Sunitinib–ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain,liver, and kidney in male and female mice differently

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC_0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC_0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC_0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue‐to‐plasma AUC_0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6‐fold higher liver‐to‐plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue‐to‐plasma partial AUC ratio, the drug tissue targeting index, and the tissue‐plasma hysteresis‐like plots also showed sex‐based ibuprofen–sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender‐based P450 and efflux/transporters differences.     

Utility of flexion–extension radiography for the detection of ligamentous cervical spine injury and its current role in the clearance of the cervical spine

Detecting the presence of injuries to the cervical spine is an important component of the initial assessment of patients sustaining blunt trauma. A small proportion of cervical spine injuries consists of ligamentous disruption. Accurate detection of ligamentous injury is essential as it may result in sequelae including radiculopathy, quadriplegia and death. Flexion–extension (FE) radiography has traditionally been utilised for the detection of ligamentous injury in patients who have been cleared of bony injury. There are controversies surrounding the use of FE for alert patients with neck pain. There are studies that call into question the diagnostic accuracy of FE, the high proportion of inadequate FE images due to muscle spasm and the adverse effects of prolonged cervical collar immobilisation while awaiting FE. Other literature indicates that FE provides no additional diagnostic information following a multi‐detector helical computed tomography. This review evaluates the literature on the utility of FE for the detection of ligamentous injury and explores alternate strategies for clearing the cervical spine of ligamentous injury.     

Combined influence of proton‐pump inhibitors,calcium‐channel blockers and CYP2C19*2 on on‐treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention

Summary. Background: The carriage of CYP2C19*2 and the use of proton‐pump inhibitors (PPIs) and calcium‐channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response. Objectives: The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on‐treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting. Methods: In a prospective, follow‐up study, on‐treatment platelet reactivity was quantified using ADP‐induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all‐cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting. Results: Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty‐four events occurred during follow‐up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)_adj 2.2 95% CI, 1.0–5.3, P = 0.044 and HR_adj 3.3 95% CI, 1.1–9.8, P = 0.032, respectively]. Conclusions: The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.     

Inhibition of MAP kinases and down regulation of TNF-α, IL-β and COX-2 genes by the crude extracts from marine bacteria

Crude ethyl acetate extracts from marine bacterial isolates Staphylococcus arlettae KP2 (GenBank accession No. EU594442) and Planococcus maritimus KP8 (GenBank accession No. EU594443) isolated from Andaman seas were studied for their anti-inflammatory effect by lymphocyte proliferation assay (LPA) employing peripheral blood mononuclear cells (PBMCs). The crude extracts from both the bacteria down regulated the synthesis of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2), besides markedly inhibiting p38 mitogen activated protein (MAP) kinase. These results suggest that the crude ethyl acetate extracts from both the isolates do contain compounds capable of inhibiting inflammation in mitogen induced PBMC and efforts to score potential bioactive molecules from these extracts may prove to be a promising preposition.     

The comparison of the effects of anesthetic doses of ketamine,propofol, and etomidate on ischemia–reperfusion injury in skeletal muscle

The fact that a considerable amount of clinical conditions suffering from ischemia–reperfusion injury (IRI) occur under general anesthesia has triggered researchers to focus on the effects of anesthetic drugs on IRI. Hence, the aim of this study was to compare the use of different anesthetic drugs in a skeletal IRI model. Tourniquet IRI method was performed and two experimental groups were established as sham‐control and IRI group. Rats in each group were anesthetized either with thiopental, ketamine, propofol or etomidate. Malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase were measured in skeletal muscle via a spectrophotometer. Zinc, iron, copper, and selenium were evaluated by atomic absorption spectrophotometer. In rats anesthetized with thiopental (40 mg/kg, i.p.), malondialdehyde values in IRI group were higher and glutathion peroxidase levels were lower compared to sham‐control group. However, superoxide dismutase and catalase activities were identical. On the other hand, while the level of zinc in IRI group attenuated, no differences in iron and copper values were determined. Rats anesthetized with ketamine (60 mg/kg), propofol (100 mg/kg), or etomidate (20 mg/kg) did not show increased malondialdehyde levels in comparison with control levels. While the drugs did not cause a distinction in the levels of superoxide dismutase, catalase, glutathion peroxidase, iron, and copper, zinc was in a lower level in IRI group compared to sham‐control. In conclusion, ketamine, propofol, and etomidate, with anesthetic doses, denoted efficacious effects on IRI; hence the drugs might be preferred in certain operations with the risk of IRI.     

Effect of Mandated Nurse–Patient Ratios on Patient Wait Time and Care Time in the Emergency Department

Objectives: The objective was to evaluate the effect of mandated nurse–patient ratios (NPRs) on emergency department (ED) patient flow. Methods: Two institutions implemented an electronic tracking system embedded within the electronic medical record (EMR) of two EDs (an academic urban, teaching medical center—Hospital A; and a suburban community hospital—Hospital B), with a combined census of 60,000/year, to monitor real‐time NPRs and patient acuity, such that compliance with state‐mandated ratios could be prospectively monitored. Data were queried for a 1‐year period after implementation and included patient wait times (WTs), ED care time (EDCT), patient acuity, ED census, and NPR status for each nurse, patient, and the ED overall. Median WT and EDCT with interquartile ranges (IQRs) were analyzed to determine the effect of NPR status of each patient, nurse, and the ED overall. To control for factors that could affect the “within the mandated ratio” and the “outside of the mandated ratio” status, including patient volume and acuity, log‐linear regression models were used controlling for specified factors for each hospital facility and combined. Results: There were a total of 30,404 (50.9%) patients who waited in the waiting room prior to being placed in an ED bed (53.8% at Hospital A and 46.4% at Hospital B). Patients who waited at Hospital A waited a median duration of 55 minutes (IQR = 15–128 minutes), compared with 32 minutes (IQR = 12–67 minutes) at Hospital B with a combined median WT of 44 minutes (IQR = 13–101 minutes). In the log‐linear regression analysis, WTs were 17% (95% confidence interval [CI] = 10% to 25%, p < 0.001) longer at Hospital A and 13% (95% CI = 3% to 24%, p = 0.008) longer at Hospital B (combined 16% [95% CI = 10% to 22%, p < 0.001] longer at both sites) when the ED overall was out‐of‐ratio compared to in‐ratio. There were a total of 45,660 patients discharged from both EDs during the study period, from which EDCT data were collected (26,894 in Hospital A and 18,766 in Hospital B). Median EDCT was 184 minutes (IQR = 97–311 minutes) at Hospital A, compared to 120 minutes (IQR = 63–208 minutes) at Hospital B, for a combined median EDCT of 153 minutes (IQR = 81–269 minutes). In the log‐linear regression analysis, the EDCT for patients whose nurse was out‐of‐ratio were 34% (95% CI = 30% to 38%, p < 0.001) longer at Hospital A and 42% (95% CI = 37% to 48%, p < 0.001) longer at Hospital B (combined 37% [95% CI = 34% to 41%, p < 0.001] longer at both sites) when compared to patients whose nurse was in‐ratio. Conclusions: In these two EDs, throughput measures of WT and EDCT were shorter when the ED nurse staffing were within state‐mandated levels, after controlling for ED census and patient acuity. ACADEMIC EMERGENCY MEDICINE 2010; 17:545–552 © 2010 by the Society for Academic Emergency Medicine