Amiodarone Enhances Anticonvulsive Effect of Oxcarbazepine and Pregabalin in the Mouse Maximal Electroshock Model

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Age influences on Propofol estimated brain concentration and entropy during maintenance and at return of consciousness during total intravenous anesthesia with target-controlled infusion in unparalyzed patients: An observational prospective trial

Purpose Aging affects pharmacodynamics/pharmacokinetics of anesthetics, but age effects on Entropy-guided total intravenous anesthesia with target-controlled infusions (TIVA-TCI) are not fully characterized. We compared aging effects on effective estimated brain concentration of Propofol (CeP) during TIVA-TCI Entropy-guided anesthesia, without neuromuscular blockade (NMB). Methods We performed an observational, prospective, single-center study enrolling 75 adult women undergoing Entropy-guided Propofol-Remifentanil TIVA-TCI for breast surgery. Primary endpoint was the relationship between age and CeP at maintenance of anesthesia (MA) during Entropy-guided anesthesia. Secondary endpoints were relationships between age and CeP at arousal reaction (AR), return of consciousness (ROC) and explicit recall evenience. We calculated a linear model to evaluate the age’s impact on observational variable and performed pairwise tests to compare old (≥65 years, n = 50) and young (<65 years, n = 25) patients or patients with and without an AR. Results We did not observe age-related differences in CeP during MA, but CeP significantly (p = 0,01) decreased with age at ROC. Entropy values during MA increased with age and were significantly higher in the elderly (RE: median 56[IQR49.3–61] vs 47.5[42–52.5],p = 0.001; SE: 51.6[45–55.5] vs 44[IQR40-50],p = 0.005). 18 patients had an AR, having higher maximum RE (92.5[78–96.3] vs 65[56.5–80.5],p<0.001), SE (79[64.8–84] vs 61[52.5–69],p = 0.03, RE-SE (12.5[9.5–16.5] vs 6 [3–9],p<0.001. Conclusion Older age was associated with lower CeP at ROC, but not during MA in unparalysed patients undergoing breast surgery. Although RE and SE during MA, at comparable CeP, were higher in the elderly, Entropy, and in particular an increasing RE-SE, is a reliable index to detect an AR.

Analysis of Infusion Patterns of Propofol and Remifentanil During Rigid Bronchoscopy Under Total Intravenous Anesthesia

Objectives: We analyzed the dosage pattern of anesthetic drugs administered to maintain anesthesia during rigid bronchoscopy. Methods: We enrolled a total of 81 patients who underwent rigid bronchoscopy under total intravenous anesthesia between April 2015 and March 2019. Anesthesia was maintained using propofol (target brain concentration 2.0 - 6.0 µg/mL) and remifentanil (target brain concentration 2.0 - 6.0 ng/mL). We analyzed the dosage patterns of the anesthetic agents during the procedure, as well as the changes in the dose of the anesthetic agents and the number of procedures repeated in the same patient. Results: The dose of propofol administered per minute to maintain anesthesia was inversely correlated with the total operation time (r2 = 0.355, β = -0.067, P < 0.000) but was not significantly correlated with the number of times the procedure was repeated. The dose of remifentanil did not significantly differ during repeated procedures in the same patient. Conclusions: The dose of propofol infusion tended to decrease over time during the rigid bronchoscopy procedure. This pattern was specific to propofol but not to remifentanil using TIVA. Understanding the pharmacokinetic properties of anesthetic drugs will help in their appropriate administration.

Environmentally relevant levels of four psychoactive compounds vary in their effects on freshwater fish condition: a brain concentration evidence approach

