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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 18, 2007
Contents
Nanochemistry-Based Immunotherapy for HIV-1 Pp. 1911-1919
F. Lori, S.A. Calarota and J. Lisziewicz
[Abstract]
New Insights on the Perturbations of T Cell Cycle
During HIV Infection Pp. 1920-1924
Domenico Galati and Marialuisa Bocchino
[Abstract]
Eosinophilopoiesis at the Cross-Roads of Research
on Development, Immunity and Drug Discovery Pp. 1925-1939
P. Xavier Elsas and M.I. Gaspar Elsas
[Abstract]
Cross-Talk Between NO and Arachidonic Acid in Inflammation
Pp. 1940-1944
Sofia Mariotto, Ylenia Suzuki, Tiziana Persichini, Marco
Colasanti, Hisanori Suzuki and Orazio Cantoni
[Abstract]
The Involvement of the Nitric Oxide in the Effects
and Expression of Opioid Receptors During Peripheral Inflammation
Pp. 1945-1955
Olga Pol
[Abstract]
Biological Markers for Multiple Sclerosis
Pp. 1956-1965
Andreas Lutterotti, Thomas Berger and Markus Reindl
[Abstract]
Antileukotriene Drugs: Clinical Application, Effectiveness
and Safety Pp. 1966-1977
G. Riccioni, T. Bucciarelli, B. Mancini, C. Di Ilio and
N. D’Orazio
[Abstract]
Monoclonal Antibody “Gold Rush”
Pp. 1978-1987
Krishan Maggon
[Abstract]
Hepatobiliary Diseases and Insulin Resistance
Pp. 1988-1999
Nahum Méndez-Sánchez, Noberto C. Chávez-Tapia,
D. Zamora Valdés, Roberto Medina-Santillán and
Misael Uribe
[Abstract]
Novel Agents in the Management of Mycobacterium
Tuberculosis Disease Pp. 2000-2008
P.J. Barry and T.M. O’Connor
[Abstract]
Abstracts
[Back to top]
Nanochemistry-Based Immunotherapy for HIV-1
F. Lori, S.A. Calarota and J. Lisziewicz
Highly active antiretroviral treatment (HAART), i.e. the combination
of three or more drugs against human immunodeficiency virus
type 1 (HIV-1), has greatly improved the clinical outcome
of HIV-1-infected individuals. However, HAART is unable to
reconstitute HIV-specific immunity and eradicate the virus.
Several observations in primate models and in humans support
the notion that cell-mediated immunity can control viral replication
and slow disease progression. Thus, besides drugs, an immunotherapy
that induces long-lasting HIV-specific T-cell responses could
play a role in the treatment of HIV/AIDS. To induce such immune
responses, DermaVir Patch has been developed. DermaVir consists
of an HIV-1 antigen-encoding plasmid DNA that is chemically
formulated in a nanoparticle. DermaVir is administered under
a patch after a skin preparation that supports the delivery
of the nanoparticle to Langerhans cells (LC). Epidermal LC
trap and transport the nanomedicine to draining lymph nodes.
While in transit, LC mature into dendritic cells (DC), which
can efficiently present the DNA-encoded antigens to naïve
T-cells for the induction of cellular immunity. Pre-clinical
studies and Phase I clinical testing of DermaVir in HIV-1-infected
individuals have demonstrated the safety and tolerability
of DermaVir Patch. To further modulate cellular immunity,
molecular adjuvants might be added into the nanoparticle.
DermaVir Patch represents a new nanomedicine platform for
immunotherapy of HIV/AIDS. In this review, the antiviral activity
of DermaVir-induced cellular immunity is discussed. Furthermore,
the action of some cytokines currently being tested as adjuvants
are highlighted and the adjuvant effect of cytokine plasmid
DNA included in the DermaVir nanopartcile is reviewed.
[Back to top]
New Insights on the Perturbations of T Cell Cycle
During HIV Infection
Domenico Galati and Marialuisa Bocchino
The role of the Human Immunodeficiency Virus (HIV) in the
pathogenesis of the Acquired Immune-Deficiency Syndrome (AIDS)
is changed. Direct HIV-mediated killing of CD4+
T cells is not the only mechanism leading to lymphocyte depletion.
There is increasing evidence that, during the chronic phases
of infection, T cell activation, accelerated cell turnover,
and cytokines imbalance induce the so-called cell cycle dysregulation
(CCD). CCD is a recently discovered immune-pathogenic mechanism
that mainly induces the depletion of both CD4+
and CD8+ uninfected T cells.
