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Pharmaceuticals, Volume 3, Issue 8 (August 2010), Pages 2362-2750

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Research

Jump to: Review, Other

Open AccessArticle Measurement of Neuropsychiatric Symptoms in Clinical Trials Targeting Alzheimer's Disease and Related Disorders
Pharmaceuticals 2010, 3(8), 2387-2397; doi:10.3390/ph3082387
Received: 2 June 2010 / Revised: 21 June 2010 / Accepted: 20 July 2010 / Published: 26 July 2010
Cited by 2 | PDF Full-text (182 KB) | HTML Full-text | XML Full-text
Abstract
Behavioral and psychological symptoms (BPSD) are now known to be frequently associated to cognitive and functional decline in Alzheimer‘s disease and related disorders. They are present since the early stages of the disease and have negative impact on the disease process. BPSD assessment
[...] Read more.
Behavioral and psychological symptoms (BPSD) are now known to be frequently associated to cognitive and functional decline in Alzheimer‘s disease and related disorders. They are present since the early stages of the disease and have negative impact on the disease process. BPSD assessment is crucial in clinical practice and also in future clinical trials targeting disease-modifying therapies for dementia. In this article, we will first review current assessment tools for BPSD, mainly global and domain-specific scales, and new assessment methods, currently available or in development, including new scales, diagnostic criteria and new technologies such as ambulatory actigraphy. Full article
(This article belongs to the Special Issue Alzheimer's Disease Drugs)
Open AccessArticle Synthesis and Antimicrobial Activity of Some New Quinoxaline Derivatives
Pharmaceuticals 2010, 3(8), 2416-2425; doi:10.3390/ph3082416
Received: 25 May 2010 / Revised: 13 July 2010 / Accepted: 16 July 2010 / Published: 30 July 2010
Cited by 22 | PDF Full-text (121 KB) | HTML Full-text | XML Full-text
Abstract
2-Chloro-3-methylquinoxaline was selected as a nucleus around which various molecular transformations were performed to obtain new compounds expected to possess optimized antimicrobial activity. As very little work regarding attachment of ether linkages replacing chlorine at C-2 has been reported, it was thought worthwhile
[...] Read more.
2-Chloro-3-methylquinoxaline was selected as a nucleus around which various molecular transformations were performed to obtain new compounds expected to possess optimized antimicrobial activity. As very little work regarding attachment of ether linkages replacing chlorine at C-2 has been reported, it was thought worthwhile to synthesize various quinoxaline derivatives by replacing the C2 chlorine with an ether linkage attached to a benzene ring possessing an aldehyde or a free amino group which can be further reacted with aromatic amines and aromatic aldehydes, respectively, to yield new Schiff bases containing quinoxaline moieties. Thus the compounds 4-(2-methylquinoxalinyloxy) benzaldehyde (4), 2-[4-(substituted-benziminomethyl)-phenoxy]-3-methyl quinoxalines 5a–e, 4-(2-methyl-quinoxaline-3-yloxy)benzamine (6) and 4-(2-methylquinoxalin-3-yloxy)-N-substituted benzylidine benzamines 7a–e were synthesized and tested for their antimicrobial activity. The structures of the compounds were confirmed on the basis of their elemental and spectral data. Full article