Background The aquatic environment has been contaminated with various anthropogenic pollutants, including psychoactive compounds that may alter the physiology and behavior of free-living organisms. The present study focused on the condition and related mortality of the juvenile chub (Squalius cephalus). The aim of the study was to test whether the adverse effects of the antidepressants sertraline and citalopram, the analgesic tramadol and the illicit drug methamphetamine, on fish condition exist under environmentally relevant concentrations and whether these effects persist after a depuration period. Innovative analyses of the fish brain concentrations of these compounds were performed with the aim to show relationship between compound brain tissue concentration and fish condition. Methods The laboratory experiment consisted of 42 days of exposure and a subsequent 14-day depuration period with regular monitoring of the condition and mortality of exposed and control fish. Identical methodology, including individual brain concentration analyses for the tested compounds, was applied for all substances. Additional study on feeding under sertraline exposure was also conducted. The feeding was measured from the 28th day of the exposure, three times in a week, by observation of food intake during 15 minutes in social environment. Results The effects of particular psychoactive compounds on chub condition varied. While sertraline induced a lower condition and increased mortality, the effects of methamphetamine were inverse, and tramadol and citalopram had no significant effect at all. Individual brain concentrations of the tested compounds showed that the effects of sertraline and methamphetamine on fish condition were increased with brain concentration increases. Additionally, the food intake was reduced in case of sertraline. In contrast, there was no relationship between tramadol and citalopram brain tissue concentration and fish condition, suggesting that the concentration-dependent effect is strongly compound-specific. Methamphetamine was the only compound with a persistent effect after the depuration period. Our results demonstrate the suitability of the brain concentration evidence approach and suggest that changes in fish condition and other related parameters can be expected in freshwater ecosystems polluted with specific psychoactive compounds.

Perbedaan Pengaruh Terapi Audio Gelombang Alpha dan Gelombang Theta terhadap Daya Konsentrasi Otak pada Pemuda GMIM Tabita Sarongsong 1 Airmadidi 2

This study was aimed to determine the differences in the effects of audio alpha and theta waves on brain concentration power among youths of GMIM Tabita Sarongsong I Airmadidi II. This was a quantitative study with a cross-sectional design. Samples were 30 youths obtained by using the systematic sampling technique. The brain concentration power was measured by the results of solving modified mathematical problems. Data were analyzed by using descriptive analysis, the normality test of Kolmogrov-Smirov, the homogeneity test was sought by the Levene test, followed by t-test to obtain the difference in the effects of audio alpha and theta waves on the brain concentration power. The results showed the average test result, as follows: of alpha wave exposure was 8.80 while of theta wave exposure was 8.53. The t-test analysis showed a p-valued of 0.000 <0.05, this meant that there was a significant difference between the effects of audio alpha and theta waves on the brain concentration power. In conclusion, alpha and theta wave therapy could influence the brain concentration power among youths of GMIM Tabita Sarongsong I Airmadidi II, however, theta wave was more effective than alpha wave.Keywords: audio wave therapy, brain concentration powerAbstrak: Penelitian ini bertujuan untuk mengetahui perbedaan pengaruh audio gelombang alpha dan gelombang theta terhadap daya konsentrasi otak pada Pemuda GMIM Tabita Sarongsong I Airmadidi II. Jenis penelitian ialah kuantitatif dengan desain potong lintang. Pengambilan sampel menggunakan teknik sampling sistematis dengan jumlah sampel 30 orang. Daya konsentrasi otak diukur dengan hasil pengerjaan masalah matematika yang dimodifikasi. Analisis data penelitian menggunakan analisis deskriptif, uji normalitas Kolmogrov-Smirnov, uji homogenitas Levene, dilanjutkan uji-t untuk mengetahui perbedaan pengaruh audio gelombang alpha dan gelombang theta. Hasil penelitian menunjukkan bahwa rerata hasil ujian dengan paparan gelombang alpha sebesar 8,80 sedangkan hasil ujian dengan paparan gelombang theta sebesar 8,53. Hasil analisis uji-t menunjukkan nilai p=0,000 <0,05. Simpulan penelitian ini ialah terapi audio gelombang alpha dan theta dapat memengaruhi daya konsentrasi otak pada Pemuda GMIM Tabita Sarongsong I Airmadidi II namun gelombang theta lebih berpengaruh daripada gelombang alpha.Kata kunci: terapi audio gelombang, daya konsentrasi otak

Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

SummaryBackground.Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.Aim.To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.Methods.The following adenosine receptor agonists were used: A1– cyclohexyladenosine, A2A– CGS 21 680, A3– N6-benzyl-NECA and A1(preferentially) and A2– 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1and A2antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.Results.Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).Conclusion.The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.