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Today, 12 Ιουλίου 2016, 4:19:34 μμ
Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM). Cardiometabolic disorders (CMDs) remain the principal cause of death in both developed and developing countries, accounting for nearly 32% of all deaths worldwide per year. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs. Existing drugs are not efficient enough to reduce the disease burden as well as mortality. Therefore, there is an urgent demand for new drugs in this area to reduce the mortality and control the associated disability. Nonetheless, new drug discovery (NDD) in CMDs has become more challenging for last couple of decades due to increased expenses and decreased success rate. In such a scenario, drug repositioning in the CMDs appears promising for introducing existing drugs for new therapeutic indication. Repositioning is quite an old strategy dating back to 1960s and mainly followed by serendipitous observations during clinical use of drugs. A major advantage of repositioning is that the safety profile of the drug is well established thus reducing the chances of failure due to adverse toxic effects. In addition, repositioning requires less time and investment than NDD. Considering these facts, pharmaceutical companies are now becoming increasingly interested in drug repositioning. In this follow-up, we have talked about the concept of repositioning with important examples of repositioned drugs in cardiometabolic disorder.
Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD)
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype- based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. We outline herein, several ASD-associated basic physiological pathways that can be regulated by the small molecule phytochemical sulforaphane, as an example of a druggable small molecule target for which much in vitro, pre-clinical, and clinical evidence already exists: (1) redox metabolism/oxidative stress, (2) mitochondrial dysfunction, (3) immune dysregulation/neuroinflammation, (4) febrile illness and the heat shock response, and (5) synaptic dysfunction. Furthermore, we identify the biomarkers that can be used to assess the functioning of these pathways as well as suggesting how these biomarkers could guide novel treatment strategies to correct these biochemical abnormalities in order to improve core and associated symptoms of ASD.
In Vitro Study of UGT Metabolism and Permeability of Orientin and Isoorientin, Two Active flavonoid C-glycosides
Today, 12 Ιουλίου 2016, 4:19:36 μμ
C-glycosides are important flavonoids with significant pharmacological activities implicated in anticancer and antioxidative effects. However, their characteristics of metabolism and transportation have been rarely investigated. This research aimed to examine the metabolic characteristics of two active C-glycosides, namely, orientin and isoorientin, in human liver microsomes (HLMs) and rat liver microsomes (RLMs) and to confirm the specific uridine 5′-diphospho glucuronosyltransferase (UGT) isoforms involved in glucuronidation by HLMs. Furthermore, the permeability of orientin and isoorientin was also determined by using Caco-2 cell monolayers. Results revealed that orientin and isoorientin could generate two metabolites, which were identified as monoglucuronides. HLM- and RLM-mediated glucuronide formations were in accordance with typical Michaelis–Menten kinetics. Conversely, RLM initially metabolized orientin to its corresponding metabolite, and this process was consistent with biphasic kinetics. Among the UGT isoform, UGT1A1, 1A8, 1A9 and 1A10 exhibited the highest enzyme activity. Passive diffusion was the predominant orientin and isoorientin transportation mechanism in Caco-2 cell monolayers, and their apparent permeability further confirmed that orientin and isoorientin were well absorbed. Therefore, orientin and isoorientin can be metabolized by UGT isoforms and microsomes; these flavonoids can also be transported via passive diffusion in Caco-2 cells, which are relatively permeable.
Repurposing of Anti-Diabetic Agents for the Treatment of Cognitive Impairment and Mood Disorders
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Impairments in cognitive function represent a consistent, non-specific, and clinically significant feature in metabolic, mood, and dementing disorders. The foregoing observation is instantiated by evidence demonstrating that these disorders share pathophysiological mechanisms including, but not limited to, aberrant insulin signaling, inflammation, and glucocorticoid activity. Moreover, these mechanisms have been consistently reported to increase vulnerability to and/or exacerbate impairments in cognitive function. Notwithstanding evidence suggesting a bidirectional relationship between disturbances in the metabolic milieu, mood, and increased risk for dementia, efficacious treatments that target cognitive impairments in these populations do not presently exist. Taken together, it is proposed that anti-diabetic agents may aid the management of mood disorders and future risk for dementia through disease modification by targeting underlying pathophysiological mechanisms (e.g., aberrant metabolic function) rather than focusing solely on symptom mitigation. The current aim is to provide a brief narrative review of extant studies that report on the potential neurotherapeutic effects of anti-diabetic agents on disturbances in mood and impairments in cognitive function.