It is due to a significant perturbation of protein metabolism
as ubiquitin pathway defects of protein degradation are associated
with an increased and unscheduled expression of cyclin B and
p34cdc kinase. Moreover,
significant changes in the nucleolar structure and post-translational
regulation of nucleolin have also been described. As modulation
of CCD by anti-retroviral and immune-therapies has been suggested
to predict a good immunological response in HIV-infected patients,
a better understanding of such a mechanism is needed in order
to further clarify its role in the pathogenesis and progression
of HIV infection.
[Back to top]
Eosinophilopoiesis at the Cross-Roads of Research
on Development, Immunity and Drug Discovery
P. Xavier Elsas and M.I. Gaspar Elsas
Eosinophils are a minority subpopulation of leukocytes whose
roles in host defense against infection remain controversial,
but which have been implicated in the pathogenesis of both
acute allergic inflammation and the chronic bronchopulmonary
remodelling in asthma. Eosinophilia, a hallmark of both helminth
infections and atopic diseases, is maintained through upregulation
of eosinophilopoiesis by means of increased production and
effectiveness of Interleukin-5 (IL-5), a major Th2 cytokine.
These mechanisms are further modulated by a wide variety of
agents, including glucocorticoids, nonsteroidal antiinflammatory
drugs and mediators of inflammation. We review recent progress
made by different groups in the study of eosinophilopoiesis
that led to the identification of the heterogeneous targets
for developmental regulation by IL-5 and other agents, and
to the ongoing characterization of the molecular mechanisms
that ensure their commitment to the eosinophil lineage. We
argue that the study of eosinophilopoiesis provides insight
into basic developmental processes, and especially into how
modulators influence the constitutive rate of eosinophil production
by controlling the rates of apoptosis and terminal differentiation.
The mechanisms underlying the apparently paradoxical effects
of dexamethasone, a drug widely employed to control inflammation,
as well as the role of specific molecular targets (including
inducible NO synthase and CD95/Fas) in developmental regulation,
are discussed in detail. We further argue that eosinophilopoiesis
offers unique insights of how immune and endocrine effector
loops interact to control both the steady-state responses
to IL-5 and the susceptibility to modulation of these responses
by drugs and cytokines. We also review the existing evidence
on the recruitment of circulating stem cells and progenitors
into inflammatory sites, and on a critical role for IL-5 in
the accumulation of eosinophil lineage-committed progenitors
in lungs of allergic mice. Finally, we review recent progress
in the study of the regulatory T cell populations present
in bone-marrow, and discuss alternative mechanisms through
which cellular immunity may influence eosinophilopoiesis.
[Back to top]
Cross-Talk Between NO and Arachidonic Acid in Inflammation
Sofia Mariotto, Ylenia Suzuki, Tiziana Persichini, Marco
Colasanti, Hisanori Suzuki and Orazio Cantoni
Inducible nitric oxide synthase (iNOS) is expressed in a variety
of cell types, in particular in inflammatory cells, in response
to diverse pro-inflammatory stimuli. This process requires
critical levels of arachidonic acid (AA), generated by constitutive
phospholipase A2 (PLA2),
promoting tyrosine kinase-dependent phosphorylation, and inhibition,
of constitutive NOS. Lowering basal NO levels is indeed critical
for the activation of nuclear factor-κB
(NF-κB),
and thus for the expression of genes (e.g. iNOS) regulated
by this trascription factor. It is interesting to note that
NO and AA, two small lipid soluble molecules, rapidly cross
the plasma membrane thereby allowing the triggering of the
above responses in distal cells. That is, constitutive NO
might inhibit NF-κ
B
activity in the same cells (e.g. astrocytes) in which it is
generated, as well as in other cells that do not express constitutive
NOS (e.g. microglia). NO from cells unable to respond to pro-inflammatory
stimuli (e.g. neurons) will also contribute to these effects.
Along the same line, AA released by pro-inflammatory molecules
in specific cell types (e.g. astrocytes) might suppress constitutive
NOS activity in the same cells as well as in other cells (e.g.
neurons). Thus, AA produced at the very early stages of the
inflammatory response is a likely critical signal switching
the regulation of the “NO tone” from physiological
(i.e. mediated by constitutive NOS) to pathological (i.e.
mediated by iNOS). This second phase of the inflammatory response
is often accompanied by the onset of deleterious effects in
the tissue in which a critical role is played by iNOS-derived
NO (directly or indirectly, i.e. via formation of
peroxynitrite) as well as by products of the AA cascade. In
summary, we suggest that the relative amounts of NO and AA,
released by their constitutive enzymes, produce autocrine
and paracrine effects regulating the onset of an inflammatory
response in which, in addition to other factors, NO and AA
are extensively released by their inducible enzymes.
