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Crumlish M.,University of Stirling | Thanh P.C.,Bayer | Koesling J.,Bayer | Tung V.T.,Bayer | Gravningen K.,PHARMAQ AS
Journal of Fish Diseases | Year: 2010

The two main diseases in the pangasius catfish industry are bacillary necrosis of Pangasianodon (BNP) and motile aeromonas septicaemia (MAS), where the aetiological agents have been identified as Edwardsiella ictaluri and Aeromonas hydrophila, respectively. In this study, apparently healthy Pangasianodon hypophthalmus were exposed to E. ictaluri, A. hydrophila or both bacterial species by intraperitoneal injection or immersion. There were 20 fish per treatment group, and the bacterial isolates used for the study were recovered from natural infections of BNP or MAS in farmed Vietnamese P. hypophthalmus. The results of the experimental infections mimicked the natural disease outbreaks reported from these pathogens in P. hypophthalmus. Furthermore, it was clearly demonstrated that E. ictaluri was only recovered from the fish exposed to the bacterium and not recovered from the animals receiving A. hydrophila. © 2010 Blackwell Publishing Ltd.

Gheorghiade M.,Northwestern University | Greene S.J.,Duke University | Butler J.,State University of New York at Stony Brook | Filippatos G.,National and Kapodistrian University of Athens | And 10 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS Dose-finding phase 2 study that randomized 456 patients acrossEurope,North America,andAsiabetweenNovember2013andJanuary2015, with follow-up ending June 2015. Patientswere clinically stable with LVEF less than 45%within 4weeks of a worseningchronicHFevent, defined asworseningsignsandsymptomsofcongestionandelevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25mg [n = 91], 2.5mg [n = 91], 5mg [n = 91], 10mg [n = 91]) for 12 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas change from baseline toweek 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. RESULTS Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2%and 71.4% among the placebo and 10-mg vericiguat groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. Copyright 2015 American Medical Association. All rights reserved.

PubMed | Chinese National Center for Safety Evaluation for Drugs, Wyss Institute for Biologically Inspired Engineering, Massachusetts Institute of Technology, ETH Zurich and 21 more.
Type: Journal Article | Journal: ALTEX | Year: 2016

The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently. Thirty-six experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted. Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale.

Christiansen N.,Medical University of South Carolina | Chen L.,Bayer | Gilmore J.,Georgia Cancer Specialists | Pechar D.,Phase Five Communications | Szabo S.,Georgia Cancer Specialists
Clinical Breast Cancer | Year: 2012

Introduction: The objective of this study was to evaluate, in a real-world context, the impact of race on disease recurrence and survival in patients with nonmetastatic triple-negative breast cancer (TNBC) treated with adjuvant chemotherapy. Patients and Methods: The study selected patients from the 2003-2008 Georgia Cancer Specialist Database with stage I-III confirmed TNBC who had received adjuvant chemotherapy. These patients were followed-up from initial diagnosis to death, cancer recurrence, or loss to follow-up. The primary outcome was disease-free survival (DFS). Kaplan-Meier curves compared DFS and recurrence between African American and non-African American groups. The impact of African American status was examined further through multivariate Cox models by adjusting for age, comorbidity, body mass index (BMI), smoking status, initial TNBC stage, surgery, and radiation therapy. Results: Among 209 patients with TNBC, 89 (42.6%) were African American. The 2 groups (African American vs. non-African American) were similar in mean age at diagnosis (53.2 vs. 54.4 years; P =.487) and with surgery and radiation rates (98.9% vs. 100%; P =.244; 68.5% vs. 62.5%; P =.365, respectively). Compared with non-African Americans, African American patients had a higher BMI (30.4 vs. 28.6 kg/m2; P =.0477) and were less likely to be diagnosed at stage I (31.5% vs. 51.7%; P =.0107). The African American patients had a lower 5-year DFS rate (45.2% vs. 79.7%; P =.0005) and a higher 5-year recurrence rate (42.5% vs. 7.0%; P =.0005) compared with the non-African American patients. Conclusions: Among patients with TNBC treated with adjuvant chemotherapy, African American race was associated with a worse outcome irrespective of later stage at presentation or higher BMI. © 2012 Elsevier Inc.

