ELECTROPHORESIS, Issue 14 2003
Klaus Altland
Abstract Familial amyloidotic polyneuropathy (FAP) is caused by mutations which destabilize transthyretin (TTR) and facilitate the aggregation into extracellular amyloid fibrils preferentially in peripheral nerve and heart tissues. Therapeutic and preventive trials for FAP at the plasma TTR level require a careful study of the destabilization of TTR under variable conditions. We have developed a simple double one-dimensional (D1-D) electrophoretic procedure with polyacrylamide gel electrophoresis (PAGE) followed by sodium dodecylsulfate (SDS) gradient PAGE to study the dimer to monomer transition. TTR is first isolated by PAGE from other plasma proteins. The gel strip containing the TTR fraction is incubated in 2% SDS under varying conditions of temperature, buffer composition, pH, and additives like urea and/or a sulfhydryl-reactive agent, followed by SDS-gradient PAGE for the separation of TTR dimers and monomers. We demonstrate that an unidirectional dimer to monomer transition of normal TTR is achieved at 70,80°C in neutral to mild alkaline buffers or at 37°C and slightly acidic pH (6,7). Addition of urea favors the transition into monomers. Amyloidogenic mutations like amyloidogenic TTR (ATTR)-V30M or ATTR-I107V favor the transition into monomers in buffer systems close to the physiological pH of human plasma. We conclude that this finding has to be considered by any hypothesis on ATTR-derived amyloidogenesis. [source]

Therapeutic and economic implications of traumatic dental injuries in Denmark: an estimate based on 7549 patients treated at a major trauma centre

INTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 4 2001
Mette Kit Borum
Aim. To analyse the type and extent of injuries presented by patients seeking treatment for traumatic dental injuries at a major trauma centre. Furthermore, to analyse acute and subsequent treatment demands and treatment costs. Methods. A therapeutic and economic analysis was performed of 7549 patients treated for traumatic dental injuries in a major trauma centre located at the University Hospital in Copenhagen, Denmark. Cases were divided into uncomplicated (concussion, subluxation, enamel and enamel-dentine fractures) and complicated cases (crown fractures with exposed pulps and crown-root fractures, luxation injuries with displacement of the tooth and bone fractures). Results. Primary tooth injuries were found in 2874 patients, involving 5443 teeth, among which 62·8% had complicated injuries. Permanent tooth injuries were found in 4525 patients, involving 10673 teeth, among which 40·4% had complicated injuries. The cost of treatment (including acute trauma service, follow-up and subsequent restoration) was estimated to be 0·6,1 mill USD a year for the patients treated in this trauma centre. If this figure is transferred to the estimated trauma population in Denmark, a yearly cost of traumatic dental injuries appears to range from 2 to 5 mill USD per 1 mill inhabitants per year according to the treatment scenario. Conclusion. Thus, treatment of traumatic dental injuries comprises an expensive part of the health services in Denmark. [source]

Review article: diagnosis and treatment of non-alcoholic fatty liver disease

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2008
M. K. OH
Summary Background, Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition affecting adults and children, leading to significant morbidity. It is often associated with the metabolic syndrome, although multiple pathogenetic mechanisms have been suggested. In the coming decades, it promises to be the leading cause of liver disease in industrial countries. Aim, To provide a comprehensive, updated review of diagnosis and management of NAFLD and to appraise the evolution of new modalities in these areas. Methods, An Ovid MEDLINE search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. Results, The diagnosis of hepatic steatosis and steatohepatitis or non-alcoholic steatohepatitis (NASH) is not yet possible without liver biopsy. This is impractical given the large numbers affected by the condition. Current therapy has focused on improving insulin resistance and mediators of inflammation, factors probably associated with disease progression. Conclusions, There are no proven non-invasive diagnostic modalities to distinguish NAFLD and NASH, but new biomarker panels are approximating the liver biopsy in accuracy. Therapeutic targets of drug development are in early stages, but a multifaceted approach will probably yield several treatment options in the years to come. [source]

The gastrointestinal safety profile of rofecoxib, a highly selective inhibitor of cyclooxygenase-2, in humans

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001
C. J. Hawkey
Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo. [source]

