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  Subjects -> BIOLOGY (Total: 3237 journals)
    - BIOCHEMISTRY (248 journals)
    - BIOENGINEERING (121 journals)
    - BIOLOGY (1548 journals)
    - BIOPHYSICS (49 journals)
    - BIOTECHNOLOGY (250 journals)
    - BOTANY (237 journals)
    - CYTOLOGY AND HISTOLOGY (29 journals)
    - ENTOMOLOGY (70 journals)
    - GENETICS (165 journals)
    - MICROBIOLOGY (268 journals)
    - MICROSCOPY (10 journals)
    - ORNITHOLOGY (28 journals)
    - PHYSIOLOGY (73 journals)
    - ZOOLOGY (141 journals)

BIOLOGY (1548 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 25)
Achievements in the Life Sciences     Open Access   (Followers: 5)
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access   (Followers: 2)
Acta Biologica Turcica     Open Access  
Acta Biologica Venezuelica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 28)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Fytotechnica et Zootechnica     Open Access   (Followers: 1)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 11)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access   (Followers: 1)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Journal of Graduate Research     Open Access  
Advanced Nonlinear Studies     Hybrid Journal  
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Bioinformatics     Open Access   (Followers: 17)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 10)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 7)
Advances in Cell Biology/ Medical Journal of Cell Biology     Open Access   (Followers: 27)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 16)
Advances in Enzyme Research     Open Access   (Followers: 11)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 4)
Advances in Life Science and Technology     Open Access   (Followers: 18)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Tropical Biodiversity and Environmental Sciences     Open Access  
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 8)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 11)
Aging Cell     Open Access   (Followers: 24)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 18)
AJP Endocrinology and Metabolism     Hybrid Journal   (Followers: 24)
AJP Lung Cellular and Molecular Physiology     Hybrid Journal   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
Alces : A Journal Devoted to the Biology and Management of Moose     Open Access  
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 8)
American Journal of Bioethics     Hybrid Journal   (Followers: 13)
American Journal of Human Biology     Hybrid Journal   (Followers: 15)
American Journal of Medical and Biological Research     Open Access   (Followers: 8)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 16)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 76)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadol University Journal of Science and Technology B : Theoritical Sciences     Open Access  
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access  
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 12)
Anatomical Science International     Hybrid Journal   (Followers: 3)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
Animal Models and Experimental Medicine     Open Access  
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 Universitatis Mariae Curie-Sklodowska, sectio C – Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 17)
Annals of Human Biology     Hybrid Journal   (Followers: 5)
Annals of Science and Technology     Open Access  
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 13)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 24)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 1)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 38)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 24)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 13)
Anthropological Review     Open Access   (Followers: 23)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 9)
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: 9)
Applied Biology     Open Access  
Applied Bionics and Biomechanics     Open Access   (Followers: 7)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 4)
Aquaculture International     Hybrid Journal   (Followers: 26)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 7)
Aquatic Biology     Open Access   (Followers: 6)
Aquatic Ecology     Hybrid Journal   (Followers: 37)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 15)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 23)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biological Sciences     Open Access  
Archives of Microbiology     Hybrid Journal   (Followers: 9)
Archives of Natural History     Hybrid Journal   (Followers: 7)
Archives of Oral Biology     Hybrid Journal   (Followers: 3)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 2)
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: 3)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 4)
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: 4)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 4)
Avian Biology Research     Full-text available via subscription   (Followers: 4)
Avian Conservation and Ecology     Open Access   (Followers: 10)
Bacteriology Journal     Open Access   (Followers: 1)
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)
Batman Üniversitesi Yaşam Bilimleri Dergisi     Open Access  
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  
Bio-Lectura     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
BioCentury Innovations     Full-text available via subscription   (Followers: 1)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 16)
Biochimie     Hybrid Journal   (Followers: 6)
BioControl     Hybrid Journal   (Followers: 6)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 6)
Biodemography and Social Biology     Hybrid Journal  
BioDiscovery     Open Access   (Followers: 2)
Biodiversidade e Conservação Marinha : Revista CEPSUL     Open Access  
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity Data Journal     Open Access   (Followers: 4)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access   (Followers: 1)
Biodiversity: Research and Conservation     Open Access   (Followers: 27)
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: 3)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 15)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 5)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 9)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 2)
Bioinformatics     Hybrid Journal   (Followers: 344)
Bioinformatics and Biology Insights     Open Access   (Followers: 11)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 7)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
BioLink : Jurnal Biologi Lingkungan, Industri, Kesehatan     Open Access   (Followers: 1)
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 6)
Biological Control     Hybrid Journal   (Followers: 5)
Biological Invasions     Hybrid Journal   (Followers: 22)

