Current Drug Targets, Volume 3, No. 3, 2002
Furosemide Protective Effect Against Airway
Obstruction Pp.197-201
Franco
Cavaliere and Simonetta Masieri
Multiple Drug Targets in the Management of
Type 2 Diabetes Pp.203-221
M.H.
Moneva and S. Dagogo-Jack
Novel Molecular Targets for Systemic Lupus
Erythematosus Pp.223-228
Maria
Marino, Maria Rossi, Menotti Ruvo and Giorgio Fassina
Purine Signaling and Potential New
Therapeutic Approach:Possible Outcomes of NTPD ase Inhibition Pp.229-245
F.P.
Gendron, O. Benrezzak B.W. Krugh, Q. Kong, G.A. Weisman and A.R. Beaudoin
The Effects of Drugs Used in Anaesthesia on
Platelet Membrane Receptors and on Platelet Function Pp.247-258
Sibylle
A. Kozek-Langenecker
The Therapeutic Potential of Host-Defense
Antimicrobial Peptides Pp.259-267
N.
Sitaram and R. Nagaraj
Catalytic DNA: A Novel Tool for Gene
Suppression Pp.269-279
M.J.
Cairns, E.G. Saravolac and L.Q. Sun
[Back to top] Furosemide Protective Effect Against Airway
Obstruction
Franco Cavaliere and Simonetta Masieri
Furosemide
(frusemide) is mainly employed as a powerful diuretic that inhibits Na and K
reabsorption in renal tubules. However other valuable pharmacological effects
have been discovered that include a protective action from bronchospasm. The
effects of furosemide on airways have been recognized to be more and more
complex as far as an increasing amount of studies have been produced on this
subject. The drug shows no acute bronchodilator effect, but prevents or
attenuates bronchospasm caused by many factors, such as hyperpnea, drugs
(metabisulphite, bradykinin, AMP), physical agents (hypo- and hypertonic
aerosols), and allergen challenge in asthmatic patients. Furosemide is also
active on upper airway mucosa, on which the drug decreases nasal resistance in
patients affected by non-allergic rhinitis and exhibits a protective effect on
nasal mucosa reactivity to the specific allergen in atopic subjects. The
mechanism of action of furosemide on airways has not yet been fully cleared and
interference with electrolyte epithelial transport, prostaglandins,
inflammatory cell activity, vascular and neural regulation has been
hypothesized. The interest for clinical application of inhaled furosemide has
grown in last years. Some Authors have investigated whether the drug is
effective in acute asthma attacks or not. Furosemide is one of the drugs
currently used to prevent exercise-induced asthma. More recently, inhaled
furosemide has been observed to decrease the sensation of
experimentally-induced dyspnea. Apart from possible therapeutic application,
studies about furosemide effects on respiratory mucosa can contribute to better
understand the physiology of upper and lower airways.
[Back to top] Multiple Drug Targets in the Management of
Type 2 Diabetes
Diabetes mellitus (DM) is being diagnosed at an alarming rate around the world. More than 90% of the estimated 200 million affected persons with diabetes worldwide have type 2 DM, an often clinically silent disorder. In the United States, nearly half of the estimated 16 million persons with diabetes remain undiagnosed. Type 2 diabetes is preceded by a long period of impaired glucose tolerance (IGT), a potentially reversible metabolic state associated with increased risk for macrovascular complications. At the time of diagnosis more than one-third of patients have already developed long-term complications of diabetes. Genetic and acquired factors contribute to the pathogenesis of type 2 diabetes. The pathophysiological hallmarks consist of progressive insulin resistance, pancreatic b-cell dysfunction, and excessive hepatic glucose production. The ideal treatment for type 2 diabetes should correct insulin resistance, b-cell dysfunction, and normalize hepatic glucose output, as well as prevent, delay, or reverse diabetic complications. Emerging targets for therapy of type 2 diabetes include inhibition of gluconeogenesis, lipolysis, and fatty acid oxidation, as well as stimulation of b3-adrenergic receptors. Drug intervention for obesity is a legitimate adjunct to diabetes management. Additional drug targets include interventions to prevent or delay the progression of specific complications. Finally, primary prevention of type 2 diabetes is an important emerging strategy. The specific pharmacological agents acting at the various targets are discussed in this review. A targeted approach to the multiple underlying pathophysiologic processes offers the best chance of controlling diabetes and complications.
[Back to top] Novel Molecular Targets for Systemic Lupus
Erythematosus
Maria Marino, Maria Rossi, Menotti Ruvo and Giorgio
Fassina
For a long time
the complement cascade has been believed to be the predominant pathway to inflammation
and tissue destruction in autoimmune diseases such as systemic lupus
erythematosus. Recently, new evidences show that FcRs may share the primacy
with complement cascade, playing an equal or greater role in the disease
process. The generation of specific mouse strains deficient in individual
components has clarified the different role played by complement and Fc
receptors in their interaction with ICs, illustrating that complement is
essential for innate immunity against microbial pathogens, requiring natural
antibodies to mediate its protective effects, whereas FcgRs have evolved as the principal system for
coupling antigen-antibody complexes to effector cells and initiate the
inflammatory cascade.
