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Introduction: Proton pump inhibitors (PPIs) are anti-ulcer drugs that have reportedly been used inappropriately in therapeutic settings, raising the risk of adverse effects, drug interactions, and costs. Aim: This study aimed to evto evaluate the inappropriate use of PPI medication and which category of PPIs frequently was used for patients in Bangladeshi hospitals. Material and Methods: A one month cross-sectional study was carried out in a tertiary care hospital to evaluate the kinds of PPI prescriptions, their appropriateness, and their tendency to be utilized among patients. Results: Among 298 patients interviewed,140 patients used PPIs inappropriately. The most common reasons for inappropriate use included gastric appetite (29.59%, 29 individuals) and nausea. Other reasons included (15%) no clear indication, (20%) gastric discomfort, (13.57%) asthma, and (8.57%) infections. Esomeprazole was the most prescribed PPI, used by 41% of patients, followed by omeprazole at 32%. Nearly 44% of the 140 patients exhibited a strong tendency to use PPIs. Conclusion: Important steps must be taken to ensure that PPIs are used properly, to increase knowledge, and implement educational TV programs that can reduce the risk of drug interactions, side effects, and unnecessary expenses. [ABSTRACT FROM AUTHOR]

Drugs are the second cause of human intoxication-related mortality and the first in intoxication records. About 1 in 4 individuals around the world will develop mental illness at some point in their lifetimes. Viral outbreaks, such as the coronavirus disease (COVID-19) pandemic, are associated with short-term and long-term psychological and societal distress. The current review of poisoning patterns in southeast Serbia is imperative. A retrospective cross-sectional study was carried out for two years, from March 2020 to March 2022, to evaluate the prevalence and trends of pharmaceutical drug poisonings. Retrospective data on poisoning cases was collected from the medical records section of the Toxicological Laboratory of the Institute of Forensic Medicine in Niš. Of the 310 cases, 59.35% of intoxications were observed in the female population. The most significant female predominance was observed in the age category 12-19 years (75%). In all age groups over 51, there are more female intoxications than male intoxications by a factor of more than 2.17. In age category 12-19, the most commonly detected drug class was sedatives, followed by analgesics and antiepileptics. In the population over 51, the most frequently detected drug classes in intoxication were sedatives (32.67%), followed by drugs for cardiovascular diseases (15.84%), antiepileptics (13.86%), and antidepressants (11.88%). Women over 51 and in the adolescent age category should be the target group for education and raising awareness about mental health. The prescription of sedatives should always be carefully considered, as this class of drugs is the most common in poisoning. [ABSTRACT FROM AUTHOR]

Background/Aim. Injecting herbal extract into platelet concentrates is one of the newer treatment protocols, which enables platelet concentrates to act as sustained drug delivery (DD) systems. Histological analysis of titanium-prepared platelet-rich fibrin (T-PRF) injected with herbal extract, could help assess the appearance (pattern) and structural changes of T-PRF. The aim of the study was to evaluate the appearance of the fibrin network, cellularity, and fibrin border area of T-PRF alone and T-PRF injected with herbal extract. Methods. A total of 40 histological slides were prepared from 10 mL of blood from each patient, 20 with T-PRF alone and 20 with T-PRF+herbal extract. The slides were divided into a group consisting of T-PRF injected with neem gel (test group) and a group consisting of T-PRF alone (control group). The preparation protocol was made according to Bankroft's manual adapted for light microscopy. Results. Regarding the fibrin network features (dense vs. loose), no statistical significance was found among the studied groups (p = 0.172). A statistically significant difference was shown in the packeting (p = 0.018) and layered (p = 0.028) patterns of the fibrin network, and there was no statistically significant difference in the scattered (p = 0.749) pattern among the examined groups. Cellularity and cell pattern values were not statistically significantly different for both groups (p = 1.00, p = 0.3111, respectively). Moreover, the values determined for red blood cells, white blood cells, and platelets were not statistically significantly different (p = 0.147), as well as for the fibrin border area between cells and meshwork (p = 0.206). Conclusion. The obtained results could be useful for the development of a new treatment strategy in dentistry, by utilizing T-PRF with incorporated herbal extracts or antibiotics, as a local sustained DD system. [ABSTRACT FROM AUTHOR]

