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BIOLOGY (1423 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 20)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Biologica Colombiana     Open Access   (Followers: 7)
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: 41)
Advances in Ecology     Open Access   (Followers: 16)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 1)
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: 22)
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: 8)
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: 8)
Aging Cell     Open Access   (Followers: 10)
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: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 15)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 65)
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 Cancer Biology     Full-text available via subscription  
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: 14)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 19)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 25)
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: 4)
Avian Conservation and Ecology     Open Access   (Followers: 10)
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     Hybrid Journal   (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: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 293)
Bioinformatics and Biology Insights     Open Access   (Followers: 15)
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: 15)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 42)
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: 42)
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)

        1 2 3 4 5 6 7 8 | Last

Journal Cover AAPS Journal
  [SJR: 1.192]   [H-I: 74]   [20 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1550-7416
   Published by Springer-Verlag Homepage  [2355 journals]
  • The Two Main Goals of Bioequivalence Studies
    • Authors: Laszlo Endrenyi; Henning H. Blume; Laszlo Tothfalusi
      Pages: 885 - 890
      Abstract: The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product’s in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0048-x
      Issue No: Vol. 19, No. 4 (2017)
  • Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight
           Junctions: Implications for Drug Delivery to the Central Nervous System
    • Authors: Jeffrey J. Lochhead; Patrick T. Ronaldson; Thomas P. Davis
      Pages: 910 - 920
      Abstract: A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB’s ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB’s permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0076-6
      Issue No: Vol. 19, No. 4 (2017)
  • Blood-Brain Barriers in Obesity
    • Authors: Elizabeth M. Rhea; Therese S. Salameh; Aric F. Logsdon; Angela J. Hanson; Michelle A. Erickson; William A. Banks
      Pages: 921 - 930
      Abstract: After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer’s disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis. In this article, we address how obesity affects the structure and function of the blood-brain barrier (BBB), the impact of obesity on Alzheimer’s disease, the effects of obesity on circulating proteins and their transport into the brain, and how these changes can potentially be reversed by weight loss.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0079-3
      Issue No: Vol. 19, No. 4 (2017)
  • Controlled Release of Vanadium from a Composite Scaffold Stimulates
           Mesenchymal Stem Cell Osteochondrogenesis
    • Authors: S. D. Schussler; K. Uske; P. Marwah; F. W. Kemp; J. D. Bogden; S. S. Lin; Treena Livingston Arinzeh
      Pages: 1017 - 1028
      Abstract: Large bone defects often require the use of autograft, allograft, or synthetic bone graft augmentation; however, these treatments can result in delayed osseous integration. A tissue engineering strategy would be the use of a scaffold that could promote the normal fracture healing process of endochondral ossification, where an intermediate cartilage phase is later transformed to bone. This study investigated vanadyl acetylacetonate (VAC), an insulin mimetic, combined with a fibrous composite scaffold, consisting of polycaprolactone with nanoparticles of hydroxyapatite and beta-tricalcium phosphate, as a potential bone tissue engineering scaffold. The differentiation of human mesenchymal stem cells (MSCs) was evaluated on 0.05 and 0.025 wt% VAC containing composite scaffolds (VAC composites) in vitro using three different induction media: osteogenic (OS), chondrogenic (CCM), and chondrogenic/osteogenic (C/O) media, which mimics endochondral ossification. The controlled release of VAC was achieved over 28 days for the VAC composites, where approximately 30% of the VAC was released over this period. MSCs cultured on the VAC composites in C/O media had increased alkaline phosphatase activity, osteocalcin production, and collagen synthesis over the composite scaffold without VAC. In addition, gene expressions for chondrogenesis (Sox9) and hypertrophic markers (VEGF, MMP-13, and collagen X) were the highest on VAC composites. Almost a 1000-fold increase in VEGF gene expression and VEGF formation, as indicated by immunostaining, was achieved for cells cultured on VAC composites in C/O media, suggesting VAC will promote angiogenesis in vivo. These results demonstrate the potential of VAC composite scaffolds in supporting endochondral ossification as a bone tissue engineering strategy.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0073-9
      Issue No: Vol. 19, No. 4 (2017)
  • Physiologically Based Pharmacokinetic and Absorption Modeling for Osmotic
           Pump Products
    • Authors: Zhanglin Ni; Arjang Talattof; Jianghong Fan; Eleftheria Tsakalozou; Satish Sharan; Dajun Sun; Hong Wen; Liang Zhao; Xinyuan Zhang
      Pages: 1045 - 1053
