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  Subjects -> BIOLOGY (Total: 2982 journals)
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BIOLOGY (1420 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 18)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Biologica Colombiana     Open Access   (Followers: 6)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 25)
Acta Biotheoretica     Hybrid Journal   (Followers: 5)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 9)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Bioinformatics     Open Access   (Followers: 18)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 8)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 6)
Advances in Cell Biology     Open Access   (Followers: 23)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39)
Advances in Ecology     Open Access   (Followers: 13)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12)
Advances in High Energy Physics     Open Access   (Followers: 20)
Advances in Human Biology     Open Access  
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 4)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 7)
Aging Cell     Open Access   (Followers: 9)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Full-text available via subscription   (Followers: 13)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 22)
AJP Lung Cellular and Molecular Physiology     Full-text available via subscription   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 12)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 10)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Biostatistics     Open Access   (Followers: 9)
American Journal of Human Biology     Hybrid Journal   (Followers: 12)
American Journal of Medical and Biological Research     Open Access   (Followers: 5)
American Journal of Plant Sciences     Open Access   (Followers: 20)
American Journal of Primatology     Hybrid Journal   (Followers: 14)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 63)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 7)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
Annales de Limnologie - International Journal of Limnology     Hybrid Journal   (Followers: 1)
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3)
Annales UMCS, Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 8)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 4)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 17)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 37)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 18)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 23)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 8)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 9)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 22)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 4)
Aquatic Ecology     Hybrid Journal   (Followers: 30)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 13)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Microbiology     Hybrid Journal   (Followers: 8)
Archives of Natural History     Hybrid Journal   (Followers: 7)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 2)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 1)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Nematology     Open Access   (Followers: 3)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 5)
Autophagy     Hybrid Journal   (Followers: 2)
Avian Biology Research     Full-text available via subscription   (Followers: 3)
Avian Conservation and Ecology     Open Access   (Followers: 7)
Bacteriology Journal     Open Access   (Followers: 2)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
Biochemistry and Cell Biology     Full-text available via subscription   (Followers: 14)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal   (Followers: 1)
Biodiversidad Colombia     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity and Natural History     Open Access   (Followers: 5)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access  
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 3)
Biogeosciences (BG)     Open Access   (Followers: 9)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 233)
Bioinformatics and Biology Insights     Open Access   (Followers: 14)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 6)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 4)
Biological Control     Hybrid Journal   (Followers: 5)
Biological Invasions     Hybrid Journal   (Followers: 16)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 14)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 41)
Biological Psychology     Hybrid Journal   (Followers: 6)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 1)
Biological Trace Element Research     Hybrid Journal  
Biologicals     Full-text available via subscription   (Followers: 9)
Biologics: Targets & Therapy     Open Access   (Followers: 1)
Biologie Aujourd'hui     Full-text available via subscription  
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 44)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 16)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 7)
Biology Letters     Full-text available via subscription   (Followers: 35)
Biology Methods and Protocols     Hybrid Journal  

        1 2 3 4 5 6 7 8 | Last

Journal Cover AAPS Journal
  [SJR: 1.192]   [H-I: 74]   [18 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1550-7416
   Published by Springer-Verlag Homepage  [2329 journals]
  • A Proposal to Redefine Clinical Immunogenicity Assessment
    • Authors: Daniel T. Mytych; M. Benjamin Hock; Mark Kroenke; Vibha Jawa; Arunan Kaliyaperumal; Yanchen Zhou
      Pages: 599 - 602
      Abstract: Abstract With more than 100 therapeutic proteins (TP) approved since the first EMA guidance on immunogenicity in 2007, a vast amount of clinical experience with a variety of therapeutic proteins has been gained. This has provided data on anti-drug antibodies (ADA) and their observed clinical impact, or lack thereof. It has become evident that not all ADA responses are clinically relevant. The current “standard practice” is to test for ADA in all patients on every study. It is essential that we acknowledge the immunogenicity data gained from marketed TPs and that options for immunogenicity testing reflect this information. Improvements in bioanalytical support throughout the drug development process will eliminate extraneous, non-impactful practices. We propose that low-risk therapeutic proteins could be supported with an event-driven (“collect-and-hold”) immunogenicity testing strategy throughout early phases of the clinical program. In the absence of an event, only pivotal studies (where ADA incidence and impact can be decisively assessed) would include default ADA testing. In keeping with the “standard practice,” immunogenicity risk assessment must be an on-going and real-time evaluation. This approach has the potential to deliver meaningful, clinically relevant immunogenicity results while maintaining an emphasis on patient safety.
      PubDate: 2017-05-01
      DOI: 10.1208/s12248-017-0059-7
      Issue No: Vol. 19, No. 3 (2017)
       
