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https://www.readbyqxmd.com/read/28097629/radiomitigation-and-tissue-repair-activity-of-systemically-administered-therapeutic-peptide-tp508-is-enhanced-by-pegylation
#1
Scott D McVicar, Kempaiah Rayavara, Darrell H Carney
TP508 is a synthetically derived tissue repair peptide that has previously demonstrated safety and potential efficacy in phase I/II clinical trials for the treatment of diabetic foot ulcers. Recent studies show that a single injection of TP508 administered 24 h after irradiation significantly increases survival and delays mortality in murine models of acute radiation mortality. Thus, TP508 is being developed as a potential nuclear countermeasure. Because of the short plasma half-life of TP508, we hypothesize that increasing the peptide bioavailability would increase TP508 efficacy or reduce the dosage required for therapeutic effects...
January 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28097628/erratum-to-optimal-affinity-of-a-monoclonal-antibody-guiding-principles-using-mechanistic-modeling
#2
Abhinav Tiwari, Anson K Abraham, John M Harrold, Anup Zutshi, Pratap Singh
No abstract text is available yet for this article.
January 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28091881/identifying-metabolites-of-meclonazepam-by-high-resolution-mass-spectrometry-using-human-liver-microsomes-hepatocytes-a-mouse-model-and-authentic-urine-samples
#3
Svante Vikingsson, Ariane Wohlfarth, Mikael Andersson, Henrik Gréen, Markus Roman, Martin Josefsson, Fredrik C Kugelberg, Robert Kronstrand
Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples...
January 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28083797/population-pharmacokinetic-pharmacodynamic-model-of-oral-fludrocortisone-and-intravenous-hydrocortisone-in-healthy-volunteers
#4
Noureddine Hamitouche, Emmanuelle Comets, Mégane Ribot, Jean-Claude Alvarez, Eric Bellissant, Bruno Laviolle
This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug...
January 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28083796/approaches-to-mitigate-the-unwanted-immunogenicity-of-therapeutic-proteins-during-drug-development
#5
Laura I Salazar-Fontana, Dharmesh D Desai, Tarik A Khan, Renuka C Pillutla, Sandra Prior, Radha Ramakrishnan, Jennifer Schneider, Alexandra Joseph
All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses...
January 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28074350/a-comparative-study-of-the-bone-regenerative-effect-of-chemically-modified-rna-encoding-bmp-2-or-bmp-9
#6
Behnoush Khorsand, Satheesh Elangovan, Liu Hong, Alexander Dewerth, Michael S D Kormann, Aliasger K Salem
Employing cost-effective biomaterials to deliver chemically modified ribonucleic acid (cmRNA) in a controlled manner addresses the high cost, safety concerns, and lower transfection efficiency that exist with protein and gene therapeutic approaches. By eliminating the need for nuclear entry, cmRNA therapeutics can potentially overcome the lower transfection efficiencies associated with non-viral gene delivery systems. Here, we investigated the osteogenic potential of cmRNA-encoding BMP-9, in comparison to cmRNA-encoding BMP-2...
January 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070717/identification-of-new-synthetic-cannabinoid-adb-chminaca-mab-chminaca-metabolites-in-human-hepatocytes
#7
Jeremy Carlier, Xingxing Diao, Cristina Sempio, Marilyn A Huestis
ADB-CHMINACA (MAB-CHMINACA) is a new synthetic cannabinoid with high potency and many reported adverse events and fatalities. The drug is currently scheduled in several countries in Europe and the USA. Analytical methods need to be developed to confirm ADB-CHMINACA intake for clinical and forensic programs. For many synthetic cannabinoids, parent compound is not detectable in biological samples after intake, making the detection of metabolites the only way to prove consumption. Therefore, detection of ADB-CHMINACA metabolites in biological specimens is critical...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070716/pharmacokinetics-and-saturable-absorption-of-gabapentin-in-nursing-home-elderly-patients
#8
Ghada F Ahmed, Sai Praneeth R Bathena, Richard C Brundage, Ilo E Leppik, Jeannine M Conway, Janice B Schwartz, Angela K Birnbaum
Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070715/an-integrated-assessment-of-the-effects-of-immunogenicity-on-the-pharmacokinetics-safety-and-efficacy-of-elotuzumab
#9
Chaitali Passey, Johanna Mora, Robert Dodge, Leonid Gibiansky, Jennifer Sheng, Amit Roy, Akintunde Bello, Manish Gupta
Elotuzumab is a humanized, immunostimulatory anti-signaling lymphocytic activation molecule F7 (SLAMF7) IgG1 monoclonal antibody indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma (MM) who have received 1-3 prior therapies. We assessed the immunogenicity of elotuzumab as a monotherapy and in combination with bortezomib/dexamethasone and lenalidomide/dexamethasone in patients with MM in five clinical studies, including the pivotal ELOQUENT-2 trial (NCT01239797). Anti-drug antibody (ADA) prevalence was determined using a validated bridging assay...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070714/influence-of-drug-load-and-physical-form-of-cinnarizine-in-new-snedds-dosing-regimens-in-vivo-and-in-vitro-evaluations
#10
Scheyla D V S Siqueira, Anette Müllertz, Kirsten Gräeser, Georgia Kasten, Huiling Mu, Thomas Rades
The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq (super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq (CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070713/porous-mannitol-carrier-for-pulmonary-delivery-of-cyclosporine-a-nanoparticles
#11
Sharon Shui Yee Leung, Jennifer Wong, Heloisa Victorino Guerra, Kevin Samnick, Robert K Prud'homme, Hak-Kim Chan
This study employed the ultrasonic spray-freeze-drying technique to prepare porous mannitol carriers that incorporated hydrophobic cyclosporine A (CsA) nanoparticles (NPs) for pulmonary delivery. Two nanosuspension stabilization systems, (1) a combination of lecithin and lactose system and (2) a D-α-tocopheryl polyethylene glycol succinate (TPGS) system, were investigated. The ability of the lecithin and TPGS in anchoring the hydrophobic CsA NPs to the porous hydrophilic mannitol structure was first reported...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070712/microdialysis-monitoring-in-clinical-traumatic-brain-injury-and-its-role-in-neuroprotective-drug-development
#12
Eric Peter Thelin, Keri L H Carpenter, Peter J Hutchinson, Adel Helmy
Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070711/immune-suppression-during-preclinical-drug-development-mitigates-immunogenicity-mediated-impact-on-therapeutic-exposure
#13
Jonathan Herskovitz, Josiah Ryman, Theingi Thway, Stephanie Lee, Lei Zhou, Narendra Chirmule, Bernd Meibohm, Vibha Jawa
In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies...
