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Medicinal Chemistry Reviews - Online, Volume 1, No. 1, 2004
Contents
The Use of Auxiliary Agents to Improve the
Mucosal Uptake of Peptides
Pp.1-10
Andreas
Bernkop-Schnurch, Andreas E. Clausen
and Davide Guggi
The Role of CD8+ T Cell Soluble Factors in
Human Immunodeficiency Virus Infection: An Update Pp.11-12
Karen
F.T. Copeland
Update to Medicinal Chemistry of Nicotinamide
in the Treatment of Ischemia and Reperfusion Pp.13-17
J.
Yang, K. Klaidman and J.D. Adams
Oxidative Stress Mechanisms and Potential
Therapeutic Modalities in Alzheimer Disease Pp.19-23
Adam
D. Cash, Mark A. Smith and George Perry
Novel Therapeutic Targets for Acute Pancreatitis
and Associated Multiple Organ Dysfunction Syndrome: An Update Pp.25-26
M.
Bhatia
Scintigraphic Imaging of Inflammatory
Processes Pp.27-38
Huub
J.J.M. Rennen, Otto C. Boerman, Wim J.G. Oyen and Frans H.M. Corstens
ETS Proteins and MMPs: Partners in Invasion
and Metastasis Pp.39-46
Sadmeet
Singh, Jane Barrett, Kenji Sakata, Richard G. Tozer and Gurmit Singh
Fluorinated Anthracyclines: Synthesis and
Biological Activity Pp.47-71
Giuseppe
Giannini
Selective PGHS-2 Inhibitors: A Rational
Approach for Treatment of the Inflammation Pp.73-90
C.R. Rodrigues, M.P. Veloso, H. Verli, C.A.M. Fraga, A.L.P. Miranda and E. J. Barreiro
GABA-A Receptor Complex and Memory Processes Pp.91-99
Georges Chapouthier and Patrice Venault
The Effects of Drugs Used in Anaesthesia on
Platelet Membrane Receptors and on Platelet Function Pp.101-110
Sibylle A. Kozek-Langenecker
Abstracts
[Back to top] The Use of Auxiliary Agents to Improve the
Mucosal Uptake of Peptides
Andreas
Bernkop-Schnurch, Andreas E. Clausen
and Davide Guggi
The mucosal
administration of peptide drugs causes a therapeutical response only if
significant amounts of the drug are enabled to permeate the absorption membrane
based on the mucus layer (I) and the epithelial tissue (II) .The peptide drug
transport across the membrane can be improved by the use of mucolytic agents
and of permeation enhancers. The generation of novel, more potent permeation
enhancers, based on a more exact knowledge of the absorption membrane in
combination with appropriate delivery systems strongly improves the
bioavailability of mucosally applied peptide drugs.
[Back to top] The Role of CD8+ T Cell Soluble Factors in
Human Immunodeficiency Virus Infection: An Update
Karen
F.T. Copeland
CD8+ T cells are
strong mediators of antiviral responses. In addition to lysis of HIV infected
cells, CD8+ T cells produce proteins which inhibit HIV replication by non-lytic
mechanisms. These proteins include b-chemokines which inhibit viral entry and
IL-16 which inhibits HIV transcription. The CD8+ T cell antiviral factor (CAF)
also inhibits HIV transcription. CAF remains unidentified. This update
summarizes the research conducted over the last two years pertaining to CD8+ T
cell antiviral activity.
[Back to top] Update to Medicinal Chemistry of Nicotinamide
in the Treatment of Ischemia and Reperfusion
J.
Yang, K. Klaidman and J.D. Adams
Nicotinamide and
its analogs are currently being used or investigated for the treatment of
ischemia reperfusion conditions.
Nicorandil has been investigated for use in cardiac ischemia and
reperfusion and is approved for use in Europe and Japan in angina. Nicotinamide has been extensively investigated
in animal models of stroke, including middle cerebral artery occlusion and
spontaneously hypertensive rats. Dose
response curves and time response curves have been produced for nicotinamide in
these models. Nicotinamide spares ATP
by increasing NAD levels and protecting DNA from fragmentation. Inhibitors of poly(ADP-ribose) polymerase,
including nicotinamide, have been investigated in ischemia reperfusion
conditions in other organs such as the testicles and liver. New evidence suggests that nicotinamide may
have other mechanisms of action involving the regulation of cellular processes.
