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Introduction: Antimicrobial resistance and the rapid spread of multiresistant bacteria represent one of the main public health problem in limited resources countries. This issue is significantly worsening since the COVID-19 pandemic due to the unreasonably increased antibiotics prescription to patients with confirmed SARS-CoV-2 infection. The aim of this study was to examine whether COVID-19 pandemic (2020, 2021) was associated with increased antibiotic consumption in inpatient and outpatient settings in the middle size urban region (Republic of Srpska/Bosnia and Herzegovina) in comparison to period before the pandemic (2019). Additionally, we aimed to determine antimicrobial resistance and the presence of multiresistant bacteria in the regional hospital (“Saint Apostol Luka” Hospital Doboj) in 2021.Methodology: The consumption of antibiotics in inpatient was calculated as Defined Daily Dose per one hundred of patient-days. The consumption of antibiotics in outpatient was calculated as Defined Daily Dose per thousand inhabitants per day. Resistance of bacteria to antibiotics is expressed as a rates and density for each observed antibiotic. The rate of resistance was calculated as a percentage in relation to the total number of isolates of individual bacteria. The density of resistance of isolated bacteria against a specific antibiotic was expressed as the number of resistant pathogens/1000 patient days.Results: Antibiotic consumption in hospital setting registered during 2019, 2020 and 2021 was as follows: carbapenems (meropenem: 0.28; 1.91; 2.33 DDD/100 patient-days, respectively), glycopeptides (vancomycin: 0.14; 1.09, 1.54 DDD/100 patient-days, respectively), cephalosporins (ceftriaxone: 6.69; 14.7; 14.0 DDD/100 patient-days, respectively) and polymyxins (colistin: 0.04; 0.25; 0.35 DDD/100 bed-days, respectively). Consumption of azithromycin increased drastically in 2020, and dropped significantly in 2021 (0.48; 5.61; 0.93 DDD/100 patient-days). In outpatient setting, an increase in the consumption of oral forms of azithromycin, levofloxacin and cefixime, as well as parenteral forms of amoxicillin-clavulanic acid, ciprofloxacin and ceftriaxone, was recorded. In 2021, antimicrobial resistance to reserve antibiotics in hospital setting was as follows: Acinetobacter baumanii to meropenem 66.0%, Klebsiella spp to cefotaxime 67.14%, Pseudomonas to meropenem 25.7%.Conclusion: Recent COVID-19 pandemic was associated with increased antibiotic consumption in inpatient and outpatient settings, with characteristic change of pattern of azithromycin consumption. Also, high levels of antimicrobial resistance to reserve antibiotics were registered in hospital setting with low prevalence of identified pathogen-directed antimicrobial prescription. Strategies toward combat antimicrobial resistance in the Doboj region are urgently needed.

The pandemic of COVID-19 has brought many changes in health care systems at all levels of health care. The increase in the number of cases of COVID-19 has led to overuse and misuse of antibiotics.The aim of this study was to compare the consumption of antibiotics for systemic use in outpatients in the Republic of Srpska (RS), before and during the first year of the COVID-19 pandemic, as well as the association between antibiotic consumption and the rate of incidence and mortality of COVID-19. The total consumption of the antibiotics for systemic use (J01) in outpatients in the Republic of Srpska during 2019 was 19.40 DDD/TID, with an increase to 30.80 DDD/TID in 2020.Significantly higher use of penicillin (10.58 ± 11.01 DDD/TID in 2019 vs. 17.10 ± 13.63 DDD/TID in 2020), cephalosporins (2.68 ± 1.90 DDD/TID in 2019 vs. 5.93 ± 2.77 DDD/TID in 2020) and macrolides (2.14 ± 2.22 DDD/TID in 2019 vs. 3.40 ± 3.44 DDD/TID in 2020) was observed during the pandemic period. It is necessary to improve the prescribing practice of antibiotics at the primary health care level, public awareness about rational use of antibiotics, as well as the current antibiotic stewardship programs and control their implementation.