Review

Jump to: Research, Other

Open AccessReview Rational Polytherapy with Antiepileptic Drugs
Pharmaceuticals 2010, 3(8), 2362-2379; doi:10.3390/ph3082362
Received: 30 June 2010 / Revised: 21 July 2010 / Accepted: 22 July 2010 / Published: 26 July 2010
Cited by 8 | PDF Full-text (154 KB) | HTML Full-text | XML Full-text
Abstract
Approximately 30–40% of patients do not achieve seizure control with a single antiepileptic drug (AED). With the advent of multiple AEDs in the past 15 years, rational polytherapy, the goal of finding combinations of AEDs that have favorable characteristics, has become of greater
[...] Read more.
Approximately 30–40% of patients do not achieve seizure control with a single antiepileptic drug (AED). With the advent of multiple AEDs in the past 15 years, rational polytherapy, the goal of finding combinations of AEDs that have favorable characteristics, has become of greater importance. We review the theoretical considerations based on AED mechanism of action, animal models, human studies in this field, and the challenges in finding such optimal combinations. Several case scenarios are presented, illustrating examples of rational polytherapy. Full article
(This article belongs to the Special Issue Antiepileptic Drugs)
Open AccessReview Combinations of drugs in the Treatment of Obesity
Pharmaceuticals 2010, 3(8), 2398-2415; doi:10.3390/ph3082398
Received: 8 June 2010 / Revised: 9 July 2010 / Accepted: 15 July 2010 / Published: 27 July 2010
Cited by 8 | PDF Full-text (188 KB) | HTML Full-text | XML Full-text
Abstract
Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations
[...] Read more.
Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry. Full article
(This article belongs to the Special Issue Anti-Obesity Drugs)
Open AccessReview The Impact of Residual Symptoms in Major Depression
Pharmaceuticals 2010, 3(8), 2426-2440; doi:10.3390/ph3082426
Received: 30 June 2010 / Revised: 2 July 2010 / Accepted: 22 July 2010 / Published: 3 August 2010
Cited by 9 | PDF Full-text (166 KB) | HTML Full-text | XML Full-text
Abstract
The current definition of remission from major depressive disorder does not fully take into account all aspects of patient recovery. Residual symptoms of depression are very common in patients who are classified as being in remission. Patients with residual symptoms are at increased
[...] Read more.
The current definition of remission from major depressive disorder does not fully take into account all aspects of patient recovery. Residual symptoms of depression are very common in patients who are classified as being in remission. Patients with residual symptoms are at increased risk of functional and interpersonal impairments, and are at high risk for recurrence of depression. This article discusses the incidence of residual symptoms of depression, as well as the risks and consequences of these symptoms, and will review the state of current treatment. Full article
(This article belongs to the Special Issue Antidepressants)
Open AccessReview Histone Deacetylase Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies
Pharmaceuticals 2010, 3(8), 2441-2469; doi:10.3390/ph3082441
Received: 16 July 2010 / Revised: 30 July 2010 / Accepted: 2 August 2010 / Published: 4 August 2010
Cited by 46 | PDF Full-text (413 KB) | HTML Full-text | XML Full-text
Abstract
Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has consequently
[...] Read more.
Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has consequently resulted in the development of HDAC inhibitors (HDACI) to overcome this. HDACI exhibit pleiotropic biological effects including inhibition of angiogenesis and the induction of autophagy and apoptosis. Although HDACI exhibit modest results as single agents in preclinical and clinical data, they often fall short, and therefore HDACI are most promising in combinational strategies with either standard treatments or with other experimental chemotherapies and targeted therapies. This review will discuss the induction of autophagy and apoptosis and the inhibition of angiogenesis by HDACI, and also pre-clinical and clinical combination strategies using these agents. Full article
(This article belongs to the Special Issue HDAC Inhibitors)
Open AccessReview Use of Generics—A Critical Cost Containment Measure for All Healthcare Professionals in Europe?
Pharmaceuticals 2010, 3(8), 2470-2494; doi:10.3390/ph3082470
Received: 1 July 2010 / Revised: 27 July 2010 / Accepted: 4 August 2010 / Published: 5 August 2010
Cited by 44 | PDF Full-text (215 KB) | HTML Full-text | XML Full-text
Abstract
Pharmaceutical expenditures in ambulatory care rose rapidly in Europe in the 1990s and early 2000s. This was typically faster than other components of healthcare spending, leading to reforms to moderate future growth. A number of these centered on generic medicines with measures to
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Pharmaceutical expenditures in ambulatory care rose rapidly in Europe in the 1990s and early 2000s. This was typically faster than other components of healthcare spending, leading to reforms to moderate future growth. A number of these centered on generic medicines with measures to lower reimbursed prices as well as enhance their prescribing and dispensing. The principal objective of this paper is to review additional measures that some European countries can adopt to further reduce reimbursed prices for generics. Secondly, potential approaches to address concerns with generics when they arise to maximize savings. Measures to enhance the prescribing of generics will also briefly be discussed. A narrative review of the extensive number of publications and associated references from the co-authors was conducted supplemented with known internal or web-based articles. In addition, health authority and health insurance databases, principally from 2001 to 2007, were analyzed to assess the impact of the various measures on price reductions for generic omeprazole and generic simvastatin vs. pre-patent loss prices, as well as overall efficiency in Proton Pump Inhibitor (PPI) and statin prescribing. The various initiatives generally resulted in considerable lowering of the prices of generics as well as specifically for generic omeprazole and generic simvastatin vs. pre-patent loss prices. At one stage in the UK, generic simvastatin was just 2% of the originator price. These measures also led to increased efficiency for PPI and statin prescribing with reimbursed expenditure for the PPIs and statins either falling or increasing at appreciably lower rates than increases in utilization. A number of strategies have also been introduced to address patient and physician concerns with generics to maximize savings. In conclusion, whilst recent reforms have been successful, European countries must continue learning from each other to fund increased volumes and new innovative drugs as resource pressures grow. Policies regarding generics and their subsequent impact on reimbursement and utilization of single sourced products will continue to play a key role to release valuable resources. However, there must continue to be strategies to address concerns with generics when they exist. Full article
(This article belongs to the Special Issue Generic Drugs)
Open AccessReview Non-Steroidal Anti-Inflammatory Drugs in the Carcinogenesis of the Gastrointestinal Tract
Pharmaceuticals 2010, 3(8), 2495-2516; doi:10.3390/ph3082495