  • Identifying Metabolites of Meclonazepam by High-Resolution Mass
           Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and
           Authentic Urine Samples
    • Authors: Svante Vikingsson; Ariane Wohlfarth; Mikael Andersson; Henrik Gréen; Markus Roman; Martin Josefsson; Fredrik C Kugelberg; Robert Kronstrand
      Pages: 736 - 742
      Abstract: Abstract Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amount of amino-meclonazepam produced increased 140 times. This study comprehensively elucidated meclonazepam metabolism and also illustrates that careful selection of in vitro model systems for drug metabolism is needed, always taking into account the expected metabolism of the tested drug.
      PubDate: 2017-05-01
      DOI: 10.1208/s12248-016-0040-x
      Issue No: Vol. 19, No. 3 (2017)
       
  • Erratum to: Reliable Rate Measurements for Active and Passive Hepatic
           Uptake Using Plated Human Hepatocytes
    • Authors: Yi-an Bi; Renato J. Scialis; Sarah Lazzaro; Sumathy Mathialagan; Emi Kimoto; Julie Keefer; Hui Zhang; Anna M. Vildhede; Chester Costales; A. David Rodrigues; Larry M. Tremaine; Manthena V. S. Varma
      Pages: 882 - 882
      PubDate: 2017-05-01
      DOI: 10.1208/s12248-017-0061-0
      Issue No: Vol. 19, No. 3 (2017)
       
  • Breaking Bad: the Structure and Function of the Blood-Brain Barrier in
           Epilepsy
    • Authors: Hadas Han; Aniv Mann; Dana Ekstein; Sara Eyal
      Abstract: Abstract Epilepsy is a neurological disease with variable etiology and clinical manifestation, affecting more than 50 million people worldwide. Although the ultimate precipitators of seizures are neurons, it is becoming evident that epileptic activity is associated with changes in the function of other cell types, including those consisting the blood-brain barrier (BBB) and regulating its permeability. The interrelationships between impaired BBB function and epilepsy are complex, as BBB dysfunction may both lead to seizures and be induced by epileptic activity. In this article, we review alterations in key BBB properties that have been found in patients with epilepsy and in animal models of the disease. We highlight emerging biomarkers for individualized treatment, implications for pharmacotherapy, and potential BBB-related targets for drug development.
      PubDate: 2017-05-26
      DOI: 10.1208/s12248-017-0096-2
       
  • QSP Toolbox: Computational Implementation of Integrated Workflow
           Components for Deploying Multi-Scale Mechanistic Models
    • Authors: Yougan Cheng; Craig J. Thalhauser; Shepard Smithline; Jyotsna Pagidala; Marko Miladinov; Heather E. Vezina; Manish Gupta; Tarek A. Leil; Brian J. Schmidt
      Abstract: Abstract Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations. Commonly accepted modeling strategies, workflows, and tools have promise to greatly improve the efficiency of QSP methods and improve productivity. In this paper, we present the QSP Toolbox, a set of functions, structure array conventions, and class definitions that computationally implement critical elements of QSP workflows including data integration, model calibration, and variability exploration. We present the application of the toolbox to an ordinary differential equations-based model for antibody drug conjugates. As opposed to a single stepwise reference model calibration, the toolbox also facilitates simultaneous parameter optimization and variation across multiple in vitro, in vivo, and clinical assays to more comprehensively generate alternate mechanistic hypotheses that are in quantitative agreement with available data. The toolbox also includes scripts for developing and applying virtual populations to mechanistic exploration of biomarkers and efficacy. We anticipate that the QSP Toolbox will be a useful resource that will facilitate implementation, evaluation, and sharing of new methodologies in a common framework that will greatly benefit the community.
      PubDate: 2017-05-24
      DOI: 10.1208/s12248-017-0100-x
       