        1 2 3 4 5 6 7 8 | Last

Similar Journals
Journal Cover
AAPS Journal
Journal Prestige (SJR): 1.118
Citation Impact (citeScore): 4
Number of Followers: 25  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1550-7416
Published by Springer-Verlag Homepage  [2351 journals]
  • A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific
           Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by
           P-Cadherin LP DART ®
    • Abstract: CD3 bispecific antibody constructs recruit cytolytic T cells to kill tumor cells, offering a potent approach to treat cancer. T cell activation is driven by the formation of a trimolecular complex (trimer) between drugs, T cells, and tumor cells, mimicking an immune synapse. A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimer concentration and linking it to tumor cell killing. The model was used to quantify the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes the disposition of PF-06671008 in the central compartment and tumor in mouse xenograft models, including binding to target and T cells in the tumor to form the trimer. The model incorporates T cell distribution to the tumor, proliferation, and contraction. PK/PD parameters were estimated for PF-06671008 and a tumor stasis concentration (TSC) was calculated as an estimate of minimum efficacious trimer concentration. TSC values ranged from 0.0092 to 0.064 pM across mouse tumor models. The model was translated to the clinic and used to predict the disposition of PF-06671008 in patients, including the impact of binding to soluble P-cadherin. The predicted terminal half-life of PF-06671008 in the clinic was approximately 1 day, and P-cadherin expression and number of T cells in the tumor were shown to be sensitive parameters impacting clinical efficacy. A translational QSP model is presented for CD3 bispecific molecules, which integrates in silico, in vitro and in vivo data in a mechanistic framework, to quantify and predict efficacy across species.
      PubDate: 2019-05-22
       
  • Application of Mechanistic Ocular Absorption Modeling and Simulation to
           Understand the Impact of Formulation Properties on Ophthalmic
           Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension
    • Abstract: Developing mathematical models to predict changes in ocular bioavailability and pharmacokinetics due to differences in the physicochemical properties of complex topical ophthalmic suspension formulations is important in drug product development and regulatory assessment. Herein, we used published FDA clinical pharmacology review data, in-house, and literature rabbit pharmacokinetic data generated for dexamethasone ophthalmic suspensions to demonstrate how the mechanistic Ocular Compartmental Absorption and Transit model by GastroPlus™ can be used to characterize ocular drug pharmacokinetic performance in rabbits for suspension formulations. This model was used to describe the dose-dependent (0.01 to 0.1%) non-linear pharmacokinetic in ocular tissues and characterize the impact of viscosity (1.67 to 72.9 cP) and particle size (5.5 to 22 μm) on in vivo ocular drug absorption and disposition. Parameter sensitivity analysis (hypothetical suspension particle size: 1 to 10 μm, viscosity: 1 to 100 cP) demonstrated that the interplay between formulation properties and physiological clearance through drainage and tear turnover rates in the pre-corneal compartment drives the ocular drug bioavailability. The quick removal of drug suspended particles from the pre-corneal compartment renders the impact of particle size inconsequential relative to viscosity modification. The in vivo ocular absorption is (1) viscosity non-sensitive when the viscosity is high and the impact of viscosity on the pre-corneal residence time reaches the maximum physiological system capacity or (2) viscosity sensitive when the viscosity is below a certain limit. This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug PK performance in rabbits.
      PubDate: 2019-05-20
       
