Dissipation and dietary risk assessment of fluoxapiprolin (and its metabolites) residues in cucumber and tomato samples under field conditions.

The present study was undertaken to understand the dissipation behaviour/kinetics of fluoxapiprolin and its metabolites in cucumber and tomato under field conditions. A QuEChERS based extraction method followed by liquid chromatography coupled to mass spectrometry (LC-MS/MS) analysis showed that all method validation parameters were within the acceptable range as per international standards with a limit of quantitation (LOQ) of 0.01 mg kg-1 for all analytes. As significant matrix effects were observed with a few metabolites, matrix matched standards were used for the whole study. Residues of fluoxapiprolin in cucumber at standard dose were steady from 0 to 3 day after application and were below LOQ on the 5th day after application. In cucumber fruit at double dose and in tomato at both the doses the residues followed second-order kinetics and were respectively ≤ LOQ from days 7 and 14 onwards. Pre-harvest intervals (PHI) of 5 days and 14 days are proposed for cucumber and tomato fruits respectively. All the metabolites were ≤ LOQ from day 0 in all the matrices. The consumer risk, assessed as Hazard Quotient (HQ), showed that HQ was ≤1 in all the cases. The results of the present study and earlier studies on other similar fungicides suggest that the use of fluoxapiprolin in cucumber and tomato fruits may not pose health or environmental hazards provided that good agricultural practices are followed and the proposed waiting period is observed. The data from the present study can be used by regulatory bodies in establishing maximum residue limits.

Behavior of trifloxystrobin and propineb as combination product in tomato (Solanum lycopersicum) and their risk assessment for human health.

Fungicides have their own unique characteristics and modes of action; a combination formulation [combination product (combi product)] of trifloxystrobin and propineb was applied to tomatoes for their dissipation kinetics and to ensure consumer safety. The combi product was applied at a 10-day interval with standard (61.25 + 1072.75 g a.i. ha-1 ) and double (122.5 + 2145.50 g a.i. ha-1 ) doses. The efficient analytical method was established using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach followed by LC-MS. The maximum residue levels of 0.15 and 0.35 mg kg-1 of trifloxystrobin were detected in tomato fruits immediately after application at standard and double doses, respectively. The corresponding levels of propineb as carbon disulfide were 0.47 and 0.90 mg kg-1 , respectively. Considering trifloxystrobin (0.7 mg kg-1 ) codex maximum residue limit and propineb as dithiocarbamate (3.0 mg kg-1 ) European Commission maximum residue limit in tomato, a pre-harvest interval of 1 day can be proposed. The anticipated residue contributions of both fungicides were far less than the acceptable daily intake. The targeted hazard quotient and hazard index were also less than 1 for both fungicides. Furthermore, the theoretical maximum residue contribution was less than its maximum permissible intake, which indicates that the consumption of tomatoes containing the measured value of each fungicide residue could not pose any health risks.

Analytical method development, validation and study on behaviour of ipfencarbazone in paddy (rice).

Supervised field trial was conducted to study persistence of a pre-emergent herbicide, ipfencarbazone (25% SC) on rice crop. Single application of two different doses, 156.25 g a.i.ha-1/625 mL formulationha-1 and 312.50 g a.i.ha-1/1250 mL formulationha-1, was applied. Method was validated to analyse ipfencarbazone in rice samples (leaf/plant, grain, straw and husk) and in soil. Initial accumulation of ipfencarbazone in rice plants was 6.72 and 14.71 mg kg-1 in standard and double dose, respectively. The residues decreased linearly with r2 values of 0.92 and 0.98 in different doses and reached below limit of quantitation (LOQ) of 0.01 µg kg-1 (for rice plant/leaf) and 0.05 µg kg-1 (for rice grain, husk, straw) on 30th and 97th (harvest) day respectively after application in both the doses. An average half-life of ipfencarbazone was approximately 4 days. Less than LOQ levels at harvest and short half-life suggest that the use of ipfencarbazone is safe, provided good agricultural practices (GAP) are followed. The data can be used by regulatory authorities like Food Safety and Standards Authority of India (FSSAI) and CODEX for establishing maximum residue limits (MRLs) of ipfencarbazone.

The Use of Continuous Ketamine for Analgesia and Sedation in Critically Ill Patients with Opioid Abuse: A Case Series.