Conversion of Th17-type into Th2-type inflammation by acetyl salicylic acid via the adenosine and uric acid pathway in the lung

ALLERGY, Issue 9 2010
H.-G. Moon
To cite this article: Moon H-G, Tae Y-M, Kim Y-S, Gyu Jeon S, Oh S-Y, Song Gho Y, Zhu Z, Kim Y-K. Conversion of Th17-type into Th2-type inflammation by acetyl salicylic acid via the adenosine and uric acid pathway in the lung. Allergy 2010; 65: 1093,1103. Abstract Background:, Allergen-specific T-cell responses orchestrate airway inflammation, which is a characteristic of asthma. Recent evidence suggests that noneosinophilic asthma can be developed by mixed Th1 and Th17 cell responses when exposed to lipopolysaccharide (LPS)-containing allergens. Objective:, To evaluate the therapeutic or adverse effects of acetyl salicylic acid (ASA) on the expression of Th1-type and Th17-type inflammation induced by airway exposure to LPS-containing allergens. Methods:, Th1 + Th17 asthma and Th2 asthma mouse models were generated by intranasal sensitization with ovalbumin (OVA) and LPS and intraperitoneal sensitization with OVA and alum, respectively. Therapeutic or adverse effects were evaluated after allergen challenge using pharmacologic and transgenic approaches. Results:, Lung infiltration of eosinophils was enhanced in OVA/LPS-sensitized mice by ASA treatment, which was accompanied by the enhanced production of eotaxin. These changes were associated with the down-regulation of Th17 cell response, which was partly dependent on adenosine receptor A1 and A3 subtypes, but up-regulation of allergen-specific IL-13 production from T cells. Lung inflammation induced by LPS-containing allergen was markedly reduced in IL-13-deficient mice in the context of ASA treatment, but not without ASA. Meanwhile, adenosine levels in the lung were enhanced by ASA treatment. Moreover, lung infiltration of eosinophils induced by ASA treatment was reversed by co-treatment of a xanthine oxidase inhibitor (allopurinol). Conclusion:, These findings suggest that ASA changes Th17-type into Th2-type inflammation mainly via the adenosine and uric acid metabolic pathway in the lung. [source]

Unlicensed Residential Programs: The Next Challenge in Protecting Youth

AMERICAN JOURNAL OF ORTHOPSYCHIATRY, Issue 3 2006
Robert M. Friedman
Over the past decade in the United States, the number of private residential facilities for youth has grown exponentially, and many are neither licensed as mental health programs by states, nor accredited by respected national accrediting organizations. The Alliance for the Safe, Therapeutic and Appropriate use of Residential Treatment (A START) is a multi,disciplinary group of mental health professionals and advocates that formed in response to rising concerns about reports from youth, families and journalists describing mistreatment in a number of the unregulated programs. This article summarizes the information gathered by A START regarding unregulated facilities. It provides an overview of common program features, marketing strategies and transportation options. It describes the range of mistreatment and abuse experienced by youth and families, including harsh discipline, inappropriate seclusion and restraint, substandard psychotherapeutic interventions, medical and nutritional neglect, rights violations and death. It reviews the licensing, regulatory and accrediting mechanisms associated with the protection of youth in residential programs, or the lack thereof. Finally, it outlines policy implications and provides recommendations for the protection of youth and families who pursue residential treatment. [source]

Hemospan: Design Principles for a New Class of Oxygen Therapeutic

ARTIFICIAL ORGANS, Issue 2 2009
Kim D. Vandegriff
Abstract Hemoglobin-based oxygen carriers have been under development for decades, but safety concerns have prevented commercial approval. Early designs for modified hemoglobins by polymerization or intramolecular cross-linking reactions increased molecular size and decreased oxygen affinity, but all exhibited side effects of vasoconstriction and reduced blood flow. A new strategy has been established by applying principles of oxygen transport to cell-free hemoglobin. Sangart has developed a new oxygen therapeutic, Hemospan, using site-specific, poly(ethylene) glycol conjugation chemistry designed on two principles: (i) increased macromolecular size to prolong intravascular retention time, and (ii) increased oxygen affinity to prevent premature oxygen offloading in arterioles. In contrast to early-generation products, Hemospan infusion maintains normal arteriolar vascular tone and capillary flow. Phase I and Phase II clinical trials have been completed, showing that Hemospan is well-tolerated in humans, with evidence of efficacy to impart hemodynamic stability in surgical patients under anesthesia. Phase III trials in orthopedic surgery have recently completed enrollment in Europe. [source]