Background/Aim. Since finding a safe and efficient strategy of multimodal postoperative analgesia and sedation is particularly critical, it is important that dexmedetomidine (DM) combined with opioid anesthetics can enhance that through a synergistic action. The aim of the study was to assess the effect of butorphanol tartrate (BT) combined with DM on postoperative analgesia. Methods. A total of 100 elderly patients undergoing general anesthesia surgery from January 2019 to June 2022 were selected. The patients were divided into two equal groups -- research group (RG) and control group (CG), using the random number table method. All patients were given postoperative patient-controlled intravenous analgesia (PCIA) plus background infusion. CG patients were given 10 mg of BT, and RG patients were given 10 mg of BT and 300 μg of DM. The analgesics were diluted in 100 mL of 0.9% normal saline. The doses of rescue analgesic tramadol within 48 hrs after surgery, the number of PCIA boluses 48 hrs after surgery, and postoperative hospitalization time were recorded. The Visual Analog Scale (VAS) score, Ramsay sedation score (RSS), inflammatory and stress responses [interleukin (IL)-6, interferon (IFN)-γ, and angiotensin II (Ang-II)], and anesthesia-related adverse reactions (ARAR) were compared at different time points. Results. The dose of tramadol within 48 hrs after surgery, the number of PCIA boluses 48 hrs after surgery, and the postoperative hospitalization time of RG were lower than those of CG (p < 0.05). VAS scores at rest and during activity and serum IL-6, IFN-γ, and Ang-II levels of both groups increased at 4 and 12 hrs after surgery, then decreased at 24 hrs after surgery. The above indicators of RG were lower than those of CG at each time point (p < 0.05). The RSSs of the two groups increased at 4, 12, and 24 hrs after surgery, then dropped at 48 hrs after surgery. The scores of RG were lower than those of CG at each time point (p < 0.05). The incidence rates of ARAR had no significant difference between RG and CG (p > 0.05). Conclusion. BT combined with DM is effective for analgesia and sedation after general anesthesia surgery in elderly patients, which can reduce inflammatory and stress responses without increasing ARAR. [ABSTRACT FROM AUTHOR]

Uvod: Inhibitori protonske pumpe (PPI) su lekovi protiv čira koji su navodno korišćeni na neodgovarajući način u terapijskim okruženjima, što povećava rizik od neželjenih efekata, interakcija lekova i troškova. Cilj: Ova studija je imala za cilj da proceni neodgovarajuću upotrebu IPP lekova i koja kategorija PPI se često koristila za pacijente u bolnicama u Bangladešu. Materijal i metode: Jednomesečna studija preseka sprovedena je u bolnici tercijarne nege da bi se procenile vrste recepata za PPI, njihovu prikladnost i njihovu sklonost da se koriste među pacijentima. Rezultati: Među 298 intervjuisanih pacijenata, 140 pacijenata je neprikladno koristilo PPI. Najčešći razlozi za neodgovarajuću upotrebu bili su gastrični apetit (29,59%, 29 osoba) i mučnina. Ostali razlozi su uključivali (15%) bez jasne indikacije, (20%) nelagodnost u želucu, (13,57%) astmu i (8,57%) infekcije. Esomeprazol je bio najčešće propisivani PPI, koji je koristilo 41% pacijenata, a zatim omeprazol sa 32%. Skoro 44% od 140 pacijenata pokazalo je jaku tendenciju da koriste PPI. Zaključak: Moraju se preduzeti važni koraci kako bi se osiguralo da se PPI pravilno koriste, kako bi se povećalo znanje i implementirali obrazovni TV programi koji mogu smanjiti rizik od interakcija sa lekovima, neželjenih efekata i nepotrebnih troškova. [ABSTRACT FROM AUTHOR]

