Drug Therapy Strategies Research Articles

Multiple myeloma maintenance therapy: A review of the pharmacologic treatment

Over the last decade, numerous drug therapies have emerged for the treatment of multiple myeloma including immunomodulating agents namely thalidomide, lenalidomide, and pomalidomide and proteasome inhibitors namely bortezomib and carfilzomib. These agents have transformed the treatment of multiple myeloma and the role of high-dose chemotherapy followed by stem cell transplantation in the treatment of the disease. There are now studies that evaluate the use of drug therapy as maintenance following autologous stem cell transplantation; these studies have shown improvements in surrogate endpoints such as progression-free survival. Studies that have evaluated thalidomide or lenalidomide maintenance therapy have demonstrated an overall survival (OS) benefit in individuals with multiple myeloma who received high-dose chemotherapy followed by stem cell transplantation. A meta-analysis of thalidomide maintenance therapy did show a possible late survival benefit. The use of dexamethasone, thalidomide, lenalidomide, or combination bortezomib with thalidomide in patients who did not undergo transplantation demonstrated progression-free survival benefit; although there was no OS advantage for these agents in this population. There are a number of important considerations when selecting a drug therapy strategy for maintenance therapy which includes practical considerations such as route of administration and frequency of administration. Additionally, patient-specific elements such as potential toxicities, end-organ function, quality of life, cytogenetics, and previous treatment should be considered. Additional studies are needed to elicit the timing for initiation and duration of maintenance therapy, determine the role of cytogenetics, further characterize possible resistance patterns, and determine the combinations necessary to achieve an optimal increase in OS. Until more data are available, the risks and benefits should be evaluated on a patient-specific basis when deciding to initiate maintenance therapy or observation.

Global stability and backward bifurcation of a general viral infection model with virus-driven proliferation of target cells

In this paper, a general viral model with virus-driven proliferation of target cells is studied. Global stability results are established by employing the Lyapunov method and a geometric approach developed by Li and Muldowney. It is shown that under certain conditions, the model exhibits a global threshold dynamics, while if these conditions are not met, then backward bifurcation and bistability are possible. An example is presented to provide some insights on how the virus-driven proliferation of target cells influences the virus dynamics and the drug therapy strategies.

Discovery and Development of Antisecretory Drugs for Treating Diarrheal Diseases

Diarrheal diseases constitute a significant global health burden and are a major cause of childhood mortality and morbidity. Treatment of diarrheal disease has centered on the replacement of fluid and electrolyte losses using oral rehydration solutions. Although oral rehydration solutions have been highly successful, significant mortality and morbidity due to diarrheal disease remains. Secretory diarrheas, such as those caused by bacterial and viral enterotoxins, result from activation of cyclic nucleotide and/or Ca(2+) signaling pathways in intestinal epithelial cells, enterocytes, which increase the permeability of Cl(-) channels at the lumen-facing membrane. Additionally, there is often a parallel reduction in intestinal Na(+) absorption. Inhibition of enterocyte Cl(-) channels, including the cystic fibrosis transmembrane conductance regulator and Ca(2+)-activated Cl(-) channels, represents an attractive strategy for antisecretory drug therapy. High-throughput screening of synthetic small-molecule collections has identified several classes of Cl(-) channel inhibitors that show efficacy in animal models of diarrhea but remain to be tested clinically. In addition, several natural product extracts with Cl(-) channel inhibition activity have shown efficacy in diarrhea models. However, a number of challenges remain to translate the promising bench science into clinically useful therapeutics, including efficiently targeting orally administered drugs to enterocytes during diarrhea, funding development costs, and carrying out informative clinical trials. Nonetheless, Cl(-) channel inhibitors may prove to be effective adjunctive therapy in a broad spectrum of clinical diarrheas, including acute infectious and drug-related diarrheas, short bowel syndrome, and congenital enteropathies.