Therapeutic Left Ventricular Assist Device and Apheresis on Dilated Cardiomyopathy

ARTIFICIAL ORGANS, Issue 2 2004
Yoshica Matoba
Abstract:, Pathogenesis and therapies of dilated cardiomyopathy (DCM) have been discussed for a long time, but both of the ultimate answers are still unknown. In the last decade, the pathogenic role of immunological factors, such as cardiac autoimmune antibodies and cytokines, have been discussed attentively. This has led to one possible new therapy, immunoadsorption, which removes antibodies, and it has made a remarkable effect. However, there are other factors to remove. For the removal of cytokines and neurohormones, the most effective method is hemofiltration (HF). Also, double-filtration plasmapheresis (DFPP) removes immunoglobulin as well as low-density lipoprotein (LDL) and coagulation factors that may improve blood circulation, including the coronary arteries. Therefore, to eliminate all deteriorative factors, both apheresis therapies, HF and DFPP, should be performed. Due to the shortage of donor hearts, left ventricular assist systems (LVAD) have been used as a bridge to transplantation. It has now been reported that the total unloading of the left ventricle does not only maintain, but also recovers, the cardiac function, even from end-stage heart failure. However, the patients who have obtained a long-lasting recovery of cardiac function from an LVAD are still in a minority. To make this the majority, therapeutic LVAD should be combined with the apheresis therapies, DFPP and HF. We believe that this concept, a combination of HF and DFPP with therapeutic LVAD, will be the next generation of treatment that has a potential to postpone, or even avoid, heart transplantation. [source]

Therapeutic and Analysis Model of Intrahepatic Metastasis Reflects Clinical Behavior of Hepatocellular Carcinoma

CANCER SCIENCE, Issue 2 2002
Shigeaki Sawada
This study was designed to establish an intrahepatic metastasis model to investigate the biology and therapy of hepatocellular carcinoma (HCC) in mice. A fragment of mouse HCC tumor CBO140C12 was orthotopically implanted into the mouse liver. The number of intrahepatic metastatic colonies and the volume of the implanted tumor increased in a time-dependent manner. At 28 days after fragment implantation, all mice showed intrahepatic metastasis. Intravenous administrations of cisplatin and doxorubicin at 7 and 21 days after the implantation significantly sup- pressed the growth of the primary tumor nodule, but tended to inhibit intrahepatic metastasis. However, a marked decrease of body weight was observed during the experiment. On the other hand, an inhibitor of matrix metalloproteinases (MMPs), ONO,4817, decreased the gelatinase activity of MMP,9 secreted by CBO140C12 cells, and significantly reduced the number of colonies of intrahepatic metastasis when administered orally. Our established model, which is focused on intrahepatic metastasis, is suitable for evaluating the therapeutic effect of HCC and for analyzing intrahepatic metastasis, because this model reflects the clinical features of HCC and all the steps of tumor metastasis. [source]

Enzymatic Release of a Surface-Adsorbed RGD Therapeutic from a Cleavable Peptide Anchor

CHEMMEDCHEM, Issue 11 2008
Steven
Implanted medical devices inevitably promote inflammation of the surrounding tissue. A method for enzymatically triggered localized drug delivery would have marked benefits in dealing with this response. Herein we present a rationally designed peptide coating for use with medical devices such as stents, that contains three distinct domains: 1),an implant-adsorptive sequence, 2),an enzymatically cleavable release mechanism, and 3),a therapeutic to be delivered. [source]

An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivatives

CONTRAST MEDIA & MOLECULAR IMAGING, Issue 5 2006
Valerie Humblet
Abstract The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, 99mTc chelates for SPECT, 90Y chelates for radiotherapy, 18F derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N -hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Liquid-based cytology for cervical screening