Phytochemical and pharmacological in-vestigations of essential oils isolated from plant species of the genus Seseli have been intensified recently. These plant species have long-term use in nutrition and traditional medicine in the treatment of various disorders. Volatile secondary metabolites of Seseli gracile Waldst. & Kit (Apiaceae) have not been pharma-cologically examined so far. The aim of the conducted research was to assess the antiradical, antimicrobial and spasmolytic ac-tivities of S. gracile essential oil isolated from the aerial parts of the plant. Methods. The antiradical activity was determined us-ing the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scaveng-ing test, antimicrobial activity using broth microdilution meth-od with standard strains of Gram (+), Gram (-) bacteria and yeast, while spasmolytic activity was evaluated on isolated rat il-eum, pre-contracted with a high concentration of potassium. Results. The results showed moderate antiradical (SC50 = 78.60 μg/mL) and good spasmolytic activity (IC50 = 271.4 nL/mL) of S. gracile essential oil. In the range of tested concen-trations, minimal inhibitory concentration (MIC) was deter-mined only for the strain of Escherichia coli (500 μg/mL). Con-clusion. Results obtained in this study justify the need for fur-ther studies to elucidate exact molecular mechanism underlay this spasmolytic effect of S. gracile herb essential oil. Etarska ulja izolovana iz vrsta roda Seseli su u poslednje vreme intenzivno farmakološki i fitohemijski proučavana. Biljke iz ovog roda se koriste već duži niz godina u ishrani i tradicionalnoj terapiji različitih oboljenja. Farmakološka aktivnost etarskog ulja izolovanog iz Seseli gracile do sada nije ispitivana. Stoga je cilj ovog istraživanja bio da se ispita antiradikalska, antimikrobna i spazmolitična aktivnost etarskog ulja izolovanog iz nadzemnih delova biljne vrste S. gracile. Metode. Antiradikalska aktivnost je utvrđena testom neutralizacije 2.2-difenil-1-pikrilhidrazil (DPPH) radikala, antimikrobna, bujon-mikrodilucionom metodom uz upotrebu standardnih sojeva Gram (+), Gram (-) bakterija i gljivica, a spazmolitična na izolovanom ileumu pacova, prethodno kontrahovanom visokom koncentarcijom kalijuma. Rezultati. Rezultati pokazuju umerenu antiradikalsku (SC50 = 78.60 μg/mL) i dobru spazmolitičnu aktivnost (IC50 = 271.4 nL/mL) etarskog ulja S. gracile. U opsegu testiranih koncentracija utvrđena je minimalna inhibitorna koncentracija (MIC) samo za soj Escherichia coli (500 μg/mL). Zaključak. Dobijeni rezultati opravdavaju potrebu za budućim istraživanjima koja bi razjasnila tačne mehanizme kojima se ostvaruje spazmolitički efekat etarskog ulja nadzemnog dela S. gracile.

MgSO 4 is used as a tocolytic agent. It is considered to be a calcium channel antagonist, but a different mechanism of its action might be involved. The aim of this study was to examine the contribution of calcium concentrations and potassium channels in the mechanism of MgSO 4 -mediated uterine relaxation. Isolated uteri from female Wister rats were treated with increasing MgSO 4 concentrations (0.1-30 mM). MgSO 4 induced dose-dependent inhibition of spontaneous activity. Addition of Ca 2+ (6 mM and 12 mM) stimulated uterine contractile activity and attenuated the inhibitory activity of MgSO 4 . In order to analyze the role of different subtypes of potassium channels, Ca 2+ -stimulated uteri were pretreated with glibenclamide (Glib), a selective ATP-sensitive potassium channel inhibitor (K ATP ), tetraethylammonium (TEA), a non-specific inhibitor of large conductance calcium-activated potassium channels (BK Ca ), and 4-aminopyridine (4-AP), a voltage-sensitive potassium channel inhibitor (Kv), at concentrations that had no effect per se . Pretreatment with 4-AP had no effect on MgSO 4 -mediated relaxation of Ca 2+ -stimulated uteri. The relaxing effect of MgSO 4 was potentiated by pretreatment with glibenclamide. Pretreatment with TEA attenuated the MgSO 4 -mediated decrease in frequency. Our results suggest that MgSO 4 acts as a general calcium antagonist that influences Ca 2+ -mediated potassium channels. Furthermore, it seems that MgSO 4 uterine relaxation activity is partially mediated by selective ATP-sensitive potassium channels, suggesting an ATP-dependent role. https://doi.org/10.2298/ABS180615031S Received: June 15, 2018; Revised: July 6, 2018; Accepted: July 6, 2018; Published online: July 16, 2018 How to cite this article: Sokolovic D, Drakul D, Orescanin-Dusic Z, Tatalovic N, Pecelj M, Milovanovic S, Blagojevic D. The role of potassium channels and calcium in the relaxation mechanism of magnesium sulfate on the isolated rat uterus. Arch Biol Sci. 2019;71(1):5-11.