  • Nanomaterial-Based Modulation of Tumor Microenvironments for Enhancing
           Chemo/Immunotherapy
    • Abstract: The tumor microenvironment (TME) has drawn considerable research attention as an alternative target for nanomedicine-based cancer therapy. Various nanomaterials that carry active substances have been designed to alter the features or composition of the TME and thereby improve the delivery and efficacy of anticancer chemotherapeutics. These alterations include disruption of the extracellular matrix and tumor vascular systems to promote perfusion or modulate hypoxia. Nanomaterials have also been used to modulate the immunological microenvironment of tumors. In this context, nanomaterials have been shown to alter populations of cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells. Despite considerable progress, nanomaterial-based TME modulation must overcome several limitations before this strategy can be translated to clinical trials, including issues related to limited tumor tissue penetration, tumor heterogeneity, and immune toxicity. In this review, we summarize recent progress and challenges of nanomaterials used to modulate the TME to enhance the efficacy of anticancer chemotherapy and immunotherapy.
      PubDate: 2019-05-17
       
  • In Vitro Metabolism and Hepatic Intrinsic Clearance of the Synthetic
           Cannabinoid Receptor Agonist JWH-122 and Its Four ω-Halogenated Analogues
           
    • Abstract: The number of new psychoactive substances (NPS) emerging on the illicit drug market has increased over the last decade. Halogenation of existing illicit drugs is a particular trend, with the purpose of both circumventing the law and altering the toxicodynamic and toxicokinetic profiles of the compounds. This study investigates the in vitro impact of JWH-122 ω-halogenation (fluoro, chloro, bromo and iodo) on the metabolism, apparent intrinsic hepatic clearance and analytical targets for detecting drug consumption. Metabolite profiling was conducted with pooled human liver microsomes, suspended rat hepatocytes and pooled human hepatocytes. The in vitro half-life was also determined in pooled human hepatocytes. All samples were analysed by liquid chromatography/high-resolution mass spectrometry. All compounds, except for JWH-122, showed high formation rates of phase I metabolites, predominantly ω-COOH and methylnaphthyl hydroxylation metabolites. Phase II metabolites were ω-O-glucuronides, methylnaphthyl O-glucuronides and ω-glutathione conjugates. The relative ion intensity of the glutathione conjugates increased with the ω-halogen size, with I-JWH-122 having the highest intensity. Stability studies gave a low half-life and a high intrinsic hepatic clearance for JWH-122 (1305 mL/min/kg) and MAM-2201 (1408 mL/min/kg). Cl-, Br- and I-JWH-122 showed increasing half-life with increasing ω-halogen size, with intrinsic clearance values of 235–502 mL/min/kg. The recommended analytical targets for consumption of JWH-122 or ω-halogenated JWH-122 analogues are the ω-COOH metabolites for unspecific profiling and the methylnaphthyl hydroxylated metabolites to distinguish the compounds. Furthermore, ω-halogenation with larger halogens appears to increase the intrinsic hepatic stability, thereby prolonging exposure and possibly the duration of action.
      PubDate: 2019-05-15
       