CYTOPATHOLOGY, Issue 6 2000
N. Payne
England and Wales' new National Institute for Clinical Excellence (NICE) has completed the first of its appraisals and issued guidance on a diagnostic technique rather than a therapeutic intervention.1 It was directed to examine the use of liquid-based cytology (LBC) for cervical screening and took evidence from a wide variety of sources. LBC is a new method of preparing cervical samples for cytological examination. Unlike the conventional ,smear' preparation it involves making a suspension of cells from the sample and this is used to produce a thin layer of cells on a slide. [source]

Surgical Treatment of Ingrown Toenail without Matricectomy

DERMATOLOGIC SURGERY, Issue 1 2008
BERNARD NOËL MD
BACKGROUND Partial excision of the nail matrix (matricectomy) is generally considered necessary in the surgical treatment of ingrown toenail. Recurrences may occur, however, and poor cosmetic results are frequently observed. OBJECTIVE The objective is to present a new surgical procedure for ingrown toenail with complete preservation of the nail matrix. METHODS Twenty-three patients with ingrown toenail were included in this study. The surgical excision was performed 1 week after the completion of treatment of the initial infection. A large volume of soft tissue surrounding the nail plate was removed under local anesthesia. No matrix excision was performed. RESULTS Short-term results were excellent. No recurrences or severe complications were observed during the minimum 12-months follow-up period. Cosmetic results were remarkable. CONCLUSIONS Ingrown toenail results from the compression of the lateral nail folds on the nail plate. This study shows that ingrown toenail can be surgically treated without matricectomy. A large volume of soft tissue surrounding the nail plate should be removed to decompress the nail and reduce inflammation. Cosmetic results are excellent and superior to the classical Emmert plasty. Postoperative nail dystrophies and spicule formation are not observed. The main advantage of this surgical approach is the complete preservation of the anatomy and function of the nail to improve both therapeutic and cosmetic results. [source]

Subjective quality of life aspects predict depressive symptoms over time: results from a three-wave longitudinal study

ACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009
C. Kuehner
Objective:, Little is known about predictive effects of quality of life aspects on the course of depressive symptoms in clinical and non-clinical settings. This study examines longitudinal associations between depressive symptoms and subjective quality of life (QOL) dimensions using a parallel sample of depressed patients and community controls. Method:, Eighty-two depressed patients were investigated 1, 6, and 42 months after hospital discharge together with 76 community controls regarding depressive symptoms measured by Montgomery Asberg Depression Rating Scale (MADRS) and QOL (WHOQOL-BREF). Data analysis included time-lagged linear models. Results:, Physical, psychological, environmental and overall QOL, controlled for depressive symptoms, predicted future depression levels. Group status did not moderate these associations. Depressive symptoms predicted future QOL levels only regarding social relations. Conclusion:, Our study suggests that subjective QOL domains have prognostic value for the course of depressive symptoms over time, both in patient and community samples. Respective self-perceptions should therefore be directly addressed by therapeutic and preventive interventions. [source]

Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration

DEVELOPMENTAL NEUROBIOLOGY, Issue 13 2009
J. Simon Lunn
Abstract Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu2+/Zn2+ superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source]

Thiazolidinediones and the preservation of ,-cell function, cellular proliferation and apoptosis

DIABETES OBESITY & METABOLISM, Issue 8 2008
Michael Decker
The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic ,-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic ,-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of ,-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving ,-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed. [source]

Cardiovascular metabolic syndrome , an interplay of, obesity, inflammation, diabetes and coronary heart disease

DIABETES OBESITY & METABOLISM, Issue 3 2007
J. S. Rana
Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho-physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the ,Cardiovascular Metabolic Syndrome' as an entity. [source]

Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2009
H. Jaïdane
Abstract The role of enteroviruses, in particular type B coxsackieviruses (CV-B), in type 1 diabetes (T1D) pathogenesis is supported by epidemiological, clinical and experimental observations. The investigation of T1D pathogenesis benefits from the contribution of animal models called spontaneously diabetic. Among these animals the non-obese diabetic (NOD) mouse and the bio-breeding diabetes-prone (BBDP) rat present a genetic susceptibility manifested by the expression of an autoimmune diabetes similar to the pathology observed in human beings. Other models whose genetic predisposition is less known are of considerable contribution as well. Numerous major observations relative to several aspects of T1D pathogenesis in the context of CV-B infections, such as susceptibility, diabetogenicity, pancreatotropism, mechanisms of , cells destruction and others, have been deduced thanks to investigations with animal models. Despite their limits, these models are necessary in improving our knowledge of the role of enteroviruses, like CV-B4, in the pathogenesis of T1D, and the recent advances ensuing from their contribution may have important therapeutic and preventive spin-offs. Copyright © 2009 John Wiley & Sons, Ltd. [source]