The Role of Plasma Renin Activity, Age, and Race in Selecting Effective Initial Drug Therapy for Hypertension

Strategies for initial drug therapy of hypertension are a thiazide diuretic for all or drug selection based on age/race criteria or on plasma renin activity (PRA). It is uncertain which of these strategies will achieve the highest control rate among patients with stage 1 essential hypertension. We sought to compare control rates among 3 drug selection strategies: (i) thiazide diuretic for all, (ii) thiazide diuretic for all black subjects and white subjects aged ≥50 years and a renin-angiotensin system blocker for white subjects aged <50 years, or (iii) thiazide diuretic for PRA < 0.6ng/ml/h (suppressed PRA) and a renin-angiotensin system blocker for PRA ≥ 0.6ng/ml/h (nonsuppressed PRA). Blood pressure responses from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study were used to determine control rates for each of the 3 strategies. In GERA, hypertensive adults were treated with hydrochlorothiazide (n = 286 black subjects and 284 white subjects) or with candesartan (n = 248 black subjects and 278 white subjects). In the overall sample, the PRA strategy was associated with the highest control rate of 69.4% vs. 61.3% with the age/race strategy (P < 0.001) and 53.8% with the thiazide for all strategy (P < 0.001). This was also true in each racial subgroup (in black subjects: 62.1% vs. 55.2% for the other 2 strategies, P = 0.02; in white subjects: 76.3% vs. 67.1% with the age/race strategy (P < 0.001) and 52.4% with the thiazide for all strategy (P < 0.001)). This exploratory analysis suggests that choice of initial therapy for hypertension using a PRA strategy may be associated with higher control rates than alternative strategies recommended in current guidelines.

Up-Regulation of Heme Oxygenase-1 Is Induced by the Leukemia Stroma-Cell Interaction and Rescues Acute Myeloid Leukaemia (AML) Cells From Cytarabin Induced Cell Death

AbstractAbstract 533Although the majority of patients achieve a complete remission after induction chemotherapy with cytarabine and antracyclines relapse is still the major cause of death in acute myeloid leukemia (AML). In order to address the question of resistance mechanisms in residual leukemic cells we employed a murine leukemia model system. We transplanted Rag2−/−gc−/− mice with human KG1a leukemia cells and treated them with four doses of cytarabine at the onset of AML. Residual human leukemic cells were collected from murine marrow and spleen and RNA was further subjected to whole genome microarray analysis. Heme Oxygenase-1 (HO-1) was found to be highly up-regulated in the persistent cell fraction that had survived cytarabine chemotherapy in vivo. The clinical relevance of HO-1 up-regulation was confirmed with two AML data sets. In a small set of 31 unselected AML patients treated in one institution, overall survival (OS) was significantly worse in patients with high HO-1 expression as determined by qPCR analysis (log rank: p < 0.0001). A second patient cohort of 286 patients was therefore retrospectively analyzed for HO-1 expression based on whole genome expression profiling. Again, OS was inferior in patients expressing HO-1 at high levels (p<0.005).HO-1 is a well-known stress-response protein also termed heat-shock protein 32 (hsp32) that catalyzes the enzymatic cleavage of heme into biliverdin, carbon monoxide and iron, but also decreases cellular levels of reactive oxygen species (ROS). Employing an in vitro co-culture system we show that mesenchymal stem cells (MSC) increase HO-1 expression in leukemic cells causing a decrease in ROS levels and protection from apoptosis particularly in the adherent fraction of leukemic cells. The cytoprotective effect induced by leukemia stromal cell interaction can be overcome by concomitant treatment of cytarabin together with zinc protophoryrin (ZnPP), a specific competitive inhibitor of HO-1. Taken together we demonstrate that expression of HO-1 may play a critical role for chemotherapy resistance in AML in particular with regard to the leukemia stromal cell interaction. ZnPP is a specific HO-1 inhibitor that has already proven anti-tumor activity in vivo and might therefore be a promising candidate for further targeted drug therapy strategies that intend to eradicate persistent leukemic cells. Disclosures:No relevant conflicts of interest to declare.