Introduction. Neurological complications related to epidural anesthesia are rare, but it is necessary to recognize and diagnose them as early as possible, in order to start appropriate therapy and prevent further neurological damage. One of the rare complications of regional anesthesia described in this paper is longitudinal extensive transversal myelitis (LETM). Case report. A 32-year-old patient, who gave birth by Caesarean section in due term, developed LETM the very same day. Considering the neuroradiological findings that indicated to the long central lesion in the thoracic and lumbar spine, and an expected reaction to the applied immunotherapy (immunosuppressive therapy and therapeutic plasma exchange), a diagnosis of LETM was made. Even with all the therapy and regression of the lesions, the patient could not stand up without support. During the subsequent treatment, according to the instructions of the physiatrist, physical therapy was carried out, to which the patient responded slowly but favorably, with a gradual return of the function of the lower extremities. Conclusion. Early diagnosis and timely treatment of LETM are crucial for the prognosis of the disease and the early recovery of the patient. [ABSTRACT FROM AUTHOR]

Background/Aim. Patients in developing countries do not always receive adequate pain-relieving treatment. Monitoring analgesics consumption is of great importance since this can help assess the quality of painful condition management. The aim of this paper was to present a five-year consumption and costs of drugs with analgesic effects in developing countries, exemplified by Serbia and Montenegro, and indicate the main reasons for their (in)adequate prescribing. Methods. The observational, retrospective, cross-sectional study was conducted in order to analyze the consumption of all analgesics, both opioid and non-opioid, in Serbia and Montenegro, as developing countries. The data concerning analgesic consumption and drug prices were obtained from annual editions of the publications of the Medicines and Medical Devices Agency of Serbia and Montenegro. The World Health Organization methodology with defined daily dose (DDD) as a unit of measure (defined by the number of DDD per 1000 inhabitants per day) was used in these publications. Results. Over the course of five years (from 2015 to 2019) in Serbia, the total allocations for analgesic therapy had a rising trend, from about 43.6 million to 63.3 million euros, while in Montenegro, expenditures showed annual variations with the highest value in 2018. Most of the money in both countries was invested in the M01A group of drugs, for which the highest consumption was also recorded. Significantly higher consumption of opioid analgesics in Montenegro compared with Serbia was observed in the same period, and it predominantly reflected the difference in fentanyl (N02AB03, transdermal patch) prescribing. In Montenegro, consumption of the M01AB group of drugs was prominently higher in comparison to the M01AE drugs group during the whole five-year period, like in Serbia, in which this was not the case just in 2018. Conclusion. Taking into account the importance of analgesics for everyday medical practice, more rational prescribing of these drugs is necessary both in Serbia and Montenegro in the future. [ABSTRACT FROM AUTHOR]

Introduction. The use of propylthiouracil can be associated with mild adverse reactions, but severe complications such as agranulocytosis and vasculitis can also be seen. Direct toxicity and immune-mediated induction of anti-neutrophile cytoplasmic antibodies have been described as possible mechanisms responsible for agranulocytosis. The majority of vasculitis is antimyeloperoxidase antibodies associated, but the exact mechanism for anti-neutrophile cytoplasmic antibodies-associated vasculitis as an adverse effect of propylthiouracil treatment is still unclear. Case report. We presented a 61-year-old female patient with Graves' disease who experienced a fever and throat pain two weeks after propylthiouracil therapy was initiated. Agranulocytosis alongside basal left-sided pneumonia was noted. Propylthiouracil was discontinued, and the treatment with broadspectrum antibiotics was started, as well as Lugol's solution, methylprednisolone, and granulocyte-colony stimulating factor. Further course of treatment was complicated by the occurrence of a generalized erythematous-papillomatous rash. The patient was diagnosed with agranulocytosis and antimyeloperoxidase, anti-neutrophile cytoplasmic antibodies positive vasculitis as an adverse effect of propylthiouracil. Conclusion. Patients presenting with concomitant agranulocytosis and anti-neutrophile cytoplasmic antibodiesassociated vasculitis as a complication of propylthiouracil therapy for Graves' disease are rare in clinical practice. Prompt discontinuation of the antithyroid drug is of great importance to reduce damage to target organs. Similarities in the pathogenesis of both conditions could be the potential explanation for these two adverse events occurring at the same time, which points out the need for a deeper understanding of this topic. [ABSTRACT FROM AUTHOR]

