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Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss  [PDF]
Takayuki Okano
Frontiers in Pharmacology , 2014, DOI: 10.3389/fphar.2014.00205
Abstract: Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.
A Comparative Study on the Cost of New Antibiotics and Drugs of Other Therapeutic Categories  [PDF]
Matthew E. Falagas, Konstantinos N. Fragoulis, Ioannis Karydis
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000011
Abstract: Background Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. Methodology/Principal Findings We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. Conclusions/Significance The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance.
Smoothened as a new therapeutic target for human osteosarcoma
Masataka Hirotsu, Takao Setoguchi, Hiromi Sasaki, Yukihiro Matsunoshita, Hui Gao, Hiroko Nagao, Osamu Kunigou, Setsuro Komiya
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-5
Abstract: To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens. To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo. Real-time PCR revealed that osteosarcoma cell lines over-expressed Sonic hedgehog, Indian hedgehog, PTCH1, SMO, and GLI. Real-time PCR revealed over-expression of SMO, PTCH1, and GLI2 in osteosarcoma biopsy specimens. These findings showed that Hedgehog pathway is activated in osteosarcomas. Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest. Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21cip1 wprotein was up-regulated by cyclopamine treatment. In addition, knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo.These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.Osteosarcoma is the most common primary bone malignant tumor occurring mainly in children [1]. After initial diagnosis is made by biopsy, treatment consists of preoperative chemotherapy, followed by definitive surgery and postoperative chemotherapy. Survival has improved over the past several decades. Indeed, patients with non-metastatic disease have a 70% chance of long-term survival. Unfortunately, patients with metastatic disease at diagnosis and those who have recurrent disease have a poor prognosis, with only 20% surviving at 5 years, indicating that new therapeutic options for them need to be actively explored. In cancer cells, dysregulation of cell division and apoptotic processes contribute to both drug resistance and metastatic potential [2,3]. It has been reported that inactivation of the cell cycle
Interleukin-6: a new therapeutic target
Josef S Smolen, Ravinder N Maini
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar1969
Abstract: Severe manifestations of rheumatoid arthritis (RA), particularly rapidly progressive and severe disability but also vasculitis and amyloidosis, have become rare. This is attributable to progress made over recent decades in treatment strategies that effectively suppress disease activity. We have learned to use traditional disease-modifying antirheumatic drugs early and intensively, especially methotrexate (MTX), which is considered the 'gold standard' of care for patients with RA. However, the responses of patients with RA to treatment with so-called standard disease-modifying antirheumatic drugs such as MTX, alone or in combination, is suboptimal in a significant proportion of patients [1]. The more recently developed biological agents, when used in combination with MTX, yield better clinical responses in MTX refractory or na?ve patients; for example, as many as 75% of patients treated with an anti-tumour necrosis factor (TNF) biological drug were reported to exhibit clinical responses [2]. Moreover, the TNF blockers have particular efficacy in inhibiting progression of joint damage.Despite the undoubted benefits attributable to current biological targeted interventions, in most studies 50% or more of patients with MTX na?ve/early RA do not achieve 50% or better clinical improvement in established disease. This unmet need for effective interventions in RA clearly mandates further research, especially when the objective, today, is clinical remission. Nonresponsiveness to TNF blockade and/or residual disease activity, as well as the continuing, albeit slower progression of joint damage in a proportion of patients treated with TNF inhibitors suggest that TNF is not the sole responsible biological target in the disease process, and therefore further novel agents and novel strategies are needed.The ideal profile for a new drug is one that targets a molecule or a cell population that is involved in pathogenesis, with equivalent (or better) efficacy compared with existing
Dorsal root ganglion – a potential new therapeutic target for neuropathic pain
Sapunar D, Kostic S, Banozic A, Puljak L
Journal of Pain Research , 2012, DOI: http://dx.doi.org/10.2147/JPR.S26603
Abstract: rsal root ganglion – a potential new therapeutic target for neuropathic pain Perspectives (4820) Total Article Views Authors: Sapunar D, Kostic S, Banozic A, Puljak L Published Date February 2012 Volume 2012:5 Pages 31 - 38 DOI: http://dx.doi.org/10.2147/JPR.S26603 Received: 29 September 2011 Accepted: 22 October 2011 Published: 16 February 2012 Damir Sapunar, Sandra Kostic, Adriana Banozic, Livia Puljak Department of Anatomy, Histology, and Embryology, University of Split Medical School, Soltanska 2, 21000 Split, Croatia Abstract: A regional approach can protect our patients from often unacceptable adverse effects produced by systematically applied drugs. Regional therapeutic approaches, as well as interventions at the level of the peripheral nervous system and particularly the dorsal root ganglion (DRG), represent an alternative to the systemic application of therapeutic agents. This article provides an overview of DRG anatomical peculiarities, explains why the DRG is an important therapeutic target, and how animal models of targeted drug delivery can help us in the translation of basic research into clinical practice.