Validation of FcRs as new therapeutic targets for autoimmune diseases, in particular for Systemic Lupus Erythematosus (SLE), has been provided by a large number of studies where the biological action of soluble forms of FcgRs or of monoclonal antibodies targeting Fc receptors has been assessed. Additional support to the role of FcRs in SLE has been provided by data obtained with compounds derived from combinatorial chemistry, such as TG19320, a tetrameric tripeptide which interferes with IgG/FcgR interaction in vitro and prevents glomerulonephritis in vivo in a SLE susceptible mouse strain. These findings might open the way to new therapeutic approaches for disorders where the role of FcRs has been established, including not only autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, but also acquired immunodeficiency syndrome (AIDS).
[Back to top] Purine Signaling and Potential New
Therapeutic Approach:Possible Outcomes of NTPD ase Inhibition
F.P. Gendron, O. Benrezzak B.W. Krugh, Q. Kong, G.A. Weisman and A.R. Beaudoin
Interest for extracellular nucleotides has increased since the pioneer work of Burnstock in the early seventies. Research on cellular functions modulated by purines and pyrimidines has led to the identification and characterization of the different components of purine signaling, namely purinoceptors and ecto-nucleotidases. Receptors for tri- and diphosphonucleosides, known as P2 nucleotide receptors, are designated either P2Y receptors, for those coupled to G-proteins, or P2X for those which are ligand gated-ion channels. Ecto-nucleoside triphosphate diphosphohydrolase (NTPDase; EC 3.6.1.5), previously identified as ecto-ATPase, ecto-ATPDase or CD39, is now considered as the main ecto-nucleotidase responsible for the sequential hydrolysis of beta and gamma phosphates of tri- and diphosphonucleosides. More recently, research has been focused on the development of specific agonists and antagonists to P2 purinoceptors. The need to develop specific inhibitors for NTPDase to understand the role of this enzyme has clearly emerged. This paper covers the development of specific molecules targeting purinergic signaling, more specifically the inhibition of NTPDase and their impact on the different physiological systems.
[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.
[Back to top] The Therapeutic Potential of Host-Defense
Antimicrobial Peptides
N.
Sitaram and R. Nagaraj
Species across the evolutionary scale from insects to mammals deploy peptides to counter microbial invaders.Although, there are considerable differences in the primary and secondary structures of these peptides, they exert their antimicrobial activity by common mechanisms ie. by membrane permeabilization. Extensive structure-function studies have been carried out on this class of antimicrobial peptides and 'designer' peptides have been generated which possess specific antimicrobial activity.In this article the physico-chemical properties and biological activities of host-defense peptides and 'designer' peptides would be reviewed with a view to explore whether they could be used as effective therapeutic agents.
[Back to top] Catalytic DNA: A Novel Tool for Gene Suppression
M.J. Cairns, E.G. Saravolac and L.Q. Sun
RNA, as an intermediate in the production of every gene encoded protein and the genetic material of many pathogenic viruses, presents an attractive target for both biological and therapeutic manipulation. Despite its extensive involvement in living systems, its chemical diversity based on four units is relatively low compared with protein. This provides the opportunity for a generic approach to targeting with specificity based on primary structure rather than complex higher order structures. This form of recognition occurs naturally in complementary nucleic acids, due to an ability to bind their single stranded target through Watson-Crick interactions. The most established nucleic acid based approach to gene suppression at the RNA level is through antisense oligodeoxynucleotides (ODNs). These compounds form heteroduplex with target RNA which are thought to either block its function or mediate its destruction by activation of RNase H. Alternatively, RNA can be targeted by catalytic RNA such as the hammerhead ribozyme. Ribozymes have the advantage of being equipped with their own RNA cleavage apparatus and are therefore independent of host nuclear protein activity. At present, the utility of ribozyme oligonucleotides is restricted by the relative difficulty synthesising active molecules with sufficient resistance to nuclease degradation. Recently the power of in vitro selection has been used to evolve catalytic DNA sequences with RNA cleavage specificity and activity rivalling the very best ribozymes, while maintaining the more robust chemistry of an ODN. These deoxyribozymes or DNAzymes have tremendous potential as gene suppression agents for both target validation and therapeutic applications. A number of studies evaluating the biological activity of these compounds have shown promising results. However, as with other oligonucleotide based strategies, future exploitation of this approach may depend on accessory technology to assist with the accessibility of a target which is folded by its own secondary structure and hidden within the intracellular compartment.