Osteoporosis drug therapy strategies in the setting of disease-modifying agents for autoimmune disease

The purpose of this systematic review is to evaluate the effects of methotrexate (MTX) and tumor necrosis factor-alpha (TNF-α) inhibitors on bone mineral properties in the clinical literature. A systematic review of the literature identifying relevant case reports, population-based studies, cohort studies, case control studies, and randomized controlled trials in Pubmed and Web of Science databases from inception to December 31, 2011 was conducted. The following keywords were used: "bone turnover," "bone mineral density," "TNF-α inhibitors," "infliximab," "adalimumab," "etanercept," and "MTX." The bibliographies of all retrieved studies were also reviewed to identify additional articles. Based on these results, a rational drug therapy strategy was suggested for treating osteoporosis in patients with inflammatory disease. MTX and TNF-α inhibitors do not appear to have an adverse effect on BMD in patients with inflammatory disease. Their negative effects on BMD and bone turnover in pre-clinical models appear to be outweighed by their anti-disease effects in clinical studies. Treatment with MTX or TNF-α inhibitors has no adverse effect on BMD in patients with inflammatory disease. Future studies will focus on developing optimal drug strategies when combining DMARDs with anti-osteoporotic agents in this patient population.

Trends in Early Outpatient Drug Therapy in Pediatric Inflammatory Bowel Disease in Finland: A Nationwide Register-Based Study in 1999–2009

Objective. There are limited data on the changes of treatment strategies of disease-modifying drugs used to treat pediatric inflammatory bowel disease (IBD). Methods. We utilized data from two national registers: the Drug Reimbursement Register for drug costs (for identifying children with IBD) and the Drug Purchase Register (for exposure to drugs), both of which are maintained by the Social Insurance Institution of Finland. The frequencies and trends of drug therapy strategies during the first year of pediatric IBD were evaluated between 1999 and 2009. Results. A total of 481 children diagnosed with IBD were identified. During the first six months, 68% of the patients purchased systemic corticosteroids; these combined with 5-aminosalicylic acid in almost all cases. The use of corticosteroids was stable from the early years compared with the end of the study period. In Crohn's disease, there was a trend towards more active use of azathioprine: the therapy was introduced earlier and proportion of pediatric patients purchasing azathioprine increased by up to 51% (P < 0.05). Conclusions. In pediatric IBD, the majority of patients purchased corticosteroid within the first six months, reflecting moderate-to-severe disease. During recent years in pediatric Crohn's disease, the therapeutic strategies of oral medication have changed towards more active immunosuppression with azathioprine.

Systematic Modeling of Pharmacokinetics Based on Multi-Scale Imaging

Cancer research has achieved dramatic advances in recent years with modern techniques and aroused extensive efforts to discover effective therapeutic drugs. As complement to time and resource intensive traditional drug development methods, application of computational models for drug pharmacokinetics and pharmacodynamics research has become increasingly popular because of its high efficiency and flexibility. Our work provides a well-designed integrated mechanistic model for developing cancer drugs by incorporating new techniques like PET, CT, and intravital microscopy. This model studies drug distribution and therapeutic effects from a systematic viewpoint at three different yet highly related levels. Firstly, a macro-scale model was established to study time course drug distributions in different organs especially in blood which circulates in whole body and delivers drug to targeted tumor. At the intratumoral level, a coupled 3D tumor growth and angiogenesis model was proposed to elaborately simulate neovasculature formation and calculate regional variations in drug distribution inside solid tumor. The third part focuses on how regional variations in drug distribution affect tumor cell death/proliferation rate by linking therapeutic response to intracellular signaling pathway blockade or alteration, which provides us a high-resolution overview of drug action in the targeted tumor cell. Hence, the first two modules which target the organ level and intratumoral microenvironment are directly coupled to pharmacokinetics analysis which is linked to the last component of the model that analyzes the pharmacodynamic effects at the cellular level. Experimental data for calibrating computational model, like drug distribution, tumor vasculature, drug penetration rate etc., were measured using PET, CT, and high resolution intravital microscopy. We perform simulations to investigate the delivery efficiency and drug efficacy of free drug and nanotherapeutics. Our model successfully predicted optimal drug property and therapy strategy. Finally, model effectiveness was validated by in vivo experimental data.

