Nifedipin ublažava djelovanje kokaina na enzimsku aktivnost u mozgu i jetri te smanjuje njegovo izlučivanje putem mokraće

The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. Male Wistar rats were divided in four groups of six: control, nifedipine group (5 mg kg-1 i.p. a day for five days); cocaine group (15 mg kg-1 i.p. a day for five days), and the nifedipine+cocaine group. Twenty-four hours after the last administration, we measured neuronal nitric oxide synthase (nNOS) activity in the brain and cytochrome P450 quantity, ethylmorphine-N-demethylase, and anilinehydroxylase activity in the liver. Urine samples were collected 24 h after the last cocaine and cocaine+nifedipine administration. Urinary cocaine concentration was determined using the GC/MS method. Cocaine administration increased brain nNOS activity by 55 % (p<0.05) in respect to control, which indicates the development of tolerance and dependence. In the combination group, nifedipine decreased the nNOS activity in respect to the cocaine-only group. In the liver, cocaine significantly decreased and nifedipine significantly increased cytochrome P450, ethylmorphine-N-demethylase, and anilinehydroxylase in respect to control. In combination, nifedipine successfully countered cocaine effects on these enzymes. Urine cocaine excretion in the cocaine+nifedipine group significantly dropped (by 35 %) compared to the cocaine-only group. Our results have confirmed the effects of nifedipine against cocaine tolerance and development of dependence, most likely due to metabolic interactions between them.Cilj je ovoga istraživanja bio utvrditi kako nifedipin ublažava djelovanje kokaina na enzimsku aktivnost u mozgu i jetri Wistar štakora te utječe li na njegovo izlučivanje putem mokraće. Mužjaci su podijeljeni u četiri skupine po šest jedinki: kontrolnu skupinu, nifedipinsku skupinu koja je pet dana intraperitonealno primala nifedipin u dozi od 5 mg kg-1; skupinu koja je pet dana primala kokain u dozi od 15 mg kg-1 na dan te skupinu koja je zajedno primala nifedipin i kokain u odgovarajućim dozama. Dvadeset i četiri sata nakon posljednje doze izmjerena je enzimska aktivnost sintaze dušičnoga oksida (nNOS) u mozgu, razina citokroma P450 te aktivnosti enzima etilmorfi n-N-demetilaze i anilinhidroksilaze u jetri štakora. Uzorci mokraće prikupljeni su 24 sata nakon posljednje doze kokaina odnosno kombinacije nifedipina i kokaina. Koncentracija kokaina u mokraći izmjerena je s pomoću vezanog sustava plinske kromatografi je i spektrometrije masa. Kokain je povećao aktivnost nNOS-a u mozgu za 55 % (p<0,05) u odnosu na kontrolnu skupinu, što upućuje na stvaranje tolerancije i ovisnosti. U kombiniranoj skupini nifedipin je značajno smanjio aktivnost nNOS-a u odnosu na skupinu koja je primila samo kokain. Kokain je značajno snizio, a nifedipin značajno povisio razinu citokroma P450 u jetri te aktivnost etilmorfi n-N-demetilaze i anilinhidroksilaze u odnosu na kontrolnu skupinu. U kombiniranoj skupini nifedipin je uspješno ublažio djelovanje kokaina na aktivnost spomenutih enzima. Izlučivanje kokaina putem mokraće u kombiniranoj skupini bilo je značajno manje (35 %) nego u skupini koja je primala samo kokain. Ovi rezultati potvrđuju da nifedipin štiti od djelovanja kokaina i stvaranja ovisnosti, najvjerojatnije zbog interakcija u metabolizmu dvaju spojeva

Promjene citokroma P450 jetre i mozga nakon višekratne primjene kokaina, samog ili u kombinaciji s nifedipinom