LBY135, a novel anti-DR5 agonistic antibody induces tumor cell,specific cytotoxic activity in human colon tumor cell lines and xenografts,

DRUG DEVELOPMENT RESEARCH, Issue 2 2008
Jing Li
Abstract TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis on binding to DR4 and DR5 receptors on the surface of tumor cells. These receptors are of particular interest in the development of cancer therapeutics as they preferentially mediate tumor cell apoptosis. We have generated a chimeric anti-DR5 agonistic antibody, LBY135, from its murine parental antibody, LCR211, identified using hybridoma technology. Both LCR211 and LBY135 specifically bind to DR5 with nanomolar affinity, mimic TRAIL to induce cell death in tumor cells, and have little effect on non-transformed cells in vitro. The anti-DR5 antibody reduced viability in 45% of a panel of 40 human colon cancer cell lines with IC50 values of 20,nM or less. In vivo, using human colorectal tumor xenograft mouse models, LCR211 induced tumor regression and showed enhanced efficacy when combined with 5-FU. Both in vitro evaluation of ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), and in vivo studies using a non-functional DR5 specific antibody or SCID-Beige mice, suggested ADCC and CDC are unlikely to be the mechanism to ablate tumors in vivo. LBY135 and LCR211 appear to mediate cell death and tumor regression mainly through apoptosis, as demonstrated by the activation of caspase 3, caspase 8, M30, and TUNEL assay. In addition, the discovery of synergy between cross-linked LBY135 and TRAIL not only revealed the unique epitope of LBY135, but also demonstrated an additional mechanism of action for LBY135 in vivo. LBY135 demonstrates promise as a novel therapeutic for cancer treatment and is currently in Phase I clinical trials. Drug Dev Res 69: 69,82, 2008. © 2008 Wiley-Liss, Inc. [source]

Oxidative damage of retinal pigment epithelial cells and age-related macular degeneration

DRUG DEVELOPMENT RESEARCH, Issue 5 2007
Suofu Qin
Abstract Damage to the retinal pigment epithelial (RPE) cells is an early and crucial event in the molecular pathways leading to clinically relevant age-related macular degeneration (AMD) changes. Oxidative stress, the major environmental risk factor for atrophic AMD, causes RPE injury that results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration ultimately leads to a progressive irreversible degeneration of photoreceptors. In vitro studies show that oxidant-treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during the early phase of atrophic AMD. The main target of oxidative injury appears to be mitochondria, an organelle known to accumulate genomic damage during aging. Addition of GSH, the most abundant intracellular thiol antioxidant, protects RPE cells from oxidant-induced apoptosis. Similar protection occurs with dietary enzyme inducers that increase GSH synthesis. In addition, enhancing survival signaling preserves RPE cells under oxidative stress. These results indicate that therapeutic or nutritional intervention to enhance the antioxidant capacity and survival signaling of RPE may provide an effective way to prevent or treat AMD. This review describes major molecular and cellular events leading to RPE death, and presents currently used and new experimental, forthcoming therapeutic strategies. Drug Dev Res 68:213,225, 2007. © 2007 Wiley-Liss, Inc. [source]

Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds

DRUG DEVELOPMENT RESEARCH, Issue 4 2007
Stephen Gately
Abstract The strategic replacement of carbon with silicon within biologically prevalidated drug scaffolds can generate focused libraries of pharmaceutically relevant agents with novel, durable and marketable intellectual property. This approach can be cost-effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods. The change in shape, charge, and lipophilicity that can result from the addition of silicon can favorably alter the biological activity and toxicology of the parent drug. Silicon-containing derivatives of indomethacin are COX-2 selective, suggesting they will not be associated with the classical toxicities associated with nonselective inhibition of the cyclooxygenases. The silicon-indomethacin derivatives also demonstrated superior anti-cancer activity at clinically achievable concentrations when tested in vitro against a human pancreatic cancer cell line, MiaPaCa-2, and a panel of 14 human multiple myeloma cell lines. Bioorganosilicon chemistry represents an attractive approach for emerging biopharmaceutical organizations seeking to rapidly develop a portfolio of novel pharmacological agents that have the potential for enhanced therapeutic and pharmacological benefit. Drug Dev Res 68:156,163, 2007. ©2007 Wiley-Liss, Inc. [source]

