myeloproliferative
Disorders. Pp. 987-1013.
Claudia Fiorani, Stefania Tonelli, Barbara Casolari and Stefano
Sacchi
[Abstract]
The Immune System and the Effects of Non-volatile Anesthetics on Neutrophil
Transmigration Through Endothelial Cell Monolayers. Pp. 1015-1027.
Roland Hofbauer, Alan D. Kaye, Stylianos Kapiotis, Oswald Wagner
and Michael Frass
[Abstract]
Adenosine and Ischemic Preconditioning. Pp. 1029-1041.
Bruce T. Liang, Tomasz A. Swierkosz, Howard C. Herrmann, Stephen
Kimmel, and Kenneth A. Jacobson
[Abstract]
Strategies and Progress Towards the Ideal Orally Active Thrombin Inhibitor.
Pp. 1043-1075.
J. B. M. Rewinkel and A. E. P. Adang
[Abstract]
Approaches to the Prevention of Coronary Vascular Dysfunction Caused
by Myocardial Ischaemia and Reperfusion. Pp. 1077-1087.
Owen L Woodman
[Abstract]
[Back to top] The Role
of Interferon-Alpha in the Treatment of Myeloproliferative Disorders. Claudia
Fiorani, Stefania Tonelli, Barbara Casolari and Stefano Sacchi.
The interferons are cytokines with a wide array of biological properties.
In hematological malignancies the most used IFN class is -a;
it has been used for thirty years but the mode of action is still not absolutely
clear. Nevertheless, the benefits of IFN-a for
the treatment of CMD have been described in particular for CML and less
for PV, ET and MMM. IFN-a is presently considered
the golden standard of therapy for CML patients not eligible for SCT; the
antileukemic effect has been well documented by hematological and cytogenetic
response. The survival advantage for IFN treated patients is remarkable
in comparison with patients treated with conventional chemotherapy. Recently,
the combination IFN-a plus Ara-C has demonstrated
to increase the rate of major cytogenetic response and to prolong survival.
To date, there is not a generally accepted treatment for ET, PV and MMM,
which can reduce the risk of thromboembolism and/or hemorragic events.
In several subsets of ET and PV patients, IFN-a can
be considered as first line therapy. IFN-a is
usually associated with the development of early and later side effects,
that reduce the enthusiasm for its use. In the future PEG-IFN-a
would improve the quality of life of IFN-treated CMD patients.
[Back to top] The Immune
System and the Effects of Non-volatile Anesthetics on Neutrophil Transmigration
Through Endothelial Cell Monolayers. Roland Hofbauer, Alan D. Kaye, Stylianos
Kapiotis, Oswald Wagner and Michael Frass.
Inflammation represents the consequence of capillary dilation with
accumulation of fluid and transmigration of leukocytes into the surrounding
tissue. Leukocytes play a major role in the defense system of the body
against invading microorganisms. This defense system has a non-specific
branch consisting of granulocytes and macrophages and a specific branch
of lymphocytes. Granulocytes release cytotoxic compounds from their intracellular
granules into their local environment when encountering microorganisms.
This random destruction happens rapidly, but it may also harm healthy tissue
of the body. Leukocytes patrol the body by circulating through the blood
and lymphatic system ensuring a continuous surveillance which is a prerequisite
for an efficient defense. Upon tissue damage and inflammation, leukocytes
are recruited from the blood to sites of injury, and this trafficking displays
exquisite specificity. In the late 1890's, Metchnikoff noted the power
of certain blood cells to move towards microorganisms and ingest them.
In fact, leukocytes adhere to the endothelium of the blood vessels, and
subsequently leave the circulation by transmigration through the intercellular
junctions of the endothelial cell monolayer. Transmigration is driven by
chemoattractants, a process known as diapedesis. Reversible adherence of
leukocytes to the endothelium, basement membranes, and other surfaces is
an essential event in the establishment of inflammation, whose molecular
basis is beginning to be understood. Inflammation may become chronic in
many pathophysiologic processes and disease states. In long-term mechanically
ventilated critically ill patients, non-volatile anesthetics are needed
over a prolonged time period. Perioperative infections are a major cause
of morbidity and mortality in critically ill patients. Therefore, the influence
of non-volatile anesthetics and opioid agents on the immune system is of
high interest. After presentation of the different effectors of the immune
system and their fluxes through the body, the aim of this review is to
propose a general model of leukocyte transmigration through endothelial
cell monolayers. It emphasizes in which way different non-volatile anesthetic
drugs may affect the non-specific branch of the immune system, i.e. the
leukocyte transmigration through endothelial cell monolayers.