Nanotechnology-based drug delivery in mucosal immune diseases: hype or hope?

Nanotechnology-based drug delivery in mucosal immune diseases: hype or hope?

Full Report from the First Annual Heart Rhythm Society Research Forum: A Vision for Our Research Future, “Dream, Discover, Develop, Deliver”

The Heart Rhythm Society (HRS) organized a research forum held on December 14–15, 2010, to develop a vision for future arrhythmia research and to design practical approaches to ensure these visions are realized. The goal of the present communication is to summarize the discussions and recommendations of this research forum. The core purpose of the HRS is to improve the health of patients with heart rhythm disorders.1 In addition to the ability to end death and suffering due to bradycardia by implanting cardiac pacemakers, members of this society were largely responsible for the invention and refinement of implantable cardioverter-defibrillators (ICDs), radiofrequency catheter ablation techniques, surgical treatment of cardiac arrhythmias and improved strategies of drug therapy. Multiple clinical trials have been performed by Society members to evaluate and document the effectiveness of therapeutic approaches to various cardiac arrhythmias. Despite these advances, heart rhythm disorders remain a major cause of mortality and morbidity in United States and in other parts of the world. Sudden cardiac death (SCD) continues to claim more than 250,000–400,000 U.S. lives annually,2,3 accounting for 15–20 percent of all deaths.4,5 Over 50 percent of all of coronary heart disease deaths are sudden, occurring out-of-hospital and in the emergency room,6 and survival rates from cardiac arrest remain poor.7 At the same time, the percentage of the population afflicted with atrial fibrillation (AF) is growing exponentially.8,9 An estimated 5.1 million people are diagnosed with AF in the United States at present, and this number is expected to rise to 7.5 million by 2020 and to 12.1 million by 2050.10 The population afflicted with AF is further affected by the clinical sequelae of AF, which include thromboembolic stroke,11 heart failure (HF),12 cognitive dysfunction,13 increased mortality,2 and a lower quality of life.14 Therefore, despite our best current efforts, heart rhythm disorders remain major public health problems. In 2009, HRS embarked upon a bold strategic plan with the “big audacious goal” of “ending death and suffering due to heart rhythm disorders.” To achieve this ambitious goal, fundamental advances in our understanding of arrhythmia mechanisms are needed to facilitate the effective treatment and/or prevention of arrhythmias in our patients. Thus, research was identified as a top priority.1,15 Several HRS initiatives were proposed, including efforts to establish a more robust research funding portfolio targeting early stage and transitional investigators, expanding the research focus during the Annual Scientific Sessions and more complete integration of biomedical investigation into the fabric of the Society—in short, to establish a sustainable research culture. To ensure that heart rhythm research receives sufficient attention from its membership, the Society organized a research forum held on December 14–15, 2010. The goal of the forum was to develop a vision for future arrhythmia research and to design practical approaches to ensure these visions are realized. Attendees included HRS members and stakeholders in arrhythmia research, as well as representatives from the National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI), the American Heart Association (AHA), Food and Drug Administration (FDA), Centers for Medicare & Medicaid Services (CMS), industry, patient care organizations, patient advocacy groups and affiliated scientists. Representatives from the European and Asian Pacific Heart Rhythm Associations also participated in the discussion. The attendees reaffirmed that “Ending death and suffering due to heart rhythm disorders” is the goal of HRS, and that this audacious goal can only be achieved through collaborative efforts between scientists and clinicians interested in heart rhythm research. While the forum was mainly convened to address American research, many of the issues raised cross geographic and political boundaries and the recommendations may also be readily transportable to other jurisdictions. In his opening remarks, 2010–2011 Heart Rhythm Society President Douglas L. Packer, MD, emphasized how creating a research culture within the Society will require the participation of all Society members in each step of the research process. While research scientists play a paramount role in this process, each individual clinician must embrace the concepts critical to progress in research. The following is a summary of the discussions in the Research Forum.