Background/Aim. Plateletpheresis (PLTP) is a medical procedure used for collecting donor platelets with multiple benefits for patients who will receive apheresis platelets. The procedure takes one hour and is well tolerated by donors. Nevertheless, adverse events (AEs) may occur during and after the PLTP procedure. The aim of the study was to determine the incidence and type of AEs associated with PLTP in donors. Methods. A retrospective analysis of AEs associated with donor PLTP was conducted at the Blood Transfusion Institute of Vojvodina from January 1, 2010, to December 31, 2019. Results. Out of 2,073 platelet donors, 94.84% were multiple blood donors, predominantly male (98.55%). AEs were identified during 180 (8.68%) platelet donations with no statistical significance in occurrence in the first time donors (10.28%) and repeat donors (8.59%). Mild local reactions related to venous access (42.22%) were the most common AEs. Generalized symptoms were exhibited in 16.67% of donors, 26.11% exhibited symptoms related to apheresis (citrate reactions), and 15% exhibited those related to other complications. It was found that 95.55% of AEs occurred during PLTP and only 4.45% after it. Conclusion. Donor PLTP is a generally safe procedure, well tolerated by donors. Understanding risk factors for a possible occurrence of AEs provides support for adopting measures to prevent them. [ABSTRACT FROM AUTHOR]

Background/Aim. Standard treatment options for the first-line treatment of metastatic colorectal carcinoma (mCRC) are 5-fluorouracil, folinic acid, oxaliplatin (FOLFOX4)/capecitabine (CapOx), plus bevacizumab (bev) and 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus bev. The aim of this study was to compare overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with mCRC who were treated in the first line with FOLFIRI/bev vs. FOLFOX4/bev. At the same time, the aim was also to compare the safety profile in the observed groups of patients and to investigate optimal treatment duration and characteristics of patients who had the best treatment outcomes. Methods. The retrospective prospective study included patients with mCRC treated with chemotherapy protocols for the first line in combination with bev (FOLFOX4/bev, respectively, FOLFIRI/bev). Treatment efficacy was evaluated on the basis of ORR, PFS, and OS, and the safety of treatment was evaluated by monitoring adverse drug reactions (ADR). Results. ORR was 70% in the FOLFIRI/bev group and 50% in the FOLFOX4/bev group. Median PFS for FOLFIRI/bev (n = 30) and for FOLFOX4/bev (n = 30) was 15.6 months and 12.1 months, respectively [hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.47-1.53; p = 0.5591]. Median OS for FOLFIRI/bev and for FOLFOX4/bev was 24.7 months and 19.9 months, respectively (HR 0.67; 95% CI 0.37-1.23; p = 0.1552). In both patient groups, the patients who received more than 9 cycles of induction therapy had better treatment response compared with patients who received less than 9 cycles of therapy. In the FOLFOX4/bev group, PFS was 16.9 vs. 9.7 months, and OS was 22.1 vs. 17.6 months, respectively. In the FOLFIRI/bev group, PFS was 9 months for patients who received less than 9 cycles of therapy vs. 18.8 months for patients who received more than 9 cycles, and OS was 18.0 months vs. 27.7 months, respectively. ADR grade 3 and 4 had 7% of the patients in the FOLFIRI/bev group vs. 27% in the FOLFOX4/bev group. Conclusion. Patients who received FOLFIRI/bev compared to those treated with FOLFOX4/bev had better ORR (70% vs. 50 %, respectively), PFS (15.6 months vs. 12.1 months, respectively), and OS (24.7 months vs. 19.9 months, respectively). In both patient groups, the patients who received induction therapy for 4-6 months (more than 9 cycles of therapy) had a better treatment response. [ABSTRACT FROM AUTHOR]