Received: 20 July 2010 / Revised: 27 July 2010 / Accepted: 6 August 2010 / Published: 9 August 2010
Cited by 3 | PDF Full-text (191 KB) | HTML Full-text | XML Full-text
Abstract
It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. Inflammation is a physiologic process in response to tissue damage resulting from microbial pathogen infection, chemical irritation, and/or wounding. Tissues injured throughout the recruitment
[...] Read more.
It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. Inflammation is a physiologic process in response to tissue damage resulting from microbial pathogen infection, chemical irritation, and/or wounding. Tissues injured throughout the recruitment of inflammatory cells such as macrophages and neutrophils, generate a great amount of growth factors, cytokines, and reactive oxygen and nitrogen species that may cause DNA damage that in turn predisposes to the transformation from chronic inflammation to neoplasia. Cyclooxygenase (COX), playing a key role in cell homeostasis, angiogenesis and tumourigenesis, may represent the link between inflammation and cancer. Currently COX is becoming a pharmacological target for cancer prevention and treatment.It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. Inflammation is a physiologic process in response to tissue damage resulting from microbial pathogen infection, chemical irritation, and/or wounding. Tissues injured throughout the recruitment of inflammatory cells such as macrophages and neutrophils, generate a great amount of growth factors, cytokines, and reactive oxygen and nitrogen species that may cause DNA damage that in turn predisposes to the transformation from chronic inflammation to neoplasia. Cyclooxygenase (COX), playing a key role in cell homeostasis, angiogenesis and tumourigenesis, may represent the link between inflammation and cancer. Currently COX is becoming a pharmacological target for cancer prevention and treatment. Full article
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
Open AccessReview Brain CB2 Receptors: Implications for Neuropsychiatric Disorders
Pharmaceuticals 2010, 3(8), 2517-2553; doi:10.3390/ph3082517
Received: 15 July 2010 / Revised: 4 August 2010 / Accepted: 9 August 2010 / Published: 10 August 2010
Cited by 15 | PDF Full-text (351 KB) | HTML Full-text | XML Full-text
Abstract
Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB2 receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB2 receptor in the brain is significantly
[...] Read more.
Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB2 receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB2 receptor in the brain is significantly lower than that of the CB1 receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB2 receptor under normal conditions. Under inflammatory conditions, CB2 receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB2 receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders. Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB2 gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB2 receptors in neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Exenatide Use in the Management of Type 2 Diabetes Mellitus
Pharmaceuticals 2010, 3(8), 2554-2567; doi:10.3390/ph3082554
Received: 2 July 2010 / Revised: 5 August 2010 / Accepted: 9 August 2010 / Published: 11 August 2010
Cited by 5 | PDF Full-text (141 KB) | HTML Full-text | XML Full-text
Abstract
Exenatide is a GLP-1 (glucagon-like peptide-1) agonist that has been approved in the UK for use in the management of Type 2 Diabetes Mellitus (T2DM) since 2006. It acts by increasing glucose-induced insulin release and by reducing glucagon secretion postprandially. It therefore increases
[...] Read more.
Exenatide is a GLP-1 (glucagon-like peptide-1) agonist that has been approved in the UK for use in the management of Type 2 Diabetes Mellitus (T2DM) since 2006. It acts by increasing glucose-induced insulin release and by reducing glucagon secretion postprandially. It therefore increases insulin secretion and reduces glucose levels, especially postprandially. It also reduces gastric emptying and acts centrally to promote satiety. In clinical practice it reduces HbA1c (range; -0.4% to -1.3%), fasting and postprandial blood glucose levels and is the only antidiabetic agent (together with liraglutide; a human GLP-1 analogue) to promote weight loss (range; -1.5 kg to -5.5 kg). It can be used as monotherapy or in combination with metformin and/or sulphonylureas (SU) and/or thiazolinediones (TZD). When compared with insulin it causes similar reductions in HbA1c and glucose levels, but unlike insulin it has the advantage of inducing weight loss. Its main side effect is gastrointestinal (GI) disturbances; nausea is the commonest GI adverse effect, albeit usually mild and transient. Hypoglycaemia is uncommon, especially when used as monotherapy or in combination with metformin. In this review article we scrutinize the currently available evidence for use of exenatide in the management of T2DM. Full article
(This article belongs to the Special Issue Antidiabetic Drugs)
Open AccessReview Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review
Pharmaceuticals 2010, 3(8), 2568-2591; doi:10.3390/ph3082568
Received: 2 July 2010 / Revised: 22 July 2010 / Accepted: 3 August 2010 / Published: 12 August 2010
Cited by 6 | PDF Full-text (205 KB) | HTML Full-text | XML Full-text
Abstract
Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised
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Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2), clearance (Cl), and volume of distribution (Vd) change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides) AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based. Full article
(This article belongs to the Special Issue Antibiotics)
Open AccessReview Mechanism of Allosteric Modulation of the Cys-loop Receptors
Pharmaceuticals 2010, 3(8), 2592-2609; doi:10.3390/ph3082592
Received: 24 June 2010 / Revised: 30 July 2010 / Accepted: 9 August 2010 / Published: 12 August 2010
Cited by 5 | PDF Full-text (522 KB) | HTML Full-text | XML Full-text
Abstract
The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls
[...] Read more.
The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls the channel function. The cys-loop receptors also are subject to allosteric modulation by many pharmaceutical agents and endogenous modulators. By binding to a site of the receptor distinct from the neurotransmitter binding site, allosteric modulators alter the response of the receptors to their agonists. The mechanism of allosteric modulation is traditionally believed to be that allosteric modulators directly change the binding affinity of receptors for their agonists. More recent studies support the notion that these allosteric modulators are very weak agonists or antagonists by themselves. They directly alter channel gating, and thus change the distribution of the receptor across multiple different affinity states, indirectly influencing receptors’ sensitivity to agonists. There are two major locations of allosteric modulator binding sites. One is in subunit interfaces of the amino-terminal domain. The other is in the transmembrane domain close to the channel gating machinery. In this review, we also give some examples of well characterized allosteric binding pockets. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Figures