Cryptolepine-Induced Cell Death ofLeishmania donovaniPromastigotes Is Augmented by Inhibition of Autophagy

Leishmania donovani are the causative agents of visceral leishmaniasis worldwide. Lack of vaccines and emergence of drug resistance warrants the need for improved drug therapy and newer therapeutic intervention strategies against leishmaniasis. In the present study, we have investigated the effect of the natural indoloquinoline alkaloid cryptolepine on L. donovani AG83 promastigotes. Our results show that cryptolepine induces cellular dysfunction in L. donovani promastigotes, which leads to the death of this unicellular parasite. Interestingly, our study suggest that cryptolepine-induced cell death of L. donovani is counteracted by initial autophagic features elicited by the cells. For the first time, we show that autophagy serves as a survival mechanism in response to cryptolepine treatment in L. donovani promastigotes and inhibition of autophagy causes an early increase in the amount of cell death. This study can be exploited for designing better drugs and better therapeutic strategies against leishmaniasis in future.

Cell Cycle and Energy Metabolism in Tumor Cells: Strategies for Drug Therapy

Recent results obtained from research on the intermediary metabolism of tumor cells have uncovered the biochemical reprogramming that takes place upon malignant transformation. Many features have been highlighted that are currently being exploited for specific chemotherapy. Many more will become available shortly as a consequence of the recognition of potentially useful targets for treatment. General interest in this area can be gauged by the number of recent patents that have been deposited, or are in the process of application. Because the metabolic subversion that is a hallmark of cancer cells involves a disruption of its homeostasis, the regulatory pathways dealt with in this review were broadly divided into those that encompass the main stages of the cell cycle and its various regulatory mechanisms and those that involve the aerobic glycolysis typical of cancer cells. It becomes apparent that both, the cell cycle and the intermediary metabolism are interconnected and rely on reactions many of which are dependent on kinases and phosphatases. Kinases and phosphatases are responsive to cellular redox signaling and may have a key role in determining whether cells progress towards malignant transformation as a result of continuous oxidative stress. The results discussed here underline aspects of the signaling pathways that lend themselves to specific inhibition by natural and synthetic compounds. The mitochondria and its role in programmed cell death are briefly commented, but special emphasis is placed on biochemical regulation at the level of chromatin structure, particularly the reactions that involve acetylation and deacetylation of histones. Within this context, inhibitors that act on histone deacetylases are discussed as promising alternatives to available treatments.

The pathology and treatment of cardiac arrhythmias: focus on atrial fibrillation

Atrial fibrillation (AF) is the most frequently encountered sustained cardiac arrhythmia in clinical practice and a major cause of morbidity and mortality. Effective treatment of AF still remains an unmet medical need. Treatment of AF is based on drug therapy and ablative strategies. Antiarrhythmic drug therapy is limited by a relatively high recurrence rate and proarrhythmic side effects. Catheter ablation suppresses paroxysmal AF in the majority of patients without structural heart disease but is more difficult to achieve in patients with persistent AF or with concomitant cardiac disease. Stroke is a potentially devastating complication of AF, requiring anticoagulation that harbors the risk of bleeding. In search of novel treatment modalities, targeted pharmacological treatment and gene therapy offer the potential for greater selectivity than conventional small-molecule or interventional approaches. This paper summarizes the current understanding of molecular mechanisms underlying AF. Established drug therapy and interventional treatment of AF is reviewed, and emerging clinical and experimental therapeutic approaches are highlighted.

Influenza Pandemic Waves under Various Mitigation Strategies with 2009 H1N1 as a Case Study

A significant feature of influenza pandemics is multiple waves of morbidity and mortality over a few months or years. The size of these successive waves depends on intervention strategies including antivirals and vaccination, as well as the effects of immunity gained from previous infection. However, the global vaccine manufacturing capacity is limited. Also, antiviral stockpiles are costly and thus, are limited to very few countries. The combined effect of antivirals and vaccination in successive waves of a pandemic has not been quantified. The effect of acquired immunity from vaccination and previous infection has also not been characterized. In times of a pandemic threat countries must consider the effects of a limited vaccine, limited antiviral use and the effects of prior immunity so as to adopt a pandemic strategy that will best aid the population. We developed a mathematical model describing the first and second waves of an influenza pandemic including drug therapy, vaccination and acquired immunity. The first wave model includes the use of antiviral drugs under different treatment profiles. In the second wave model the effects of antivirals, vaccination and immunity gained from the first wave are considered. The models are used to characterize the severity of infection in a population under different drug therapy and vaccination strategies, as well as school closure, so that public health policies regarding future influenza pandemics are better informed.

