Current Drug Targets, Volume 5, No. 5, 2004
Chronic Tendon Pain-Implications for
Treatment: An Update Pp.407-410
New Indications for Corticosteroids in
Intensive Care Units Pp.411-417
Franco
Cavaliere, Simonetta Masieri, Giuseppina Annetta, Flavio Gargano and Rodolfo
Proietti
New Trends in the Development of
Transcription Factor Decoy (TFD) Pharmacotherapy Pp.419-430
Roberto
Gambari
Protein Kinase C and Prostate Carcinogenesis:
Targeting the Cell Cycle and Apoptotic Mechanisms Pp.431-443
M.
Veronica Gavrielides, Anita F. Frijhoff, Claudio J. Conti and Marcelo G.
Kazanietz
Is Surfactant a Promising Additive Drug in
ALI/ARDS-Patients? Pp.445-448
Marcus
J. Schultz and Jozef Kesecioglu
Drug Delivery Systems: Past, Present, and
Future Pp.449-455
Rubiana
M. Mainardes1 and Luciano P. Silva
Secondary Prevention of Ischemic Stroke Pp.457-472
Kirsi
Rantanen and Turgut Tatlisumak
Epileptogenicity and Epileptic Activity:
Mechanisms in an Invertebrate Model Nervous System Pp.473-484
U.
Altrup
Development of New Drugs in Angiogenesis Pp.485-493
Marina
Ziche, Sandra Donnini and Lucia Morbidelli
Abstracts
[Back to top] Chronic Tendon Pain-Implications for
Treatment: An Update
Hakan
Alfredson
In previous studies we found high concentrations of the neurotransmitter glutamate in chronic painful tendons. To evaluate the possible importance, the high intra-tendinous glutamate concentrations had for the pain suffered in chronic Achilles tendinosis, microdialysis was performed before and after treatment. The results showed that in patients that were pain-free after treatment there were no significant differences in the glutamate levels before compared to after treatment. With this finding in mind, also other possibly pain-related mechanisms were evaluated. Using ultrasonography and colour doppler technique, we found that in chronic painful tendinosis tendons, but not in normal pain-free tendons, there was a neovascularisation inside and outside the area with structural tendon changes and pain. To test the hypothesis that there was an association between neovascularisation and pain, in a pilot study, under ultrasound and colour doppler guidance the area with neovascularisation was destroyed by injecting the sclerosing agent Polidocanol. The clinical results showed that 8/10 patients were pain-free and had no remaining neovessels. The 2 patients that were not pain-free had remaining neovessels. In a following investigation combining ultrasonography + colour doppler, immunohistochemical analyses of biopsies, and diagnostic injections, the results showed that in the area with tendon changes and neovascularisation, biopsies showed nerve structures in close relation to the blood vessels, and injetions of local anaesthesia temporarily cured the pain in all patients. Althogether, the findings indicate that the area with neovascularisation (neovessels and nerves) might be responsible for the pain suffered in chronic Achilles tendinosis, and that a locally administrated (in the area with neovascularisation) sclerosing drug (Polidocanol) has the potential to cure the pain.
[Back to top] New Indications for Corticosteroids in Intensive
Care Units
Franco
Cavaliere, Simonetta Masieri, Giuseppina Annetta, Flavio Gargano and Rodolfo
Proietti
In last years an increasing number of evidences has been gained that inflammatory response plays a major role in critical illness. The acronym SIRS (Systemic Inflammatory Response Syndrome) has been introduced to define the condition in which the inflammatory reaction exceeds local mechanisms of containment and inflammatory mediators invade the bloodstream causing systemic disturbances. Theoretically, the use of corticosteroids offers a potent tool to control the excess of inflammatory reaction, but initial trials on Adult Respiratory Distress Syndrome (ARDS), head trauma, and septic shock showed not only that mortality was unaffected, but also that morbidity could increase. Recently, however, some new studies have suggested that corticosteroids given at dosages lower than those initially tested, could positively affect late stages of ARDS by preventing pulmonary fibrosis, and septic shock by improving hemodynamics and facilitating the weaning from catecholamines. To date, it is not clear whether these effects are related to the correction of an adrenocortical dysfunction.
[Back to top] New Trends in the Development of Transcription
Factor Decoy (TFD) Pharmacotherapy
Roberto
Gambari
Many recent published observations firmly demonstrate that one of the ways to study and artificially modulate gene expression at the transcriptional level is offered by the “transcription factor decoy” (TFD) strategy. This experimental approach is based on the competition for trans-acting factors between endogenous cis-elements present within regulatory regions of target genes and exogenously added DNA sequences (the DNA-based drug) mimicking the specific cis-elements. The objective of this molecular intervention is to cause a decrease of the interactions of trans-factors with the target genomic cis-elements, leading to alteration of transcription. The characterisation of the biological activity of the designed decoy molecules is routinely assessed by molecular technologies, such as electrophoretic mobility gel shift assay (EMSA), competitive DNase I footprinting, in vitro transcription. New advances in this field employ biospecific interaction analysis (BIA) based on surface plasmon resonance (SPR) and biosensor technology. With respect to the design of the decoy biomolecules, in addition to double-stranded DNA/DNA hybrids, cross-linking between two DNA molecules either via photocrosslinking or by the introduction of a covalently linked, non-nucleotide bridge has been reported. Furthermore, RNA decoys have been described able to bind transcription factors via aptameric interactions. In addition, circular decoys assuming a dumbbell configuration or single-stranded decoys with intramolecular palindromic sequences have also been described. Decoy molecules were also produced by polymerase-chain reaction (PCR). More recently, peptide nucleic acids-DNA chimeras have been shown to exhibit decoy activity and high level of stability. This variety of decoy biomolecules facilitate the establishment of suitable delivery approaches, including pressure-mediated transfer, electrically enhanced transfer, biolistic bombardment, cationic liposomes, hemagglutinating virus of Japan (HVJ)-liposomes, microsphere-aided delivery, nano-particles, peptide-mediated delivery, steroid mediated gene transfer, and red-blood cells.
