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Pharmaceuticals, Volume 3, Issue 10 (October 2010), Pages 3021-3354

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Research

Jump to: Review

Open AccessArticle Non-Steroidal Anti-Inflammatory Drugs, Variation in Inflammatory Genes, and Aggressive Prostate Cancer
Pharmaceuticals 2010, 3(10), 3127-3142; doi:10.3390/ph3103127
Received: 9 August 2010 / Revised: 27 September 2010 / Accepted: 28 September 2010 / Published: 8 October 2010
Cited by 1 | PDF Full-text (123 KB) | HTML Full-text | XML Full-text
Abstract
Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use [...] Read more.
Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use and the risk of aggressive prostate cancer is modulated by variants in several inflammatory genes. We found that NSAIDs may have differential effects on prostate cancer development, depending on one’s genetic makeup. Further study of these inflammatory pathways may clarify the mechanisms through which NSAIDs impact prostate cancer risk. Full article
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
Open AccessArticle Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach
Pharmaceuticals 2010, 3(10), 3167-3185; doi:10.3390/ph3103167
Received: 13 August 2010 / Accepted: 25 September 2010 / Published: 11 October 2010
Cited by 3 | PDF Full-text (395 KB) | HTML Full-text | XML Full-text
Abstract
A comparative Hantzsch type QSAR study was conducted using multiple regression analysis on various sets of quinoxalines, quinoxalin-4-ones, quinazoline-2-carboxylates, 4-hydroxyquinolin-2(1H)-ones, 2-carboxytetrahydroquinolines, phenyl-hydroxy-quinolones, nitroquinolones and 4-substituted-3-phenylquinolin-2(1H)-ones as selective glycine/NMDA site antagonists. Ten statistically validated equations were developed, which indicated [...] Read more.
A comparative Hantzsch type QSAR study was conducted using multiple regression analysis on various sets of quinoxalines, quinoxalin-4-ones, quinazoline-2-carboxylates, 4-hydroxyquinolin-2(1H)-ones, 2-carboxytetrahydroquinolines, phenyl-hydroxy-quinolones, nitroquinolones and 4-substituted-3-phenylquinolin-2(1H)-ones as selective glycine/NMDA site antagonists. Ten statistically validated equations were developed, which indicated the importance of CMR, Verloop’s sterimol L1 and ClogP parameters in contributing towards biological activity. Interestingly, normal and inverse parabolic relationships were found with CMR in different series, indicating a dual allosteric binding mode in glycine/NMDA antagonism. Equations reveal an optimum CMR of 10 ± 10% is required for good potency of antagonists. Other equations indicate the presence of anionic functionality at 4-position of quinoline/quinolone ring system is not absolutely required for effective binding. The observations are laterally validated and in accordance with previous studies. Full article
(This article belongs to the Special Issue Allosteric Modulation)