  • Ultra-Sensitive Measurement of IL-17A and IL-17F in Psoriasis Patient
           Serum and Skin
    • Authors: Catherine Soderstrom; Gabriel Berstein; Weidong Zhang; Hernan Valdez; Lori Fitz; Max Kuhn; Stephanie Fraser
      Abstract: Abstract Interleukin 17 is a family of cytokines that play a central role in many autoimmune and inflammatory diseases. IL-17A has been implicated as a key driver of psoriasis, mediating a chronic cycle of T-cell activation, keratinocyte proliferation and angiogenesis. It has been hypothesized that expression of IL-17A and the related cytokine IL-17F could be used as predictive biomarkers for therapeutic response, though they have been difficult to measure locally or in circulation because of their low abundance. We developed ultrasensitive methods for measuring IL-17A and IL-17F in human serum samples and found that serum from psoriasis patients had higher and a broader range of concentrations of both IL-17 proteins compared to healthy volunteers. We also adapted these methods for tissue biopsies and saw higher concentrations of both IL-17 proteins in psoriatic lesions, but they were undetectable in non-lesional skin from the same patients.
      PubDate: 2017-05-22
      DOI: 10.1208/s12248-017-0094-4
       
  • Development and Characterization of a Neutralizing Anti-idiotype Antibody
           Against Mirvetuximab for Analysis of Clinical Samples
    • Authors: Sven Loebrich; Mingfang Shen; Erika Cohen; Gillian Payne; Ying Chen; Megan Bogalhas; Yiwei Zhao
      Abstract: Abstract Antibody-drug-conjugates (ADCs) are an emerging class of biological therapeutics. Mirvetuximab soravtansine is a novel folate receptor alpha (FRα)-targeting ADC which represents a potential new treatment for patients with ovarian and other FRα-positive cancers. Since patient immune responses to biological therapeutics may negatively affect drug efficacy and patient safety, regulatory authorities require rigorous monitoring of patient samples. Taking advantage of the immune system’s ability to generate highly specific antibodies, the field has turned to anti-idiotype antibodies as powerful tools for the development of sensitive and specific bioassays. Here, we report the generation and characterization of a highly specific neutralizing anti-idiotype antibody directed against M9346A, the antibody moiety of mirvetuximab soravtansine. The anti-idiotype antibody recognizes M9346A with double-digit picomolar affinity, competes with folate receptor antigen for binding to M9346A, and can be used to develop both anti-drug-antibody and neutralizing antibody assays.
      PubDate: 2017-05-22
      DOI: 10.1208/s12248-017-0098-0
       
  • Incorporation of the Time-Varying Postprandial Increase in Splanchnic
           Blood Flow into a PBPK Model to Predict the Effect of Food on the
           Pharmacokinetics of Orally Administered High-Extraction Drugs
    • Authors: Rachel H. Rose; David B. Turner; Sibylle Neuhoff; Masoud Jamei
      Abstract: ABSTRACT Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals. This was integrated within a PBPK model and used to predict the contribution of increased splanchnic blood flow to the observed food effect for two orally administered high-extraction drugs, propranolol and ibrutinib. The model predicted geometric mean fed/fasted AUC and C max ratios of 1.24 and 1.29 for propranolol, which were within the range of published values (within 1.0–1.8-fold of values from eight clinical studies). For ibrutinib, the predicted geometric mean fed/fasted AUC and C max ratios were 2.0 and 1.84, respectively, which was within 1.1-fold of the reported fed/fasted AUC ratio but underestimated the reported C max ratio by up to 1.9-fold. For both drugs, the interindividual variability in fed/fasted AUC and C max ratios was underpredicted. This suggests that the postprandial change in splanchnic blood flow is a major mechanism of the food effect for propranolol and ibrutinib but is insufficient to fully explain the observations. The proposed model is anticipated to improve the prediction of food effect for high-extraction drugs, but should be considered with other mechanisms.
      PubDate: 2017-05-19
      DOI: 10.1208/s12248-017-0099-z
       