January 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28058529/erratum-to-tumor-static-concentration-curves-in-combination-therapy
#14
Tim Cardilin, Joachim Almquist, Mats Jirstand, Alexandre Soselly, Christiane Amendt, Samer El Bawab, Johan Gabrielsson
No abstract text is available yet for this article.
January 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28050713/metabolic-profiling-of-human-long-term-liver-models-and-hepatic-clearance-predictions-from-in-vitro-data-using-nonlinear-mixed-effects-modeling
#15
Nicole A Kratochwil, Christophe Meille, Stephen Fowler, Florian Klammers, Aynur Ekiciler, Birgit Molitor, Sandrine Simon, Isabelle Walter, Claudia McGinnis, Johanna Walther, Brian Leonard, Miriam Triyatni, Hassan Javanbakht, Christoph Funk, Franz Schuler, Thierry Lavé, Neil J Parrott
Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities...
January 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28028730/exposure-response-and-tumor-growth-inhibition-analyses-of-the-monovalent-anti-c-met-antibody-onartuzumab-metmab-in-the-second-and-third-line-non-small-cell-lung-cancer
#16
Kelong Han, Pascal Chanu, Fredrik Jonsson, Helen Winter, René Bruno, Jin Jin, Mark Stroh
The phase III trial comparing onartuzumab + erlotinib vs. erlotinib in the second- and third-line non-small cell lung cancer (NSCLC) did not meet its primary endpoint of overall survival (OS). The objective was to assess whether doses higher than the phase III dose (15 mg/kg) might yield better efficacy without compromising the safety profile. Data were from 636 patients from the phase II and III NSCLC studies. Tumor growth inhibition (TGI) models were fit to longitudinal tumor size data to estimate individual TGI metrics including time to tumor re-growth (TTG)...
December 27, 2016: AAPS Journal
https://www.readbyqxmd.com/read/28028729/cardiovascular-ion-channel-inhibitor-drug-drug-interactions-with-p-glycoprotein
#17
Kaitlyn V Ledwitch, Arthur G Roberts
P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally diverse range of cardiovascular therapeutics. Unfortunately, drug-drug interactions (DDIs) with the transporter have become a major roadblock to effective cardiovascular drug administration because they can cause adverse drug reactions (ADRs) or reduce the efficacy of drugs. Cardiovascular ion channel inhibitors are particularly susceptible to DDIs and ADRs with Pgp because they often have low therapeutic indexes and are commonly coadministered with other drugs that are also Pgp substrates...
December 27, 2016: AAPS Journal
https://www.readbyqxmd.com/read/28028728/tissue-concentration-of-dodecafluoropentane-ddfp-following-repeated-iv-administration-in-the-new-zealand-white-rabbit
#18
Christine Arthur, Lin Song, William Culp, Aliza Brown, Michael Borrelli, Robert Skinner, Howard Hendrickson
IV injection of dodecafluoropentane emulsion (DDFPe) increases oxygen transportation and reduces brain infarct volume in a rabbit stroke model. Tissue distribution of the parent perfluorocarbon dodecafluoropentane (DDFP) is unknown but is critical to understanding the mechanism by which DDFPe is effective in treating ischemia and for determining safe dosing. Previous studies showed a DDFP blood half-life of <2 min yet therapeutic effects lasted >90 min after injection. We describe DDFP distribution in brain, kidney, liver, spleen, and lung following nine dosing regimens in New Zealand White (NZW) rabbits...
December 27, 2016: AAPS Journal
https://www.readbyqxmd.com/read/28004347/optimal-affinity-of-a-monoclonal-antibody-guiding-principles-using-mechanistic-modeling
#19
Abhinav Tiwari, Anson K Abraham, John M Harrold, Anup Zutshi, Pratap Singh
Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant ([Formula: see text]) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general [Formula: see text] to achieve 90% coverage for a soluble target is one tenth of its baseline concentration ([Formula: see text]), and is independent of the dosing interval, target turnover rate or the presence of competing ligands...
December 21, 2016: AAPS Journal
https://www.readbyqxmd.com/read/28004346/bioavailability-and-bioequivalence-aspects-of-oral-modified-release-drug-products
#20
Rong Wang, Dale P Conner, Bing V Li
Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product...
December 21, 2016: AAPS Journal
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