[Back to top] Oxidative Stress Mechanisms and Potential
Therapeutic Modalities in Alzheimer Disease
Adam D. Cash, Mark A. Smith and George Perry
Alzheimer disease
is characterized by oxidative damage to every class of biological
macromolecule. Disruptions in iron and copper homeostasis are implicated as
having key roles in neurodegenerative disease pathogenesis. Metal homeostasis as
it pertains to alterations in brain function and its relation to oxidative
stress in neurodegenerative diseases is reviewed here. While there is
documented evidence for alterations in transition metal metabolism,
redox-activity and localization, it is important to note that alterations in
specific copper- and iron-containing metalloenzymes contribute to the
neurodegeneration in AD. Understanding these changes offers the opportunity to
identify pathways where modification of the disease process can offer effective
clinical intervention, from gene therapy to pharmaceuticals with antioxidant
and chelating properties.
[Back to top] Novel Therapeutic Targets for Acute
Pancreatitis and Associated Multiple Organ Dysfunction Syndrome: An Update
M.
Bhatia
In an article
published in Current Drug Targets – Inflammation and Allergy in December 2002,
I had reviewed the critical role played by inflammatory mediators in the
pathogenesis of acute pancreatitis and associated multiple organ dysfunction
syndrome (MODS) and the potential for these mediators as therapeutic targets.
Recent work, by us as well as other investigators, has further substantiated a
potential for these mediators as therapeutic targets for this condition.
[Back to top] Scintigraphic Imaging of Inflammatory
Processes
Huub
J.J.M. Rennen, Otto C. Boerman, Wim J.G. Oyen and Frans H.M. Corstens
Nuclear medicine
offers ideal techniques to visualize inflammatory processes using noninvasive
methods of whole-body scanning, enabling the determination of both the
localization and the number of inflammatory foci. In nuclear medicine, a
radiolabeled compound is injected (mostly) intravenously and accumulates in the
inflammatory lesion due to the locally changed physiological condition. These
changes are enhanced blood flow, enhanced vascular permeability and enhanced
influx of leukocytes. Radiopharmaceuticals can be primarily divided into two
classes: those accumulating in the inflammatory lesion based on non-specific
processes and those accumulating in connection to leukocytes. Nonspecific
tracers like 67Ga-citrate, radiolabeled non-specific immunoglobulins and
radiolabeled liposomes are discussed in detail. Studies using specific tracers
mainly focus on radiolabeling leukocytes, either directly or indirectly. Direct
labeling of isolated leukocytes and reinjecting them is considered the “gold
standard” nuclear medicine technique for imaging inflammation. Labeling
leukocytes in vivo (the indirect approach) can be achieved by the use of
radiolabeled antibodies or by compounds binding to leukocyte receptors with
high affinity. At least three anti-granulocyte antibodies have been tested for
infection imaging: anti-NCA-95 IgG (BW250/183), anti-NCA-90 Fab' (Immu-MN3,
leukoscan®: anti-CD66), and anti-SSEA-1 IgM (LeuTech®: anti-CD15). In addition,
a wide variety of peptides binding to leukocyte receptors has been
investigated, e.g. chemotactic peptide formyl-Met-Leu-Phe, cytokines such as
interleukin-1, interleukin-2, interleukin-8 and platelet factor 4 (derivatives)
and complement factors such as C5a. Furthermore, positron emission tomography
with 18F-fluorodeoxyglucose takes advantage of the enhanced glucose
requirements of leukocytes and macrophages in inflammatory foci. A totally
different approach is to target directly micro-organisms, without intervention
of leukocytes. This strategy is adopted in radiopharmaceuticals such as
Infecton and antimicrobial peptides. The discussed radiopharmaceuticals enable
accurate diagnosis of the inflammatory condition and with these agents the
effectiveness of anti-inflammatory therapies can be monitored.
[Back to top] ETS Proteins and MMPs: Partners in Invasion
and Metastasis
Sadmeet
Singh, Jane Barrett, Kenji Sakata, Richard G. Tozer and Gurmit Singh
Binding sites for
the ETS domain family of transcription factors are found in the promoters of
the matrix metalloproteinase (MMP) family of matrix degrading enzymes. Evidence
is accumulating that both these groups of molecules are important in the
process of angiogenesis in addition to matrix degradation. Furthermore, they
are both expressed in tumor tissue as well as in the normal surrounding stroma.
These factors along with various sites at which they may be regulated
collectively makes them attractive targets to consider for therapeutic
intervention in the processes of invasion and metastasis.
[Back to top] Fluorinated Anthracyclines: Synthesis and
Biological Activity
Giuseppe
Giannini
Organic structures
with fluorine atom are slightly diffuse in nature.
Starting ‘80s
researchers have discovered that the selective introduction of fluorine into
biologically active molecules exercised an influence on activity. So an
important endeavour in drug design have been described and numerous compounds
incorporating fluorine as either a bioisosteric replacement for hydrogen or an
isoelectronic replacement for the hydroxyl group have been reported.
