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Himebauch A.S.,Center for Clinical Pharmacology | Moorthy G.S.,Center for Clinical Pharmacology | Zuppa A.F.,Center for Clinical Pharmacology | Fox E.,Center for Clinical Pharmacology | And 2 more authors.
British Journal of Anaesthesia | Year: 2016

Background Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery. Methods This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated. Results Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) μg ml-1 within 30-60 min after the first cefazolin 30 mg kg-1 dose. For patients who received a second 30 mg kg-1 dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) μg ml-1 within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively. Conclusions For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens. © 2016 The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


PubMed | Children's Hospital of Philadelphia, Center for Clinical Pharmacology and Texas Childrens Hospital
Type: Journal Article | Journal: British journal of anaesthesia | Year: 2016

Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery.This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated.Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) g ml(-1) within 30-60 min after the first cefazolin 30 mg kg(-1) dose. For patients who received a second 30 mg kg(-1) dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) g ml(-1) within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively.For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens.


News Article | February 17, 2017
Site: www.biosciencetechnology.com

Washington University in St. Louis is collaborating with the biopharmaceutical company Pfizer Inc. on research aimed at speeding the development of new drugs. The university is the first academic institution in the Midwest to join Pfizer’s Centers for Therapeutic Innovation’s (CTI) collaborative network. The new collaboration is aimed at supporting translational research that has the greatest potential to bring innovative therapies to patients. The collaboration will focus on certain rare diseases, as well as on immunology and inflammation, oncology, neuroscience, and cardiovascular and metabolic diseases. In particular, the program will focus on approaches that involve large-molecule therapeutics and antibodies that have the potential to address multiple diseases. “We are excited to be combining the resources and expertise of Pfizer scientists with the talents of our Washington University faculty in this effort to develop the next generation of therapeutics,” said Jennifer K. Lodge, Ph.D., vice chancellor for research at Washington University and a professor of molecular microbiology at the School of Medicine. “With our strength in basic science and translational research and the expertise of Pfizer in drug development, the new collaboration could help St. Louis and our region become even better positioned to make major contributions to benefit patients.” CTI brings together academic and National Institutes of Health (NIH) researchers with Pfizer scientists and patient foundations, to collaborate in drug discovery in broad areas of interest to the global pharmaceutical maker. “We look forward to beginning this new collaboration with Washington University,” said Anthony Coyle, Ph.D., senior vice president and CTI’s chief scientific officer. “Washington University’s world-class scientific expertise is an excellent addition to CTI’s network of academic collaborators, and CTI is proud to complement Pfizer’s long-standing relationship with this institution.” As part of the collaboration, Washington University researchers will be able to apply for funding to support research projects aimed at drug discovery. A joint steering committee made up of Washington University researchers and Pfizer scientists will be responsible for selecting the research projects and tracking their progress. If the steering committee selects a project, the project team would have access to Pfizer’s resources, scientific equipment and opportunities to collaborate with Pfizer scientists, who have extensive expertise in drug development and protein science. “I am pleased that our faculty will be able to participate in this program and have the potential to work on important projects in collaboration with Pfizer,” said David H. Perlmutter, M.D., executive vice chancellor for medical affairs and dean of the School of Medicine. “We are moving into an era in which academic-industry collaborations could capitalize on our considerable research talents and activities and, by collaborating with outstanding pharmaceutical companies like Pfizer, we can facilitate our goal of getting new drugs to patients as soon as possible.” The Washington University faculty serving on the joint steering committee include Karen Seibert, Ph.D., a professor of anesthesiology and of pathology and immunology and of genetics; Michael S. Kinch, Ph.D., associate vice chancellor and director of Washington University’s Center for Research Innovation in Business; Thaddeus S. Stappenbeck, M.D., Ph.D., the Conan Professor of Laboratory and Genomic Medicine; Leena M. Prabhu, Ph.D., associate director of Washington University’s Office of Technology Management; and Patricia J. Gregory, Ph.D., assistant vice chancellor and executive director of corporate and foundation relations. “This kind of collaboration between academic medical centers and private industry holds great potential for identifying the best ideas and moving them through the research pipeline as quickly as possible,” said Seibert, who served as vice president of research and development for Pfizer at the company’s St. Louis site before joining Washington University. “The fact that Pfizer has a long history of operating in St. Louis with well-established laboratories, equipment and a local team of experienced scientists means we have the potential to begin our collaborations and joint projects right away,” added Seibert, who also co-directs the Center for Clinical Pharmacology, which is a collaboration between the St. Louis College of Pharmacy and the School of Medicine.