  • Distribution of Exogenous and Endogenous CYP3A Markers and Related Factors
           in Healthy Males and Females
    • Authors: Jieon Lee; Andrew HyoungJin Kim; SoJeong Yi; SeungHwan Lee; Seo Hyun Yoon; Kyung-Sang Yu; In-Jin Jang; Joo-Youn Cho
      Abstract: Abstract Cytochrome P450 (CYP) 3A is an important drug-metabolizing enzyme in humans. Assessing CYP3A activity is necessary for predicting therapeutic outcomes or the potential adverse events of various therapeutics. This study sought to evaluate the distribution of endogenous and exogenous markers reflecting hepatic CYP3A activity and related factors affecting its activity in healthy male and female. Each subject was given a single 1 mg dose of midazolam intravenously. Pharmacokinetics, pharmacometabolomics, and pharmacogenomics analyses were performed to evaluate CYP3A activity. Urinary and plasma steroids were quantified with gas chromatography coupled with triple-quadrupole mass spectrometry (GC-MS), and the concentrations of midazolam and its metabolites were quantified with liquid chromatography coupled with electrospray tandem mass spectrometry (LC-MS/MS). A total of 100 subjects completed this study. Midazolam clearance (MDZ CL) and the metabolic ratio (MDZ MR) were significantly correlated with 6β-OH-cortisol/cortisol and 6β-OH-cortisone/cortisone. MDZ CL, 6β-OH-cortisol/cortisol, and 6β-OH-cortisone/cortisone decreased with increasing age (Pearson r = −0.333, −0.329, and −0.528, respectively; P < 0.05). When the markers were compared according to sex, MDZ CL and 6β-OH-cortisol/cortisol showed significant difference between sexes. However, MDZ CL was higher in female group than male group and 6β-OH-cortisol/cortisol was higher in male group than female group. No significant differences in markers were found when comparing progesterone levels. Our results indicate that both exogenous and endogenous markers showed decreased CYP3A activity with increasing age, which suggested that age could be a factor that significantly influences CYP3A activity.
      PubDate: 2017-05-18
      DOI: 10.1208/s12248-017-0090-8
       
  • Evolution of Choice of Solubility and Dissolution Media After Two Decades
           of Biopharmaceutical Classification System
    • Authors: Nadia Bou-Chacra; Katherine Jasmine Curo Melo; Ivan Andrés Cordova Morales; Erika S. Stippler; Filippos Kesisoglou; Mehran Yazdanian; Raimar Löbenberg
      Abstract: Abstract The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance’s solubility or a drug product’s in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today’s different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.
      PubDate: 2017-05-17
      DOI: 10.1208/s12248-017-0085-5
       
  • Mechanistic Modeling of the Pharmacodynamic and Pharmacokinetic
           Relationship of Tissue Factor Pathway Inhibitor-Neutralizing Antibody (BAY
           1093884) in Cynomolgus Monkeys
    • Authors: Jian-Ming Gu; Xiao-Yan Zhao; Thomas Schwarz; Joachim Schuhmacher; Andreas Baumann; Elena Ho; Babu Subramanyan; Kathy Tran; Timothy Myles; Chandra Patel; Maria Koellnberger
      Abstract: Abstract BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively. The BAY 1093884 pharmacokinetic (PK) profile and its PD effects on dPT and free TFPI levels were assessed after intravenous and subcutaneous administration of BAY 1093884 (5 and 20 mg/kg) to female cynomolgus monkeys. Free TFPI concentrations in plasma decreased rapidly and increased to baseline in a dose-dependent manner. dPT clotting time was shortened and correlated with free TFPI levels and drug concentration in plasma, demonstrating the relationship between PD activities (dPT clotting time and free TFPI levels) and drug concentration. BAY 1093884 exhibited nonlinear PK, and a target-mediated drug disposition model was used to characterize the BAY 1093884 versus TFPI concentration–response relationship. We concluded that a mechanism-based PK/PD binding model could be useful for predicting human response to BAY 1093884. For the first-in-human study, measurement of free TFPI will be included as part of the dose-escalation design.
      PubDate: 2017-05-17
      DOI: 10.1208/s12248-017-0086-4
       