Clinical Trials Legislation - Preparing for the Revision of the European Directive Scheduled for 2011

The aim of the Round Table was to make recommendations with regard to the imminent revision of the European Directive on clinical drug trials (2001/20/CE).While recognising the importance of compliance with this Directive, which is not optimal in some member states of the European Union, it would be constructive to simplify further and harmonise its application in every country. Without necessarily resorting to a revision, some of the Directive’s dispositions could be improved, such as the definition of “investigational medicinal products” (IMP) and what should be considered as “substantial amendements”, as well as harmonising and improving the way in which Ethics Committees are run, either on a European Commission level, or by relying more on the European Network of Research Ethics Committees (EUREC) which already exists in several European member states.Other points in the Directive do require revision, especially those relating to:• the definition of the respective roles of Ethics Committees and Competent Authorities.• the simplification of safety information to Ethics Committees (giving them access to the Eudravigilance database for adverse reactions occurring during clinical trials and providing them with only new safety issues or with a summary of the Annual Safety Report).• the possibility of one single European authorisation for the trial, centralised and/or decentralised, when the trial is multinational.The recommended changes could be made within the scope of a European Regulation, avoiding the need to transpose it at a later date into each country’s regulations, which is a source of possible lack of harmonisation. More specifically, for trials with institutional sponsors and/or investigator driven trials such as “drug therapy strategy trials”, modulating restrictions according to the “risk added by the research” would enable the trial’s organisation to be simplified regarding monitoring, adverse reactions reporting and study drugs labelling.

F25 Anthracyclines in elderly cancer patient: a SIOG expert position paper

Kidney cancer, also known as renal cell carcinoma (RCC), is one of the top 10 diagnosed cancers in the USA, and the incidence is rising. Despite major improvements in drug therapy strategies, RCC remains a deadly malignancy if not found and removed in its early stages. RCC is so highly drug-resistant that no effective life-prolonging regimen of cytotoxic chemotherapy has been demonstrated for RCC, despite several decades of effort. It is also highly radiation-resistant, thus circumventing therapies to prevent local recurrence or to control metastatic disease. In the last few years, extensive research has been conducted to elucidate the functional significance of the plant-derived compounds, and their derivatives, as anticancer agents. This review is focussed on a chemo-dietary prevention strategy against RCC using a citrus-derived compound called 2′-hydroxyflavanone. RCC is frequently caused by VHL gene mutations, which contribute to 75% of all RCCs. These mutations are positively linked to cigarette smoking, and exposure to the tobacco carcinogen, N-nitrosodimethylamine and benzopyrene, can disrupt VHL. According to in vitro and preclinical mouse studies, 2′-hydroxyflavanone can both protect the VHL locus and prevent the progression of VHL-mutant cancer. Human clinical trials examining the effect of supplementation of 2′-hydroxyflavanone, either alone or in combination with chemotherapeutic drugs, on RCC prevention have not been conducted, although there is considerable potential for 2′-hydroxyflavanone and its derivatives to be developed as RCC chemoprevention agents. Therefore, the discovery of plant-derived cancer therapies, such as 2′-hydroxyflavanone, offers a new strategy for combating this highly resistant cancer.