[Back to top] Protein Kinase C and Prostate
Carcinogenesis: Targeting the Cell Cycle and Apoptotic Mechanisms
M.
Veronica Gavrielides, Anita F. Frijhoff, Claudio J. Conti and Marcelo G.
Kazanietz
A series of both genetic and epigenetic factors have been implicated in the genesis and progression of prostate cancer. Recent evidence revealed that protein kinase C (PKC) isozymes play a crucial role in the control of cell proliferation and apoptosis in prostate cancer models, as well as in the transition from an androgen-dependent to an androgen-independent status. Indeed, PKCa and PKCd promote apoptosis in androgen-dependent prostate cancer cells. Due to the relevance of PKC isozymes in the control of cell cycle, both in G1/S and G2/M, the elucidation of such complex intracellular networks using cellular and animal models has become of outmost importance. In this review, we present the current knowledge on the regulation of apoptosis and tumorigenicity by PKC isozymes and the functional roles of cell cycle regulators in prostate carcinogenesis. The development of animal models where overexpression of discrete PKCs or cell cycle regulators is targeted to the prostate will greatly contribute to the understanding of the molecular basis of the disease, and more importantly, it will have profound implications for the development of novel strategies for prostate cancer therapy.
[Back to top] Is Surfactant a Promising Additive Drug in ALI/ARDS-Patients?
Marcus
J. Schultz and Jozef Kesecioglu
The rationale for surfactant replacement therapy in patients with acute respiratory distress syndrome (ARDS) is to restore the normal composition of the surfactant system, as well as to overcome ongoing inactivation of present surfactant. Indeed, surfactant replacement therapy can normalize the composition of the surfactant system and restore its surface activity, which results in restoration of the gas exchange. Several phase II- and phase III-studies have been performed to investigate safety and efficacy of surfactant replacement therapy in patients with ARDS. In this manuscript we will discuss the differences in the composition of exogenous surfactant, the diverse modes of delivery of surfactant, and timing of therapy, in relation to the efficacy of surfactant instillation in several published and yet unpublished studies.
[Back to top] Drug Delivery Systems: Past, Present, and
Future
Rubiana
M. Mainardes1 and Luciano P. Silva
Drug delivery systems are essential components of drugs controlled release. In the last decades, several drug delivery technologies have emerged including capsules, liposomes, microparticles, nanoparticles, and polymers. These components must be biocompatible, biodegradable, and display a desired biodistribution providing a long-term availability of the therapeutic at specific target over time.
[Back to top] Secondary Prevention of Ischemic Stroke
Kirsi
Rantanen and Turgut Tatlisumak
Stroke strikes often suddenly, causes long-term disability and death, and is a huge economical burden for the society, not to mention the human tragedy for the patient and the family. At least 15% of stroke survivors will have a second stroke during the next five years, quarter of which prove out to be fatal within four weeks [1]. Secondary prevention of ischemic stroke (IS) targets at reducing stroke recurrence by means of 1) detection and modification of risk factors, 2) antithrombotic or anticoagulant treatment, and 3) surgical interventions for selected patient subgroups. In this review we will discuss these issues in detail and also offer our personal suggestions for treatment choices. Detecting and treating the modifiable risk factors is the major challenge of secondary prevention of IS.
[Back to top] Epileptogenicity and Epileptic Activity:
Mechanisms in an Invertebrate Model Nervous System
U.
Altrup
Epileptic seizures are based on paroxysmal depolarization shifts (PDS) which are synchronized in many neurons. Mechanisms underlying PDS and seizures are still not understood. The present review is based on studies using the buccal ganglia of the snail Helix pomatia as a model nervous system. Essential mechanisms of epileptic activity in nervous systems are thought to be identical in whatever part of the human or animal nervous system epileptic activity appears. From studies using the buccal ganglia of Helix pomatia, epileptic activity is essentially non-synaptic. PDS are “giant pacemaker potentials”, which are generated non-synaptically by the single neurons. It is, however, not yet clear which processes transform pacemaker potentials into PDS. Synchronization of PDS follows generation of PDS and results mainly from a non-synaptic, unspecific release of intracellular substances from the dendrites of a PDS-generating neuron to the dendrites of neighbouring neurons. This explains the existence of small epileptic foci. From the above observations epileptogenicity is introduced or intensified when the proteins underlying pacemaker potentials are expressed. The first chapter of the present review presents the model system. The second chapter describes epileptiform activity in the model system to correspond in all aspects to epileptiform activity recorded in vertebrate nervous systems including man. Subsequently, antiepileptic and epileptogenic properties of drugs are described using the buccal ganglia. Two following chapters concern neuronal structures and neuronal functions affected by epileptiform activity, and in the final chapter the mechanisms underlying epileptiform activities are described.
[Back to top] Development of New Drugs in Angiogenesis
Marina
Ziche, Sandra Donnini and Lucia Morbidelli
Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to “silence” endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.