  • Fc-Fusion Drugs Have FcγR/C1q Binding and Signaling Properties That May
           Affect Their Immunogenicity
    • Abstract: Fusing the human immunoglobulin G1 (IgG1) constant region (Fc-domain) to therapeutic proteins or peptides increases their circulating plasma half-life via neonatal Fc receptor (FcRn) binding and recycling. However, Fc-mediated interactions with other molecules including complement C1q and Fc gamma receptors (FcγRs) can have immunological consequences and the potential to modulate the immunogenicity of Fc-fusion therapeutics. In a comparative study, we carried out a comprehensive assessment of Fc-mediated interactions for five FDA-approved Fc-fusion therapeutics. C1q binding and complement activation were measured by ELISA, while FcγR binding and signaling were evaluated using BW5147:FcγR-ζ reporter cell lines. We demonstrate that FIX-Fc and FVIII-Fc bound C1q as well as activating and inhibitory FcγRs (I, IIA, IIB, IIIA). These coagulation factor Fc-fusions also signaled via FcγRIIIA, and to a lesser extent via FcγRI and FcγRIIB. TNFR-Fc and CTLA4-Fc bound FcγRI, while TNFR-Fc also bound FcγRIIIA, but these interactions did not result in FcγR signaling. Our comprehensive assessment demonstrates that (i) different Fc-fusion drugs have distinct C1q/FcγR binding and signaling properties, (ii) FcγR binding does not predict signaling, and (iii) the fusion partner (effector molecule) can influence Fc-mediated interactions.
      PubDate: 2019-05-06
       
  • Towards Improved Pharmacokinetic Models for the Analysis of
           Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron
           Emission Tomography
    • Abstract: Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [11C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [11C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [11C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions.
      PubDate: 2019-04-29
       
  • A Novel Method for Analysing Frequent Observations from Questionnaires in
           Order to Model Patient-Reported Outcomes: Application to EXACT® Daily
           Diary Data from COPD Patients
    • Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with approximately 174 million cases worldwide. Electronic questionnaires are increasingly used for collecting patient-reported-outcome (PRO) data about disease symptoms. Our aim was to leverage PRO data, collected to record COPD disease symptoms, in a general modelling framework to enable interpretation of PRO observations in relation to disease progression and potential to predict exacerbations. The data were collected daily over a year, in a prospective, observational study. The e-questionnaire, the EXAcerbations of COPD Tool (EXACT®) included 14 items (i.e. questions) with 4 or 5 ordered categorical response options. An item response theory (IRT) model was used to relate the responses from each item to the underlying latent variable (which we refer to as disease severity), and on each item level, Markov models (MM) with 4 or 5 categories were applied to describe the dependence between consecutive observations. Minimal continuous time MMs were used and parameterised using ordinary differential equations. One hundred twenty-seven COPD patients were included (median age 67 years, 54% male, 39% current smokers), providing approximately 40,000 observations per EXACT® item. The final model suggested that, with time, patients more often reported the same scores as the previous day, i.e. the scores were more stable. The modelled COPD disease severity change over time varied markedly between subjects, but was small in the typical individual. This is the first IRT model with Markovian properties; our analysis proved them necessary for predicting symptom-defined exacerbations.
      PubDate: 2019-04-26
       
  • Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4
           Metabolite 4β-Hydroxycholesterol—an Interaction Study in Healthy
           Volunteers
    • Abstract: 4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4βOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4βOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.
      PubDate: 2019-04-24
       
  • Biodegradable Thermosensitive PLGA-PEG-PLGA Polymer for Non-irritating and
           Sustained Ophthalmic Drug Delivery
    • Abstract: Challenges of ophthalmic drug delivery arise from not only the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of the eyes. Biodegradable thermosensitive polymer, poly(dl-lactide-co-glycolide-b–ethylene glycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) is a desirable ophthalmic drug delivery system because it can be formulated into injectable solution which forms gel in situ to provide prolonged drug release. In this study, excellent biocompatibility of blank PLGA-PEG-PLGA (1800-1500-1800) thermogel was demonstrated with insignificant difference from saline noted in rat eye enucleation test, in vivo inflammation test upon topical instillation, and subconjunctival injection. After subconjunctival injection, thermogel formulations loaded with hydrophilic (rhodamine B) or hydrophobic (coumarin 6) fluorescent dyes were retained up to 4 weeks in eye tissues and significantly higher level was detected than rhodamine B solution or coumarin 6 suspension in weeks 3 and 4. Moreover, in vivo whole body imaging showed that dye-loaded (sulfo-cyanine 7 NHS ester, Cy7; or cyanine 7.5 alkyne, Cy7.5) thermogels had longer retention at the injection site and retarded release to other body parts than dye solutions. Generally, the release rate of hydrophobic dyes (coumarin 6 and Cy7.5) was much slower than that of the hydrophilic dyes (rhodamine B and Cy7) from the thermogel. In summary, the thermogel was safe for ophthalmic drug delivery and could deliver both hydrophobic and hydrophilic compounds for sustained drug release into eye tissues with single subconjunctival injection for better patient compliance and reduced risks on repeated injection.
      PubDate: 2019-04-24
       
  • Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration:
           Focusing on In Vivo Evidence
    • Abstract: Resveratrol (RSV) is a polyphenol endowed with potential therapeutic effects in chronic diseases, particularly in cancer, the second leading cause of death worldwide in the twenty-first century. The advent of nanotechnology application in the field of drug delivery allows to overcome the constrains associated with the conventional anticancer treatments, in particular chemotherapy, reducing its adverse side effects, off target risks and surpassing cancer multidrug chemoresistance. Moreover, the use of nanotechnology-based carriers in the delivery of plant-derived anticancer agents, such as RSV, has already demonstrated to surpass the poor water solubility, instability and reduced bioavailability associated with phytochemicals, improving their therapeutic activity, thus prompting pharmaceutical developments. This review highlights the in vivo anticancer potential of RSV achieved by nanotherapeutic approaches. First, RSV physicochemical, stability and pharmacokinetic features are described. Thereupon, the chemotherapeutic and chemopreventive properties of RSV are underlined, emphasizing the RSV numerous cancer molecular targets. Lastly, a comprehensive analysis of the RSV-loaded nanoparticles (RSV-NPs) developed and administered in different in vivo cancer models to date is presented. Nanoparticles (NPs) have shown to improve RSV solubility, stability, pharmacokinetics and biodistribution in cancer tissues, enhancing markedly its in vivo anticancer activity. RSV-NPs are, thus, considered a potential nanomedicine-based strategy to fight cancer; however, further studies are still necessary to allow RSV-NP clinical translation.
      PubDate: 2019-04-23
       
  • Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry:
           “Drug Products, Including Biological Products, that Contain
           Nanomaterials”
    • Abstract: To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: “Drug Products, Including Biological Products, that Contain Nanomaterials” in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials' During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.
      PubDate: 2019-04-17
       
  • In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by
           Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate
           
    • Abstract: We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.
      PubDate: 2019-04-16
       
  • Report on the AAPS Immunogenicity Guidance Forum
    • Abstract: In September 2018, the American Association of Pharmaceutical Scientists (AAPS) conducted an Annual Guidance Forum on the considerations related to immunogenicity testing for therapeutic protein products. In addition to a broad representation by the pharmaceutical industry, the event included strong representation by leading scientists from the US Food and Drug Administration (FDA). The agency and industry perspectives and updates to the guidance were presented. Specific topics that were discussed included the strategies of anti-drug antibody (ADA) assay cut-point assessments, the selection of ADA-positive controls (PCs), and the evaluation of PC performance. Assessment strategies and relevance of ADA assay attributes were also discussed, including assay drug tolerance and ADA assay sensitivity. The following is a summary of the discussion.
      PubDate: 2019-04-16
       
  • Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in
           Mice
    • Abstract: The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [3H]-BUD or a high dose of [3H]-FP (1590 μg/kg). In a separate experiment, pregnant mice (N = 12) received subcutaneously either the P-gp inhibitor zosuquidar (20 mg/kg) or vehicle, followed by an intravenous infusion of [3H]-BUD (104.9 μg/kg). Total and free (protein unbound) corticosteroid concentrations were determined in plasma, brain, fetus, placenta, kidney, and liver. The ratios of free BUD concentrations in fetus versus plasma K(fetus, plasma, u, u) 0.42 ± 0.17 (mean ± SD) for low-dose and 0.38 ± 0.18 for high-dose BUD were significantly different from K = 1 (P < 0.05), contrary to 0.87 ± 0.25 for FP, which was moreover significantly higher than that for matching high-dose BUD (P < 0.01). The BUD brain/plasma ratio was also significantly smaller than K = 1, while these ratios for other tissues were close to 1. In the presence of the P-gp inhibitor, K(fetus, plasma, u, u) for BUD (0.59 ± 0.16) was significantly increased over vehicle treatment (0.31 ± 0.10; P < 0.01). This is the first in vivo study demonstrating that transplacental transfer of BUD is significantly lower than FP’s transfer and that placental P-gp may be involved in reducing the fetal exposure to BUD. The study provides a mechanistic rationale for BUD’s use in pregnancy.
      PubDate: 2019-04-16
       
  • Induction and Impact of Anti-Drug Responses Elicited by a Human
           Recombinant Coagulation Factor FXa I16L in Preclinical Species
    • Abstract: This paper presents a systemic investigation of ADA development and ADA impact of a human coagulation factor in nonclinical species during drug development and provides insights into potential implications in human if a similar ADA occurs. FXaI16L-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXaI16L were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXaI16L elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or persistent response. Increase in exposure day and increase in dose generally enhanced ADA incidence except for a decrease in ADA incidence was observed in monkeys after repeated high-dose administrations. The observable ADA impact on pharmacokinetics was only found in some ADA+ animals and included decrease in clearance and increase in systemic exposure but no increase in half-life. In addition, no or limited effect on pharmacodynamics by ADA was observed. The earliest ADA response was observed after three exposure days, marked elevation of drug exposure was observed in some animals at log titer > 2.0, and the highest antibody titer excited was about 4 (Log10) in all species. A correlation between ADA induction and accumulative exposure after various repeat treatments in different species was found for FXaI16L. In addition, potential immunogenicity risk and mitigation of ADA in clinics are discussed.
      PubDate: 2019-04-11
       
  • Dissolution Chamber for Small Drug Delivery System in the Periodontal
           Pocket
    • Abstract: Existing dissolution chambers have relatively large volume compared to the size of the periodontal pocket. A small volume dissolution method that simulates the physiological release environment for periodontal drug delivery is needed. The objectives were to construct a small, more physiologically relevant, dissolution chamber and investigate the properties of the new dissolution chamber for the assessment of sustained drug release systems in periodontal delivery. Flow-through dissolution chambers were constructed using three-dimensional (3D) printing. Drug release experiments were performed using the dissolution chamber and a commercially available long-acting periodontal insert product, PerioChip®. Similar experiments were performed under more traditional larger volume bulk solution conditions for comparison. Computer simulations and experimental results showed that drug clearance from the dissolution chamber was fast compared to drug release from the periodontal product. Drug clearance from the flow-through dissolution chamber and drug release from the sustained release product in the chamber were related to the dissolution medium flow rate and chamber volume. Drug release in the flow-through chamber was slower than that observed in bulk solution, but approached it when the medium flow rate increased. The presence of trypsin in the dissolution medium enhanced drug release from the product. A flow-through dissolution system was constructed that could evaluate drug release from a sustained release product in a small dimension environment by modifying the flow rate and composition of the dissolution medium.
      PubDate: 2019-04-10
       
  • CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the
           Odds Against Hematological Malignancies
    • Abstract: The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20–100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.
      PubDate: 2019-04-08
       