Biological Rationale for Regular Physical Exercise as an Effective Intervention for the Prevention and Treatment of Depressive Disorders
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Depression is a major medical and social problem. Here we review current body of knowledge on the benefits of exercise as an effective strategy for both the prevention and treatment of this condition. We also analyze the biological pathways involved in such potential benefits, which include changes in neurotrophic factors, oxidative stress and inflammation, telomere length, brain volume and microvessels, neurotransmitters or hormones. We also identify major caveats in this field of research: further studies are needed to identify which are the most appropriate types of exercise interventions (intensity, duration, or frequency) to treat and prevent depression.
mTOR, a Potential Target to Treat Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.
A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. </p><p> The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. </p><p> Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)<sub>A</sub> receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)<sub>1A</sub> and 5-HT<sub>2A/C</sub> receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. </p><p> Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents. </p><p>
Sulforaphane Treatment of Young Men with Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders that begin in early childhood. They are characterized by differences in behavior and delays in communication and affect at least 1% of children. Observational studies have now confirmed that behaviors of a substantial percentage of children with autism tend to improve with the onset of febrile illness, which might be the downstream effects of altered metabolic pathways involving increased expression of heat shock proteins (HSP) and cellular stress responses. Sulforaphane, a phytochemical derived from a number of cruciferous vegetables, most notably broccoli sprouts, has metabolic effects that in some ways resemble that of fever. This review paper discusses this “fever effect” and the intracellular effects of sulforaphane as well as the results of our recent clinical trial of sulforaphane in young adults with autism. The accompanying review by Liu et al. describes the cellular actions of sulforaphane and potential biomarkers in the study of ASD.
Editorial (Thematic Issue: New Therapeutic Targets for Autism Spectrum Disorders)
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Efficiency in Drug Discovery: Liver S9 Fraction Assay As a Screen for Metabolic Stability
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Background: A rapid and comprehensive metabolic stability screen at the top of a drug discovery flow chart serves as an effective gate in eliminating low value compounds. This imparts a significant level of efficiency and saves valuable resources. While microsomes are amenable to high throughput automation and are cost effective, their enzymatic make-up is limited to that which is contained in endoplasmic reticulum, thereby informing only on Phase I metabolism. Lack of Phase II metabolism data can become a potential liability later in the process, adversely affecting discovery projects’ timelines and budget. Hepatocytes offer a full complement of metabolic enzymes and retain their cellular compartments, better representing liver metabolic function. However, hepatocyte screens are relatively expensive, labor intensive, and not easily automatable. Liver S9 fractions include Phase I and II metabolic enzymes, are relatively inexpensive, easy to use, and amenable to automation, making them a more appropriate screening system. We compare the data from the three systems and present the results. </p><p> Results: Liver S9 and hepatocyte stability assays binned into the same category 70-84% of the time. Microsome and hepatocyte data were in agreement 73-82% of the time. The true rate for stability versus plasma clearance was 45% for hepatocytes and 43% for S9. </p><p> Conclusion: In our opinion, replacing liver microsome and hepatocyte assays with S9 assay for high throughput metabolic screening purposes provides the combined benefit of comprehensive and high quality data at a reasonable expense for drug discovery programs. </p><p>
Recent Advances Using Phosphodiesterase 4 (PDE4) Inhibitors to Treat Inflammatory Disorders: Animal and Clinical Studies
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.
Personalized Treatment of Obsessive-Compulsive Disorder: Radiology, EEG, Pharmacogenetics and Biochemistry
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. </p><p> Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. </p><p> Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. </p><p> Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree. </p><p>
Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:36 μμ
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.
Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.