Vaccines, Viagra, and Vioxx: medicines, markets, and money,when life-saving meets life-style,

DRUG DEVELOPMENT RESEARCH, Issue 2 2005
David J. Triggle
Abstract In this Commentary, life-style drugs will be termed as "those drugs for which there is a definable and real, but limited, therapeutic need, but a need that has been significantly stimulated by the cycle of pharmaceutical company advertising and pressure and public demand." The key to the continuing expansion of the life-style drug market is a progressive narrowing of the definition of "normal" coupled with campaigns launched by the pharmaceutical industry that persuade both patients and clinicians that a major and treatable disease does exist and that drug treatment, rather than acceptance of hair loss or occasional lack of sexual interest, and so on, is both necessary and appropriate. The expansion of the market for prescription drugs in this manner is now an integral part of the business model of the pharmaceutical industry. For society, the expanding role of these drugs, particularly those directed at "desires rather than diseases," raises ethical issues of our increasing obsession with a medically directed quest for perfection, and financial issues of the cost of this quest on the health care system and its priorities. For the pharmaceutical industry, there are questions of whether its role is life-saving or life-styling for a Huxleyan "Brave New World." Drug Dev Res 64:90,98, 2005. © 2005 Wiley-Liss, Inc. [source]

,-Amyloid immunization approaches for Alzheimer's disease

DRUG DEVELOPMENT RESEARCH, Issue 2 2002
Bruno P. Imbimbo
Abstract Alzheimer's disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of efficiently combating this devastating disease. The deposition of ,-amyloid (A,) is the major pathological hallmark of AD brains. Genetic, biochemical, and pharmacological evidence support the hypothesis that A, plays a key role in the development of the disease. Thus, in the last 5 years a number of pharmacological strategies have been developed to interfere with the A, cascade. The most revolutionary of these approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against A, transgenic mice with spontaneously developing A, pathology. The immunization was achieved by subcutaneous injections of a preaggregated form of the synthetic human 42-amino acid A, emulsified with Freund's adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of A, plaque formation in younger animals and a marked reduction of the A, burden in older animals. The effects on A, plaques were accompanied by a reduction of A,-associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups with similar vaccination protocols, which also demonstrated that the A, immunization of transgenic animals normalize or reduce the cognitive impairment associated with A, pathology. Interestingly, effective removal of brain A, plaques was also obtained by peripherally administering A, antibodies. The mechanism with which the vaccine increases A, clearance is not fully understood. Centrally, the vaccine appears to activate A, phagocytosis by microglial monocytes. Peripherally, serum A, antibodies bind and sequester A,, thus altering its equilibrium between CNS and plasma. The dramatic results obtained in animal models of AD raised unprecedented hopes for both a preventive and a curative intervention for this devastating disorder. A vaccine preparation for human use (AN-1792) composed of preaggregated human A,42 peptide and a highly purified saponin derivative (QS-21) was developed by Elan Pharmaceuticals and Wyeth Ayerst and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN-1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity. Other therapeutic A, vaccination strategies are being pursued, including immuno-conjugates and monoclonal antibodies. The future of these and other A, immunization approaches depend on a clear understanding of the mechanism of A, clearance and additional insight into the role of inflammation in the AD brain. Drug Dev. Res. 56:150,162, 2002. © 2002 Wiley-Liss, Inc. [source]

Characterization of basic drug,human serum protein interactions by capillary electrophoresis

