Showing papers in "Current Pharmaceutical Design in 2005"
TL;DR: The current evidence regarding the antioxidant role of uric acid is presented and it is suggested that it has an important role as an oxidative stress marker and a potential therapeutic roles as an antioxidant.
Abstract: Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase. The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products. The role of uric acid in conditions associated with oxidative stress is not entirely clear. Evidence mainly based on epidemiological studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant. This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.
827 citations
TL;DR: Some of the major principles and concepts relating to cytokine transport and BBB function which have emerged as important to neuroimmunology and neuropathology are addressed.
Abstract: Cytokines circulating in the blood affect CNS function through a variety of pathways. One of these pathways is by being transported directly across the blood-brain barrier (BBB). Transport of blood-borne cytokines across the BBB is now known to be an operational pathway by which cytokines can directly affect CNS functions. Cytokine transport across the BBB, however, is a complex event. Not all cytokines are transported and, for those which are, transport rates differ among cytokines, among brain regions, with physiological circumstances, and with disease. Here we address some of the major principles and concepts relating to cytokine transport and BBB function which have emerged as important to neuroimmunology and neuropathology.
447 citations
TL;DR: The molecular mechanisms of diabetic vascular complications and the potential therapeutic interventions that may prevent these disorders even in the presence of hyperglycemia are summarized, which is often difficult with current therapeutic options.
Abstract: Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large prospective clinical studies have shown that intensive glucose control reduces effectively microvascular complications among patients with diabetes, and insulin resistance and postprandial hyperglycemia seem to be involved in diabetic macrovascular complications. Chronic hyperglycemia is a major initiator of diabetic vascular complications. Indeed, high glucose, via various mechanisms such as increased production of advanced glycation end products, activation of protein kinase C, stimulation of the polyol pathway and enhanced reactive oxygen species generation, regulates vascular inflammation, altered gene expression of growth factors and cytokines, and platelet and macrophage activation, thus playing a central role in the development and progression of diabetic vascular complications. This article summarizes the molecular mechanisms of diabetic vascular complications and the potential therapeutic interventions that may prevent these disorders even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.
409 citations
TL;DR: Increased levels of pro-inflammatory cytokines and decreased levels of neurotrophins are found in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid from patients with sporadic PD, and in animal models.
Abstract: Parkinson's disease (PD) is a movement disorder caused by degeneration of the nigrostriatal dopamine (DA) neurons in the substantia nigra pars compacta and the resultant deficiency in the neurotransmitter DA at the nerve terminals in the striatum. We and other investigators found increased levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, and decreased levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patients with sporadic PD, and in animal models, such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced PD. These changes in cytokine and neurotrophin levels may be initiated by activated microglia, which may then promote apoptotic cell death and subsequent phagocytosis of DA neurons. Cytokines as pleiotropic factors, promote signals that either lead to cell death or exert neuroprotective effects. The discovery of toxic changes in trophic microglia by M. Sawada and co-workers is important to this point. Ultimately, microglial cells may regulate cellular changes that cause either harm or benefit by producing cytokines or neurotrophins depending upon the primary cause and the circumstances during the inflammatory process of PD.
388 citations
TL;DR: The results of this study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade.
Abstract: Over 90% of the market withdrawals were caused by drug toxicity. Hepatotoxicity and cardiovascular toxicity proved to be the major causes for two out of three market withdrawals in the respective time period. In clinical phases I-III 43% of drug development project terminations were due to insufficient efficacy of the investigated compound. The second important issue, which caused one third of the projects to be closed, was toxicity. ADME parameters and economic and other reasons played a minor role. The results of our study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade.
354 citations
TL;DR: The future of cationic lipid-based gene delivery will probably require the development of sophisticated virus-like systems, which can be viewed as "programmed supramolecular systems" incorporating the various functions required to perform in a chronological order the different steps involved in gene transfection.