Commentary: A Myriad Aberrations on Information of Ontogeny of Drug Metabolizing Enzymes in the Pediatric Population: An Obstacle for Personalizing Drug Therapy in the Pediatric Population
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Major lacunae exist in our understanding of how developmental changes in drug biotransformation influence drug’s exposure and thus its efficacy and toxicity in children. It is not just about smaller weight in children, which modifies the pattern of the drug's exposure. There are developmental, functional changes in organ systems, liver to body mass ratios, and changes in metabolism. Understanding these changes and conducting studies to obtain data on ontogeny of drug metabolizing enzymes is essential for implementation of personalized dosing schedules in the pediatric population.
Editorial (Thematic Selection: Mitochondrial Dysfunction & Neurological Disorders)
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Competitive Interaction Between Plasma Omega-3 Fatty Acids and Arachidonic Acid is Related to Down-Regulation of A Signaling Mediator
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Autism spectrum disorders (ASD) may be attributed to altered composition of polyunsaturated fatty acids. We examined the relationships between the plasma ratios of docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid (EPA)/AA, and biomarkers of AA-related signaling mediators, i.e., ceruloplasmin, transferrin and superoxide dismutase, with the behavioral symptoms of 30 individuals with ASD (mean age, 13.0 years old) and 20 age- and gender-matched normal controls (mean age, 13.6 years old). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). The ASD group had significantly higher plasma DHA/AA and EPA/AA ratios, as well as ABC scores, compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group. Multiple linear regression demonstrated that plasma DHA/AA ratio was a fitting model for distinguishing the ASD group from the control group. These findings suggested that increased plasma DHA/AA ratio may be related to lower plasma levels of ceruloplasmin, which may contribute to the pathophysiology of behavioral symptoms in 30 individuals with ASD.
Isoniazid Induced Metabolic Acidosis and Renal Dysfunction in an Elderly Patient with Chronic Renal Disease
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Metabolic acidosis is one of the common manifestations of Isoniazid toxicity but rare with normally used doses of the drug. Among anti tubercular drugs, rifampicin, streptomycin and capreomycin are commonly implicated in renal injury. Here we report the first case of metabolic acidosis and renal injury caused by isoniazid at normal prescribed dose.
Population Studies of Association Between Lithium and Risk of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Background: Lithium shows neuroprotective and neurotrophic effects in vitro and in vivo. Due to its involvement in hippocampal neurogenesis and the interaction with beta-amyloid and neurofibrillary tangle metabolism it has been hypothesized that lithium could have the potential to influence the development of dementia. Method: Using the PubMed database and cross-reference search strategies our aim was to specifically identify population (cohort or case-control) studies investigating the association between lithium and dementia. Results: Data from large cohort studies suggest an association between lithium treatment and dementia risk reduction or reduced dementia severity. Studies with smaller sample sizes yield more variable findings. Conclusions: Lithium may reduce the risk of dementia among middle-aged and older people. Beneficial lithium effects are possibly limited to specific types of neurodegenerative processes.
A Possible Case of Bipolar Disorder Unmasked by Dextromethorphan in a 16-year-old Adolescent
Today, 12 Ιουλίου 2016, 4:19:36 μμ
Background/Objective: Several case reports have described psychosis or mania in patients abusing dextromethorphan. In each of the cases of mania, the symptoms resolved rapidly after the dextromethorphan was metabolized. To our knowledge, no cases have been reported of an underlying diagnosis of bipolar disorder that has been revealed by abuse of dextromethorphan. This report describes such a possible case. </p><p> Method: We describe clinical observations and treatment of patient who received standard level of care for bipolar disorder. </p><p> Results: Our patient presented with symptoms of mania after ingesting 300 mg of dextromethorphan. His symptoms lasted for over one week after the dextromethorphan was out of his system, even after an antimanic agent was started. This is a significantly longer symptomatic period of time than has previously been reported in the literature. </p><p> Conclusions: While this case technically meets criteria for dextromethorphan-induced bipolar disorder according to DSM-5, we suggest that the prolonged course of symptoms may be more indicative of a primary bipolar disorder. We propose that this case might be more similar to the unmasking of bipolar symptoms by anti-depressant medications, which would be supported by the hypothesized acute anti-depressant effects of dextromethorphan. </p><p>
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