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1. Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Author

Martin E. Dowty, Tsung H. Lin, Michael I. Jesson, Martin Hegen, David A. Martin, Vaibhav Katkade, Sujatha Menon, and Jean‐Baptiste Telliez

Subjects
cytokine receptors, immunopharmacology, inhibition, JAK‐STAT, rheumatoid arthritis, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor‐mediated signaling of multiple cytokines and growth factors, including those with pro‐inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head‐to‐head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long‐term clinical data, and when available, real‐world experience.

Published
2019
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2. Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation

Author

Edmund H. Jooste, Gregory B. Hammer, Christian R. Reyes, Vaibhav Katkade, and Peter Szmuk

Subjects
alpha2 agonist, dexmedetomidine, non-intubated, pediatric, sedation, NCT01519167, https://clinicaltrials.gov/ct2/show/NCT01519167, Therapeutics. Pharmacology, RM1-950
Abstract

Dexmedetomidine (Precedex™) may be used as an alternative sedative in children, maintaining spontaneous breathing, and avoiding tracheal intubation in a non-intubated moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged ≥28 weeks' gestational age to

Published
2017
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3. Real world data: an opportunity to supplement existing evidence for the use of long-established medicines in health care decision making

Author

Kafi N. Sanders, Vaibhav Katkade, and Kelly H. Zou

Subjects
Computer science, real world evidence, Real world evidence, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Health care, 030212 general & internal medicine, General Nursing, Scope (project management), business.industry, Journal of Multidisciplinary Healthcare, General Medicine, Evidence-based medicine, Clinical trial, real world data, electronic health records, Risk analysis (engineering), 030220 oncology & carcinogenesis, randomized controlled trial, Information source, evidence-based medicine, business, Real world data, Perspectives
Abstract

Vaibhav B Katkade, Kafi N Sanders, Kelly H Zou Pfizer Inc, New York, NY, USA Abstract: Evidence from medication use in the real world setting can help to extrapolate and/or augment data obtained in randomized controlled trials and establishes a broad picture of a medication’s place in everyday clinical practice. By supplementing and complementing safety and efficacy data obtained in a narrowly defined (and often optimized) patient population in the clinical trial setting, real world evidence (RWE) may provide stakeholders with valuable information about the safety and effectiveness of a medication in large, heterogeneous populations. RWE is emerging as a credible information source; however, there is scope for enhancements to real world data (RWD) sources by understanding their complexities and applying the most appropriate analytical tools in order to extract relevant information. In addition to providing information for clinicians, RWE has the potential to meet the burden of evidence for regulatory considerations and may be used in approval of new indications for medications. Further understanding of RWD collection and analysis is needed if RWE is to achieve its full potential. Keywords: electronic health records, evidence-based medicine, real world data, real world evidence, randomized controlled trial

Published
2018

4. Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation

Author

Gregory B. Hammer, Edmund H. Jooste, Christian Russel D. Reyes, Vaibhav Katkade, and Peter Szmuk

Subjects
medicine.medical_specialty, medicine.drug_class, Sedation, medicine.medical_treatment, Population, Bradypnea, alpha2 agonist, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, 030225 pediatrics, medicine, Intubation, Pharmacology (medical), Dexmedetomidine, Adverse effect, education, NCT01519167, https://clinicaltrials.gov/ct2/show/NCT01519167, Pharmacology, education.field_of_study, business.industry, Tracheal intubation, lcsh:RM1-950, dexmedetomidine, Clinical Trial, Surgery, lcsh:Therapeutics. Pharmacology, pediatric, sedation, Anesthesia, Sedative, non-intubated, medicine.symptom, business, medicine.drug
Abstract

Dexmedetomidine (Precedex™) may be used as an alternative sedative in children, maintaining spontaneous breathing and avoiding tracheal intubation in a non-intubated moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged ≥28 weeks’ gestational age to

Published
2017

5. Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt

Author

Harlan N. Bradford, Vaibhav Katkade, John P. Gaughan, Irma Isordia-Salas, Tracee S. Panetti, Abigail A. Soyombo, and Robert W. Colman

Subjects
Vascular Endothelial Growth Factor A, Kininogen, High-Molecular-Weight, Time Factors, Angiogenesis, Morpholines, Biology, Focal adhesion, Glycogen Synthase Kinase 3, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Cell Movement, Sphingosine, Animals, Humans, Phosphorylation, Protein kinase B, Cells, Cultured, Paxillin, Phosphoinositide-3 Kinase Inhibitors, Focal Adhesions, Chemotaxis, Endothelial Cells, Cell migration, Hematology, Peptide Fragments, Protein Structure, Tertiary, Cell biology, Androstadienes, Vascular endothelial growth factor, Endothelial stem cell, chemistry, Biochemistry, Chromones, biology.protein, Cattle, Human umbilical vein endothelial cell, Lysophospholipids, Wortmannin, Signal Transduction
Abstract

SummaryDomain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the PI3-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response to VEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3α.HKa and D5 inhibit phosphorylation of Akt and GSK-3α after stimulation withVEGF and S1P. Inhibitors of Akt and PI3-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P. Therefore we suggest that HKa through its D5 domain alters PI3-kinase- Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions.

Published
2005

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