Greenberg B.M.,EMD Serono, Inc. | Khatri B.O.,Bayer | Kramer J.F.,Bayer
CONTINUUM Lifelong Learning in Neurology | Year: 2010

For a disease whose cause remains elusive, there has been a paradoxical growth in multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs forMS were brought to market. All of these disease-modifying therapies (DMTs) have shown a beneficial effect in reducing the number of exacerbations in double-blind placebocontrolled trials, and three drugs (subcutaneous [SC]/IMinterferon beta-1a, natalizumab) have been shown to reduce relapses, decrease MRI activity, and reduce the risk of sustained disability after 2 years of treatment. No controlled studies exist to show longterm benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies continue to play a role in the management of patients who fail to respond to immunomodulatory agents. These agents, however, have shownmixed data in terms of efficacy and put patients at higher risk for the development of secondary cancers. Plasma exchange for severe relapses not responsive to corticosteroid therapy has regained interest in the past few years. Furthermore, six new agents that will dramatically impact our ability to prevent disability in patients with MS are in late-stage or have completed phase 3 clinical development. Determining the risk-benefit calculations that we will need to employ toward these new drugs and the algorithms for switching therapies will be critical issues in the next 5 years. This article highlights the clinical efficacy of the current DMTs/ISDs and discusses the current treatment options for clinically isolated syndrome, relapsing-remitting MS (RRMS), and exacerbations of RRMS. It also addresses the management of a suboptimal response to the DMTs; discusses the challenge of primary progressive MS; and presents an overview of emerging therapeutic options.

Mishra D.,Bayer | Vishnupriya M.R.,CSIR - Central Electrochemical Research Institute | Anil M.G.,CSIR - Central Electrochemical Research Institute | Konda K.,Bayer | And 2 more authors.
PLoS ONE | Year: 2013

A number of rice resistance genes, called Xa genes, have been identified that confer resistance against various strains of Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight. An understanding of pathotype diversity within the target pathogen population is required for identifying the Xa genes that are to be deployed for development of resistant rice cultivars. Among 1024 isolates of Xoo collected from 20 different states of India, 11 major pathotypes were distinguished based on their reaction towards ten Xa genes (Xa1, Xa3, Xa4, xa5, Xa7, xa8, Xa10, Xa11, xa13, Xa21). Isolates belonging to pathotype III showing incompatible interaction towards xa8, xa13 and Xa21 and compatible interaction towards the rest of Xa genes formed the most frequent (41%) and widely distributed pathotype. The vast majority of the assayed Xoo isolates were incompatible with one or more Xa genes. Exceptionally, the isolates of pathotype XI were virulent on all Xa genes, but have restricted distribution. Considering the individual R-genes, Xa21 appeared as the most broadly effective, conferring resistance against 88% of the isolates, followed in decreasing order by xa13 (84%), xa8 (64%), xa5 (30%), Xa7 (17%) and Xa4 (14%). Fifty isolates representing all the eleven pathotypes were analyzed by southern hybridization to determine their genetic relatedness using the IS1112 repeat element of Xoo. Isolates belonging to pathotype XI were the most divergent. The results suggest that one RFLP haplotype that is widely distributed all over India and is represented in strains from five different pathotypes might be an ancestral haplotype. A rice line with xa5, xa13 and Xa21 resistance genes is resistant to all strains, including those belonging to pathotype XI. This three gene combination appears to be the most suitable Xa gene combination to be deployed in Indian rice cultivars. © 2013 Mishra et al.

Markowitz C.,Bayer
CONTINUUM Lifelong Learning in Neurology | Year: 2010

Despite the important advances being made in disease-modifying multiple sclerosis (MS) therapies, patients are often affected by a wide variety of symptoms caused by neurologic injury in MS. Common symptoms that patients with MS experience during the course of their illness include weakness, ambulatory impairment, sensory disturbances that may be unpleasant or even painful, ataxia and tremor, bladder and bowel dysfunction, sexual dysfunction, fatigue, spasticity, vertigo, depression and other psychiatric symptoms, cognitive impairment, and paroxysmal symptoms such as cramps, spasms, Lhermitte symptom, and Uhthoff phenomenon. These MS symptoms can cause loss of vocation and social isolation. Neurologic care of patients with MS often involves a greater degree of management of the symptoms caused by MS than appropriate prescription of disease-modifying treatments. In addition, many of the disease-modifying therapies have unpleasant side effects that may also require treatment. This article will focus on medical treatments, use of rehabilitation medicine, and, in select cases, surgical interventions for management of MS symptoms.

