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https://www.readbyqxmd.com/read/28650129/in-vitro-efficacy-and-in-silico-analysis-of-cefixime-ofloxacin-combination-for-salmonella-typhi-from-bloodstream-infection
#1
Yamuna Devi Bakthavatchalam, Thirumal Kumar D, Iftikhar Aslam Tayubi, Baby Abirami S, Priyanka Babu, Elakkiya Munusamy, Bhuvaneswari Thukkaram, Raji Ravi, George Priya Doss C, Balaji Veeraraghavan
AIMS: Recently, the cefixime-ofloxacin combination is approved by drug controller general of India (DCGI) to treat typhoid fever. We sought to evaluate the antimicrobial activity of cefixime-ofloxacin combination against S. Typhi. METHODS AND RESULTS: 283 non-duplicate S. Typhi isolates collected during 2012 to 2014 were included in this study. Minimum inhibitory concentration (MIC) of cefixime and ofloxacin was determined by using broth microdilution method. Combinational testing was performed by using checkerboard assay...
June 26, 2017: Journal of Applied Microbiology
https://www.readbyqxmd.com/read/28646408/a-mechanism-based-pk-pd-model-for-hematological-toxicities-induced-by-antibody-drug-conjugates
#2
Sihem Ait-Oudhia, Weiyan Zhang, Donald E Mager
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia...
June 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28645327/impact-of-growth-matrix-on-pharmacodynamics-of-antimicrobial-drugs-for-pig-pneumonia-pathogens
#3
Lucy Dorey, Peter Lees
BACKGROUND: The most widely used measure of potency of antimicrobial drugs is Minimum Inhibitory Concentration (MIC). MIC is usually determined under standardised conditions in broths formulated to optimise bacterial growth on a species-by-species basis. This ensures comparability of data between laboratories. However, differences in values of MIC may arise between broths of differing chemical composition and for some drug classes major differences occur between broths and biological fluids such as serum and inflammatory exudate...
June 23, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28642891/safety-tolerability-of-the-anti-semaphorin-4d-antibody-vx15-2503-in-a-randomized-phase-1-trial
#4
Christopher LaGanke, Lawrence Samkoff, Keith Edwards, Lily Jung Henson, Pavle Repovic, Sharon Lynch, Lael Stone, David Mattson, Aaron Galluzzi, Terrence L Fisher, Christine Reilly, Laurie A Winter, John E Leonard, Maurice Zauderer
OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated...
July 2017: Neurology® Neuroimmunology & Neuroinflammation
https://www.readbyqxmd.com/read/28642710/tacrolimus-updated-guidelines-through-poppk-modeling-how-to-benefit-more-from-cyp3a-pre-emptive-genotyping-prior-to-kidney-transplantation
#5
Jean-Baptiste Woillard, Michel Mourad, Michael Neely, Arnaud Capron, Ron H van Schaik, Teun van Gelder, Nuria Lloberas, Dennis A Hesselink, Pierre Marquet, Vincent Haufroid, Laure Elens
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28642571/pharmacokinetic-and-pharmacodynamic-modeling-of-cyadox-against-clostridium-perfringens-in-swine
#6
Lei Yan, Shuyu Xie, Dongmei Chen, Yuanhu Pan, Yanfei Tao, Wei Qu, ZhenLi Liu, Zonghui Yuan, Lingli Huang
The purpose of this study was to evaluate the activity of cyadox against Clostridium perfringens in swine and optimize the dosage regimen using ex vivo pharmacokinetic-pharmacodynamic (PK-PD) modeling. After oral administration, the ileum fluid of pigs containing the free cyadox was collected by implanted ultrafiltration probes. The Tmax, AUC24h, and CL/F of free cyadox in the ileum fluid were 1.96 h, 106.40 μg/h/mL, and 0.27 L/kg/h, respectively. Cyadox displayed a concentration-dependent killing action against C...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28642145/new-and-improved-a-review-of-novel-antibiotics-for-gram-positive-bacteria
#7
REVIEW
Mohamed Abbas, Mical Paul, Angela Huttner
BACKGROUND: The number of antibiotics in the pipeline targeting Gram-positive pathogens has increased in recent years. AIMS: This narrative review aims to provide a summary of existing evidence on efficacy, microbiologic spectrum, and safety of novel systemic antibiotics that have either recently been licenced or completed phase III trials, and possess activity predominantly against Gram-positive organisms. SOURCES: A review of the published literature via the MEDLINE database was performed...
June 19, 2017: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/28640596/drug-target-kinetics-in-drug-discovery
#8
Peter J Tonge
The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28638727/identification-of-an-immunogenic-neo-epitope-encoded-by-mouse-sarcoma-using-cxcr3-ligand-mrnas-as-sensors
#9
Keisuke Fujii, Yoshihiro Miyahara, Naozumi Harada, Daisuke Muraoka, Mitsuhiro Komura, Rui Yamaguchi, Hideo Yagita, Junko Nakamura, Sahoko Sugino, Satoshi Okumura, Seiya Imoto, Satoru Miyano, Hiroshi Shiku
The CXCR3 ligands CXCL9, 10, and 11 play critical roles in the amplification of immune responses by recruiting CXCR3(+) immune effector cells to the tumor site. Taking advantage of this property of CXCR3 ligands, we aimed to establish a novel approach to identify immunogenic mutated-antigens. We examined the feasibility of using CXCR3 ligand mRNAs as sensors for detection of specific immune responses in human and murine systems. We further investigated whether this approach is applicable for the identification of immunogenic mutated-antigens by using murine sarcoma lines...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28637670/a-randomised-double-blind-trial-to-demonstrate-bioequivalence-of-gp2013-and-reference-rituximab-combined-with-methotrexate-in-patients-with-active-rheumatoid-arthritis
#10
Josef S Smolen, Stanley B Cohen, Hans-Peter Tony, Morton Scheinberg, Alan Kivitz, Andra Balanescu, Juan Gomez-Reino, Liyi Cen, Peijuan Zhu, Tamas Shisha
OBJECTIVES: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. METHODS: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid...