  • Controlled Ion Release from Novel Polyester/Ceramic Composites Enhances
           Osteoinductivity
    • Authors: Soheila Ali Akbari Ghavimi; Rama Rao Tata; Andrew J. Greenwald; Brittany N. Allen; David A. Grant; Sheila A. Grant; Mark W. Lee; Bret D. Ulery
      Abstract: Abstract Due to the growing number of patients suffering from musculoskeletal defects and the limited supply of and sub-optimal outcomes associated with biological graft materials, novel biomaterials must be created that can function as graft substitutes. For bone regeneration, composite materials that mimic the organic and inorganic phases of natural bone can provide cues which expedite and enhance endogenous repair. Specifically, recent research has shown that calcium and phosphate ions are inherently osteoinductive, so controllably delivering their release holds significant promise for this field. In this study, unique aliphatic polyesters were synthesized and complexed with a rapidly decomposing ceramic (monobasic calcium phosphate, MCP) yielding novel polymer/ceramic composite biomaterials. It was discovered that the fast dissolution and rapid burst release of ions from MCP could be modulated depending on polymer length and chemistry. Also, controlled ion release was found to moderate solution pH associated with polyester degradation. When composite biomaterials were incubated with mesenchymal stems cells (MSCs) they were found to better facilitate osteogenic differentiation than the individual components as evidenced by increased alkaline phosphate expression and more rapid mineralization. These results indicate that controlling calcium and phosphate ion release via a polyester matrix is a promising approach for bone regenerative engineering.
      PubDate: 2017-05-11
      DOI: 10.1208/s12248-017-0072-x
       
  • Erratum to: Microdialysis: the Key to Physiologically Based Model
           Prediction of Human CNS Target Site Concentrations
    • Authors: Yumi Yamamoto; Meindert Danhof; Elizabeth C. M. de Lange
      PubDate: 2017-05-09
      DOI: 10.1208/s12248-017-0080-x
       
  • Characterization of Apolipoprotein C3 (Apo C3) LNA/DNA Impurities and
           Degradation Products by LC-MS/MS
    • Authors: Olga V. Friese; Justin B. Sperry; Yan He; Liji Joseph; James A. Carroll; Jason C. Rouse
      Abstract: ABSTRACT Apolipoprotein C3 (Apo C3) LNA/DNA gapmer was evaluated under various stress and formulation conditions for the purpose of its development as a potential biotherapeutic for low density lipoprotein (LDL) lowering. Using ion-pairing (IP) reversed-phase (RP) liquid chromatography ultra-high resolution (UHR) tandem mass spectrometry (IP-RPLC-MS/MS), a combination of accurate mass measurements and collision-induced dissociation enabled in-depth characterization of Apo C3 LNA/DNA oligonucleotide, in particular the inherent impurities following synthesis and degradation products after exposure to stress conditions. In this study, oligonucleotide samples were stressed under different pH and UV exposure conditions. The primary impurities in Apo C3 LNA/DNA were losses of nucleotide moieties from both the 5′- and 3′-terminus leading to n-1, n-2, etc. species. Desulfurization and depurination were observed in Apo C3 LNA/DNA after a week under UV light stress conditions at low pH. Guanine oxidation and dimerization were the primary degradation products detected under UV light exposure for 1 week at high pH. The effect of antioxidants on the levels of these degradation products was evaluated under neutral pH conditions. In the presence of all antioxidants, levels of guanine oxidation and desulfurization under tested conditions were the same as those in the unstressed sample, except for sodium ascorbate. The thorough understanding of the Apo C3 LNA/DNA oligonucleotide structure, its impurities, and degradation products laid the foundation for the successful formulation development of this novel biotherapeutic modality.
      PubDate: 2017-05-09
      DOI: 10.1208/s12248-017-0088-2
       