Abstract: Synthetic gene delivery vectors are gaining increasing importance in gene therapy as an alternative to recombinant viruses. Among the various types of non-viral vectors, cationic lipids are especially attractive as they can be prepared with relative ease and extensively characterised. Further, each of their constituent parts can be modified, thereby facilitating the elucidation of structure-activity relationships. In this forward-looking review, cationic lipid-mediated gene delivery will mainly be discussed in terms of the structure of the three basic constituent parts of any cationic lipid: the polar headgroup, hydrophobic moiety and linker. Particular emphasis will be placed on recent advances in the field as well as on our own original contributions. In addition to reviewing critical physicochemical features (such as headgroup hydration) of monovalent lipids, the use of headgroups with known nucleic-acid binding modes, such as linear and branched polyamines, aminoglycosides and guanidinium functions, will be comprehensively assessed. A particularly exciting innovation in linker design is the incorporation of environment-sensitive groups, the intracellular hydrolysis of which may lead to more controlled DNA delivery. Examples of pH-, redox- and enzyme-sensitive functional groups integrated into the linker are highlighted and the benefits of such degradable vectors can be evaluated in terms of transfection efficiency and cationic lipid-associated cytotoxicity. Finally, possible correlations between the length and type of hydrophobic moiety and transfection efficiency will be discussed. In conclusion it may be foreseen that in order to be successful, the future of cationic lipid-based gene delivery will probably require the development of sophisticated virus-like systems, which can be viewed as "programmed supramolecular systems" incorporating the various functions required to perform in a chronological order the different steps involved in gene transfection.
301 citations
TL;DR: The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.
Abstract: There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An "optimal" gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.
292 citations
TL;DR: Functional consequences of modulation of three groups of genes are described: Scavenger Receptors, the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors.
Abstract: Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL- and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARalpha and PPARgamma agonists, such as thiazolidinediones and fibrates, and PPARdelta agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.
281 citations
TL;DR: The emphasis of this review is on the rich chemical diversity of ligands that influence GABA(A) receptor function, which provides many avenues for the design and development of new chemical entities acting on GABA (A) receptors.
Abstract: GABA(A) receptor channels are ubiquitous in the mammalian central nervous system mediating fast inhibitory neurotransmission by becoming permeant to chloride ions in response to GABA. The emphasis of this review is on the rich chemical diversity of ligands that influence GABA(A) receptor function. Such diversity provides many avenues for the design and development of new chemical entities acting on GABA(A) receptors. There is also a significant diversity of GABA(A) receptor subtypes composed of different protein subunits. The discovery of subtype specific agents is a major challenge in the continuing development of GABA(A) receptor pharmacology. Leads for the discovery of new chemical entities that influence GABA(A) receptors come from using recombinant GABA(A) receptors of known subunit composition as has been elegantly demonstrated by the refining of benzodiazepine actions with alpha1 subunit preferring agents showing sedative properties but not anxiolytic properties. The most recent advances in the therapeutic use of agents acting on GABA(A) receptors concern the promotion of sound sleep. Many herbal medicines are used to promote sleep and many of their active ingredients include flavonoids and terpenoids known to modulate GABA(A) receptor function.
281 citations
TL;DR: Although the mechanism of cellular uptake remains unclear, there is an increasing amount of reports on biological effects of CPPs and their cargos, and they are an attractive pharmaceutical and biochemical tool that needs more attention.
Abstract: A major obstacle in the development of new therapeutic agents is the low bioavailability of hydrophilic substances. Drugs that bind to intracellular targets must penetrate the lipid bilayer surrounding the cell in order to exert their effect. A relatively new research area that addresses this problem by introducing novel transport peptides that facilitate the cellular penetration of potential drugs has emerged. These peptides predominantly have a positive net charge and/or an amphipathic nature, but can otherwise have very different characteristics. This group of peptides, although sometimes called protein transduction domains (PTDs), is here referred to as cell-penetrating peptides (CPPs). For many years it was believed that these peptides were internalized into cells via a non-endocytotic, receptor-independent pathway. However, recent publications have suggested that an endocytotic pathway cannot be ruled out, and that earlier results might be based on artifacts associated with fixation of cells and membrane association of peptides. Although the mechanism of cellular uptake remains unclear, there is an increasing amount of reports on biological effects of CPPs and their cargos. Thus, CPPs are an attractive pharmaceutical and biochemical tool that needs more attention. This review will discuss some recent results in this research field with focus on the cell-penetrating peptide transportan.