Crabtree-Hartman E.,Bayer
CONTINUUM Lifelong Learning in Neurology | Year: 2010

Sex and sex hormones affect the CNS and the immune system differentially, and thus a sexual dimorphism may be anticipated across arenas in multiple sclerosis (MS). Information from the past few decades has elucidated the impact of sex on broad aspects of MS, such as susceptibility, disease course, and radiologic phenotypes. Specific concerns regarding family planning and managing reproductive issues influenced by MS are likely to arise, given the typical age of onset during reproductive years. Thus, information regarding reproductive health in male and female patients with MS can potentiate the role of the neurologist in the management of these important aspects of clinical care.

Schafer K.,University of California at San Diego | de Santi S.,Bayer | de Santi S.,New York University | Schneider L.S.,University of Southern California
Current Alzheimer Research | Year: 2011

The Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) is the most widely used cognitive outcome measure in AD trials. Although errors in administration and scoring have been suggested as factors masking accurate estimates and potential effects of treatments, there have been few formal examinations of errors with the ADAS-cog. Methods: We provided ADAS-cog administration training using standard methods to raters who were designated as experienced, potential raters by sponsors or contract research organizations for two clinical trials. Training included 1 hour sessions on test administration, scoring, question periods, and required that raters individually view and score a model ADAS-cog administration. Raters scores were compared to the criterion scores established for the model administration. Results: A total of 108 errors were made by 80.6% of the 72 raters; 37.5% made 1 error, 25.0% made 2 errors and 18.0% made 3 or more. Errors were made in all ADAS-cog subsections. The most common were in word finding difficulty (67% of the raters), word recognition (22%), and orientation (22%). For the raters who made 1, 2, or> 3 errors the ADAS-cog score was 17.5 (95% CI, 17.3 - 17.8), 17.8 (17.0 - 18.5), and 18.8 (17.6 - 20.0), respectively, and compared to the criterion score, 18.3. ADAS-cog means differed significantly and the variances were more than twice as large between those who made errors on word finding and those who did not, 17.6 (SD=1.4) vs. 18.8 (SD=0.9), respectively (x = 37.2, P <.001). Conclusions: Most experienced raters made at least one error that may affect ADAS-cog scores and clinical trials outcomes. These errors may undermine detection of medication effects by contributing both to a biased point estimate and increased variance of the outcome. © 2011 Bentham Science Publishers Ltd.

Alemanni M.,Bayer S.p.A. | Gatoulis S.C.,Bayer | Voelker M.,Bayer
Minerva Medica | Year: 2016

BACKGROUND: We wanted to compare the dissolution profile of several over-the-counter analgesics to understand whether the different formulation techniques employed to enhance absorption were associated with variations in the dissolution rate, a parameter known to affect drug absorption. METHODS: We considered 5 formulations currently marketed in Italy: aspirin tablets (Aspirina Dolore e Infiammazione ®), ibuprofen tablets and liquid capsules (Moment®), ibuprofen lysine tablets (Nurofenimmedia®) and dexketoprofen trometamol tablets (Enantyum®). Dissolution tests were performed according to the current USP/NF monograph dissolution procedure. Drug dissolution was evaluated at 1, 3, 6, 15, and 30 minutes since the start of the test. Dissolution was evaluated at three different pH: 1.2, 4.5 and 6.8. Every test was repeated 12 times. RESULTS: The aspirin formulation was by far the most rapid dissolving formulation, among those tested, with more than 80% of the tablet dissolved at 6 minutes for every pH considered. At pH 1.2 and 4.5, only the dexketoprofen formulation was able to reach the dissolution level of aspirin at 30 minutes, but had lower levels of dissolution at the previous time points. Instead, at pH 6.8, most of the formulations approached aspirin dissolution level, but only after 15 minutes. Ibuprofen capsules had the slowest kinetics, with a lag phase the first 6 minutes. CONCLUSIONS: Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia. © 2016 edizioni minerva medica.

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