      Abstract: Physiologically based pharmacokinetic (PBPK) and absorption modeling approaches were employed for oral extended-release (ER) drug products based on an osmotic drug delivery system (osmotic pumps). The purpose was to systemically evaluate the in vivo relevance of in vitro dissolution for this type of formulation. As expected, in vitro dissolution appeared to be generally predictive of in vivo PK profiles, because of the unique feature of this delivery system that the in vitro and in vivo release of osmotic pump drug products is less susceptible to surrounding environment in the gastrointestinal (GI) tract such as pH, hydrodynamic, and food effects. The present study considered BCS (Biopharmaceutics Classification System) class 1, 2, and 3 drug products with half-lives ranging from 2 to greater than 24 h. In some cases, the colonic absorption models needed to be adjusted to account for absorption in the colon. C max (maximum plasma concentration) and AUCt (area under the concentration curve) of the studied drug products were sensitive to changes in colon permeability and segmental GI transit times in a drug product-dependent manner. While improvement of the methodology is still warranted for more precise prediction (e.g., colonic absorption and dynamic movement in the GI tract), the results from the present study further emphasized the advantage of using PBPK modeling in addressing product-specific questions arising from regulatory review and drug development.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0075-7
      Issue No: Vol. 19, No. 4 (2017)
  • Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and
           UR-144 by Cunninghamella elegans
    • Authors: Shimpei Watanabe; Unnikrishnan Kuzhiumparambil; My Ann Nguyen; Jane Cameron; Shanlin Fu
      Pages: 1148 - 1162
      Abstract: The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoid metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H–indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with C. elegans and the metabolites were identified using liquid chromatography-quadrupole time-of-flight mass spectrometry. The obtained metabolites were compared with reported human metabolites to assess the suitability of the fungus to extrapolate human metabolism. 5F-PB-22 underwent dihydroxylation, dihydrodiol formation, oxidative defluorination, oxidative defluorination to carboxylic acid, ester hydrolysis and glucosidation, alone and/or in combination. The metabolites of PB-22 were generated by hydroxylation, dihydroxylation, trihydroxylation, dihydrodiol formation, ketone formation, carboxylation, ester hydrolysis and glucosidation, alone and/or in combination. XLR-11 was transformed through hydroxylation, dihydroxylation, aldehyde formation, carboxylation, oxidative defluorination, oxidative defluorination to carboxylic acid and glucosidation, alone and/or in combination. UR-144 was metabolised by hydroxylation, dihydroxylation, trihydroxylation, aldehyde formation, ketone formation, carboxylation, N-dealkylation and combinations. These findings were consistent with previously reported human metabolism except for the small extent of ester hydrolysis observed and the absence of glucuronidation. Despite the limitations, C. elegans demonstrated the capacity to produce a wide variety of metabolites including some major human metabolites of XLR-11 and UR-144 at high abundance, showing the potential for metabolism of newly emerging synthetic cannabinoids.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0078-4
      Issue No: Vol. 19, No. 4 (2017)
  • Clinical Evaluation of Modified Release and Immediate Release Tacrolimus
    • Authors: Simon Tremblay; Rita R. Alloway
      Abstract: The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index. For these reasons, it represents an agent that could benefit from modified release formulations to overcome these limitations. The objective of this review is to discuss the clinical evaluation of immediate and modified release tacrolimus formulations in renal transplant recipients. Clinical trials from early development of immediate release tacrolimus to formulation-specific post-marketing trials of modified release tacrolimus formulations are reviewed with an emphasis on key elements relating to trial design end endpoint assessment. Particular elements that can be addressed with formulation alterations, such as pharmacokinetics, pharmacogenomics, and toxicity and corresponding clinical evaluations are discussed. In addition, current knowledge gaps in the clinical evaluation of immediate and modified release tacrolimus formulations are discussed to highlight potential avenues for the future development of different tacrolimus formulations with outcomes relevant to the regulators, the transplant community, and to transplant recipients. This review shows that new formulations may alter tacrolimus bioavailability, alleviate certain adverse events while potentially enhancing patient convenience.
      PubDate: 2017-07-17
      DOI: 10.1208/s12248-017-0119-z
  • Utility of Physiologically Based Pharmacokinetic Absorption Modeling to
           Predict the Impact of Salt-to-Base Conversion on Prasugrel HCl Product
           Bioequivalence in the Presence of Proton Pump Inhibitors
    • Authors: Jianghong Fan; Xinyuan Zhang; Liang Zhao
      Abstract: Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility. The intrinsic solubility was obtained by deconvoluting the model against the observed active metabolite PK profiles with various fractions of base in healthy subjects with or without PPI. The developed PBPK absorption model accurately predicted the average active metabolite PK profiles in healthy subjects without PPI for the product containing 100% salt. A model based on assumptions of the fraction of a dose absorbed remaining unchanged for formulations containing different fractions of base over predicted the reduction of bioavailability upon conversion to the base. Therefore, this represented the conservative estimate with respect to the impact of free base in a product on BE evaluation. Virtual BE trial simulation predicted that less than 20% free base in prasugrel HCl product ensures in vivo BE of the generic product including in subjects that may be taking PPI.
