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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.

Ivashchenko C.Y.,Metabolic Pathways CEDD | Bradley B.T.,Metabolic Pathways CEDD | Ao Z.,Metabolic Pathways CEDD | Leiper J.,Center for Clinical Pharmacology | And 2 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

Asymmetric dimethylarginine (ADMA) has been implicated in the progression of cardiovascular disease as an endogenous inhibitor of nitric oxide synthase. The regulation of dimethylarginine dimethyl-aminohydrolase (DDAH), the enzyme responsible for metabolizing ADMA, is poorly understood. The transcription factor sterol response element binding protein (SREBP) is activated by statins via a reduction of membrane cholesterol content. Because the promoters of both DDAH1 and DDAH2 isoforms contain sterol response elements, we tested the hypothesis that simvastatin regulates DDAH1 and DDAH2 transcription via SREBP. In cultured endothelial cells, simvastatin increased DDAH1 mRNA expression compared with vehicle. In an ADMA loading experiment, simvastatin treatment resulted in a decrease in ADMA content, an indication of increased DDAH activity. The knockdown of SREBP1c protein led to an increase in DDAH1 mRNA expression and activity, whereas the knockdown of SREBP2 led to a decrease in DDAH1 mRNA expression. The role of SREBP2 in the activation of the DDAH1 was supported by chromatin immuno-precipitation studies demonstrating increased binding of SREBP2 to the DDAH1 promoter upon simvastatin stimulation. These data indicate that SREBP1c might act as a repressor and SREBP2 as an activator of DDAH transcription and activity. This study describes a novel mechanism of reciprocal regulation by the SREBP family members of the DDAH-ADMA system, which represents a potential link between cellular cholesterol content and endothelial dysfunction observed in cardiovascular disease. © 2010 the American Physiological Society.

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.

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.

Dragojevic-Simic V.,Center for Clinical Pharmacology | Dragojevic-Simic V.,University of Belgrade | Dobric S.,Institute for Scientific Information | Dobric S.,University of Belgrade | And 10 more authors.
Vojnosanitetski Pregled | Year: 2013

Background/Aim. Amifostine (AMI) is a broad-spectrum cytoprotector which protects against variety of radio-and chemotherapy-related toxicities without decreasing their antitumor action. The aim of the study was to investigate the potential protective effects of AMI against acute cardiotoxic effects of doxorubicin (DOX) in male Wistar rats. Methods. AMI (300 mg/kg ip) was given 30 min before DOX (6 mg/kg and 10mg/kg b.w., iv). The evaluation of DOX- induced cardiotoxic effects, as well as cardioprotective efficacy of AMI was performed 48 h after their administration by determining serum activities of enzymes known to be markers of cardiac damage (creatine kinase - CK, aspartate aminotransferase - AST, lactate dehydrogenase - LDH, and its isoenzyme α-hydroxybutirate dehydrogenase - α - HBDH), as well as the histopathological and ultrastructural analysis of the heart tissue. Results. AMI successfully prevented a significant increase in serum activity of CK, AST, LDH and α -HBDH in animals treated with DOX in the dose of 6 mg/kg (121.14 ± 18.37 vs 167.70 ± 44.24; 771.42 ± 161.99 vs 1057.00 ± 300.00; 3230.00 ± 1031.73 vs 4243.10 ± 904.06; 202.57 ± 42.46 vs 294.90 ± 80.20 UI/l, respectively), and ameliorated DOX-induced structural damage of the rat myocardium. Pretreatment with AMI in rats given 10 mg/kg DOX reduced the cardiac damage score (CDS) from 2.62 ± 0.51 to 1.62 ± 0.51, i.e. to the CDS value obtained with the lower dose of DOX (6 mg/kg). The ultrastructural analysis of the rat myocardium showed that AMI successfully protected the sarcolemma of cardiomyocytes and reduced mitochondria damage induced by DOX given in the dose of 6 mg/kg. Besides, capillaries were less morphologically changed and apoptosis of endothelial cells was extremely rare in AMI-protected animals. AMI itself did not cause any prominent changes in the examined parameters in comparison with the control rats. Conclusion. AMI provided a significant protection against DOX-induced acute cardiotoxic effects in rats. This finding implies its potential to be a successful cardioprotector in patients treated with DOX due to malignant diseases.

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