Review

Jump to: Research

Open AccessReview Endogenous Matrix-Derived Inhibitors of Angiogenesis
Pharmaceuticals 2010, 3(10), 3021-3039; doi:10.3390/ph3103021
Received: 10 August 2010 / Revised: 19 September 2010 / Accepted: 25 September 2010 / Published: 28 September 2010
Cited by 4 | PDF Full-text (404 KB) | HTML Full-text | XML Full-text
Abstract
Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which can inhibit the angiogenic process. These molecules can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived [...] Read more.
Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which can inhibit the angiogenic process. These molecules can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived inhibitors of angiogenesis, such as endostatin, tumstatin, canstatin and arresten, are bioactive fragments of larger ECM molecules. These substances become released upon proteolysis of the ECM and the vascular basement membrane (VBM) by enzymes of the tumor microenvironment. Although the role of matrix-derived angiogenesis inhibitors is well studied in animal models of cancer, their role in human cancers is less established. In this review we discuss the current knowledge about these molecules and their potential use as cancer therapeutics and biomarkers. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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Open AccessReview Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants
Pharmaceuticals 2010, 3(10), 3040-3100; doi:10.3390/ph3103040
Received: 28 May 2010 / Revised: 7 September 2010 / Accepted: 25 September 2010 / Published: 29 September 2010
Cited by 8 | PDF Full-text (524 KB) | HTML Full-text | XML Full-text
Abstract
About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship [...] Read more.
About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia. Full article
(This article belongs to the Special Issue Alzheimer's Disease Drugs)
Open AccessReview Endocannabinoids and Schizophrenia
Pharmaceuticals 2010, 3(10), 3101-3126; doi:10.3390/ph3103101
Received: 10 September 2010 / Accepted: 25 September 2010 / Published: 8 October 2010
Cited by 6 | PDF Full-text (183 KB) | HTML Full-text | XML Full-text
Abstract
The endocannabinoids anandamide and 2-arachydonoylglycerol (2-AG) are lipids naturally derived from membrane precursors which bind cannabinoid receptors (CB1, CB2). This endocannabinoid system is disturbed in schizophrenia. Indeed, there seems to be an association between schizophrenia and polymorphisms of [...] Read more.
The endocannabinoids anandamide and 2-arachydonoylglycerol (2-AG) are lipids naturally derived from membrane precursors which bind cannabinoid receptors (CB1, CB2). This endocannabinoid system is disturbed in schizophrenia. Indeed, there seems to be an association between schizophrenia and polymorphisms of the CB1 receptor gene. Moreover, CB1 receptors are found in higher density in the prefrontal cortex, hippocampus and basal ganglia of patients with schizophrenia. Similarly, anandamide levels are increased in the cerebrospinal fluid (CSF) and in the serum of schizophrenia patients, including during the prodromal state, suggesting that they may play a protective role in psychosis homeostasis. Future studies are needed to further explore the role of the endocannabinoid system in the pathophysiology of schizophrenia. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Beneficial Effects of Tianeptine on Hippocampus-Dependent Long-Term Memory and Stress-Induced Alterations of Brain Structure and Function
Pharmaceuticals 2010, 3(10), 3143-3166; doi:10.3390/ph3103143
Received: 19 July 2010 / Revised: 26 August 2010 / Accepted: 31 August 2010 / Published: 11 October 2010
Cited by 4 | PDF Full-text (116 KB) | HTML Full-text | XML Full-text
Abstract
Tianeptine is a well-described antidepressant which has been shown to prevent stress from producing deleterious effects on brain structure and function. Preclinical studies have shown that tianeptine blocks stress-induced alterations of neuronal morphology and synaptic plasticity. Moreover, tianeptine prevents stress from impairing [...] Read more.
Tianeptine is a well-described antidepressant which has been shown to prevent stress from producing deleterious effects on brain structure and function. Preclinical studies have shown that tianeptine blocks stress-induced alterations of neuronal morphology and synaptic plasticity. Moreover, tianeptine prevents stress from impairing learning and memory, and, importantly, demonstrates memory-enhancing properties in the absence of stress. Recent research has indicated that tianeptine works by normalizing glutamatergic neurotransmission, a mechanism of action that may underlie its effectiveness as an antidepressant. These findings emphasize the value in focusing on the mechanisms of action of tianeptine, and specifically, the glutamatergic system, in the development of novel pharmacotherapeutic strategies in the treatment of depression. Full article