[Back to top] Adenosine
and Ischemic Preconditioning. Bruce T. Liang, Tomasz A. Swierkosz, Howard
C. Herrmann, Stephen Kimmel, and Kenneth A. Jacobson.
Adenosine is released in large amounts during myocardial ischemia and
is capable of exerting potent cardioprotective effects in the heart. Although
these observations on adenosine have been known for a long time, how adenosine
acts to achieve its anti-ischemic effect remains incompletely understood.
However, recent advances on the chemistry and pharmacology of adenosine
receptor ligands have provided important and novel information on the function
of adenosine receptor subtypes in the cardiovascular system. The development
of model systems for the cardiac actions of adenosine has yielded important
insights into its mechanism of action and have begun to elucidate the sequence
of signalling events from receptor activation to the actual exertion of
its cardioprotective effect. The present review will focus on the adenosine
receptors that mediate the potent anti-ischemic effect of adenosine, new
ligands at the receptors, potential molecular signalling mechanisms downstream
of the receptor, mediators for cardioprotection, and possible clinical
applications in cardiovascular disorders.
[Back to top] Strategies
and Progress Towards the Ideal Orally Active Thrombin Inhibitor. J. B.
M. Rewinkel and A. E. P. Adang.
Thrombin plays a key role in the control of thrombus formation, for
which reason its inhibition has become a target for new antithrombotics.
Important issues in the profile of the ideal thrombin inhibitor are: potency,
selectivity, oral bioavailability, half-life in the circulatory system
and safety. Although many potent direct inhibitors of thrombin have been
discovered, most of these inhibitors lack sufficient oral bioavailability.
This is often associated with the presence of highly basic functionalities
such as guanidine or amidine. These basic functionalities in the P1
moiety are preferred by thrombin and are present in the first generation
of thrombin inhibitors. Recently, several orally active direct thrombin
inhibitors have been disclosed. Most of these inhibitors originate from
leads of the first generation. Two major optimization strategies could
be identified to further improve these leads: A: maintain the highly basic
P1 moiety and compensate its negative effects, and B: reduce
the basicity of the P1 moiety and compensate for the decrease
in inhibitory activity. The progress made using these strategies is evaluated.
In addition, screening large sets of compounds yielded new structures that
provide useful starting points for optimization. The optimization strategy
used to convert leads from screening into potent orally active thrombin
inhibitors is also be evaluated.
[Back to top] Approaches
to the Prevention of Coronary Vascular Dysfunction Caused by Myocardial
Ischaemia and Reperfusion. Owen L Woodman.
The endothelium is an important regulator of coronary vascular tone
due to its ability to release potent vasoactive substances such as the
vasodilators nitric oxide (NO), endothelium-derived hyperpolarizing factor
(EDHF), prostacyclin (PGI2) and the potent vasoconstrictor endothelin.
Endothelial dysfunction has been associated with a number of pathological
states such as atherosclerosis, hypertension, diabetes and congestive heart
failure. A disturbance of endothelial function may also contribute to the
adverse effects that ischaemia and reperfusion exerts on the coronary vasculature.
After ischaemia and reperfusion there is usually a selective impairment
of endothelium-dependent relaxation in isolated coronary arteries. However,
in the intact coronary circulation, there is a general loss of vasodilator
reserve as responses to both endothelium-dependent and endothelium-independent
agonists are attenuated. The release of vasoconstrictor(s) and plugging
of capillaries with leukocytes may contribute to that impairment of the
capacity of the coronary circulation to dilate together with the reduction
in basal blood flow (no-reflow phenomenon). Ischaemic preconditioning is
able to prevent ischaemic damage to the myocardium but the vasculature
is less well protected as reperfusion is enhanced but the vasodilator reserve
continues to be limited. Pharmacological preservation of vascular function
has proved more successful with inhibitors of leukocyte adhesion, calcium
channel blockers, endothelin receptor antagonists and inhibitors of oxygen
radical generation all offering protection. Further refinement of protocols
to preserve endothelial and vascular function after ischaemia will aid
reperfusion, enhance vasodilator reserve and maximise recovery of myocardial
function.