Open AccessReview Pharmacogenetics of Anti-Diabetes Drugs
Pharmaceuticals 2010, 3(8), 2610-2646; doi:10.3390/ph3082610
Received: 14 July 2010 / Revised: 9 August 2010 / Accepted: 10 August 2010 / Published: 13 August 2010
Cited by 48 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides,
[...] Read more.
A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D. Full article
(This article belongs to the Special Issue Antidiabetic Drugs)
Open AccessReview The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism
Pharmaceuticals 2010, 3(8), 2647-2660; doi:10.3390/ph3082647
Received: 13 July 2010 / Revised: 6 August 2010 / Accepted: 11 August 2010 / Published: 13 August 2010
Cited by 3 | PDF Full-text (252 KB) | HTML Full-text | XML Full-text
Abstract
Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC). The suppressive effect
[...] Read more.
Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC). The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview The Role of Cannabinoid Receptors in the Descending Modulation of Pain
Pharmaceuticals 2010, 3(8), 2661-2673; doi:10.3390/ph3082661
Received: 28 June 2010 / Revised: 30 July 2010 / Accepted: 16 August 2010 / Published: 16 August 2010
Cited by 6 | PDF Full-text (123 KB) | HTML Full-text | XML Full-text
Abstract
The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain
[...] Read more.
The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate. Evidence of the involvement of cannabinoid receptors (CB) in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain. Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord. Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA) and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway. Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease) and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain. Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system diseases such as anxiety and depression. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Overview of Histone Deacetylase Inhibitors in Haematological Malignancies
Pharmaceuticals 2010, 3(8), 2674-2688; doi:10.3390/ph3082674
Received: 23 July 2010 / Revised: 12 August 2010 / Accepted: 13 August 2010 / Published: 17 August 2010
Cited by 2 | PDF Full-text (163 KB) | HTML Full-text | XML Full-text
Abstract
Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated single
[...] Read more.
Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated single agent HDACi to have activity in hematological malignancies, in particular T-cell lymphoma and Hodgkin lymphoma. Combination strategies with standard therapies based on pre-clinical data are being employed with significant success due to their excellent side effect profile. Correlative studies will provide valuable information on the sub-groups of patients more likely to respond or be resistant to HDACi therapy, while long-term monitoring for toxicities is also needed. Full article
(This article belongs to the Special Issue HDAC Inhibitors)
Open AccessReview Cannabinoids and Dementia: A Review of Clinical and Preclinical Data
Pharmaceuticals 2010, 3(8), 2689-2708; doi:10.3390/ph3082689
Received: 23 June 2010 / Revised: 5 August 2010 / Accepted: 16 August 2010 / Published: 17 August 2010
Cited by 5 | PDF Full-text (98 KB) | HTML Full-text | XML Full-text
Abstract
The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have
[...] Read more.
The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy
Pharmaceuticals 2010, 3(8), 2709-2732; doi:10.3390/ph3082709
Received: 31 May 2010 / Revised: 10 August 2010 / Accepted: 17 August 2010 / Published: 20 August 2010
Cited by 7 | PDF Full-text (224 KB) | HTML Full-text | XML Full-text
Abstract
Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450
[...] Read more.
Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed. Full article
(This article belongs to the Special Issue Antiepileptic Drugs)
Open AccessReview Dendritic Cell Regulation by Cannabinoid-Based Drugs
Pharmaceuticals 2010, 3(8), 2733-2750; doi:10.3390/ph3082733
Received: 2 July 2010 / Revised: 11 August 2010 / Accepted: 20 August 2010 / Published: 23 August 2010
Cited by 2 | PDF Full-text (318 KB) | HTML Full-text | XML Full-text
Abstract
Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory
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Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes. Full article
(This article belongs to the Special Issue Cannabinoids)