Objective. Patients and medical professionals have a common misconception that cardiovascular diseases (CVD) predominantly affect men, which can lead to less prescribing of cardiovascular drugs to women. This study examined whether there were sex differences in the administration of cardiovascular (CV) drugs in patients admitted to the intensive care unit of the Internal Medicine Clinic of Foča University Hospital (ICFUH).Materials and Methods. The study comprised 332 patients hospitalized at the ICFUH from January 1st to June 30th, 2019. The following data on leading CVD and risks related to CV drug administration were collected: age, hyperlipidemia (HLD), diabetes mellitus (DM), chronic kidney disease (CKD), liver disease (LD), heart failure (HF), hypertension (HTN), myocardial infarction (MI), and stroke (S). The amount of the CV drugs of interest (statins, antiplatelet drugs, calcium channel blockers, ACE inhibitors, beta blockers, diuretics) administered during hospitalization was expressed as the Defined Daily Dose (DDD)/100 bed-days (BD) for patients of both sexes separately.Results. During hospitalization in the intensive care unit of ICFUH, female patients were less likely to be treated with statins than male patients (30.1 vs. 57.5 DDD/100 BD, PConclusion. Our study indicates that there were sex differences in CV drug administration in ICFUH. Presuming that drugs used during hospitalization were at least partially a continuation of the previous therapy prescribed by the family doctor, it is possible that such differences exist in primary care.

Uvod. Podtip, ekspresija, distribucija i funkcija K+ kanala u glatkim mišićimakrvnih sudova su promjenljivi i vjerovatno zavise od očuvanosti endotela,azot monoksida (NO) i patoloških stanja kao što je hipertenzija. Ispitivali smouticaj modulatora kalijumskih kanala i njihove interakcije sa NO na krvnesudove. Ovo ispitivanje je značajno za pronalaženje novih terapijskih koncepatau liječenju poremećaja kontraktilnosti krvnih sudova. Cilj rada je bio dase ispita uloga pola, endotela i hipertenzije u relaksantnom efektu pinacidilana izolovane mezenterične i renalne arterije, uzete od normotenzivnih (NT)i spontano hipertenzivnih (HT) pacova.Metode. Eksperimenti su izvedeni na izolovanim mezenteričnim i renalnimarterijama uzetim od mužjaka i ženki NT i HT Wistar pacova. Arterije suinkubirane 30 min u kupatilu za izolovane organe sa Krebs-Ringerovim rastvorom,na 360C i aerisane smješom 95% O2 i 5% CO2. Kontrakcije izolovanihkrvnih sudova su izazivane fenilefrinom (10-6 mol), a na stabilan tonus jedodavan pinacidil (10-8 – 10-4M). Funkcionalni integritet endotela je potvrđivanacetilholinom (10-5 mol).Rezultati. Pinacidil je koncentracijski zavisno relaksirao mezenterične arterije,bez obzira da li su arterije uzete od mužjaka ili ženki pacova. Relaksantniefekat pinacidila je bio veoma izražen na segmentima arterija sa endotelom.Značaj endotela je bio manje izražen na krvnim sudovima uzetim od HT,nego od NT životinja. Stepen relaksacije je bio veći kod mezenteričnih, negokod renalnih arterija.Zaključak. Pinacidil (10-8 – 10-4 mol) je prouzrokovao koncentracijski i endotelzavisnu relaksaciju izolovanih renalnih i mezenteričnih arterija pacova, uzetihod NT i HT pacova bez obzira na pol.

Vascular stents are general medical devices of class III or IIb, which are placed along the walls of the constricted coronary and peripheral blood vessels thus keeping them viable. According to the mechanism of expansion, stents may be balloon-expandable or self-expanding. Depending on the geometry they can be classified into: coil stents, open-cell modular stents and multi-cell closed cell stents. The most important characteristic of vascular stents is their flexibility, but a number of additional requirements must also be met: high radial strength, low elastic deformation, small diameter, the possibility of monitoring through the bloodstream, minimum subsequent shortening, minimum elastic longitudinal deformation, and the optimal retention at target site. Materials for production of stents must be biologically inert, visible by radiological techniques, biocompatible, corrosion-resistant and resistant to stress due to blood flow. The most significant adverse event after stent implantation is the occurrence of restenosis, which is most efficiently overcome by the application of drug releasing stents. These stents are composed of three parts: stent platform, drug carrier and a drug that inhibits neointimal hyperplasia - paclitaxel and limuses (sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, etc.). In recent years, stents with surfaces coated with substances that accelerate endothelialisation and thus reduce thrombosis have been developed. The latest approach is represented by a stent with the lumen coated with CD34 antibody, and the outer side coated with sirolimus. By using these devices a double effect is achieved: acceleration of endothelialisation and inhibition of neointimal hyperplasia. Vaskularni stentovi su opšta medicinska sredstva klase III ili IIb, koja se postavljaju uz zidove koronarnih i perifernih krvnih sudova kada postoji suženje i na taj način ih održavaju prohodnim. Prema mehanizmu ekspanzije, stentovi mogu biti balon-ekspandirajući ili samoekspandirajući, a u zavisnosti od geometrijskog oblika dele se na: stentove u obliku spirale, modularne stentove sa otvorenim ćelijama i multićelijske stentove sa zatvorenim ćelijama. Najznačajnija karakteristika vaskularnih stentova je fleksibilnost, ali moraju da ispunjavaju i čitav niz dodatnih zahteva, kao što su: velika radijalna snaga, nizak stepen elastične deformacije, mali prečnik, mogućnost praćenja kroz krvotok, minimalno naknadno skraćivanje, minimalna elastična longitudinalna deformacija i optimalno zadržavanje na ciljnom mestu. Materijali za proizvodnju stentova moraju biti biološki inertni, vidljivi radiološkim tehnikama, biokompatibilni, otporni na koroziju i otporni na stres zbog protoka krvi. Najznačajniji neželjeni događaj nakon ugradnje stentova je pojava restenoze, koja se najefikasnije prevazilazi primenom stentova koji oslobađaju lek. Ovi stentovi se sastoje iz tri dela: platforme stenta, nosača leka i leka koji inhibira neointimalnu hiperplaziju, paklitaksel i limusi (sirolimus, everolimus, zotarolimus, takrolimus, pimekrolimus i dr). Poslednjih godina razvijeni su i stentovi kod kojih se površine oblažu supstancama koje ubrzavaju endotelizaciju i tako smanjuju trombozu. Najnoviji pristup predstavlja stent kod koga se lumen stenta oblaže CD34 antitelom, a spoljašnja strana sirolimusom. Primenom ovih stentova postiže se dvostruki efekat: ubrzavanje endotelizacije i inhibicija neointimalne hiperplazije.