(This article belongs to the Special Issue Antidepressants)
Open AccessReview The Biochemical Basis of Hydroxymethylglutaryl-CoA Reductase Inhibitors as Neuroprotective Agents in Aneurysmal Subarachnoid Hemorrhage
Pharmaceuticals 2010, 3(10), 3186-3199; doi:10.3390/ph3103186
Received: 30 August 2010 / Revised: 29 September 2010 / Accepted: 11 October 2010 / Published: 12 October 2010
Cited by 5 | PDF Full-text (279 KB) | HTML Full-text | XML Full-text
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) has the highest morbidity and mortality rates of all types of stroke. Many aneurysmal SAH patients continue to suffer from significant neurological morbidity and mortality directly related to delayed cerebral ischemia. Pilot clinical studies of the use of [...] Read more.
Aneurysmal subarachnoid hemorrhage (SAH) has the highest morbidity and mortality rates of all types of stroke. Many aneurysmal SAH patients continue to suffer from significant neurological morbidity and mortality directly related to delayed cerebral ischemia. Pilot clinical studies of the use of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) in aneurysmal SAH patients have reported a reduction in delayed cerebral ischemia and better clinical outcomes. We review the biochemical effects of statins on endothelium vascular function, glutamate-mediated neurotoxicity, inflammatory changes, and oxidative injuries, with reference to their possible neuroprotective effects in aneurysmal SAH. Full article
Open AccessReview Endocannabinoids and Human Sperm Cells
Pharmaceuticals 2010, 3(10), 3200-3211; doi:10.3390/ph3103200
Received: 6 September 2010 / Accepted: 20 September 2010 / Published: 12 October 2010
Cited by 2 | PDF Full-text (136 KB) | HTML Full-text | XML Full-text
Abstract
N-acylethanolamides (NAEs) are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence [...] Read more.
N-acylethanolamides (NAEs) are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA), the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA) and oleylethanolamide (OEA) in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1) and type-2 (CB2) cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1), while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs). This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Malaria Prophylaxis: A Comprehensive Review
Pharmaceuticals 2010, 3(10), 3212-3239; doi:10.3390/ph3103212
Received: 1 September 2010 / Revised: 7 October 2010 / Accepted: 11 October 2010 / Published: 13 October 2010
Cited by 5 | PDF Full-text (202 KB) | HTML Full-text | XML Full-text
Abstract
The flow of international travellers to and from malaria-endemic areas, especially Africa, has increased in recent years. Apart from the very high morbidity and mortality burden imposed on malaria-endemic areas, imported malaria is the main cause of fever possibly causing severe disease [...] Read more.
The flow of international travellers to and from malaria-endemic areas, especially Africa, has increased in recent years. Apart from the very high morbidity and mortality burden imposed on malaria-endemic areas, imported malaria is the main cause of fever possibly causing severe disease and death in travellers coming from tropical and subtropical areas, particularly Sub-Saharan Africa. The importance of behavioural preventive measures (bed nets, repellents, etc.), adequate chemoprophylaxis and, in selected circumstances, stand-by emergency treatment may not be overemphasized. However, no prophylactic regimen may offer complete protection. Expert advice is needed to tailor prophylactic advice according to traveller (age, baseline clinical conditions, etc.) and travel (destination, season, etc.) characteristics in order to reduce malaria risk. Full article
(This article belongs to the Special Issue Tropical Medicine)
Open AccessReview Allosteric Inhibitors of NMDA Receptor Functions
Pharmaceuticals 2010, 3(10), 3240-3257; doi:10.3390/ph3103240
Received: 10 August 2010 / Revised: 9 October 2010 / Accepted: 12 October 2010 / Published: 14 October 2010
Cited by 4 | PDF Full-text (1442 KB) | HTML Full-text | XML Full-text
Abstract
NMDA receptors are glutamate-activated ion-channels involved in many essential brain functions including learning, memory, cognition, and behavior. Given this broad range of function it is not surprising that the initial attempts to correct NMDA receptor-mediated pathologies with en-mass receptor blockade were derailed [...] Read more.
NMDA receptors are glutamate-activated ion-channels involved in many essential brain functions including learning, memory, cognition, and behavior. Given this broad range of function it is not surprising that the initial attempts to correct NMDA receptor-mediated pathologies with en-mass receptor blockade were derailed by unacceptable side effects. Recent successes with milder or more targeted pharmaceuticals and increasing knowledge of how these receptors operate offer new incentives for rational development of effective NMDA receptor-targeted therapies. In this article we review evidence that L-alanine, a glycine-site partial agonist and pregnanolone sulfate, a use-dependent allosteric inhibitor, while attenuating NMDA receptor activity to similar levels elicit remarkably dissimilar functional outcomes. We suggest that detailed understanding of NMDA receptor activation mechanisms and of structural correlates of function will help better match modulator with function and neurological condition and may unleash the yet untapped potential of NMDA receptor pharmaceutics. Full article