Immunomodulatory actions of antibiotics  [PDF]
Mini? Svetlana,Boji? Milena,Vukadinov Jovan,?anak Grozdana
Medicinski Pregled , 2009, DOI: 10.2298/mpns0908327m
Abstract: Introduction. Antimicrob drugs and immune system interaction has been studied since the pioneer works of Metchnikoff. After the introduction of antibiotics in clinical practice this area has attracted little attention of investigators, because of the lack of standards. This is the reason that the studying of the influence of antibiotics on immune system is still at its beginning. Aim: To point out the immunomodulatory action of some antibiotics on certain components of immune system. Methods and results. The literaure findings show that antibiotics exspress immunomodulatory action on some components of immune system such as fagocytes (polymorphonucleary, macrophages, monocytes), cytokines, immunoglobulines, and on cellular immunity. The principles of antibiotics action on phagocyte are the inhibition of chemotaxis and oxidants production. Macrolides applied for a short time enchance the phagocytic functions while their long use leads to immunosupression. Some cephalosporines and rifampicin in therapeutic doses inhibit the oxydative metabolism of macrophages. Tetracyclines, clindamycines, chloramphenicol and tobramycin inhibit the synthesis of superoxyd anione. The action of some antibiotics on cytokine and specific antibodies is also important. Cellular immunity can be affected as well. After administration of certain antibiotics it takes 1-2 weeks to reestablish normal cellular immunity, and for other even more. Conclusion. There is still no clear standing on real effects of antibiotics on the immune system. Clinicians should search for more information from this new-old field of investigation in order to give more adequate therapy to patients.
Beneficial and Harmful Interactions of Antibiotics with Microbial Pathogens and the Host Innate Immune System  [PDF]
Ronald Anderson,Gregory Tintinger,Riana Cockeran,Moliehi Potjo,Charles Feldman
Pharmaceuticals , 2010, DOI: 10.3390/ph3051694
Abstract: In general antibiotics interact cooperatively with host defences, weakening and decreasing the virulence of microbial pathogens, thereby increasing vulnerability to phagocytosis and eradication by the intrinsic antimicrobial systems of the host. Antibiotics, however, also interact with host defences by several other mechanisms, some harmful, others beneficial. Harmful activities include exacerbation of potentially damaging inflammatory responses, a property of cell-wall targeted agents, which promotes the release of pro-inflammatory microbial cytotoxins and cell-wall components. On the other hand, inhibitors of bacterial protein synthesis, especially macrolides, possess beneficial anti-inflammatory/cytoprotective activities, which result from interference with the production of microbial virulence factors/cytotoxins. In addition to these pathogen-directed, anti-inflammatory activities, some classes of antimicrobial agent possess secondary anti-inflammatory properties, unrelated to their conventional antimicrobial activities, which target cells of the innate immune system, particularly neutrophils. This is a relatively uncommon, potentially beneficial property of antibiotics, which has been described for macrolides, imidazole anti-mycotics, fluoroquinolones, and tetracyclines. Although of largely unproven significance in the clinical setting, increasing awareness of the pro-inflammatory and anti-inflammatory properties of antibiotics may contribute to a more discerning and effective use of these agents.
Ceramide in Cystic Fibrosis: A Potential New Target for Therapeutic Intervention  [PDF]
Gabriella Wojewodka,Juan B. De Sanctis,Danuta Radzioch
Journal of Lipids , 2011, DOI: 10.1155/2011/674968
Abstract: Patients with cystic fibrosis (CF) are afflicted with many symptoms but the greatest challenge is the fight against chronic bacterial infections, leading to decreased lung function and ultimately death. Our group has recently found reduced levels of ceramides in CF patients and mice. Ceramides are sphingolipids involved in the structure of cell membranes but also participate in the inflammatory response, in cell signalling through membrane microdomains (lipid rafts), and in apoptosis. These characteristics of ceramides make them strong candidates for therapeutic intervention in CF. As more studies have come to evaluate the role of ceramide in CF, conflicting results have been described. This paper discusses various views regarding the potential role of ceramide in CF, summarizes methods of ceramide detection and their role in the regulation of cellular and molecular processes. 