Background/Aim. About 1.8 million new lung cancer cases are diagnosed worldwide every year, and about 1.6 million cases have a fatal outcome. Despite improvements in treatment in the previous decades, the survival of patients with lung cancer is still poor. The five-year survival rate is about 50% for patients with localized disease, 20% for patients with regionally advanced disease, 2% for patients with metastatic disease, and about 14% for all stages. The median survival of patients with untreated nonsmall cell lung carcinoma (NSCLC) in the advanced stage is four to five months, and the annual survival rate is only 10%. The aim of the study was to determine the results of treatment with concomitant chemoradiotherapy (CHRT) in terms of efficacy and toxicity in selected patients with advanced inoperable NSCLC. Methods. The study included data analysis of 31 patients of both sexes who were diagnosed and histopathologically verified with NSCLC in inoperable stage III and were referred by the Council for Malignant Lung Diseases to the Radiotherapy Department of the Military Medical Academy in Belgrade, Serbia for concomitant CHRT treatment. Upon expiry of the three months from the performed radiation treatment (RT), the tumor resonance was assessed based on multislice computed tomography (MSCT) examination of the chest and upper abdomen according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. According to the same criteria, progression-free survival (PFS), as well as overall survival (OS), was assessed every three months during the first two years, then every 6 months or until the onset of disease symptoms. Results. The median PFS was 13 months, and the median OS was 20 months. During and immediately after RT, 9 (29%) patients had a grade 2 or higher adverse events. Conclusion. The use of concomitant CHRT in patients in the third stage of locally advanced inoperable NSCLC provides a good opportunity for a favorable therapeutic outcome with an acceptable degree of acute and late toxicity and represents the standard therapeutic approach for selected patients in this stage of the disease. [ABSTRACT FROM AUTHOR]

The presence of pharmaceutical contaminants in nature is an environmental problem generating increasing concerns. Due to this, it is necessary to evaluate treatments capable of degrading these contaminants, such as the advanced oxidation processes (AOPs). In this work, the photoperoxidation and photo-Fenton AOP were applied to degrade a mixture of lamivudine and zidovudine in an aqueous medium and synthetic effluent (SE). To this end, a bench reactor (UV-C; UV-A and sunlight irradiations) was built. The AOP treatments efficiency was evaluated by ultraviolet/visible spectrophotometry. The tests involved the application of the irradiations individually and combined. The best operational conditions were [H2O2 ] of 600 mg L-1 and [Fe] of 0.5 mg L-1, for both matrices, with degradations of 90.53% and 89.32% for the photoperoxidation and photo-Fenton processes in aqueous media and 88.69% and 85.79% in SE. Kinetic studies showed a good fit for two pseudo-first-order models with R² > 0.93. Toxicity tests involving the application of lettuce, carrot, and tomato seeds showed an inhibition for the three seeds when submitted to solutions after treatment, for both matrices, this fact is corroborated by the HPLC analysis, in which the formation of small peaks was verified, suggestive of the formation of byproducts. Thus, it can be affirmed that both photo-Fenton and photoperoxidation processes efficiently degrade the drug mixture when applying UV-C radiation. [ABSTRACT FROM AUTHOR]

Background/Aim. The growing number of older adults means higher medicine utilization. The aim of the study was to determine the frequency and identify risk factors of potentially inappropriate medication (PIM) in the elderly population with cardiovascular diseases. Methods. The retrospective, cross-sectional study was performed in 2018, and the relevant data were collected during the period from January 2016 to December 2017. The study sample included 1,500 patients over 65 years with cardiovascular disease who had medical records at the Institute for Gerontology and Palliative Care, Belgrade. Assessment of PIM was done by standard international criteria such as the American Geriatrics Society 2015 updated Beers Criteria for PIM use in older adults. Results. PIM frequency in the elderly population was 70.3%. In relation to gender, it was more frequent in female elders. The mean number of prescribed drugs was similar for 2016 and 2017, 7.2 and 7.3, respectively. The most common were: medium-acting benzodiazepines (70.9%), central a blockers (23.98%), and antipsychotics (typical and atypical) (20.94%). The most common comorbidity was noted in a group labeled with the International Disease Classification I00-I99, which includes heart and blood vessel diseases [n = 2,658 (36.9%)]. The most common diagnoses belonged to the subgroups I10-I15 [hypertensive diseases, n = 1,298 (18%)], I20-I25 [ischemic heart diseases n = 542 (7.5%)], I30-I52 [other forms of heart disease, n = 705 (9.8%)], I60-I69 [cerebrovascular diseases, n = 94 (1.3%)], and I80-I89 [diseases of veins, lymph vessels, and lymph nodes n = 12 (0.17%)]. The risk factors for PIM were: polypharmacy, gender, nicotine use, cognitive status, nutrition state, and the number of diseases registered in the study sample. Conclusion. Cardiovascular diseases in the elderly population are associated with a high prevalence of PIM. Creating health recommendations for prescribing drugs to the elderly that would emphasize these factors could reduce the prevalence of PIM in this population. [ABSTRACT FROM AUTHOR]