(This article belongs to the Special Issue Allosteric Modulation)
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Open AccessReview The Role of Monoclonal Antibodies in the Management of Leukemia
Pharmaceuticals 2010, 3(10), 3258-3274; doi:10.3390/ph3103258
Received: 20 September 2010 / Accepted: 18 October 2010 / Published: 18 October 2010
PDF Full-text (133 KB) | HTML Full-text | XML Full-text
Abstract
This article will review the monoclonal antibodies more commonly used in leukemias. In the last three decades, scientists have made considerable progress understanding the structure and the functions of various surface antigens, such as CD20, CD33. The introduction of rituximab, an anti [...] Read more.
This article will review the monoclonal antibodies more commonly used in leukemias. In the last three decades, scientists have made considerable progress understanding the structure and the functions of various surface antigens, such as CD20, CD33. The introduction of rituximab, an anti CD20 monoclonal antibody, had a great impact in the treatment of lymphoproliferative disorders. Gemtuzumab, an anti CD 33 conjugated monoclonal antibody has activity in acute mylegenous leukemia (AML). As this field is undergoing a rapid growth, the years will see an increasing use of monoclonal antibodies in hematological malignancies. Full article
(This article belongs to the Special Issue Monoclonal Antibody)
Open AccessReview Cannabinoids and Reproduction: A Lasting and Intriguing History
Pharmaceuticals 2010, 3(10), 3275-3323; doi:10.3390/ph3103275
Received: 12 August 2010 / Revised: 9 September 2010 / Accepted: 21 October 2010 / Published: 25 October 2010
Cited by 11 | PDF Full-text (401 KB) | HTML Full-text | XML Full-text
Abstract
Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the [...] Read more.
Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the signal transduction mechanisms, activated by cannabinoid receptors stimulation, will also be discussed. In particular, we will point out the action of cannabinoids and endocannabinoids on the different neuronal networks involved in reproductive axis, and locally, on male and female reproductive tracts, by emphasizing the pivotal role played by this system in the control of fertility. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands
Pharmaceuticals 2010, 3(10), 3324-3342; doi:10.3390/ph3103324
Received: 9 August 2010 / Revised: 17 October 2010 / Accepted: 25 October 2010 / Published: 25 October 2010
Cited by 5 | PDF Full-text (1294 KB) | HTML Full-text | XML Full-text
Abstract
G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also [...] Read more.
G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also observed that small molecule ligands can bind in the cytoplasmic domain, and modulate binding and response to extracellular or transmembrane ligands. Thus, all three domains in GPCRs are potential sites for allosteric ligands, and whether a ligand is allosteric or orthosteric depends on the receptor. Here, we will review the evidence supporting the presence of putative binding pockets in all three domains of GPCRs and discuss possible pathways of communication between these pockets. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessReview Anti-Viral Drugs for Human Adenoviruses
Pharmaceuticals 2010, 3(10), 3343-3354; doi:10.3390/ph3103343
Received: 2 September 2010 / Revised: 23 October 2010 / Accepted: 25 October 2010 / Published: 25 October 2010
Cited by 6 | PDF Full-text (607 KB) | HTML Full-text | XML Full-text
Abstract
There are many stages in the development of a new drug for viral infection and such processes are even further complicated for adenovirus by the fact that there are at least 51 serotypes, forming six distinct groups (A–F), with different degree of [...] Read more.
There are many stages in the development of a new drug for viral infection and such processes are even further complicated for adenovirus by the fact that there are at least 51 serotypes, forming six distinct groups (A–F), with different degree of infectivity. This review attempts to address the importance of developing pharmaceuticals for adenovirus and also review recent development in drug discovery for adenovirus, including newer strategies such as microRNA approaches. Different drug screening strategies will also be discussed. Full article
(This article belongs to the Special Issue Antivirals)

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