Managing pain and agitation in patients with opioid abuse is becoming more common in intensive care units. Tolerance to commonly used agents is often observed, leading to inadequate pain control and increased agitation. Ketamine's unique mechanism of action and opioid-sparing effects make it an ideal agent for patients with suboptimal response to opioid therapy. This report describes our experience using continuous ketamine infusions for analgesia and sedation in four mechanically ventilated patients with histories of opioid abuse that had suboptimal response to standard therapy. Ketamine was successful in improving analgesia and sedation in three patients while reducing the need for other analgesics and sedatives with minimal adverse effects. Continuous ketamine infusions may be useful to facilitate mechanical ventilation in patients with histories of opioid abuse with minimal toxicity. More information is needed on the optimal dose and titration parameters.

Firefighter burn injuries: predictable patterns influenced by turnout gear.

Approximately 100 firefighters suffer fatal injuries annually and tens of thousands receive nonfatal injuries. Many of these injuries require medical attention and restricted activity but may be preventable. This study was designed to elucidate etiology, circumstances, and patterns of firefighter burn injury so that further prevention strategies can be designed. In particular, modification of protective equipment, or turnout gear, is one potential strategy to prevent burn injury. An Institutional Review Board-approved retrospective review was conducted with records of firefighters treated for burn injury from 2005 to 2009. Data collected included age, gender, TBSA, burn depth, anatomic location, total hospital days per patient, etiology, and circumstances of injury. Circumstances of injury were stratified into the following categories: removal/dislodging of equipment, failure of equipment to protect, training errors, and when excessive external temperatures caused patient sweat to boil under the gear. Over the 4-year period, 20 firefighters were treated for burn injury. Mean age was 38.9 ± 8.9 years and 19 of 20 patients were male. Mean burn size was 1.1 ± 2.7% TBSA. Eighteen patients suffered second-degree burns, while two patients suffered first-degree burns. Mean length of hospitalization was 2.45 days. Scald burns were responsible for injury to 13 firefighters (65%). Flame burns caused injury to four patients (20%). Only three patients received contact burns (15%). The face was the site most commonly burned, representing 29% of injuries. The hand/wrist and ears were the next largest groups, with 23 and 16% of the injuries, respectively. Other areas burned included the neck (10%), arm (6.5%), leg (6.5%), knees (3%), shoulders (3%), and head (3%). Finally, the circumstance of injury was evaluated for each patient. Misuse and noncontiguous areas of protective equipment accounted for 14 of the 20 injuries (70%). These burns were caused when hot steam/liquid entered the gear via gaps in the sleeve or face mask. Three patients (15%) received injury due to removal/dislodging of their safety equipment, two patients (10%) suffered their injuries during training exercises when they were not wearing their safety equipment, and the final patient (5%) received burns due to sweat evaporation. Firefighter burn injuries occur to predictable anatomic sites with common injury patterns. Modification and optimization of gear to eliminate gaps that allow steam/hot liquid entry may decrease burn injury. Improving education regarding the use of protective equipment may also be beneficial.

Modeled dalbavancin transmembrane clearance during intermittent and continuous renal replacement therapies.

BACKGROUND/AIMS: Knowledge of dalbavancin renal replacement therapy (RRT) disposition is vital to ensure appropriate dosing. In vitro models of continuous RRT and intermittent hemodialysis (IHD) were used to determine dalbavancin transmembrane clearance (CLtm). METHODS: Dalbavancin saturation and sieving coefficients (SCs) were determined for hemodialysis and hemofiltration therapies, respectively, using various hemodiafilter and effluent rate combinations. Dalbavancin CLtm estimates were calculated from observed saturation and SCs. RESULTS: Saturation and SCs for both modalities of continuous dialysis and hemofiltration and IHD with high permeability hemodiafilters were small. Nonetheless, during continuous RRT with high dialysate and ultrafiltration rates, dalbavancin CLtm (0.20-1.26 ml/min) matched and often exceeded literature-derived dalbavancin renal clearances. Dalbavancin CLtm was undetectable during IHD with low-permeability hemodialyzers, but with high-permeability hemodialyzers, substantial CLtm (1.90-2.43 ml/min) was noted. CONCLUSION: Dalbavancin CLtm is dependent on RRT modality, hemodiafilter, and effluent flow. Dalbavancin doses may need to be adjusted depending on RRT parameters.

Single-dose daptomycin pharmacokinetics in chronic haemodialysis patients.