ELECTROPHORESIS, Issue 17 2006
María A. Martínez-Gómez
Abstract Drug,protein interactions are determining factors in the therapeutic, pharmacodynamic and toxicological drug properties. The affinity of drugs towards plasmatic proteins is apparently well established in bibliography. Albumin (HSA) especially binds neutral and negatively charged compounds; ,1 -acid glycoprotein,(AGP) binds many cationic drugs, lipoproteins bind to nonionic and lipophilic drugs and some anionic drugs while globulins interact inappreciably with the majority of drugs. In this paper, the characterization of the interaction between cationic drugs, ,-blockers and phenotiazines towards HSA, AGP, and both HSA + AGP mixtures of proteins under physiological conditions by CE-frontal analysis is presented. Furthermore, the binding of these drugs to all plasmatic proteins is evaluated by using ultrafiltration and CE. The results indicate that the hydrophobic character of compounds seems to be the key factor on the interaction between cationic drugs towards proteins. In fact, hydrophobic basic drugs bind in great extension to HSA, while hydrophilic basic drugs present low interactions with proteins and bind especially to AGP. [source]

Procedural sedation in children in the emergency department: A PREDICT study

EMERGENCY MEDICINE AUSTRALASIA, Issue 1 2009
Meredith Borland
Abstract Objective: To investigate current procedural sedation practice and compare clinical practice guidelines (CPG) for procedural sedation at Paediatric Research in Emergency Departments International Collaborative (PREDICT) sites. This will determine areas for improvement and provide baseline data for future multicentre studies. Methods: A questionnaire of specialist emergency physicians regarding demographics, general procedural sedation practice and specific sedation agents given to children. CPG for general sedation and sedation agents were obtained for each site. Results: Seventy-five (71%) useable surveys returned from 105 potential respondents. Most commonly used agents were nitrous oxide (N2O) (75, 100%), ketamine (total 72, 96%; i.v. 59, 83% and i.m. 22, 31%) and midazolam (total 68, 91%; i.v. 52, 81%, oral 47, 73%, intranasal 26, 41% and i.m. 6, 9%). Sedation was used for therapeutic and diagnostic procedures. Forty-three (57%) used formal sedation records and sedation checklists and thirty-one (41%) respondents reported auditing sedations. Four sites ran staff education and competency programmes. Nine sites had general sedation CPG, eight for ketamine, nine for N2O, eight for midazolam (four parenteral, five oral and six intranasal) and three for fentanyl. No site had a guideline for propofol administration. Conclusion: Procedural sedation in this research network commonly uses N2O, ketamine and midazolam for a wide range of procedures. Areas of improvement are the lack of guidelines for certain agents, documentation, staff competency training and auditing processes. Multicentre research could close gaps in terms of age cut-offs, fasting times and optimal indications for various agents. [source]

Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3,-azido-3,-deoxythymidine and 2,,3,-dideoxyinosine,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2002
Quanxin Meng
Abstract Combinations of antiretroviral drugs that include nucleoside reverse transcriptase inhibitors (NRTIs) are superior to single-agent regimens in treating or preventing HIV infection, but the potential long-term health hazards of these treatments in humans are uncertain. In earlier studies, our group found that coexposure of TK6 human lymphoblastoid cells to 3,-azido-2,,3,-dideoxythymidine (AZT) and 2,,3,-dideoxyinosine (ddI), the first two NRTIs approved by the FDA as antiretroviral drugs, produced multiplicative synergistic enhancement of DNA incorporation of AZT and mutagenic responses in both the HPRT and TK reporter genes, as compared with single-drug exposures (Meng Q et al. [2000a]: Proc Natl Acad Sci USA 97:12667,12671). The purpose of the current study was to characterize the mutational specificity of equimolar mixtures of 100 ,M or 300 ,M AZT + ddI at the HPRT and TK loci of exposed cells vs. unexposed control cells, and to compare the resulting mutational spectra data to those previously found in cells exposed to AZT alone (Sussman H et al. [1999]: Mutat Res 429:249,259; Meng Q et al. [2000b]: Toxicol Sci 54:322,329). Molecular analyses of HPRT mutant clones were performed by reverse transcription,mediated production of cDNA, PCR amplification, and cDNA sequencing to define small DNA alterations, followed by multiplex PCR amplification of genomic DNA to define the fractions of deletion events. TK mutants with complete gene deletions were distinguished by Southern blot analysis. The observed HPRT mutational categories included point mutations, microinsertions/microdeletions, splicing-error mutations, and macrodeletions including partial and complete gene deletions. The only significant difference or shift in the mutational spectra for NRTI-treated cells vs. control cells was the increase in the frequency of complete TK gene deletions following exposures (for 3 days) to 300 ,M AZT,ddI (P = 0.034, chi-square test of homogeneity); however, statistical analyses comparing the observed mutant fraction values (measured mutant frequency × percent of a class of mutation) between control and NRTI-treated cells for each class of mutation showed that the occurrences of complete gene deletions of both HPRT and TK were significantly elevated over background values (0.34 × 10,6 in HPRT and 6.0 × 10,6 in TK) at exposure levels of 100 ,M AZT,ddI (i.e., 1.94 × 10,6 in HPRT and 18.6 × 10,6 in TK) and 300 ,M AZT,ddI (i.e., 5.6 × 10,6 in HPRT and 34.6 × 10,6 in TK) (P < 0.05, Mann,Whitney U -statistic). These treatment-related increases in complete gene deletions were consistent with the spectra data for AZT alone (ibid.) and with the known mode of action of AZT and ddI as DNA chain terminators. In addition, cotreatments of ddI with AZT led to substantial absolute increases in the mutant fraction of other classes of mutations, unlike cells exposed solely to AZT [e.g., the frequency of point mutations among HPRT mutants was significantly increased by 130 and 323% over the background value (4.25 × 10,6) in cells exposed to 100 and 300 ,M AZT,ddI, respectively]. These results indicate that, at the same time that AZT,ddI potentiates therapeutic or prophylactic efficacy, the use of a second NRTI with AZT may confer a greater cancer risk, characterized by a spectrum of mutations that deviates from that produced solely by AZT. Environ. Mol. Mutagen. 39:282,295, 2002. Published 2002 Wiley-Liss, Inc. [source]

Interaction between Anticonvulsants and Human Placental Carnitine Transporter

EPILEPSIA, Issue 3 2004
Shu-Pei Wu
Summary: Purpose: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. Methods: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. Results: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 ,M)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. Conclusions: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant. [source]

Contrasting Effects of Zonisamide and Acetazolamide on Amygdaloid Kindling in Rats

EPILEPSIA, Issue 11 2001
Koichi Hamada
Summary: ,Purpose: Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy. Methods: Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18. Results: ZNS (10,40 mg/kg; n = 6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25,200 mg/kg; n = 7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50,200 mg/kg; n = 6). ZNS, 25 or 40 mg/kg (n = 8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50,200 mg/kg (n = 6), also retarded seizure development, with 14.0,14.8 stimulations required. Conclusions: ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs. [source]

Ultrasonographic examination of the caudal structures of the distal antebrachium in the horse

EQUINE VETERINARY EDUCATION, Issue 3 2010
J. S. Jorgensen
Summary Evaluation of the caudal distal antebrachium using ultrasound is a very useful diagnostic procedure for identification of soft tissue abnormalities in flexor structures of the equine limb. In this article we describe how ultrasonographic imaging may be used to complement radiography of the carpus in evaluating horses that present with peri-carpal swelling and/or lameness localised to the carpal region. Ultrasonographic examination assists with the identification or exclusion of significant injuries to muscular, tendonous and ligamentous structures within the distal antebrachium and enables practitioners to proceed with appropriate therapeutic and rehabilitation plans for the immediate benefit for their patients while also recognising pathology that could progress to cause long-term, chronic lameness issues without aggressive and effective intervention. [source]

Antimicrobial therapy for multidrug resistant pathogens

EQUINE VETERINARY EDUCATION, Issue 6 2009
J. S. Weese
Summary Multidrug resistant bacteria are tremendous causes of morbidity and mortality in human medicine, and emerging pathogens in equine medicine. A variety of organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus spp. (VRE) and multidrug resistant Acinetobacter spp., Pseudomonas spp. and Enterobacteriaceae are of concern in equine medicine. Veterinary practitioners need to be aware of key diagnostic, clinical, therapeutic, epidemiological and infection control aspects to limit the impact of these organisms on the equine, and perhaps human, population. [source]