Carcinogenicity of Styrene Oxide: Calculation of Chemical Reactivity

In this article the calculations of the activation free energy for a chemical reaction between styrene-7,8-oxide and DNA, in particular guanine at position N7, are reported. Calculations were performed by Hartree-Fock and DFT methods in conjunction with flexible basis sets. Effects of solvation were considered using the Langevin dipoles method. The calculated activation free energies are in good agreement with the experimental value of 26.52 kcal mol−1

The pharmacokinetics of levobupivacaine 0.5% after infraorbital or inferior alveolar block in anesthetized dogs

IntroductionData are lacking on the pharmacokinetic profile and safety of levobupivacaine (LB) used for regional anesthesia of the maxilla and mandibles in dogs.MethodsInfraorbital block (n = 10), inferior alveolar block (n = 10) or both infraorbital and inferior alveolar blocks (n = 10) were administered to dogs undergoing dental surgery under isoflurane anesthesia. The dose of LB was calculated as 0.11 ml/kg2/3 for the infraorbital block and 0.18 ml/kg2/3 for the inferior alveolar block. Blood samples were collected before and immediately after administration of the oral blocks, and 3, 4, 7, 12, 17, 32, 47, 62, 92, and 122 min thereafter. Quantification of LB in plasma was performed by LC-MS/MS.Results and discussionThe results are presented as median and interquartile range. In dogs in which all four quadrants of the oral cavity were desensitized with LB, the Cmax was 1,335 (1,030–1,929) ng/ml, the Tmax was 7 (4–9.5) min, and the AUC(0 → 120) was 57,976 (44,954–96,224) ng min/ml. Plasma concentrations of LB were several times lower than the reported toxic concentrations, and no signs of cardiovascular depression or neurotoxicity were observed in any of the dogs, suggesting that the occurrence of severe adverse effects after administration of LB at the doses used in this study is unlikely

Expression of serotonin receptor subtypes in rat brain and astrocyte cell cultures: an ageand tissue-dependent process

Background and Purpose: Serotonin (5-HT) mediates its effects on neuronal and non-neuronal cells in rat brain through thirteen receptor subtypes. To obtain better insight into 5-HT responsive cells, we investigated the expression of all known rat 5-HT receptors in various brain regions, at various animal ages, and in various sample types. Materials and Methods: The presence of all 5-HT receptor mRNAs was studied with the reverse transcriptase-polymerase chain reaction (RT-PCR) in eight sample groups. We isolated brain cortex and erebellum from 3-day-old and adult Wistar rats of both sexes, which were used directly for the experiment and for growing the astrocyte cell cultures.We performed the experiment on the astrocyte cell cultures after 3 weeks of growth in culture. Results and Conclusions:We determined that neonatal brain tissue and astrocyte cultures from neonatal rats express more 5-HT receptor subtypes than their adult counterparts. In all tissue samples we detected the same or a larger number of 5-HT receptor subtypes than in the corresponding astrocyte cultures. The expression pattern of 5-HT receptor subtypes also differed between rat cortex and cerebellum. Only subtypes 5-HT1B and 5-HT2A were found in all the samples studied, and we did not detect the message for subtype 5-HT3 in any of the samples. In conclusion, the expression of 5-HT receptors is age- and brain region-dependent, and astrocyte cultures do not reflect the situation in vivo

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N–H and O–H bonds to assess the effect of deuteration on the binding of agonists (2-methylhistamine and 4-methylhistamine) and antagonists (cimetidine and famotidine) to the histamine H2 receptor. The results show that deuteration significantly increases the affinity for 4-methylhistamine and reduces it for 2- methylhistamine, while leaving it unchanged for both antagonists, which is found in excellent agreement with experiments. The revealed trends are interpreted in the light of the altered strength of the hydrogen bonding upon deuteration, known as the Ubbelohde effect, which affects ligand interactions with both active sites residues and solvent molecules preceding the binding, thus providing strong evidence for the relevance of hydrogen bonding for this process. In addition, computations further underline an important role of the Tyr250 residue for the binding. The obtained insight is relevant for the therapy in the context of (per)deuterated drugs that are expected to enter therapeutic practice in the near future, while this approach may contribute towards understanding receptor activation and its discrimination between agonists and antagonists

Degradation of water soluble poly(vinyl alcohol) with acoustic and hydrodynamic cavitation: laying foundations for microplastics

Abstract Water-soluble poly(vinyl alcohol) (PVOH) is widely used in the textile and paper industries and in households as detergent pods. In addition to conventional microplastics, water-soluble PVOH poses an environmental threat because it is usually washed down the drain unnoticed and unobstructed. If not treated during wastewater treatment, it enters the aquatic ecosystem in estimated quantities of several thousand tons annually. The present study aims to address the degradation of PVOH on a laboratory scale by acoustic and hydrodynamic cavitation, assisted or not with an oxidative agent. A hydrodynamic cavitation generator, designed with consideration for real-life application, presents an innovative technology adapted for wastewater treatment. The effects of temperature, addition of external oxidant, and methanol as a hydroxyl radical (•OH) scavenger to PVOH solutions were systematically studied. At optimal operating conditions, PVOH molar mass averages significantly decreased (from weight average molar mass of 124 to 1.6 kg mol−1 in case of 60 min treatment with hydrodynamic cavitation and addition of external oxidant) with concomitant narrowing of molar mass distribution. The SEC/MALS, FTIR, and 1H NMR results show that mechanical degradation of PVOH chains predominates in acoustic cavitation, while chemical effects also play an important role in hydrodynamic cavitation. Findings from this study could serve as model research for the degradation of other carbon-backbone polymers and provide a route to improved ultimate (bio)degradation of functionalized polymers in the environment