Background. Pentoxifylline, used for treating peripheral vascular deceases is a derivate of methylxanthines. One way of pentoxifylline action is by causing vasodilatation of blood vessels. In this study, the effect of increasing concentrations of pentoxifylline, in the presence of potassium channel antagonist, on contractility of isolated rat uterus was examined. Methods . Uteruses were isolated from virgin Wistar rats (180-220 g) and suspended in an isolated organ bath chamber containing De Jalon's solution and aerated with 95% O 2 and 5% CO 2 . Temperature was maintained at 37oC. Isometric contractions were recorded using an isometric force transducer (Ugo Basile). The preload of the preparation was about 1g. Uteri were allowed to contract spontaneously or in the presence of Ca 2+ (0.018 and 0.36 mM ) and acetylcholine and treated with pentoxifylline. Results. Pentoxifylline caused concentration-dependent inhibition of spontaneous rhythmic uterine activity and uterine activity caused by calcium Ca 2+ (0.018 mM and 0,36 mM). We showed that the inhibitory effect of pentoxifylline depends on type of muscle contraction activation, and that it is significantly stronger in spontaneous rhythmic activity and contraction of isolated rat uterus induced by Ca 2+ . The relaxing effect of pentoxifylline depends on calcium concentration of in the medium. Pentoxifylline exerted the weakest relaxant effects on contractions induced by acetylcholine (Ach). As opposed to methylene blue, tetraethylammonium, and 4-aminopyridine, glibenclamide did not antagonize the relaxing effect of pentoxifylline on the isolated rat uterus. Conclusion. Results obtained suggest that the mechanism of action of pentoxifylline did not lead to the opening of K ATP channels. However, the opening of BKCa and of voltage dependent Ca 2+ channel had some significance, but to varying degrees, in the mechanism of the relaxing effect of pentoxifylline on spontaneous rhythmic activity and contraction of the isolated rat uterus induced by calcium. Our results are additional confirmation of the dominance of the NO/cGMP signaling pathway in the mechanism of the relaxing effect of pentoxifylline (because the presence of methylene blue significantly antagonizes its effect) in relation to the opening of potassium channels, especially K ATP channels. These results indicate that pentoxifylline could be a potential tocolytic drug. Keywords: pentoxifylline, rat uterus, potassium channel blockers, glibenclamide (GLB), tetraethylammonium (TEA), 4-aminopyridine (4-AP ), methylene blue (MB) Running title: Potassium Channels in Action of Pentoxifylline

The present paper describes environmental and seasonal-related chemical composition variations, vasorelaxant and angiotensin I-converting enzyme (ACE) activities of essential oil from aerial parts of Seseli pallasii BESSER. The composition was analyzed by GC and GC/MS. Monoterpenes were found to be the most abundant chemical class with alpha-pinene (42.7 - 48.2%) as the most prevalent component. Seseli pallasi essential oil relaxed isolated endothelium-intact mesenteric arteries rings precontracted with phenylephrine with IC50 = 3.10 nl/ml (IC50 = 2.70 mu g/ml). Also, S. pallasii essential oil was found to exhibit a dose-dependent ACE inhibitory activity with an IC50 value of 0.33 mg/ml. In silico evaluation of ACE inhibitory activity of the individual components showed that spathulenol exhibited the best binding affinity with ACE, and the lowest binding energy of -7.5 kcal/mol. The results suggested that combination of vasorelaxing and ACE inhibitory effects of the analyzed S. pallasii essential oil might have the potential therapeutic significance in hypertension.