[Back to top]
The Involvement of the Nitric Oxide in the Effects
and Expression of Opioid Receptors During Peripheral Inflammation
Olga Pol
Peripheral inflammation enhances the antinociceptive effects
of opioid receptor agonists through the activation of peripheral
opioid receptors whose expression also increases during inflammatory
pain. Similarly, intestinal inflammation also increases the
antitransit and antiexudative effects of opioids as well as
the expression of neuronal and extra-neuronal opioid receptors
located in the gut.
Nitric oxide has been described either as pro- or antiinflammatory
and could produce both pro- and antinociceptive effects. In
addition, numerous studies have shown that the L-arginine-nitric
oxide-cGMP system participates in the antinociceptive and
in the intestinal effects produced by opioids during peripheral
inflammation by enhancing their effects. Thus, substances
capable of inhibiting cyclic guanosine-3’,5’-monophosphate
(cGMP) degradation or nitric oxide donors increase the analgesic
effects of opioid receptor agonists during peripheral inflammation.
At the same time, the administration of nitric oxide synthase
(NOS) or guanylate cyclase inhibitors decreases those effects.
In accordance with these results, different clinical trials
have also demonstrated that the co-administration of nitric
oxide donors with opioids is highly beneficial in the treatment
of pain in patients.
In the gut, nitric oxide has a further pro- and antiinflammatory
action. It is also involved in the enhanced antitransit and
antiexudative effects produced by opioids and in the up-regulation
of the μ-opioid
receptor gene transcription observed in the inflamed intestine.
To sum up, a better knowledge of the involvement of the L-arginine-nitric
oxide- cGMP pathway in the opioid mechanisms of action and
a better understanding of the pathways that regulate the expression
of opioid receptors during peripheral inflammation are essential
to developing improved analgesic/antiinflammatory therapies.
[Back to top]
Biological Markers for Multiple Sclerosis
Andreas Lutterotti, Thomas Berger and Markus Reindl
Multiple sclerosis (MS) is the most common disabling neurological
disease in young adults and is thought to result from an autoimmune
attack against autoantigens within the myelin sheath. A characteristic
feature of MS is the broad heterogeneity of clinical, histopathological
and immunological phenotypes, which urges a more differentiated
defining of patients by biological markers that reflect the
underlying disease process and allow the prediction of disease
courses and treatment responses. Here we review the current
research on the identification of biomarkers for MS in cerebrospinal
fluid and/or blood. We will focus on antibodies to myelin
and non-myelin antigens, cells and soluble molecules of the
immune system and the brain as biomarkers for 1) the diagnosis
and prediction of clinical courses, 2) disease activity and
3) treatment response in MS.
[Back to top]
Antileukotriene Drugs: Clinical Application, Effectiveness
and Safety
G. Riccioni, T. Bucciarelli, B. Mancini, C. Di Ilio and
N. D’Orazio
Cysteinyl leukotrienes (Cys-LTs) are potent proinflammatory
mediators derived from arachidonic acid through the 5-lypoxigenase
(5-LO) pathway. They exert important pharmacological effects
by interaction with at least two different receptors: Cys-LT1
and Cys-LT2. By competitive
binding to the Cys-LT1 receptor,
leukotriene receptor antagonist drugs such as montelukast,
zafirlukast, and pranlukast, block the effects of Cys-LTs
and alleviate the symptoms of many chronic diseases, especially
bronchial asthma and allergic rhinitis.
Evidence obtained by randomized clinical trials as also by
direct experience derived from patients suffering from asthma
and allergic rhinitis justifies a broader role for leukotrienes
receptor antagonists (LTRAs). Recently published studies and
case reports have demonstrated beneficial effects of LTRAs
on other diseases commonly associated with asthma (exercise
induced asthma, rhinitis, chronic obstructive pulmonary disease,
interstitial lung disease, chronic urticaria, atopic dermatitis,
allergic fungal disease, nasal polyposis, and paranasal sinus
disease) as well as other diseases not connected to asthma
(migraine, respiratory syncytial virus postbronchiolitis,
systemic mastocytosis, cystic fibrosis, pancreatitis, vulvovaginal
candidiasis, cancer, atherosclerosis, eosinophils cystitis,
otitis media, capsular contracture, and eosinophilic gastrointestinal
disorders). The aim of this review is to show the most recent
applications and effectiveness in clinical practice of the
LTRAs.