Pharmacokinetics of carprofen in anaesthetized pigs

Objective To investigate the pharmacokinetics of carprofen after a single intravenous (IV) dose and multiple oral doses administered to pigs undergoing electroporation of the pancreas. Study design Prospective experimental study. Animals A group of eight female pigs weighing 31.74 ± 2.24 kg (mean ± standard deviation). Methods Carprofen 4 mg kg−1 was administered IV after placement of a central venous catheter during general anaesthesia with isoflurane. Blood samples were collected 30 seconds before and 5, 10, 20, 30 and 60 minutes and 2, 4, 6, 8, 12 and 24 hours after carprofen administration. Subsequently, the same dose of carprofen was administered orally, daily, for 6 consecutive days and blood collected at 36, 48, 60, 72, 96, 120, 144 and 168 hours after initial carprofen administration. Plasma was analysed using liquid chromatography with mass spectrometry. Standard pharmacokinetic parameters were calculated by compartmental analysis of plasma concentration–time curves. Data are presented as mean ± standard error. Results The initial plasma concentration of IV carprofen was estimated at 54.57 ± 3.92 μg mL−1 and decreased to 8.26 ± 1.07 μg mL−1 24 hours later. The plasma elimination curve showed a bi-exponential decline: a rapid distribution phase with a distribution half-life of 0.21 ± 0.03 hours and a slower elimination phase with an elimination half-life of 17.31 ± 3.78 hours. The calculated pharmacokinetic parameters were as follows: the area under the plasma concentration–time curve was 357.3 ± 16.73 μg mL−1 hour, volume of distribution was 0.28 ± 0.07 L kg−1 and plasma clearance rate was 0.19 ± 0.009 mL minute−1 kg−1. The plasma concentration of carprofen, administered orally from days 2 to 7, varied from 9.03 ± 1.87 to 11.49 ± 2.15 μg mL−1. Conclusions and clinical relevance Carprofen can be regarded as a long-acting non-steroidal anti-inflammatory drug in pigs

Cardiopulmonary effects and pharmacokinetics of dexmedetomidine used as an adjunctive analgesic to regional anesthesia of the oral cavity with levobupivacaine in dogs

This study investigated the cardiopulmonary effects and pharmacokinetics of dexmedetomidine (DEX) used as an adjunctive analgesic for regional anesthesia of the oral cavity with levobupivacaine in anesthetized dogs. Forty dogs were randomly assigned to four groups of 10 dogs. All dogs received levobupivacaine (4 blocks) with DEX IO (infraorbital block, n = 10) or IA (inferior alveolar block, n = 10) or placebo (PLCn = 10) or DEX (n = 10) was injected intravenously (IV) after administration of levobupivacaine. The dose of DEX was always 0.5 µg/kg. Cardiopulmonary parameters were recorded, and blood was drawn for the quantification of DEX in plasma using LC-MS/MS. Heart rate was lower in all LB + DEX groups, while mean arterial pressure (MAP) was higher in the LB + DEX IV and LB + DEX IA groups compared to the LB + PLC IV group. Compared to DEX IV, IO and IA administration resulted in lower MAP up to 2 min after application. Absorption of DEX was faster at IO administration (Cmax and Tmax were 0.47 ± 0.08 ng/mL and 7.22 ± 1.28 min and 0.76 ± 0.09 ng/mL and 7.50 ± 1.63 min for the IO and IA block, respectively). The IA administration resulted in better bioavailability and faster elimination (t1/2 was 63.44 ± 24.15 min and 23.78 ± 3.78 min for the IO and IA block, respectively). Perineural administration of DEX may be preferable because of the less pronounced cardiovascular response compared to IV administration

Intoxication in a pig (Sus scrofa domesticus) after transdermal fentanyl patch ingestion

An experimental study on the effects of electroporation on pancreatic tissue was performed in pigs, and the fentanyl transdermal patch (FTP) was used postoperatively as part of multimodal pain management. Ingestion of an FTP, which resulted in fentanyl intoxication, was suspected 5 days after placement in one of the experimental pigs. The pig was first dysphoric, running in the stall, panting and vocalizing until it finally became depressed and it remained lying on the floor. Ingestion of an FTP was not observed but the fentanyl plasma concentration on the day of intoxication was 20.7 ng/ml, while at its peak after FTP administration it was only 0.492 ng/ml. The intoxication was successfully treated with a single intramuscular naloxone injection

Bleomycin concentration in patientsʹ plasma and tumors after electrochemotherapy

The plasma concentration profile of bleomycin in the distribution phase of patients younger than 65 years is needed to determine the suitable time interval for efficient application of electric pulses during electrochemotherapy. Additionally, bleomycin concentrations in the treated tumors for effective tumor response are not known. In this study, the pharmacokinetic profile of bleomycin in the distribution phase in 12 patients younger than 65 years was determined. In 17 patients, the intratumoral bleomycin concentration was determined before the application of electric pulses. In younger patients, the pharmacokinetics of intravenously injected bleomycin demonstrated a faster plasma clearance rate than that in patients older than 65 years. This outcome might indicate that the lowering of the standard bleomycin dose of 15,000 IU/m$^2$ with intravenous bleomycin injection for electrochemotherapy is not recommended in younger patients. Based on the plasma concentration data gathered, a time interval for electrochemotherapy of 5–15 min after bleomycin injection was determined. The median bleomycin concentration in tumors 8 min after bleomycin injection, at the time of electroporation, was 170 ng/g. Based on collected data, the reduction of the bleomycin dose is not recommended in younger patientshowever, a shortened time interval for application of electric pulses in electrochemotherapy to 5–15 min after intravenous bleomycin injection should be considered