The objective of this study was to evaluate possible changes caused by multiple cocaine administration, alone and in combination with 1,4-dihydropiridine calcium channel blocker nifedipine, on cytochrome P450 levels both in the brain and liver. The experiment was done on male Wistar rats divided in four groups: control, treated with nifedipine (5 mg kg-1 i.p. for five days), treated with cocaine (15 mg kg-1 i.p. for five days), and treated with nifedipine and 30 minutes later with cocaine (also for five days). Total cytochrome P450 was measured spectrometrically in liver and brain microsomes. Multiple administration of cocaine alone and in combination with nifedipine did not change the brain P450 significantly. In the liver, nifedipine significantly increased P450 by 28 % vs. control. In contrast, cocaine significantly decreased P450 by 17 % vs. control. In animals treated with nifedipine and cocaine, cytochrome P450 increased 11 % (p<0.01) vs. control, decreased 12.5 % (p<0.001) vs. nifedipine group and increased 34 % (p<0.0001) vs. cocaine group. These results suggest that the cocaine and nifedipine interact at the metabolic level.Cilj je ovog istraživanja bio ocijeniti moguće promjene uzrokovane višestrukom primjenom kokaina kao jedinog agensa odnosno u kombinaciji s nifedipinom, 1,4-dihidropiridinskim blokatorom kalcijevih kanala, na razine citokroma P450 u mozgu i jetri štakora. Životinje (mužjaci Wistar štakora) podijeljene su u četiri skupine: kontrolnu skupinu, skupinu koja je primala nifedipin (5 mg kg-1 ip. pet dana), skupinu koja je primala kokain (15 mg kg-1 ip. pet dana) i skupinu koja je primala nifedipin te pola sata kasnije kokain (također pet dana). Ukupna količina citokroma P450 mjerena je spektrofotometrijski u mikrosomima jetre i mozga. Višestruka primjena samo kokaina odnosno u kombinaciji s nifedipinom nije značajno promijenila razine citokroma P450 u mozgu. U jetri je međutim nifedipin u odnosu na kontrolnu skupinu uzrokovao povišenje razina P450, za statistički značajnih 28 %. Kokain je uzrokovao statistički značajan pad razine P450 za 17 % u odnosu na kontrolnu skupinu. U životinja koje su primale kombinaciju nifedipina i kokaina razina citokroma P450 narasla je za 11 % (p<0.01) u odnosu na kontrolu, bila je 12.5 % (p<0.001) niža u odnosu na skupinu koja je primala nifedipin te viša za 34 % (p<0.0001) u odnosu na skupinu koja je primala samo kokain. Rezultati ovog istraživanja upućuju na interakcije ovih spojeva koje se odvijaju na razini metabolizm

Effect of cytisine on some brain and hepatic biochemical parameters in spontaneously hypertensive rats

Tobacco smoking is a risk factor for variety of cardio-vascular diseases, such as hypertension, myocardial infarction, stroke and many others. It is of great importance for hypertensive patients to stop smoking. One of the medicines widely used for smoking cessation in Bulgaria is the original Bulgarian product Tabex®, which is developed on the basis of natural plant alkaloid cytisine. The aim of the following study was to ivestigate the effects of cytisine on some brain and hepatic biochemical parameters in spontaneously hypertensive rats (SHR), an widely used rodent model for human essential hypertension, and to compare the obtained results with their age-matched normotensive controls Wistar Kyoto (WKY). Multiple cytisine administration did not affect the activity of ethylmorphine-N-demethylase (EMND) and anylinehydroxylase (AH), as well as the quantity of cytochrome P 450, nor in WKY neither in SHR In the liver cytisine increased the MDA quantity both in SHR and in WKY, by 25% (p<0.05) and by 29% (p<0.05) respectively, while the GSH level was not significantly changed by the compound in both strains. In contrast, on the brain level, cytisine administration to SHR caused more prominent toxicity, resulted in GSH depletion and increased MDA quantity, while in WKY strain did not exert any toxicity. Cytisine did not significantly affect ALAT and ASAT activity in both strains. In conclusion, the results of our study suggest higher brain toxicity of cytisine in spontaneously hypertensive rats, that might be due to their pathophysiological characteristics