TL;DR: It is proposed that chronic cytokine elevations engender neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression.
Abstract: Cytokines whose primary function is that of acting as signaling molecules of the immune system, have been implicated in the provocation or exacerbation of mood disorders such as depression. This position has been supported by several lines of evidence; (1) proinflammatory cytokines (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha) and bacterial endotoxins elicit sickness behaviors (e.g., fatigue, soporific effects) and symptoms of anxiety/depression that may be attenuated by chronic antidepressant treatment. Interleukin-2 (IL-2) induces less profound sickness, but elicits anhedonia, a key symptom of depression; (2) neuroendocrine and central neurotransmitter changes, reminiscent of those implicated in depression, may be elicited by some of these cytokines, and these effects are exacerbated by stressors; (3) severe depressive illness is accompanied by elevations of cytokine production or levels, although these effects are not necessarily attenuated with antidepressant medication; and (4) immunotherapy, using IL-2 or IFN-alpha, promote depressive symptoms that are attenuated by antidepressant treatment. It is proposed that chronic cytokine elevations engender neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression. Further, the effects of the cytokine treatments may act synergistically with stressors, and cytokines may provoke a sensitization effect so that the effects of later stressor experiences are exacerbated.
TL;DR: Up-to-date summary of hypericin, its activities and potentials, is aimed to contribute to the process of achieving a new and promising status as an effective agent in medical diagnostic and therapeutic applications.
Abstract: Hypericin is a naturally occurring substance found in the common St. John's Wort (Hypericum species) and can also be synthesized from the anthraquinone derivative emodin. As the main component of Hypericum perforatum, it has traditionally been used throughout the history of folk medicine. In the last three decades, hypericin has also become the subject of intensive biochemical research and is proving to be a multifunctional agent in drug and medicinal applications. Recent studies report antidepressive, antineoplastic, antitumor and antiviral (human immunodeficiency and hepatitis C virus) activities of hypericin; intriguing information even if confirmation of data is incomplete and mechanisms of these activities still remain largely unexplained. In other contemporary studies, screening hypericin for inhibitory effects on various pharmaceutically important enzymes such as MAO (monoaminoxidase), PKC (protein kinase C), dopamine-beta-hydroxylase, reverse transcriptase, telomerase and CYP (cytochrome P450), has yielded results supporting therapeutic potential. Research of hypericin and its effect on GABA-activated (gamma amino butyric acid) currents and NMDA (N-methyl-D-aspartat) receptors also indicate the therapeutic potential of this substance whereby new insights in stroke research (apoplexy) are expected. Also in the relatively newly established fields of medical photochemistry and photobiology, intensive research reveals hypericin to be a promising novel therapeutic and diagnostic agent in treatment and detection of cancer (photodynamic activation of free radical production). Hypericin is not new to the research community, but it is achieving a new and promising status as an effective agent in medical diagnostic and therapeutic applications. New, although controversial data, over the recent years dictate further research, re-evaluation and discussion of this substance. Our up-to-date summary of hypericin, its activities and potentials, is aimed to contribute to this process.
TL;DR: This analysis supports the view that the differences in the nonprime side pockets provide better opportunities for designing inhibitors with higher specificity, and Pros and cons of inhibitors with non-hydroxamate Zinc-binding groups in terms of specificity, toxicity and pharmacokinetic properties are discussed.
Abstract: It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP) was revealed for the first time in 1994. More than 80 structures of different MMPs in apo and inhibited forms, determined by X-ray crystallography and NMR methods, have been published by the end of year 2003. A large number of very potent inhibitors have been disclosed in published and patent literature. Several MMP inhibitors entered clinical trials for the treatment of cancer and arthritis. Most of the first generation inhibitors have hydroxamic acid as the Zinc-binding group and have limited specificity. With the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups in recent years. This review will summarize all the published structural information and focus on the inhibitors that were designed to take advantage of the nonprime side of the MMP active site using structural information and computational analysis. Representative structures from all MMPs are aligned to a target structure to provide a better understanding of the similarities and differences of the active site pockets. This analysis supports the view that the differences in the nonprime side pockets provide better opportunities for designing inhibitors with higher specificity. Published information on all the Zinc-binding groups of MMP inhibitors is reviewed for the first time. Pros and cons of inhibitors with non-hydroxamate Zinc-binding groups in terms of specificity, toxicity and pharmacokinetic properties are discussed.