  • Controlled Release of Second Generation mTOR Inhibitors to Restrain
           Inflammation in Primary Immune Cells
    • Authors: Emily A. Gosselin; Lisa H. Tostanoski; Christopher M. Jewell
      Abstract: Abstract Autoimmune disease occurs when the immune system incorrectly targets the body’s own tissue. Inflammatory CD4+ T cell phenotypes, such as TH1 and TH17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin—a key inhibitor of the mTOR pathway—can skew T cell development, moving T cell responses away from inflammatory phenotypes and toward regulatory T cells (TREGS). TREGS are important in inducing and maintaining tolerance to self-antigens, creating new potential to treat autoimmune diseases more effectively and specifically. Next generation analogs of rapamycin, such as everolimus and temsirolimus, confer increased potency with reduced toxicity, but are understudied in the context of autoimmunity. Further, these drugs are still broadly-acting and require frequent treatment due to short half-lives. Thus, there is strong interest in harnessing the unique properties of biomaterials—controlled drug release and targeting, for example, to improve autoimmune therapies. Using second generation mTOR inhibitors and rapamycin, we prepared sets of degradable polymer particles from poly(lactide-co-glycolide). We then used these materials to assess physicochemical properties and the ability to control autoimmune inflammation in a primary cell co-culture model. Treatment with particle formulations resulted in significant dose-dependent decreases in dendritic cell activation, T cell proliferation, inflammatory cytokines, and frequencies of inflammatory TH1 phenotypes. Considering the current limitations of rapamycin, and the potential of next-generation analogs, this work provides a screening platform for biomaterials and sets the stage for in vivo evaluation, where delivery kinetics, stability, and targeting could improve autoimmune therapies through biomaterial-enabled delivery.
      PubDate: 2017-05-08
      DOI: 10.1208/s12248-017-0089-1
       
  • Blood-Brain Barrier Protection as a Therapeutic Strategy for Acute
           Ischemic Stroke
    • Authors: Ali Ehsan Sifat; Bhuvaneshwar Vaidya; Thomas J. Abbruscato
      Abstract: Abstract The blood-brain barrier (BBB) is a vital component of the neurovascular unit (NVU) containing tight junctional (TJ) proteins and different ion and nutrient transporters which maintain normal brain physiology. BBB disruption is a major pathological hallmark in the course of ischemic stroke which is regulated by the actions of different factors working at different stages of cerebral ischemia including matrix metalloproteinases (MMPs), inflammatory modulators, vesicular trafficking, oxidative pathways, and junctional-cytoskeletal interactions. These components interact further to disrupt maintenance of both the paracellular and transport barriers of the central nervous system (CNS) to worsen ischemic brain injury and the propensity for hemorrhagic transformation (HT) associated with injury and/or thrombolytic therapy with tissue-type plasminogen activator (tPA). We propose that these complex molecular pathways should be evaluated further so that they could be targeted alone or in combination to protect the BBB during cerebral ischemia. These types of novel interventions should be guided by advanced imaging techniques for better diagnosis of BBB damage which may exert significant therapeutic benefit including the extension of therapeutic window of tPA. This review will focus on the different stages and mechanisms of BBB damage in acute ischemic stroke and novel therapeutic strategies to target those pathways for better therapeutic outcome in stroke.
      PubDate: 2017-05-08
      DOI: 10.1208/s12248-017-0091-7
       
  • Minipig and Human Metabolism of Aldehyde Oxidase Substrates: In Vitro
           – In Vivo Comparisons
    • Authors: David J. Wilkinson; Rosalind L. Southall; Mingguang Li; Lisa M. Wright; Lindsay J. Corfield; Thomas A. Heeley; Benjamin Bratby; Ranbir Mannu; Sarah L. Johnson; Victoria Shaw; Holly L. Friett; Louise A. Blakeburn; John S. Kendrick; Michael B. Otteneder
      Abstract: Abstract The importance of aldehyde oxidase (AOX) is becoming increasingly recognized in the prediction of human pharmacokinetic parameters from animal data. The objectives of these studies were to ascertain whether an in vitro–in vivo correlation existed in the clearance and metabolic pathways of AOX substrates and to establish whether the minipig represented an appropriate non-rodent model for man in the pre-clinical development of drugs metabolized by AOX. Using the AOX substrates carbazeran, 6-deoxypenciclovir and zaleplon, clearance was estimated from in vitro depletion experiments with minipig and human liver cytosol and microsomes and scaled before comparison with data generated in parallel in vivo studies in minipigs. In vitro and in vivo metabolic pathways were characterized by LC–MS/MS. Scaling of in vitro metabolism data to predict in vivo clearance underestimated in vivo values, although the rank order of clearance for the three compounds was preserved. Prediction of human in vivo clearance from scaled minipig in vivo data produced results which correlated well with published clinical values. Overall, this study is the first to compare minipig in vitro metabolism data with in vivo pharmacokinetic data for compounds metabolized by AOX and provides a scientific rationale for the selection of this species as a model for humans in the development of drugs which are substrates of AOX.
      PubDate: 2017-05-04
      DOI: 10.1208/s12248-017-0087-3
       
