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Clinical Drug studies

Ekkehard Grünig, Nicola Benjamin, Tobias J Lange, Ulrich Krueger, Hans Klose, Claus Neurohr, Heinrike Wilkens, Michael Halank, Hans-Jürgen Seyfarth, Matthias Held, Andrew Traube, Michelle Pernow, E Robert Grover, Benjamin Egenlauf, Felix Gerhardt, Thomas Viethen, Stephan Rosenkranz
BACKGROUND: Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. OBJECTIVES: The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. METHODS: Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study...
October 27, 2016: Respiration; International Review of Thoracic Diseases
Ju Hui Jeong, Yong Jin Oh, Yunmee Lho, Sun You Park, Kwang-Hyeon Liu, Eunyoung Ha, Young Ho Seo
The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50 = 50...
October 18, 2016: European Journal of Medicinal Chemistry
Hiroshi Kaji
Adipose tissue has recently been reevaluated as an endocrine organ, and adipose-tissue-derived endocrine factors are termed adipokines. Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of PAs, which convert plasminogen into plasmin, a critical protease involved in fibrinolysis. PAI-1 induces fibrinogenesis by suppressing intravascular and tissue fibrinolysis. Moreover, PAI-1 exerts various cellular effects independently of fibrinolysis. Although PAI-1 is expressed in various tissues, its expression is regulated by numerous growth factors, cytokines, and hormones in a paracrine and endocrine manner...
September 15, 2016: Comprehensive Physiology
Nilesh Chande, Cassandra M Townsend, Claire E Parker, John K MacDonald
BACKGROUND: The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease. OBJECTIVES: The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease...
October 26, 2016: Cochrane Database of Systematic Reviews
E L Andrade, A F Bento, J Cavalli, S K Oliveira, C S Freitas, R Marcon, R C Schwanke, J M Siqueira, J B Calixto
This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies...
October 24, 2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Athumani M Ramadhani, Tamsyn Derrick, David Macleod, Martin J Holland, Matthew J Burton
BACKGROUND: Trachoma is a blinding disease, initiated in early childhood by repeated conjunctival infection with the obligate intracellular bacterium Chlamydia trachomatis. The population prevalence of the clinical signs of active trachoma; ''follicular conjunctivitis" (TF) and/or ''intense papillary inflammation" (TI), guide programmatic decisions regarding the initiation and cessation of mass drug administration (MDA). However, the persistence of TF following resolution of infection at both the individual and population level raises concerns over the suitability of this clinical sign as a marker for C...
October 2016: PLoS Neglected Tropical Diseases
Corey A Lester, Kevin A Look, Michelle A Chui
BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) adopted the proportion of days covered (PDC) calculation for use in their Five-Star Quality Rating System for Medicare Advantage and Prescription Drug Plans. This calculation uses the prescription adjudication date (i.e., date the prescription is billed to the benefits manager by a pharmacy) as a proxy for medication adherence. Adherence programs, such as automatic refill programs, have become commonplace in community pharmacy and have been identified by industry leaders as interfering with the ability to accurately measure adherence using PDC...
November 2016: Journal of Managed Care & Specialty Pharmacy
Wendy S Bibeau, Haoda Fu, April D Taylor, Anita Y M Kwan
BACKGROUND: Medication adherence is pivotal for the successful treatment of diabetes. However, medication adherence remains a major concern, as nonadherence is associated with poor health outcomes. Studies have indicated that increasing patients' share of medication costs significantly reduces adherence. Little is known about a potential out-of-pocket (OOP) cost threshold where substantial reduction in adherence may occur. OBJECTIVE: To examine the impact of diabetes OOP pharmacy costs on antihyperglycemic medication adherence and identify the potential threshold at which significant reduction in adherence may occur among patients with type 2 diabetes mellitus (T2DM)...
November 2016: Journal of Managed Care & Specialty Pharmacy
Joanna P MacEwan, Felicia M Forma, Jason Shafrin, Ainslie Hatch, Darius N Lakdawalla, Jean-Pierre Lindenmayer
BACKGROUND: Poor medication adherence contributes to negative treatment response, symptom relapse, and hospitalizations in schizophrenia. Many health plans use claims-based measures like medication possession ratios or proportion of days covered (PDC) to measure patient adherence to antipsychotics. Classifying patients solely on the basis of a single average PDC measure, however, may mask clinically meaningful variations over time in how patients arrive at an average PDC level. OBJECTIVE: To model patterns of medication adherence evolving over time for patients with schizophrenia who initiated treatment with an oral atypical antipsychotic and, based on these patterns, to identify groups of patients with different adherence behaviors...
November 2016: Journal of Managed Care & Specialty Pharmacy
Jason Shafrin, Taylor T Schwartz, Darius N Lakdawalla, Felicia M Forma
BACKGROUND: Nonadherence to antipsychotic medication among patients with schizophrenia results in poor symptom management and increased health care and other costs. Despite its health impact, medication adherence remains difficult to accurately assess. New technologies offer the possibility of real-time patient monitoring data on adherence, which may in turn improve clinical decision making. However, the economic benefit of accurate patient drug adherence information (PDAI) has yet to be evaluated...