TL;DR: To be effective, therapies that target the immune system must limit the destructive effects of neutrophil, macrophage and lymphocyte activation, while simultaneously preserving their reparative functions.
Abstract: Spinal cord trauma activates the immune system and elicits leukocyte recruitment to the site of injury. This increase in immunological activity contributes to acute lesion expansion over a period of days to weeks following the initial trauma. At the same time, inflammatory cells and mediators facilitate endogenous repair processes such as axonal sprouting and remyelination. Thus, to be effective, therapies that target the immune system must limit the destructive effects of neutrophil, macrophage and lymphocyte activation, while simultaneously preserving their reparative functions.
TL;DR: A review on the pharmacology and interactions of these agents with other drugs is presented, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.
Abstract: Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120 - CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process - with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.
TL;DR: The state of the art of various computational aspects of docking-based virtual screening of database of small molecules is presented and the different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets are reviewed.
Abstract: The state of the art of various computational aspects of docking-based virtual screening of database of small molecules is presented. The review encompasses the different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets. Recent progress made in the development and application of methods to include target flexibility are summarized. The fundamental issues and challenges involved in comparing various docking methods are discussed. Limitations of current technologies as well as future prospects are presented.
TL;DR: The current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.
Abstract: Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.
TL;DR: Evidence purporting the differentiation of MSCs into neural cell lineages is reviewed and how the varied functions of M SCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease is theorized.
Abstract: Mesenchymal stem cells resident in adult bone marrow are best characterized by their capacity to differentiate into connective tissue cell types such as adipocytes, chondrocytes, osteoblasts and hematopoiesis-supporting stroma. Accordingly, these cells are being evaluated in human clinical trials for efficacy in treating genetic diseases of bone, to speed hematopoietic recovery after bone marrow transplantation and reduce the severity of graft versus host disease. In the past few years MSCs have also been reported to exhibit a broad degree of plasticity commensurate with other adult stem cell populations, including the ability to differentiate in vitro and in vivo into non-mesodermal cell types such as neurons and astrocytes. MSCs have also been reported to promote repair and regeneration of nervous tissue within the central and peripheral nervous system, although the mechanism by which this occurs remains indeterminate. Herein, we review evidence purporting the differentiation of MSCs into neural cell lineages and evaluate the utility of MSCs as cellular vectors for treating neurological disorders and spinal cord injury. Based on our analysis of their transcriptome, we also theorize how the varied functions of MSCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease.
TL;DR: The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.
Abstract: The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.
TL;DR: The guidelines constitute a set of parameters required for a product/strain to be termed "probiotic" and also the clinically relevant steps to be followed to move probiotics closer to being embraced by the medical community.
Abstract: Probiotics, defined as "Live microorganisms which when administered in adequate amounts confer a health benefit on the host" have many attributes including the lack of adverse side effects associated with their use. While probiotics have proven benefits, the optimism associated with their use is counterbalanced by the fact that many so-called "probiotic" products are unreliable in content and unproven clinically. Therefore much remains to be done to gain the acceptance of the broader medical community. Recognition of the obvious product inequality and the lack of any regulatory guidelines lead to the development of Operating Standards in 2002 (FAO/WHO), that would ensure product safety, reliability and a level playing field for all companies producing probiotic products. The guidelines constitute a set of parameters required for a product/strain to be termed "probiotic" and also the clinically relevant steps to be followed to move probiotics closer to being embraced by the medical community. These include i) implementation of Guidelines for use of probiotics; ii) phase I, II and III clinical trials to prove health benefits that are as good as or better than standard prevention or treatments for a particular condition or disease; iii) Good Manufacturing Practice and production of high quality products; iv) studies to identify mechanism of action in vivo; v) informative/ precise labelling; vi) development of probiotic organisms that can carry vaccines to hosts and/or anti- viral probiotics; vii) expansion of proven strains to benefit the oral cavity, nasopharynx, respiratory tract, stomach, vagina, bladder and skin as well as for cancer, allergies and recovery from surgery/ injury.