BACKGROUND: Daptomycin has concentration-dependent antibacterial activity against Gram-positive bacteria. Its use is increasing in haemodialysis units. The manufacturer recommends a 4-6-mg/kg dose administered every 48 hrs for patients receiving haemodialysis. However, there are no published data about daptomycin pharmacokinetics and clearance during haemodialysis. The recommended dosing regimen would conflict with asymmetric thrice-weekly haemodialysis, which yields two ~44-hr and one ~68-hr interdialytic periods. This is the first study to evaluate daptomycin pharmacokinetics in haemodialysis patients, assess the extent of daptomycin dialytic removal and model serum concentrations at 44 and 68 hrs. METHODS: Six otherwise healthy subjects on chronic haemodialysis (55.3 +/- 16.1 years old, three females, 66.2 +/- 14.2 kg) received a single 6-mg/kg dose of daptomycin post-haemodialysis infused over 30 minutes. Serial blood samples were collected for ~44 hrs (pre-next haemodialysis) and throughout the subsequent haemodialysis session with a high permeability haemodialyser. Individual pharmacokinetic parameters determined by compartmental analysis were used to model trough serum concentrations at 44 and 68 hrs with 6-, 8- and 10-mg/kg post-haemodialysis doses. RESULTS: The haemodialysis session in this trial yielded mean urea and daptomycin reduction ratios of 79.6 +/- 5.8% and 57.6 +/- 9.2%, respectively. Daptomycin half-life was 19.4 +/- 6.5 and 3.8 +/- 1.1 hrs 'off' and 'on haemodialysis', respectively, with minimal rebound 1 hr post-haemodialysis. All modelled trough concentrations at 44 and 68 hrs at all doses exceed typical minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus and Enterococcus faecalis. CONCLUSIONS: Daptomycin serum concentrations declined by ~50% after a 4-hr haemodialysis session with a high permeability haemodialyser. A 6-mg/kg i.v. post-haemodialysis thrice-weekly dose should result in sufficient pre-haemodialysis daptomycin serum concentrations even after a 68-hr interdialytic period.

Novel targets in esophageal and gastric cancer: beyond antiangiogenesis.

Cancers of the stomach, gastroesophageal junction and esophagus are a major cause of cancer-related deaths worldwide. In Western countries, adenocarcinomas of the distal esophagus, gastroesophageal junction and proximal stomach have been increasing in frequency more rapidly than other malignancies. The majority of newly diagnosed patients present with advanced disease and the overall survival remains dismal at approximately 10% at 5 years. Better understanding of tumor biology has led to the development of promising novel therapeutic strategies. There is therefore increasing optimism that some of these approaches will improve the outcomes in these increasingly common cancers. Given the success of antiangiogenesis as a therapeutic strategy in various types of cancer, there are ongoing efforts to investigate the utility of other targeted therapies in the treatment of gastric and esophageal cancers. This review will focus on novel therapeutic targets other than angiogenesis and provide a rationale for the further clinical evaluation of these agents in patients with upper gastrointestinal tract cancers.

Intradialytic administration of daptomycin in end stage renal disease patients on hemodialysis.

BACKGROUND AND OBJECTIVES: Infusion of intravenous antibiotics after hemodialysis (HD) may delay initiation of treatment for the next HD shift. Intradialytic administration of drugs such as vancomycin during the final hour of HD obviates these delays. Daptomycin has potent activity against Gram-positive bacteria, but the manufacturer recommends that the dose be infused after HD ends. This study determined the pharmacokinetics of intradialytically dosed daptomycin in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective crossover study compared single-dose daptomycin (6 mg/kg, 30-min intravenous infusion) pharmacokinetics administered after HD versus during the last part of HD with high-permeability (HP) and low-permeability (LP) dialyzers to seven patients who had ESRD and were on thrice-weekly HD. Serial blood samples were collected to determine daptomycin serum concentrations and protein binding. Statistical analysis was done using linear mixed model analysis. RESULTS: The maximum serum concentration observed with a 6 mg/kg post-HD dose was 61.1 +/- 7.6 microg/ml with a mean protein binding of 89.2%. Intradialytic daptomycin administration resulted in reduced maximum serum concentration and area under the curve values that were approximately 12 to 20% lower when administered during HD with LP dialyzers and approximately 35% lower with HP dialyzers. CONCLUSIONS: Intradialytic daptomycin administration during the last 30 min of HD is feasible, provided that larger dosages are used to compensate for intradialytic drug loss. On the basis of our findings, intradialytic doses of approximately 7 mg/kg (LP) or approximately 9 mg/kg (HP) theoretically should be bioequivalent to 6 mg/kg infused after HD. The calculated dosages are mathematically driven and must be validated in prospective clinical trials.