November 2016: Journal of Managed Care & Specialty Pharmacy
Claudiu T Supuran
The enzyme carbonic anhydrase (CA, EC is found in numerous organisms across the tree of life, with seven distinct classes known to date. CA inhibition can be exploited for the treatment of edema, glaucoma, seizures, obesity, cancer and infectious diseases. A myriad of CA inhibitor (CAI) classes and inhibition mechanisms have been identified over the past decade, mainly through structure-based drug design approaches. Five different CA inhibition mechanisms are presently known. Areas covered: Recent advances in structure-based CAI design are reviewed, with periodic table-based organization of inhibitor classes...
October 26, 2016: Expert Opinion on Drug Discovery
Ghareb M Soliman, Gihan Fetih, Ahmed M Abbas
OBJECTIVE: To develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness...
October 26, 2016: Drug Development and Industrial Pharmacy
Luis Sendra Gisbert, Antonio Miguel Matas, Luis Sabater Ortí, María José Herrero Cervera, Laura Sabater Olivas, Eva María Montalvá Orón, Matteo Frasson, Rafael Abargues López, Rafael López-Andújar, Eduardo García-Granero Ximénez, Salvador Francisco Aliño Pellicer
: Different diseases lead, during their advanced stages, to chronic or acute liver failure, whose unique treatment consists in organ transplantation. The success of intervention is limited by host immune response and graft rejection. Immunosuppressant drugs permitted improving organ transplantation but they cannot completely solve the problem and their management is delicate, especially during the early stages of treatment. Thus, new tools to set an efficient modulation of immune response are required...
October 26, 2016: Liver Transplantation
Martin Skov, Frank V de Paoli, Ole B Nielsen, Thomas H Pedersen
INTRODUCTION: In myotonia congenita, loss of ClC-1 Cl(-) -channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage gated sodium channel in skeletal muscle (Nav1.4). This study explored whether 3 sodium channel modulating anti-epileptics can reduce myotonia in isolated rat and human muscle. METHODS: Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from sub-clinical to maximal clinical concentrations...
October 26, 2016: Muscle & Nerve
F G A Silva, M F S F de Moura, N Dourado, J Xavier, F A M Pereira, J J L Morais, M I R Dias, P J Lourenço, F M Judas
Fracture characterization of human cortical bone under mode II loading was analyzed using a miniaturized version of the end-notched flexure test. A data reduction scheme based on crack equivalent concept was employed to overcome uncertainties on crack length monitoring during the test. The crack tip shear displacement was experimentally measured using digital image correlation technique to determine the cohesive law that mimics bone fracture behavior under mode II loading. The developed procedure was validated by finite element analysis using cohesive zone modeling considering a trapezoidal with bilinear softening relationship...
October 25, 2016: Medical & Biological Engineering & Computing
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
Takuya Hirai, Keigo Ikeda, Maki Fujishiro, Hiroshi Tsushima, Kunihiro Hayakawa, Satoshi Suzuki, Ayako Yamaguchi, Kazuhisa Nozawa, Shinji Morimoto, Yoshinari Takasaki, Hideoki Ogawa, Kenji Takamori, Naoto Tamura, Iwao Sekigawa
The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy...
October 25, 2016: Clinical Rheumatology
Salem A Beshyah, Ibrahim H Sherif, Farida Chentli, Amir Hamrahian, Aly B Khalil, Hussein Raef, Mohamed El-Fikki, Selim Jambart
BACKGROUND: Prolactinomas are the commonest functional tumors of the pituitary gland. There are still controversies regarding medical therapy in specific clinical situations. Patients may be managed by different specialists in the Middle East and North Africa (MENA) region and no data exist on patterns of clinical management. OBJECTIVES: To ascertain the diagnostic and therapeutic approaches to prolactinomas among relevant professionals from the MENA region. METHODS: An online survey of a large sample of physicians was conducted...
October 25, 2016: Pituitary
Kaname Miyashita, Kei Fujii, Kenichi Taguchi, Mototsugu Shimokawa, Mitsuaki A Yoshida, Yasunobu Abe, Jun Okamura, Shinya Oda, Naokuni Uike
PURPOSE: Microsatellite instability (MSI) has been a long-standing biomarker candidate for drug resistance in tumour cells. Despite numerous clinical studies, the data in the literature are not conclusive. The complexity of the MSI phenomenon in some malignancies may, at least partly, account for the discrepancy. In addition, methodological problems are also pointed out in the assay techniques. We previously established a unique fluorescent technique in which the major methodological problems in conventional assays are overcome...
October 25, 2016: Journal of Cancer Research and Clinical Oncology
Thilini Piushani Keerthirathne, Dhammika Nayoma Magana-Arachchi, Dushantha Madegedara, Suneth Sithumini Sooriyapathirana
BACKGROUND: Mycobacteria have a spectrum of virulence and different susceptibilities to antibiotics. Distinguishing mycobacterial species is vital as patients with non-tuberculous mycobacterial (NTM) infections present clinical features that are similar to those of patients with tuberculosis. Thus, rapid differentiation of Mycobacterium tuberculosis complex from NTM is critical to administer appropriate treatment. Hence the aim of the study was to rapid identification of mycobacterial species present in bronchial washings using multiplex real time Polymerase Chain Reaction (PCR) and to determine the drug susceptibility in identified mycobacterial species...
October 26, 2016: BMC Infectious Diseases
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