The effect of exenatide (a GLP-1 analogue) and sitagliptin (a DPP-4 inhibitor) on asymmetric dimethylarginine (ADMA) metabolism and selected biomarkers of cardiac fibrosis in rats with fructose-induced metabolic syndrome.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis. We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism. Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections. Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis. In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.

Pharmacokinetics of propofol in rainbow trout following bath exposure.

Propofol, 2,6-diisopropylphenol, seems to be a good candidate as a fish anaesthetic, however, no study regarding propofol influence on fish has yet been reported. The aim of this study was to examine propofol pharmacokinetics in rainbow trout (Oncorhynchus mykiss) following bath exposure. Fish (n = 100) were exposed to an aqueous propofol bath at 12°C and 17°C; propofol concentration in the bath was 10 mg L(-1). Plasma concentration-time profiles were determined using LC-MS, and pharmacokinetic parameters were calculated. Propofol was absorbed quickly at both temperatures. Its concentration reached 13.8 ± 2.7 µg mL(-1) and 16.1 ± 2.1 µg mL(-1) at 12°C and 17°C, respectively, during the first minute of exposure. Blood plasma propofol decreased rapidly to 6.8 ± 0.7 µg mL(-1) and 6.3 ± 2.2 µg mL(-1) at 12°C and 17°C respectively, during the first 10 minutes of the recovery. The half-life time of propofol was 1.5 h and 1.1 h at 12°C and 17°C, respectively. We found propofol anaesthesia in trout effective and safe. However, it caused a gradual decrease of respiratory rate, and therefore a specific anaesthesia protocol should be developed.

Influence of blood cell transfusion on the presence of propofol in blood components.

BACKGROUND: Understanding propofol distribution in blood is important for optimizing drug usage during TIVA. We studied changes in the propofol concentration in plasma and formed blood elements separated from blood samples taken before and after transfusion of blood cells to patients during TIVA with propofol. MATERIAL AND METHODS: Twelve patients were studied (ASA I-II). Propofol TIVA was performed at infusion rates of 12-9-6 mg x kg(-1) x h(-1). Fentanyl and pancuronium bromide were administered in fractional doses. After tracheal intubation the lungs were ventilated to normocapnia with oxygen-air mixture (FiO2=0.33). Blood samples for propofol analysis were taken 5 min before and 30 min after blood cell transfusion. At that point the propofol infusion rate was 6 mg x kg(-1) x h(-1). Propofol concentrations were measured by means of HPLC. RESULTS: Blood cell transfusion leads to a change in the propofol level in plasma and formed blood elements. The transfusion process lowers the ratio of the plasma propofol concentration to the propofol concentration in formed blood elements. CONCLUSIONS: Formed blood elements show a greater ability to bind propofol after transfusion of 5-15 day erythrocytes.

The influence of blood sample storage time on the propofol concentration in plasma and solid blood elements.

In order to describe the changes of propofol concentration in whole blood and in its components during the blood storage we examined venous blood samples collected from patients anaesthetized either with or without propofol. Blood samples from patients anaesthetized without propofol were spike with propofol 45 min before analysis. Propofol concentration was examined in whole blood, plasma, rinsed formed elements and rinsed and lysed formed blood elements by means of HPLC after 1, 4, 7, 13, 21, 25 and 28 days of storage. There was significant decrease in plasma concentration of propofol during the first few days of sample storage followed by its increase during subsequent days. The opposite phenomenon was observed for formed blood elements. The findings support the hypothesis that propofol distribution between blood components changes in time.

The advantages of cell lysis before blood sample preparation by extraction for HPLC propofol analysis.

Propofol (2,6-diisopropylphenol) is a short-acting drug with a large volume of distribution and high body clearance. It is suitable both for the induction of anaesthesia by bolus injection and the maintenance of anaesthesia by repeated injections or a continuous infusion. Examining the drug concentration its analysis in whole blood is recommended. This results from the fact that propofol molecules strongly bind with plasma proteins and cellular blood constituents and blood composition variations are observed between individuals or in different disease states or resulting from transfusion etc. In most cases the HPLC analysis follows the extraction of samples. The degree of propofol binding with blood cells can be different, depending on the blood type, and it can change in time, which may affect the results of the analysis. The paper discusses and shows the necessity of blood cell lysis before the extraction procedure. The cell lysis makes possible to determine the total amount of propofol in blood independently of the degree of propofol binding with cellular blood constituents and its changes.

The role of human lungs in the biotransformation of propofol.

BACKGROUND: The metabolism of propofol is very rapid, and its transformation takes place mainly in the liver. There are reports indicating extrahepatic metabolism of the drug, and the alimentary canal, kidneys, and lungs are mentioned as the most probable places where the process occurs. The aim of this study was to determine whether the human lungs really take part in the process of propofol biotransformation. METHODS: Blood samples were taken from 55 patients of American Society of Anesthesiologists grade 1-3 scheduled for elective intracranial procedures (n = 47) or for pulmonectomy (n = 8). All patients were premedicated with diazepam (10 mg) administered orally 2 h before anesthesia. Propofol total intravenous anesthesia was performed at the following infusion rates: 12 mg. kg-1. h-1, 9 mg. kg-1. h-1, and 6 mg. kg-1. h-1. Fentanyl and pancuronium bromide were also administered intermittently. After tracheal intubation, the lungs were ventilated to normocapnia with an oxygen-air mixture (fraction of inspired oxygen = 0.33). Blood samples for propofol and 2,6-diisopropyl-1, 4-quinol analysis were taken simultaneously from the right atrium and the radial artery, or the pulmonary artery and the radial artery. The concentration of both substances were measured with high-performance liquid chromatography and gas chromatography-mass spectroscopy. RESULTS: The concentration of propofol in the central venous system (right atrium or pulmonary artery) is greater than in the radial artery, whereas the opposite is observed for propofol's metabolite, 2,6-diisopropyl-1,4-quinol. Higher propofol concentrations are found in blood taken from the pulmonary artery than in the blood collected from the radial artery. CONCLUSIONS: Human lungs take part in the elimination of propofol by transforming the drug into 2,6-diisopropyl-1,4-quinol.

Determining the influence of storage time on the level of propofol in blood samples by means of chromatography.

Due to unsatisfactory equipment efficiency and the time consuming manual procedures of sample preparation, drug analyses in physiological fluids and tissues frequently have to be carried out a few days after the sample collection. This is especially the case with investigations which require the examination of materials for which a large number of samples is necessary. The paper deals with the influence of storing blood samples on the level of propofol in blood and plasma. Propofol (2,6-diisopropylphenol, Diprivan) is a very popular intravenous agent used both for the induction and the maintenance of anaesthesia in human and veterinary patients as well as in laboratory animals. The results obtained show that, due to distinct losses of propofol in samples during their storage, the comparison of data estimated for subsequent days after sampling can lead to misleading or even wrong conclusions. The speed of drug diminution depends both on the type of blood and the anticoagulant used. The established interdependencies between the change in the level of propofol in blood and plasma samples and their storage time show that analogous investigations of other pharmaceutical agents are necessary.