[Back to top]
Monoclonal Antibody “Gold Rush”
Krishan Maggon
The market, sales and regulatory approval of new human medicines,
during the past few years, indicates increasing number and
share of new biologics and emergence of new multibillion dollar
molecules. The global sale of monoclonal antibodies in 2006
were $20.6 billion. Remicade had annual sales gain of $1 billion
during the past 3 years and five brands had similar increase
in 2006. Rituxan with 2006 sales of $4.7 billion was the best
selling monoclonal antibody and biological product and the
6th among the top selling
medicinal brand. It may be the first biologic and monoclonal
antibody to reach $10 billion annual sales in the near future.
The strong demand from cancer and arthritis patients has surpassed
almost all commercial market research reports and sales forecast.
Seven monoclonal antibody brands in 2006 had sales exceeding
$1 billion. Humanized or fully human monoclonal antibodies
with low immunogenicity, enhanced antigen binding and reduced
cellular toxicity provide better clinical efficacy. The higher
technical and clinical success rate, overcoming of technical
hurdles in large scale manufacturing, low cost of market entry
and IND filing, use of fully human and humanized monoclonal
antibodies has attracted funds and resources towards R&D.
Review of industry research pipeline and sales data during
the past 3 years indicate a real paradigm shift in industrial
R&D from pharmaceutical to biologics and monoclonal antibodies.
The antibody bandwagon has been joined by 200 companies with
hundreds of new projects and targets and has attracted billions
of dollars in R&D investment, acquisitions and licensing
deals leading to the current Monoclonal Antibody Gold Rush.
[Back to top]
Hepatobiliary Diseases and Insulin Resistance
Nahum Méndez-Sánchez, Noberto C. Chávez-Tapia,
D. Zamora Valdés, Roberto Medina-Santillán and
Misael Uribe
In recent years, there has been an increasing prevalence of
obesity and related diseases. This epidemiological change
has increased the interest of researchers in the molecular
and biochemical pathways involved in the pathogenesis of hepatic
and biliary diseases. Insulin resistance is considered the
major mechanism involved in the hepatic and biliary manifestations
of obesity. Epidemiological, clinical, and basic research
demonstrates that insulin resistance is associated with gallstone
disease, nonalcoholic fatty liver disease, and poor outcomes
in viral hepatitis C treatments. Fascinating experimental
evidence demonstrates that fat-induced hepatic insulin resistance
may result from the activation of kinases leading to impaired
insulin signaling. The insulin-sresistant state is characterized
by a failure to suppress hepatic glucose production and glycogenolysis,
with enhanced fat accumulation in hepatocytes because of increased
lipolysis, increased free fatty acid uptake by hepatocytes,
and increased hepatic synthesis of triglycerides. This molecular
signaling induces a low-grade chronic inflammatory state,
characterized by increased levels of proinflammatory molecules
and acute-phase proteins. This review summarizes the most
important molecular and biochemical issues in the hepatic
and biliary diseases associated with insulin resistance.
[Back to top]
Novel Agents in the Management of Mycobacterium
Tuberculosis Disease
P.J. Barry and T.M. O’Connor
The goals of tuberculosis control are to cure active disease,
prevent relapse, reduce transmission and avert the emergence
of drug resistance. However, since the 1960s, there have been
few developments in available therapies. Currently available
agents are complicated by numerous side-effects, drug interactions
and the need for a long duration of therapy. Rifampicin-containing
regimes lead to hepatic enzyme induction which can complicate
or preclude the use of protease inhibitors and non-nucleoside
reverse transcriptase inhibitors in patients infected with
the human immunodeficiency virus. Furthermore, emerging drug
resistance has complicated management for many patients and
clinicians. Therefore, new chemotherapeutic agents are urgently
needed.
Existing antimicrobials are emerging as potent antituberculous
agents. Recent studies have demonstrated the antituberculous
activity of newer fluoroquinolones including levofloxacin,
moxifloxacin, and gatifloxacin. Their use as first line antituberculous
agents is currently under investigation. Furthermore, the
oxazolidinones linezolid and PNU-100480 have been shown to
have antituberculous activity in addition to their antibacterial
effects.
Several other agents are currently being developed for the
treatment of tuberculosis. These agents include diarylquinolones
(R207910), nitroimidazopyrans (PA-824, OPC-67683), ethambutol
analogues (SQ109), cerulenin, trans-cinnamic acid, macrolides,
pyrroles (LL3858), long-acting rifamycins and inhaled interferon-gamma.
Furthermore, vaccines are being explored for pre-exposure
and post-exposure use.
This review will describe therapeutic developments in the
management of tuberculosis, highlighting mechanisms of action
of new pharmacological agents and their potential for clinical
use.
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