TL;DR: In the future, one of the most interesting challenges is certainly the use of metallic nanoparticles for an innovating, effective and selective physical treatment of solid tumors via targeted intracellular hyperthermia.
Abstract: In recent years the fields of medicine and biology assist to an ever-growing innovation related to the development of nanotechnologies. In the pharmaceutical domain, for example, liposomes, polymer based micro and nanoparticles have been subjects of intense research and development during the last three decades. In this scenario metallic particles, which use was already suggested in the first half of the '80, are now experiencing a real renaissance. In the field of diagnosis, magnetic resonance imaging is one of the first and up to now the most developed application of metallic particles. But beside this application, a very new generation of biosensors based on the optical properties of colloidal gold and fluorescent nanocrystals, called quantum dots seems to be ready to be implemented in diagnosis and medical imaging. Concerning therapeutic applications, the potentialities of metal nanoparticles to help fulfilling the need of time and space controlled release of drugs has been intuited for a long time. Nowadays, magnetically guided carriers or thermal responsive matrices, in which drug release is triggered by the heating of metal nanoparticles, are effective examples of their application in drug delivery, while more recently efforts to develop metallic nanoobjects to be used as vectors of nucleic acids for vaccination and transfection have been multiplied. In the future, one of the most interesting challenges is certainly the use of metallic nanoparticles for an innovating, effective and selective physical treatment of solid tumors via targeted intracellular hyperthermia.
TL;DR: Clinically, evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders and hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors.
Abstract: The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.
TL;DR: The combination of mutational study of the cloned Na channels and patch clamp offers the opportunity to understand the detailed molecular mechanism of drug action and to resolve drug structure-function.
Abstract: Local anesthetic drugs interfere with excitation and conduction by action potentials in the nervous system and in the heart by blockade of the voltage-gated Na channel. Drug affinity varies with gating state of the channel. The drugs show low affinity at slow excitation rates, but high affinity when the channels are opened and inactivated during action potentials at high frequency, as they are during pain or during a cardiac arrhythmia. The drugs are thought to access their binding site in the inner pore by passage through the membrane and entry through the inner pore vestibule. There have been three major developments in the last decade that greatly increase our understanding of their mechanism of action. Firstly, amino acid residues critical to drug binding have been located by mutagenesis, and it is possible to develop a molecular model of the drug binding site. Secondly, a path for drug access directly from the outside has been characterized in the cardiac isoform of the channel. Thirdly, the hypothesis that high affinity binding stabilizes the fast inactivated conformation of the channel has been challenged. Rather, the drug may stabilize a slow inactivated state and immobilize the voltage sensor in domain III in its activated outward position. The combination of mutational study of the cloned Na channels and patch clamp offers the opportunity to understand the detailed molecular mechanism of drug action and to resolve drug structure-function.
TL;DR: This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.
Abstract: The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.
TL;DR: Agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.
Abstract: NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg ++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca ++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.
TL;DR: Studies carried out in the laboratory suggest that those drugs and neurotrophic factors capable to attenuate the BSCB dysfunction following trauma are neuroprotective in nature, and agents that do not exert any influence on the B SCB disruption failed to reduce cell injury.
Abstract: Blood-spinal cord barrier (BSCB) plays an important role in the regulation of the fluid microenvironment of the spinal cord. Trauma to the spinal cord impairs the BSCB permeability to proteins leading to vasogenic edema formation. Several endogenous neurochemical mediators and growth factors contribute to trauma induced BSCB disruption. Studies carried out in our laboratory suggest that those drugs and neurotrophic factors capable to attenuate the BSCB dysfunction following trauma are neuroprotective in nature. Whereas, agents that do not exert any influence on the BSCB disruption failed to reduce cell injury. These observations are in line with the idea that BSCB disruption plays an important role in the pathophysiology of spinal cord injuries. The probable mechanism(s) of trauma induced BSCB dysfunction and its contribution to cell injuries are discussed.
TL;DR: The protective role of antioxidants against homeostatic disturbances such as those caused by endotoxin toxicity, their potential clinical use and the effects on the redox state of the immune cells is discussed.