      PubDate: 2017-07-14
      DOI: 10.1208/s12248-017-0116-2
  • Pharmacokinetics and Pharmacogenomics of Bupropion in Three Different
           Formulations with Different Release Kinetics in Healthy Human Volunteers
    • Authors: Jamie N. Connarn; Stephanie Flowers; Marisa Kelly; Ruijuan Luo; Kristen M. Ward; Gloria Harrington; Ila Moncion; Masoud Kamali; Melivin McInnis; Meihua R. Feng; Vicki Ellingrod; Andrew Babiskin; Xinyuan Zhang; Duxin Sun
      Abstract: The purpose of this pharmacokinetics (PK) study was to investigate whether different release kinetics from bupropion hydrochloride (HCl) immediate release (IR), sustained release (SR), and extended release (ER) formulations alter its metabolism and to test the hypothesis that the unsuccessful bioequivalence (BE) study of the higher strength (300 mg) of bupropion HCl ER tablets based on the successful BE study of the lower strength (150 mg) was due to metabolic saturation in the gastrointestinal (GI) lumen. A randomized six-way crossover study was conducted in healthy volunteers. During each period, subjects took a single dose of IR (75/100 mg), SR (100/150 mg), or ER (150/300 mg) formulations of bupropion HCl; plasma samples for PK analysis were collected from 0–96 h for all formulations. In addition, each subject’s whole blood was collected for the genotyping of various single-nucleotide polymorphisms (SNPs) of bupropion’s major metabolic enzymes. The data indicates that the relative bioavailability of the ER formulations was 72.3–78.8% compared with IR 75 mg. No differences were observed for ratio of the area under the curve (AUC) of metabolite to AUC of parent for the three major metabolites. The pharmacogenomics analysis suggested no statistically significant correlation between polymorphisms and PK parameters of the various formulations. Altogether, these data suggested that the different release kinetics of the formulations did not change metabolites-to-parent ratio. Therefore, the differing BE result between the 150 and 300 mg bupropion HCl ER tablets was unlikely due to the metabolic saturation in the GI lumen caused by different release patterns.
      PubDate: 2017-07-06
      DOI: 10.1208/s12248-017-0102-8
  • Application of Exposure-Response Analyses to Establish the Pharmacodynamic
           Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing
           Regimen for the Treatment of HCV Infection
    • Authors: Akshanth R. Polepally; Haoyu Wang; Patrick J. Marroum; Mukul Minocha; Balakrishna Hosmane; Amit Khatri; Sven Mensing; Thomas J. Podsadecki; Daniel E. Cohen; Walid M. Awni; Rajeev M. Menon
      Abstract: The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C trough, paritaprevir C max, and ritonavir C max. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product’s labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C trough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.
      PubDate: 2017-07-06
      DOI: 10.1208/s12248-017-0115-3
  • Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release
    • Authors: Rong-Kun Chang; Neil Mathias; Munir A. Hussain
      Abstract: This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.