1. Introduction Cystic fibrosis (CF) is the most common autosomal recessive disorder found in populations of European descent. It is estimated that 70,000 individuals live with the disease around the world (see http://www.cff.org/AboutCF/) with 70% of patients having the ΔF508 mutation. The disease is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which encodes for a chloride channel. Mutations in the gene cause decreased chloride transport out of the cell; consequently, there is an increased absorption of sodium and reduction in the airway surface liquid. Mucociliary clearance is thus impaired creating a perfect environment for bacterial colonization. Phenotypes of CF are recurrent and chronic pulmonary infections, decreased lung function, pancreatic insufficiency, diabetes, meconium ileus, infertility in males, osteoporosis, and fatty acid defects [1–4]. Current therapies for CF include aerosolized antibiotics such as tobramycin, recombinant human DNase such as dornase alfa for improved mucus clearance, hypertonic saline for increases in airway surface liquid, and nonsteroidal antiinflammatory drugs (NSAIDs) like Ibuprofen to decrease the inflammatory response. Other antibiotics such as azithromycin are commonly used to fight P. aeruginosa infections [5]. Bronchodilators are also commonly prescribed to improve breathing [5]. CF patients take a combination of drugs to improve or maintain lung function not to mention vitamins and pancreatic enzymes and, at times, insulin for pancreatic insufficiency [6] and diabetes [7]. Despite prophylactic treatments, CF patients still suffer from chronic infections and exacerbations which have
Inhibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy
El-Khalawany M, Shaaban D, Sultan M, Abd AlSalam F
Clinical, Cosmetic and Investigational Dermatology , 2012, DOI: http://dx.doi.org/10.2147/CCID.S26200
Abstract: hibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy Original Research (2501) Total Article Views Authors: El-Khalawany M, Shaaban D, Sultan M, Abd AlSalam F Published Date December 2011 Volume 2012:5 Pages 1 - 6 DOI: http://dx.doi.org/10.2147/CCID.S26200 Mohamed El-Khalawany1, Dalia Shaaban2, Maha Sultan1, Fatma Abd AlSalam1 1Departments of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, 2Department of Dermatology, Faculty of Medicine, Tanta University, Gharbia, Egypt Background: Angiogenesis was suggested to have a significant role in the pathogenesis of leprosy. However, the benefit of inhibiting angiogenesis in lepromatous leprosy patients has not previously been studied. The purpose of this study was to evaluate angiogenesis in leprosy patients before and after treatment with multidrug therapy (MDT) with and without minocycline. Methods: A total of 40 patients with lepromatous leprosy were enrolled in this study. They were categorized into two equal groups (A and B), each formed of 20 patients. Group A received World Health Organization MDT, and Group B received MDT combined with minocycline, which has a known antiangiogenic effect. Microvascular density (MVD) in dermal granuloma was evaluated in both groups by immunostaining with CD31 and CD34 markers before and after 6 months of treatment. Results: With CD31 immunostaining, the mean MVD in Group A significantly decreased from 39.1 ± 3.1 vessels (v)/high power field (HPF) to 16.5 ± 2.7 v/HPF, and in Group B it significantly decreased from 38.3 ± 2.5 v/HPF to 7.6 ± 1.9 v/HPF. CD34 immunostaining also showed a significant decrease of MVD from 42.2 ± 3.1 v/HPF to 18.8 ± 2.4 v/HPF in Group A, and in Group B it significantly decreased from 43.7 ± 2.3 v/HPF to 11.5 ± 1.6 v/HPF. The reduction of MVD was significantly higher in Group B compared with in Group A (P < 0.0001). Moreover, there was a significant reduction in bacterial density (assessed by bacterial index) in the cutaneous lesions of in Group B (decreased from 4.9 ± 0.3 to 1.4 ± 0.2) compared with in Group A (decreased from 5.1 ± 0.4 to 2.3 ± 0.4). Conclusion: The synergistic effect of MDT and minocycline seems to be promising in the treatment of lepromatous leprosy. It significantly reduces angiogenesis and rapidly eliminates lepra bacilli from the skin that enables a rapid control and elimination of the disease.
Coronary endothelial dysfunction after ischemia and reperfusion: a new therapeutic target?
Laude, K.;Thuillez, C.;Richard, V.;
Brazilian Journal of Medical and Biological Research , 2001, DOI: 10.1590/S0100-879X2001000100001
Abstract: although cardiac ischemia is usually characterized as a disease of the myocyte, it is clear that the vasculature, and especially endothelial cells, is also a major target of this pathology. indeed, using a rat model of ischemia/reperfusion, we were able to detect severe endothelial dysfunction (assessed as a decreased response to acetylcholine) after acute or chronic reperfusion. given the essential role of the endothelium in the regulation of vascular tone, as well as platelet and leukocyte function, such a severe dysfunction could lead to an increased risk of vasospasm, thrombosis and accelerated atherosclerosis. this dysfunction can be prevented by free radical scavengers and by exogenous nitric oxide. endothelial dysfunction can also be prevented by preconditioning with brief periods of intermittent ischemia, thus extending to coronary endothelial cells the concept of endogenous protection previously described at the myocyte level. experiments performed on cultured cells showed that the endothelial protection induced by free radical scavengers or by preconditioning was due to a lesser expression of endothelial adhesion molecules such as intercellular adhesion molecule-1, leading to a lesser adhesion of neutrophils to endothelial cells. identification of the mechanisms of this protection may lead to the development of new strategies aimed at protecting the vasculature in ischemic heart diseases.
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