  • Bacteriophage PEV20 and Ciprofloxacin Combination Treatment Enhances
           Removal of Pseudomonas aeruginosa Biofilm Isolated from Cystic Fibrosis
           and Wound Patients
    • Abstract: Antibiotic resistance in Pseudomonas aeruginosa biofilms necessitates the need for novel antimicrobial therapy with anti-biofilm properties. Bacteriophages (phages) are recognized as an ideal biopharmaceutical for combating antibiotic-resistant bacteria especially when used in combination with antibiotics. However, previous studies primarily focused on using phages against of P. aeruginosa biofilms of laboratory strains. In the present study, biofilms of six P. aeruginosa isolated from cystic fibrosis and wound patients, and one laboratory strain was treated singly and with combinations of anti-Pseudomonas phage PEV20 and ciprofloxacin. Of these strains, three were highly susceptible to the phage, while one was partially resistant and one was completely resistant. Combination treatment with PEV20 and ciprofloxacin enhanced biofilm eradication compared with single treatment. Phage and ciprofloxacin synergy was found to depend on phage-resistance profile of the target bacteria. Furthermore, phage and ciprofloxacin combination formulation protected the lung epithelial and fibroblast cells from P. aeruginosa and promoted cell growth. The results demonstrated that thorough screening of phage-resistance is crucial for designing phage-antibiotic formulation. The addition of highly effective phage could reduce the ciprofloxacin concentration required to combat P. aeruginosa infections associated with biofilm in cystic fibrosis and wound patients.
      PubDate: 2019-04-04
       
  • HER3-Targeted Affibodies with Optimized Formats Reduce Ovarian Cancer
           Progression in a Mouse Xenograft Model
    • Abstract: Expression of the receptor tyrosine kinase HER3 is negatively correlated with survival in ovarian cancer, and HER3 overexpression is associated with cancer progression and therapeutic resistance. Thus, improvements in HER3-targeted therapy could lead to significant clinical impact for ovarian cancer patients. Previous work from our group established multivalency as a potential strategy to improve the therapeutic efficacy of HER3-targeted ligands, including affibodies. Others have established HER3 affibodies as viable and potentially superior alternatives to monoclonal antibodies for cancer therapy. Here, bivalent HER3 affibodies were engineered for optimized production, specificity, and function as evaluated in an ovarian cancer xenograft model. Enhanced inhibition of HER3-mediated signaling and increased HER3 downregulation associated with multivalency could be achieved with a simplified construct, potentially increasing translational potential. Additionally, functional effects of affibodies due to multivalency were found to be specific to HER3 targeting, suggesting a unique molecular mechanism. Further, HER3 affibodies demonstrated efficacy in ovarian cancer xenograft mouse models, both as single agents and in combination with carboplatin. Overall, these results reinforce the potential of HER3-targeted affibodies for cancer therapy and establish treatment of ovarian cancer as an application where multivalent HER3 ligands may be useful. Further, this work introduces the potential of HER3 affibodies to be utilized as part of clinically relevant combination therapies (e.g., with carboplatin).
      PubDate: 2019-04-04
       
  • Trial Design and Statistical Considerations on the Assessment of
           Pharmacodynamic Similarity
    • Abstract: Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection. For PD data that have high baseline variability, one conventional similarity assessment method was to apply baseline-normalization followed by the standard bioequivalence (BE) test (Lancet Haematol. 4:e350–61, 2017, Ann Rheum Dis. 2017). This study showcased the drawbacks of the conventional method for PD data that were close to inhibition saturation, as the baseline-normalization significantly skewed the distribution of the PD data toward non-log-normal. In such cases, the standard BE test can produce an inflated type I error. Alternatively, ANCOVA, when applied to the un-normalized PD data with the baseline as a covariate, produced a satisfactory type I error with sufficient power. Therefore, ANCOVA was recommended for equivalence test of PD markers that has a saturated inhibition profile and high variability at baseline. Moreover, the relationship between PD readouts and drug potency was used to explore the sensitivity of the PD endpoint and it could help justify the equivalence margins, since the standard 80% to 125% BE margin often does not apply to PD. Finally, a decision tree was proposed to help guide the design of the PD equivalence study in the choice of PD endpoints and statistical methods.
      PubDate: 2019-04-03
       
 
 
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