  • Erratum to: Systematic Verification of Bioanalytical Similarity Between a
           Biosimilar and a Reference Biotherapeutic: Committee Recommendations for
           the Development and Validation of a Single Ligand-Binding Assay to Support
           Pharmacokinetic Assessments
    • Authors: Joseph C. Marini; Michael Anderson; Xiao-Yan Cai; John Chappell; Todd Coffey; Dominique Gouty; Aparna Kasinath; Vera Koppenburg; Philip Oldfield; Shannon Rebarchak; Ronald R. Bowsher
      PubDate: 2017-04-03
      DOI: 10.1208/s12248-017-0074-8
       
  • Evaluation of the Potency, Neutralizing Antibody Response, and Stability
           of a Recombinant Fusion Protein Vaccine for Streptococcus pyogenes
    • Authors: E. Burlet; H. HogenEsch; A. Dunham; G. Morefield
      Abstract: Abstract Streptococcus pyogenes or group A streptococcus (GAS) is a Gram-positive bacterium that can cause a wide range of diseases, including pharyngitis, impetigo, scarlet fever, necrotizing fasciitis, rheumatic fever, and streptococcal toxic shock syndrome. Despite the increasing burden on global health caused by GAS, there is currently no licensed vaccine available. In this study, we evaluated immunogenicity, induction of neutralizing antibodies, and stability of a new recombinant fusion protein vaccine that targets infections from GAS. The recombinant fusion protein (SpeAB) combines inactive mutant forms of streptococcal pyrogenic exotoxin A (SpeA) and streptococcal pyrogenic exotoxin B (SpeB). The SpeAB vaccine evaluated in this study was adsorbed to an aluminum adjuvant and demonstrated robust immunogenicity, eliciting production of specific neutralizing antibodies against SpeA and SpeB, two major virulence factors of S. pyogenes. Stability studies suggest that the vaccine will retain immunogenicity for at least 2 years when stored at refrigerated temperatures. This novel vaccine shows great potential to provide protection against GAS infections and to reduce the burden of GAS disease globally.
      PubDate: 2017-03-10
      DOI: 10.1208/s12248-017-0069-5
       
  • Structure-Promiscuity Relationship Puzzles—Extensively Assayed Analogs
           with Large Differences in Target Annotations
    • Authors: Ye Hu; Swarit Jasial; Erik Gilberg; Jürgen Bajorath
      Abstract: Abstract Publicly available screening data were systematically searched for extensively assayed structural analogs with large differences in the number of targets they were active against. Screening compounds with potential chemical liabilities that may give rise to assay artifacts were identified and excluded from the analysis. “Promiscuity cliffs” were frequently identified, defined here as pairs of structural analogs with a difference of at least 20 target annotations across all assays they were tested in. New assay indices were introduced to prioritize cliffs formed by screening compounds that were extensively tested in comparably large numbers of assays including many shared assays. In these cases, large differences in promiscuity degrees were not attributable to differences in assay frequency and/or lack of assay overlap. Such analog pairs have high priority for further exploring molecular origins of multi-target activities. Therefore, these promiscuity cliffs and associated target annotations are made freely available. The corresponding analogs often represent equally puzzling and interesting examples of structure-promiscuity relationships.
      PubDate: 2017-03-06
      DOI: 10.1208/s12248-017-0066-8
       
 
 
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