Parallely, an
enormous literature on anthracyclines exists, a class of compounds used in
clinical since ‘70s, as antitumor drugs. Unfortunately, the anthracyclines are
known as well for several toxical effects that frequently condition the
clinical use.
In the last decade
a lot of anthracycline derivatives has been described in which has been
introduced a fluorine atom in different position of molecule.
This review wishes
to represent an updated collection of compounds with anthracycline structure
where a fluorine atom has been introduced on aglycon or/and sugar moiety.
Together with the
chemical structures, the synthetic indications are furnished and succinct
explanations of biological activity are summarised (if available).
[Back to top] Selective PGHS-2 Inhibitors: A Rational
Approach for Treatment of the Inflammation
C.R.
Rodrigues, M.P. Veloso, H. Verli, C.A.M. Fraga, A.L.P. Miranda and E. J. Barreiro
Prostaglandin-H
synthase exists in two isoforms, PGHS-1 and PGHS-2. PGHS-1 is present and is
constitutively expressed in most cells and tissues, whereas PGHS-2 is mainly
thought to mediate inflammation. Selective prostaglandin-H synthase-2 (or
cyclooxygenase-2) inhibitors have been
shown to be potent antiinflammatory agents with fewer side effects than
currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). This review
addresses the main classes of the selective PGHS-2 inhibitors whose selectivity
is documented by supporting PGHS-1 and PGHS-2 enzyme data. In addition, we also
describe our experience in design, synthesis and pharmacological in vivo
evaluation of new 1,2-benzodioxole derivatives as candidate of the selective
PGHS-2 inhibitors, with special attention to molecular dynamics simulations of
these derivatives attached to the active site of PGHS-2.
[Back to top] GABA-A Receptor Complex and Memory Processes
Georges
Chapouthier and Patrice Venault
Considerable
evidence has been provided these last years for the involvement of the GABAA
receptor complex in memory processes. Compounds that enhance the action of
GABA, such as benzodiazepines, impair memory processing. On the contrary,
compounds that reduce the action of GABA, such as ß-CCM, pentylenetetrazol or
picrotoxin, have the opposite action, that is : enhance memory processing. All
these actions seem to focus mainly on the acquisition (learning) processes.
Depending on the dose, the same compounds also have effects on anxiety and on
seizuring. Benzodiaze-pines are well-known
anxiolytic and anticonvulsant agents whereas compounds
that reduce the action of GABA have been found to produce anxiogenic and
convulsant actions. The GABAA receptor complex might thus be the location of a
possible link between a pathological state (epilepsy) and two normal functions
(anxiety and learning). This link is likely to involve common genetic pathways.
In the normal subject, these data also emphasize the idea that normal memory
processing involves a moderate level of anxiety.
[Back to top] The Effects of Drugs Used in Anaesthesia on Platelet Membrane Receptors
and on Platelet Function
Sibylle
A. Kozek-Langenecker
Platelet
dysfunctions are known origins of perioperative bleeding disorders which are a
major concern in the management of surgical patients. Among multiple factors,
interactions of drugs used in anaesthesia with platelets have been implicated
to aggravate the risk of haemorrhagic complications. This paper reviews in
vitro and in vivo studies which have examined the effects of inhalational,
intravenous, and local anaesthetics, opioids, and muscle relaxants on
platelets. A brief summary of platelet physiology, function tests, and flow
cytometric assessment of membrane receptors is included. Although the results
of many studies have been conflicting, it appears that halothane, sevoflurane,
and propofol inhibit platelet function in a reversible and dose-related manner
at concentrations used clinically. Halothane affects the intracellular
activating second messenger inositol triphosphate, platelet calcium
homeostasis, thromboxane A2 formation, and the inhibiting signal
transduction pathway including cyclic adenosine monophosphate. The proposed
platelet inhibiting mechanism of sevoflurane involves the suppression of thromboxane
A2 formation. Propofol appears to cause platelet dysfunctions by inhibiting
calcium mobilisation upon agonist stimulation. Nitrous oxide causes a modest
suppression of calcium mobilisation. An interaction of local anaesthetics with
components in the platelet membrane appears to account for their inhibiting
effect, but only at concentrations far higher than that found during clinical
use. A clinically relevant antithrombotic effect of regional anaesthesia has
been observed, though. Isoflurane, enflurane, desflurane, barbiturates,
etomidate, opioids, and muscle relaxants seem to have negligible effects on
platelets at therapeutic concentrations. Anaesthetists should be aware of the
potential impairment of the coagulation profile by anaesthetic agents.