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Open AccessOpinion Rational Use of Antibiotics in the Treatment of Functional Bowel Disorders
Pharmaceuticals 2010, 3(8), 2380-2386; doi:10.3390/ph3082380
Received: 13 May 2010 / Revised: 8 July 2010 / Accepted: 13 July 2010 / Published: 26 July 2010
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Abstract
Functional gastrointestinal symptoms such us bloating, fullness, flatulence, diarrhea, and constipation due to irritable bowel syndrome (IBS) were recently attributed to small bowel bacterial overgrowth, a condition depending on the presence of an increased number of bacteria in the small bowel. However, the
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Functional gastrointestinal symptoms such us bloating, fullness, flatulence, diarrhea, and constipation due to irritable bowel syndrome (IBS) were recently attributed to small bowel bacterial overgrowth, a condition depending on the presence of an increased number of bacteria in the small bowel. However, the methodology used to describe this association may be harshly criticized, since it has already been shown to be quite inaccurate. As a result an inappropriate use of antibiotics was consequently generated. In fact, antibiotics could be effective in the treatment of functional complaints, but only in a limited subgroup of patients, characterized by an increase of fermentation at colonic level. In this review, we have examined the papers suggesting a pathophysiological link between IBS and small bowel bacterial overgrowth, underlining its inappropriateness, and put forth our personal view on the rationale for antibiotic use in IBS. Full article
(This article belongs to the Special Issue Antibiotics)

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