The NEVERMIND e-health system in the treatment of depressive symptoms among patients with severe somatic conditions: A multicentre, pragmatic randomised controlled trial

Background This study assessed the effectiveness of the NEVERMIND e-health system, consisting of a smart shirt and a mobile application with lifestyle behavioural advice, mindfulness-based therapy, and cognitive behavioural therapy, in reducing depressive symptoms among patients diagnosed with severe somatic conditions. Our hypothesis was that the system would significantly decrease the level of depressive symptoms in the intervention group compared to the control group.Methods This pragmatic, randomised controlled trial included 425 patients diagnosed with myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants were recruited from hospitals in Turin and Pisa (Italy), and Lisbon (Portugal), and were randomly assigned to either the NEVERMIND intervention or to the control group. Clinical interviews and structured questionnaires were administered at baseline, 12 weeks, and 24 weeks. The primary outcome was depressive symptoms at 12 weeks measured by the Beck Depression Inventory II (BDI-II). Intention-to-treat analyses included 425 participants, while the per-protocol analyses included 333 participants. This trial is registered in the German Clinical Trials Register, DRKS00013391.Findings Patients were recruited between Dec 4, 2017, and Dec 31, 2019, with 213 assigned to the intervention and 212 to the control group. The sample had a mean age of 59.41 years (SD=10.70), with 44.24% women. Those who used the NEVERMIND system had statistically significant lower depressive symptoms at the 12-week follow-up (mean difference=-3.03, p < 0.001; 95% CI-4.45 to-1.62) compared with controls, with a clinically relevant effect size (Cohen's d=0.39).Interpretation The results of this study show that the NEVERMIND system is superior to standard care in reducing and preventing depressive symptoms among patients with the studied somatic conditions. Copyright (C) 2022 The Authors. Published by Elsevier Ltd

Djelovanje miozmina na antioksidativne sustave u jetri štakora

Myosmine [3-(1-pyrrolin-2-yl) pyridine] is an alkaloid structurally similar to nicotine, which is known to induce oxidative stress. In this study we investigated the effects of myosmine on enzymatic and nonenzymatic antioxidative defence in rat liver. Wistar rats received a single i.p. injection of 19 mg kg-1 of myosmine and an oral dose of 190 mg kg-1 by gavage. Nicotine was used as a positive control. Through either route of administration, myosmine altered the hepatic function by decreasing the levels of reduced glutathione, superoxide dismutase, and glutathione peroxidase activities on one hand and by increasing malondialdehyde, catalase, and glutathione reductase activity on the other. Compared to control, both routes caused significant lipid peroxidation in the liver and altered hepatic enzymatic and non-enzymatic antioxidative defences. The pro-oxidant effects of myosmine were comparable with those of nicotine.Miozmin (3-(1-pirolin-2-il)piridin) alkaloid je strukturno sličan nikotinu, za koji se zna da potiče oksidativni stres. Istražili smo djelovanje miozmina na enzimske i neenzimske antioksidativne sustave u jetri štakora. Wistar štakori primili su jednokratno pokusni spoj intraperitonealno u dozi od 19 mg kg-1, odnosno na usta u dozi od 190 mg kg-1. Za pozitivnu kontrolu rabili smo nikotin. Nakon primjene, bez obzira na put, zamijećena je promjena u jetrenoj funkciji u obliku pada razina glutationa, aktivnosti superoksid dismutaze i glutation peroksidaze te rasta razina malondialdehida, aktivnosti katalaze i glutation reduktaze. Ovi nalazi upućuju na to da intraperitonealna i oralna primjena miozmina dovode do značajne lipidne peroksidacije u jetrenome tkivu te promjena u enzimskoj i neenzimskoj zaštiti jetre. Prooksidativno djelovanje miozmina pokazalo se sličnim onomu nikotina