Bell's palsy: new evidence provides a definitive drug therapy strategy

Bell's palsy is acute, idiopathic, unilateral paralysis of the facial nerve1 and most GPs will see a new case about once every 5 years. Although most patients recover well, up to 30% have a poor outcome, with persistent facial weakness, psychological difficulties, and facial pain. The rapid, often painful onset of facial weakness is distressing for patients, leading them to present urgently to their GP. Primary care management has included various options, such as prednisolone and/or antiviral drugs, or neither, but evidence for these or other strategies has been weak or absent. This persisting uncertainty about ideal management can be disconcerting for GPs and their patients. In 2001, the American Academy of Neurology published guidelines on the management of Bell's palsy, concluding that, while the benefit of steroids and/or aciclovir had not been established, the available evidence indicated that steroids were ‘probably effective’, and that aciclovir combined with prednisolone was ‘possibly effective’.1 Subsequently, two articles published in the British Medical Journal triggered controversy when they recommended the early use of steroids and aciclovir,2,3 although no further reliable data had been published since the American guideline. After decades of little persuasive evidence, four randomised controlled trials, involving over 1800 patients, …

Adult Neurogenesis and Drug Therapy

Current drug therapy strategies for the nervous system are based on the assumption that the adult central nervous system (CNS) lacks the capacity to make new nerve cells and regenerate after injury. Contrary to a long-held dogma, adult neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult CNS. Neurogenesis in the adult brain is modulated in a broad range of environmental conditions, and physio- and pathological processes, as well as by trophic factors and drugs. This suggests that newborn neuronal cells of the adult brain may be involved in the functioning of the nervous system and may mediate a broad range of physio- and pathological processes, as well as the activities endogenous and exogenous factors and molecules. Hence, the confirmation that adult neurogenesis occurs in the adult brain and NSCs reside in the adult CNS force us to rethink how drugs are functioning and whether their activity may be mediated through adult neurogenesis. This will lead to the development and design of new strategies to treat neurological diseases and injuries, particularly drug therapy. Keywords: Antidepressants, bromodeoxyuridine, neural stem cells, neurological diseases, pharmacology, trophic factors

Phenidone protects the nigral dopaminergic neurons from LPS-induced neurotoxicity

Anti-inflammatory drugs such as ibuprofen appear to prevent the development of Parkinson's disease (PD); however, long-term use has undesirable side-effects. A new strategy for anti-inflammatory drug therapy is using a dual inhibitor of COX and lipooxygenase (LOX). Here, we compared the dopaminergic neuroprotective property of phenidone (a dual COX and LOX inhibitor) with COX or LOX inhibitors including SC-560 (a COX-1 inhibitor), aspirin (a COX-1/2 inhibitor), meloxicam (a preferential COX-2 inhibitor), caffeic acid (a 5-LOX inhibitor), and esculetin (a 5, 12-LOX inhibitor) in our lipopolysaccharide (LPS)-induced PD animal model. Our results show that COX-2 and 5-LOX play a major role in LPS-induced dopaminergic neurotoxicity, as meloxicam and phenidone attenuated LPS-induced oxidative stress and meloxicam, phenidone, and caffeic acid attenuated dopaminergic neurodegeneration, while SC-560, aspirin, and esculetin did not. In addition, phenidone was superior in attenuating LPS-induced dopaminergic neurodegeneration and microglia activation, probably as a result of dual inhibition of COX-2 and LOX. Therefore, dual inhibition of COX and LOX with phenidone represents a promising new candidate for anti-inflammatory drug therapy, and may provide a novel therapeutic approach for inflammation-related neurodegenerative diseases including PD.

MicroRNAs and the regulation of glucose and lipid metabolism

Over recent years, metabolic disorders such as type 2 diabetes have finally become recognized as a major challenge to global health. The attention of scientists therefore has to focus on improving our understanding of the molecular mechanisms behind these diseases and towards the design of new drug therapy strategies. The pathophysiology of diabetes is undoubtedly complex, oftentimes characterized by varying states of insulin resistance and impaired beta-cell function; however, the identification of new pathways is constantly improving our understanding of the disease. We and others have recently shown that microRNAs (miRNAs) can play a role in insulin secretion and glucose homostasis. Thus, in this review, we will discuss the potential role of miRNAs in type 2 diabetes and related metabolic diseases.