June 21, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28637099/aggregation-and-phosphorylation-of-%C3%AE-synuclein-with-proteinase-k-resistance-in-focal-%C3%AE-synucleinopathy-predominantly-localized-to-the-cardiac-sympathetic-nervous-system
#11
Nei Fukasawa, Takahiro Fukuda, Masato Nagaoka, Tohru Harada, Hiroyuki Takahashi, Masahiro Ikegami
Aggregates of α-synuclein, a major component of Lewy bodies (LBs) and Lewy neurites (LNs), are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system (ENS), cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin, in incidental Lewy body disease (ILBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and pure autonomic failure (PAF) [1-3]. Here we report focal α-synucleinopathy predominantly localized to the cardiac sympathetic nervous system (SNS)...
June 21, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#12
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28636184/pharmacokinetics-pharmacodynamics-of-bococizumab-a-monoclonal-antibody-to-pcsk9-after-single-subcutaneous-injection-at-3-sites-nct-02043301
#13
Ellen Q Wang, Anna Plotka, Joanne Salageanu, Catherine Sattler, Carla Yunis
AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL and not on background lipid-lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm...
June 21, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28634551/mechanisms-and-consequences-of-dopamine-depletion-induced-attenuation-of-the-spinophilin-neurofilament-medium-interaction
#14
Andrew C Hiday, Michael C Edler, Asma B Salek, Cameron W Morris, Morrent Thang, Tyler J Rentz, Kristie L Rose, Lisa M Jones, Anthony J Baucum
Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28630197/pharmacodynamics-of-cefepime-combined-with-tazobactam-against-clinically-relevant-enterobactereaceae-in-a-neutropenic-mouse-thigh-model
#15
Maria J Melchers, Anita C van Mil, Claudia Lagarde, Jan den Hartigh, Johan W Mouton
The lack of new antibiotics prompted the investigation of the combination of two existing agents cefepime, a broad-spectrum cephalosporin and tazobactam to broaden its efficacy against extended-spectrum beta-lactamase producing Enterobacteriaceae. We determined the pharmacokinetic and pharmacodynamic properties of the combination in a murine neutropenic thigh model in order to establishing its exposure- response relationships (ERR). The PK of cefepime was determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al Antimicrob...
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28629344/antiresorptive-effect-of-a-cathepsin-k-inhibitor-ono-5334-and-its-relationship-to-bmd-increase-in-a-phase-ii-trial-for-postmenopausal-osteoporosis
#16
Makoto Tanaka, Yoshitaka Hashimoto, Chihiro Hasegawa, Steve Deacon, Richard Eastell
BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship...
June 19, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28624123/population-pharmacokinetic-pharmacodynamics-modeling-of-ibutilide-in-chinese-healthy-volunteers-and-patients-with-atrial-fibrillation-af-and-or-atrial-flutter-afl
#17
Zhijun Zeng, Li Wang, Lu Hua, Juanjuan Jiang, Huimin Pang, Yiling Huang, Yishi Li, Lei Tian
PURPOSE: The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. METHODS: The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL)...
June 14, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28623849/population-pharmacokinetics-pharmacodynamics-of-3-4-diaminopyridine-free-base-in-patients-with-lambert-eaton-myasthenia
#18
Nilay Thakkar, Jeffrey T Guptill, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez
Lambert-Eaton Myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine free base (3,4-DAP) is an investigational orphan drug used to treat LEM-related weakness. We performed a population PK/PD analysis using 3,4-DAP and metabolite concentrations collected from a phase 2 study in LEM patients. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1270 PK samples (49 patients) and 1091 3TUG data points (32 randomized patients) were included in the PK/PD analysis...
June 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28623717/baicalein-exerts-anti-neuroinflammatory-effects-to-protect-against-rotenone-induced-brain-injury-in-rats
#19
Xue Zhang, Yulin Yang, Lida Du, Wen Zhang, Guanhua Du
Baicalein, a major bioactive flavone constituent isolated from Scutellaria baicalensis Georgi, has been shown to be neuroprotective in several Parkinson's disease (PD) animal models. Since neuroinflammation has been known to play a critical role in the pathogenesis of PD, potential explanation for the neuroprotective action of anti-PD compounds involves among others reduced inflammation. Our study investigated that one of the mechanisms of protection afforded by baicalein in rotenone-induced parkinsonian rats was associated with anti-inflammatory action and explored its underlying mechanism in vivo and in vitro...
June 14, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28619503/clinical-pharmacokinetics-of-levornidazole-in-elderly-subjects-and-dosing-regimen-evaluation-using-pharmacokinetic-pharmacodynamic-analysis
#20
Beining Guo, Gaoli He, Xiaojie Wu, Jicheng Yu, Guoying Cao, Yi Li, Yaxin Fan, Yuancheng Chen, Yaoguo Shi, Yingyuan Zhang, Jing Zhang
PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years)...
June 12, 2017: Clinical Therapeutics
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