Barchiesi F.,University of Zürich | Lucchinetti E.,University of Alberta | Zaugg M.,University of Alberta | Ogunshola O.O.,Institute of Veterinary Physiology | And 11 more authors.
Hypertension | Year: 2010

2-Methoxyestradiol (2-ME; estradiol metabolite) inhibits vascular smooth muscle cell (VSMC) growth and protects against atherosclerosis and vascular injury; however, the mechanisms by which 2-ME induces these actions remain obscure. To assess the impact of 2-ME on biochemical pathways regulating VSMC biology, we used high-density oligonucleotide microarrays to identify differentially expressed genes in cultured human female aortic VSMCs treated with 2-ME acutely (4 hours) or long term (30 hours). Both single gene analysis and Gene Set Enrichment Analysis revealed 2-ME-induced downregulation of genes involved in mitotic spindle assembly and function in VSMCs. Also, Gene Set Enrichment Analysis identified effects of 2-ME on genes regulating cell-cycle progression, cell migration/adhesion, vasorelaxation, inflammation, and cholesterol metabolism. Transcriptional changes were associated with changes in protein expression, including inhibition of cyclin D1, cyclin B1, cyclin-dependent kinase 6, cyclin-dependent kinase 4, tubulin polymerization, cholesterol and steroid synthesis, and upregulation of cyclooxygenase 2 and matrix metalloproteinase 1. Microarray data suggested that 2-ME may activate peroxisome proliferator-activated receptors (PPARs) in VSMCs, and 2-ME has structural similarities with rosiglitazone (PPARγ agonist). However, our finding of weak activation and lack of binding of 2-ME to PPARs suggests that 2-ME may modulate PPAR-associated genes via indirect mechanisms, potentially involving cyclooxygenase 2. Indeed, the antimitogenic effects of 2-ME at concentrations that do not inhibit tubulin polymerization were blocked by the PPAR antagonist GW9662 and the cyclooxygenase 2 inhibitor NS398. Finally, we demonstrated that 2-ME inhibited hypoxia-inducible factor 1α. Identification of candidate genes that are positively or negatively regulated by 2-ME provides important leads to investigate and better understand the mechanisms by which 2-ME induces its vasoprotective actions. © 2010 American Heart Association, Inc.


News Article | October 10, 2016
Site: www.biosciencetechnology.com

Many children with sickle cell disease experience frequent and severe pain episodes, requiring emergency room visits or hospitalization. In search of more effective ways to treat such pain, researchers at Washington University School of Medicine in St. Louis have found that adding a low dose of the drug methadone to standard treatment can limit pain experienced by children with the condition. The study is available online in the journal Pediatric Blood & Cancer. “More than half of sickle cell patients have at least one episode of significant pain every year, and about 20 percent experience multiple episodes each year that require hospital stays,” said first author Jennifer Horst, M.D., an instructor of pediatrics at the School of Medicine and an emergency room physician at St. Louis Children’s Hospital. “In this study, the pediatric patients who received a one-time dose of methadone rated their pain levels much lower than those who took standard pain-killing drugs. In many cases, their pain went away, so we believe methadone has the potential to make life better for these pediatric patients.” The researchers followed 24 children and 23 adults who were hospitalized after suffering episodes of severe sickle cell pain. Patients are treated with pain-killing drugs, usually opioids such as morphine, until their pain is under control. In this study, the researchers gave half of the patients a single, low dose of the long-duration opioid methadone. The result was that many of them then needed lower amounts than usual of other opioid drugs to control their pain. Severe pain occurs when the shape of red blood cells becomes sickle-like in shape, making it more difficult for the cells to flow through blood vessels. As a result, the red blood cells don’t supply enough oxygen to tissues in the body that need it. Horst and senior investigator Evan D. Kharasch, M.D., Ph.D., the Russell D. and Mary B. Shelden Professor of Anesthesiology, compared pain relief in patients given morphine with pain relief in those whose treatments were supplemented with methadone. Morphine is the standard painkiller prescribed to sickle cell patients. Methadone also frequently is used to treat pain, particularly in patients having surgery or those with cancer. The latter drug also is used in detoxification and maintenance therapy for individuals who are dependent on opioid drugs, including heroin. Study patients who did not receive methadone were given morphine to treat their pain. All of the patients in the study were able to regulate the amount of pain-killing drugs they received. The children who received methadone rated their pain lower on a standard scale that indicated no pain to severe pain. They also rated their pain relief as better, at 7 to 8 on a scale of 1 to 10, while those who didn’t get methadone rated their pain relief at around 4 or 5 during the first 72 hours of their hospital stays. In adults, however, pain relief linked to methadone was not statistically significant. Kharasch — also a professor of biochemistry and molecular biophysics and director of the Center for Clinical Pharmacology, a research center operated by St. Louis College of Pharmacy and the School of Medicine — said the problem in adults may have been that their doses were too low. “Because adult patients have lived with sickle cell disease their entire lives, it’s possible they develop a tolerance to pain medications, and pain-killing drugs, including methadone, become generally less effective,” he said. “However, we wanted to make sure methadone was safe to use in sickle cell patients, so we actually gave very low doses of the drug. That might be why the adults didn’t register the same improvements in pain scores.” Kharasch and Horst said methadone may help relieve pain from sickle cell disease because the drug has pain-killing properties that are different from morphine and because it remains in the body longer. “Methadone has a faster onset and lasts longer than other, typical pain medicines, so we think it may be useful in getting some patients relief before they have to be hospitalized,” Horst said. “We’d like to treat pain more quickly, especially in children, so that their pain crises can be resolved more quickly and they can go home sooner. Children who come in several times a year can miss a lot of school. That affects their quality of life.” Horst and Kharasch believe they have demonstrated that the drug can be used safely in children but said they will have to study larger numbers of kids and adults before determining whether methadone can be incorporated as a standard treatment for sickle cell-related pain. They also believe larger studies could help establish the most effective doses of the drug in children and adults. In addition, they plan to evaluate whether treating patients with methadone in the emergency department might potentially prevent the need for hospitalization in some patients.