      PubDate: 2017-07-05
      DOI: 10.1208/s12248-017-0112-6
  • The impact of gastric pH, volume, and emptying on the food effect of
           ziprasidone oral absorption
    • Authors: Steven C Sutton; Richard Nause; Kuan Gandelman
      Abstract: ABSTRACT In a recent food effect clinical study, the authors concluded that a meal consisting of ≥500 kcal, regardless of fat content, produced the maximal bioavailability for ziprasidone. Using GastroPlus™, a commercially available pharmacokinetic simulation software, a semiphysiological model—a kind of physiologically based pharmacokinetic (PBPK) absorption model—was developed that could predict the concentration-time profiles when ziprasidone was administered with any one of the five test meals or fasting. Ziprasidone intravenous pharmacokinetics and oral absorption permeability were determined from clinical studies following the intravenous and duodenal infusion of ziprasidone to volunteers. From the detailed dietary information of each meal provided in the previously published food effect study, the stomach pH, volume, and gastric emptying could be predicted. Incorporating these meal-specific parameters into the model improved the predictions beyond the default fed/fasted parameters commonly used in the software. Compared to the default models, the improved models resulted in an improved prediction of the average ziprasidone concentration-time profile for each meal. Using this type of semiphysiological absorption model, we have shown that the dietary contents of the meals should be taken into account to predict food effects for ziprasidone and perhaps other BCS class I or II compounds.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0065-9
  • Dissolution comparisons using a Multivariate Statistical Distance (MSD)
           test and a comparison of various approaches for calculating the
           measurements of dissolution profile comparison
    • Authors: J-M. Cardot; B. Roudier; H. Schütz
      Abstract: The f 2 test is generally used for comparing dissolution profiles. In cases of high variability, the f 2 test is not applicable, and the Multivariate Statistical Distance (MSD) test is frequently proposed as an alternative by the FDA and EMA. The guidelines provide only general recommendations. MSD tests can be performed either on raw data with or without time as a variable or on parameters of models. In addition, data can be limited—as in the case of the f 2 test—to dissolutions of up to 85% or to all available data. In the context of the present paper, the recommended calculation included all raw dissolution data up to the first point greater than 85% as a variable—without the various times as parameters. The proposed MSD overcomes several drawbacks found in other methods.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0063-y
  • Site Selection: a Case Study in the Identification of Optimal Cysteine
           Engineered Antibody Drug Conjugates
    • Authors: L. Nathan Tumey; Fengping Li; Brian Rago; Xiaogang Han; Frank Loganzo; Sylvia Musto; Edmund I. Graziani; Sujiet Puthenveetil; Jeffrey Casavant; Kimberly Marquette; Tracey Clark; Jack Bikker; Eric M. Bennett; Frank Barletta; Nicole Piche-Nicholas; Amy Tam; Christopher J. O’Donnell; Hans Peter Gerber; Lioudmila Tchistiakova
      Abstract: As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs. However, we demonstrate that the rate of cathepsin-mediated linker cleavage is heavily dependent upon site and is closely correlated with ADC hydrophobicity, thus confirming other recent reports of this phenomenon. Interestingly, conjugates with high rates of cathepsin-mediated linker cleavage did not exhibit decreased plasma stability. In fact, the major source of plasma instability was shown to be retro-Michael mediated deconjugation. This process is known to be impeded by succinimide hydrolysis, and thus, we undertook a series of mutational experiments demonstrating that basic residues located nearby the site of conjugation can be a significant driver of succinimide ring opening. Finally, we show that total antibody PK exposure in rat was loosely correlated with ADC hydrophobicity. It is our hope that these observations will help the ADC community to build “design rules” that will enable more efficient prosecution of next-generation ADC discovery programs.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0083-7
  • In Vitro and In Vivo Metabolite Identification Studies for the New
           Synthetic Opioids Acetylfentanyl, Acrylfentanyl, Furanylfentanyl, and
    • Authors: Shimpei Watanabe; Svante Vikingsson; Markus Roman; Henrik Green; Robert Kronstrand; Ariane Wohlfarth
      Abstract: New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoro-isobutyrylfentanyl, and furanylfentanyl. All compounds were incubated at 10 μM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed. Data acquisition was performed in data-dependent acquisition mode during liquid chromatography high-resolution mass spectrometry analyses. Data was analyzed (1) manually based on predicted biotransformations and (2) with MetaSense software using data-driven search algorithms. Acetylfentanyl, acrylfentanyl, and 4-fluoro-isobutyrylfentanyl were predominantly metabolized by N-dealkylation, cleaving off the phenethyl moiety, monohydroxylation at the ethyl linker and piperidine ring, as well as hydroxylation/methoxylation at the phenyl ring. In contrast, furanylfentanyl’s major metabolites were generated by amide hydrolysis and dihydrodiol formation, while the nor-metabolite was minor or not detected in case samples at all. In general, in vitro results matched the in vivo findings well, showing identical biotransformations in each system. Phase II conjugation was observed, particularly for acetylfentanyl. Based on our results, we suggest the following specific and abundant metabolites as analytical targets in urine: a hydroxymethoxy and monohydroxylated metabolite for acetylfentanyl, a monohydroxy and dihydroxy metabolite for acrylfentanyl, two monohydroxy metabolites and a hydroxymethoxy metabolite for 4-fluoro-isobutyrylfentanyl, and a dihydrodiol metabolite and the amide hydrolysis metabolite for furanylfentanyl.
      PubDate: 2017-07-01
      DOI: 10.1208/s12248-017-0070-z
  • 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: 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
  • 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: 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: 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
  • Controlled Ion Release from Novel Polyester/Ceramic Composites Enhances
    • 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: 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
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