Abstract: Severe sepsis leading to shock is the principal cause of death in intensive care units. It is a systemic inflammatory response caused by excessive secretion of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFalpha) and reactive oxygen species (ROS), mainly induced by endotoxin (a major component of the Gram-negative bacterial outer membrane). Immune cells use ROS in order to support their functions and need adequate levels of antioxidant defenses to avoid harmful effects of an excessive ROS production. In addition, nitric oxide (NO) is thought to play a key role in the pathogenesis of sepsis and in the development of multiple organ failure. This article discusses the toxic effects of endotoxin, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, and the pathway leading to nuclear factor-kappaB (NF-kappaB) activation and pro-inflammatory gene transcription. In relation to this process, this review focuses on the involvement of reactive oxygen and nitrogen species. Finally, the protective role of antioxidants against homeostatic disturbances such as those caused by endotoxin toxicity, their potential clinical use and the effects on the redox state of the immune cells is discussed.
TL;DR: This review will examine the available evidence of central vasopressinergic system involvement in psychiatric disorders, and the potential opportunities for development of novel psychopharmaceuticals around this system will be discussed.
Abstract: Arginine vasopressin (AVP) is a cyclic nonapeptide synthesized exclusively by neurosecretory cells of the central nervous system (CNS). Two functionally distinct vasopressinergic systems can be defined based on differences in the sites of action and release of AVP. The peripheral vasopressinergic system encompasses the sites of action for AVP released into peripheral circulation (e.g. vascular smooth muscle, liver, kidney) from nerve terminals in the posterior pituitary. Peripherally circulating AVP is responsible for the classic endocrine functions ascribed to this neurohormone (e.g. vasoconstriction, glycogen metabolism, antidiuresis). The central vasopressinergic system, on the other hand, includes the sites of AVP synthesis and release within the CNS, where AVP acts as a neuromodulator/neurotransmitter regulating an array of CNS-mediated functions (e.g. learning and memory, neuroendocrine reactivity, social behaviors, circadian rhythmicity, thermoregulation, and autonomic function). Historically, pharmaceutical interest has focused on drug development efforts that sought to exploit the peripheral effects of AVP. Evidence, however, from clinical studies and animal models of CNS disorders has directly implicated disturbances in vasopressinergic activity in the pathophysiology of a number of human psychiatric disorders (mood, anxiety, and cognitive disorders). This review will examine the available evidence of central vasopressinergic system involvement in psychiatric disorders, and the potential opportunities for development of novel psychopharmaceuticals around this system will be discussed. Specific lines of evidence will be presented which rationalize each AVP receptor subtype (V(1)R or V(1a), V(2)R, V(3)R or V(1b)) as a molecular target for particular psychiatric indications.
TL;DR: This review focuses on the medicinal plants and bacteria for which there is significant published in vitro, in vivo and clinical data available and indicates that medicinal plants offer significant potential for the development of novel antibacterial therapies and adjunct treatments.
Abstract: Infectious diseases are a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the Americas. Despite the significant progress made in microbiology and the control of microorganisms, sporadic incidents of epidemics due to drug resistant microorganisms and hitherto unknown disease-causing microbes pose an enormous threat to public health. These negative health trends call for a global initiative for the development of new strategies for the prevention and treatment of infectious disease. For over 100 years chemical compounds isolated from medicinal plants have served as the models for many clinically proven drugs, and are now being re-assessed as antimicrobial agents. The reasons for this renaissance include a reduction in the new antibacterial drugs in the pharmaceutical pipeline, an increase in antimicrobial resistance, and the need of treatments for new emerging pathogens. Literally thousands of plant species have been tested against hundreds of bacterial strains in vitro and many medicinal plants are active against a wide range of gram positive and gram negative bacteria. However, very few of these medicinal plant extracts have been tested in animal or human studies to determine safety and efficacy. This review focuses on the medicinal plants and bacteria for which there is significant published in vitro, in vivo and clinical data available. The examples provided in this review indicate that medicinal plants offer significant potential for the development of novel antibacterial therapies and adjunct treatments (i.e. MDR pump inhibitors).