Joshi A.D.,Merck | Sanabria-Bohorquez S.M.,Merck | Bormans G.,Catholic University of Leuven | Koole M.,Catholic University of Leuven | And 7 more authors.
Synapse | Year: 2015

Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type-1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [18F]MK-6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [18F]MK-6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK-2637. Studies were also performed to measure radiation burden and the baseline test-retest (T-RT) variability of the tracer. The effective dose from sequential whole-body dosimetry scans in three male subjects was estimated to be 24.5±2.9 μSV/MBq (mean±SD). The time-activity curves from T-RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (VT=6.7±0.9, BPND=4.1±0.43) and lowest in the cortex (VT=2.1±0.5, BPND=0.60±0.23). VT T-RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ50) of MK-2637 was determined using two methods: A: Lassen plot with a population input function (Occ50=106 nM, SE=20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ50=141 nM, SE=21 nM). Synapse 69:33-40, 2015. © 2014 Wiley Periodicals, Inc.


Husted S.,Center for Clinical Pharmacology | Husted S.,Hospital Unit West
Therapeutics and Clinical Risk Management | Year: 2015

Patients with acute coronary syndrome (ACS) represent a major clinical burden, because they tend to experience recurrent ischemic events. Acute management of patients with ACS includes combination antithrombotic therapy composed of a parenteral anticoagulant and dual-antiplatelet therapy. Dual-antiplatelet therapy is also recommended for long-term secondary prevention of ACS. Despite advances in the antithrombotic therapies available, clinical trials suggest that patients with ACS still face a ~10% risk of another event within 12-15 months of the index event. Certain patient populations, such as elderly patients and those with renal impairment or heart failure, are at higher risk of recurrent ACS events, because these patients have more vascular ischemic and bleeding risk factors than most other patients. Evidence from the GRACE and CRUSADE registries suggests underuse of the guideline-recommended evidence-based therapies for the management of ACS in such patients. This review summarizes the current standard of care for patients with ACS, focusing on long-term secondary antithrombotic strategies. Registry data are used to identify high-risk patient populations; the recent antiplatelet and anticoagulant Phase III trial data are summarized to highlight any patient populations who receive greater or lesser benefit from specific long-term antithrombotic strategies. Guideline recommendations are discussed and suggestions are provided to help improve implementation of long-term secondary prevention strategies and patient prognosis after an ACS event. © 2015 Husted.


Kapil V.,Queen Mary, University of London | Milsom A.B.,Queen Mary, University of London | Okorie M.,Center for Clinical Pharmacology | Okorie M.,Institute of Child Health | And 12 more authors.
Hypertension | Year: 2010

Ingestion of dietary (inorganic) nitrate elevates circulating and tissue levels of nitrite via bioconversion in the entero-salivary circulation. In addition, nitrite is a potent vasodilator in humans, an effect thought to underlie the blood pressure-lowering effects of dietary nitrate (in the form of beetroot juice) ingestion. Whether inorganic nitrate underlies these effects and whether the effects of either naturally occurring dietary nitrate or inorganic nitrate supplementation are dose dependent remain uncertain. Using a randomized crossover study design, we show that nitrate supplementation (KNO3 capsules: 4 versus 12 mmol [n=6] or 24 mmol of KNO3 (1488 mg of nitrate) versus 24 mmol of KCl [n=20]) or vegetable intake (250 mL of beetroot juice [5.5 mmol nitrate] versus 250 mL of water [n=9]) causes dose-dependent elevation in plasma nitrite concentration and elevation of cGMP concentration with a consequent decrease in blood pressure in healthy volunteers. In addition, post hoc analysis demonstrates a sex difference in sensitivity to nitrate supplementation dependent on resting baseline blood pressure and plasma nitrite concentration, whereby blood pressure is decreased in male volunteers, with higher baseline blood pressure and lower plasma nitrite concentration but not in female volunteers. Our findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation. In addition, our post hoc analyses intimate sex differences in nitrate processing involving the entero-salivary circulation that are likely to be major contributing factors to the lower blood pressures and the vasoprotective phenotype of premenopausal women. © 2010 American Heart Association, Inc.


Tawbi H.A.,University of Pittsburgh | Beumer J.H.,University of Pittsburgh | Tarhini A.A.,University of Pittsburgh | Moschos S.,University of Pittsburgh | And 6 more authors.
Annals of Oncology | Year: 2013

Background: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. Patients and methods: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m. 2 qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). Results: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m. 2. The phase II portion enrolled 35 patients, 88 had M1c disease; 42 had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18 ORR and 61 clinical benefit rate (CR PR SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56. Grade 3/4 neutropenia was common but lasted >7 days in six patients. Conclusions: The combination of DAC and TMZ is safe, leads to 18 ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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