Urgentna medicina nije skup urgentnih stanja iz raznih oblasti medicine, već urgentni pristup stanjima koja prete da ugroze život. Sa razvojem savremene medicine menja se i urgentni pristup. Uvode se savremeni protokoli za zbrinjavanje povređenih i obolelih koji zahtevaju sve više znanja i veština, ali i sve savremeniju opremu i sve širi dijapazon neophodnih lekova. Novine savremenih protokola ne prate i izmene lista lekova koje donosi Republički fond za zdravstveno osiguranje (RFZO). U radu su prikazani lekovi neophodni za adekvatno zbrinjavanje stanja koja ugrožavaju život na prehospitalnom nivou, a koji lekarima nisu dostupni zbog administrativnih ograničenja. Na jednoj strani su lekovi na Listi B koji su neophodni, ali su oni odobreni samo za stacionarni nivo rada i zato upotreba bilo kojeg od ovih lekova na prehospitalnom nivou može da dovede do ozbiljnih sankcija za lekara ukoliko dođe do razvoja komplikacija ili neželjenih reakcija kod pacijenta. Na drugoj strani su lekovi na Listi D koji su, takođe, neophodni za urgentno zbrinjavanje životno ugroženih pacijenata prema poslednjim preporukama. Ovi lekovi se mogu primenjivati prehospitalno, ali je njihova nabavka zbog propisa RFZO-a komplikovana i zato se neki od njih retko mogu prehospitalno koristiti (Propafenon i Magnezijum sulfat). Posebno naglašavamo da jedan od najefikasnijih lekova za medikamentoznu konverziju srčanog ritma, Adenosin (ampule 6mg/2ml i 10mg/2ml), nije registrovan u Republici Srbiji i zato se ne može prehospitalno primeniti. Ovakvim, isključivo administrativnim, zabranama onemogućen je adekvatan rad, ali i degradiran sistem urgentnog zbrinjavanja vitalno ugroženih pacijenata na prehospitalnom nivou. [ABSTRACT FROM AUTHOR]

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Background/Aim. Contrast echocardiography (CE) is an echocardiographic modality where ultrasound contrast echocardiographic agent (CEA) is introduced peripherally for the image enhancement. The aim of this study was to present the initial clinical experience of the use of CEA Optison™ (GE Healthcare, Princeton, NJ) at the Institute for Cardiovascular Diseases of Vojvodina, Serbia and prospectively monitor the occurrence of possible side effects. Methods. A total of 357 patients were referred for resting or stress echocardiographic examinations, with an approved indication for CEA administration. The average age of patients was 63.3 years (range, 21-92 years), 62% of them were men. Most of the patients (77.31%) had some form of ischemic heart diseases. Hypertension was the most frequent risk factor (77.03%), but 57 patients had diabetes mellitus and 33 patients had chronic kidney disease as comorbidity. Most (90.5%) of the patients were on beta blocker therapy, 83.5% of them on angiotensin converting enzyme/angiotensin receptor blockers. Majority (80.3%) of the patients received single or dual (49.5%) antiagregation therapy, 74 (26.3%), of them were on anticoagulation therapy, 55.1% of the patients were taking diuretics. The global ejection fraction (EF) was preserved in 39.85% of them, the majority (136 of them), had left ventricle (LV) impairment, with an EF less than 50%. Patients were followed up for 30 minutes after CEA administration for potential side effects. In 118 patients, vital signs (heart rate, oxygen saturation, body temperature, systolic and diastolic blood pressure) were measured before and 30 minutes after CEA administration. Results. The administration of CEA was not associated with side effects. Diastolic blood pressure drop and heart rate increase were statistically, but not clinically significant (p = 0.027 and p = 0.028, respectively). Conclusion. Changes in analyzed vital signs were clinically non relevant. CE is a safe noninvasive diagnostic modality for patients undergoing rest and stress echocardiography. [ABSTRACT FROM AUTHOR]

Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by noncompartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation. [ABSTRACT FROM AUTHOR]

Introduction. The development of inflammatory bowel disease during the treatment with tumor necrosis factor-a inhibitors is seen in patients with ankylosing spondylitis. Crohn's disease is the mainly developing form, and etaner-cept is the most frequently associated agent. Although thrombocytosis in patients with ankylosing spondylitis and inflammatory bowel diseases is often seen due to chronic inflammation, iron deficiency anemia or drug administration, presence of essential thrombocythemia is not common. To our knowledge, there is no published data of coexistence of these three diseases in one patient. Case report. We reported a 35-year-patient with simultaneous presentation of ankylosing spondylitis and essential thrombocythemia. Due to hepatotoxicity of initial treatment with sulfasal-azine and metotrexate, tumor necrosis factor-α inhibitor (etanercept) was introduced. Both diseases were well controlled until Crohn's disease emerged. Two years after switching from etanercept to adalimumab all three coexisting diseases were in remission. Conclusion. Treatment with tumor necrosis factor-a inhibitors significantly improved clinical outcome of patients with chronic inflammatory diseases. However, the appearance of adverse effects may cause a discontinuation or change of a drug. The existence of comorbidities additionally complicates the treatment of such patients. [ABSTRACT FROM AUTHOR]

Background/Aim. Treatment of neurological diseases usually requires polypharmacy, and it is crucial to detect potential drug-drug interactions (DDIs) and recognize risk factors on time, as consequences of DDIs could be serious. The aim of the study was to analyze risk factors for the occurrence and the number of potential DDIs among patients in a general neurological ward. Methods. This study was conducted with 144 inpatients in a general-care neurological department of a tertiary care hospital. The effects of risk factors for potential DDIs were evaluated by multiple linear regression. The study had retrospective cohort design. Frequencies of various types of potential DDIs (according to severity) were discovered by Medscape, Epocrates and Micromedex online interaction checkers. Results. The number of prescribed drugs, age of a patient, value of the Charlson comorbidity index and prescription of an antidepressant increase risk of potential DDIs in a general neurology ward. On the other hand, being paralyzed, number of prescribers for a single patient, being bedridden for at least one day of hospitalization decreased the number of potential DDIs per patient. Number of prescribed drugs per patient [odds ratio (OR) = 1.466 ± 0.250; p = 0.000) and age (OR = 1.027 ± 0.026; p = 0.041)] increased, and number of prescribers per patient (OR = 0.056 ± 0.028; p = 0.016), especially if the patients were paralyzed (OR = 0.214 ± 0.294; p = 0.007), decreased the risk of contraindicated, serious, "use alternative" or major potential DDIs. Antidepressants increased the risk of absolute number of all monitor/modify potential DDIs (OR = 1.257 ± 0.726; p = 0.035). Conclusion. Frequency of potential DDIs among neurological patients is considerable and influenced to the largest extent by advanced age, comorbidities, total number of prescribed drugs per patient and concomitant use of antidepressants. [ABSTRACT FROM AUTHOR]

Introduction. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of various drugs and chemicals. The forensic pathologist should consider not only pharmacodynamic interactions by multiple drugs but also the pharmacokinetic drug interactions of each drug in the case of multiple drug ingestion. Case report. A female in her forties, receiving therapy for alcohol dependence, was found dead in her house. The medicolegal autopsy revealed no findings suggestive of natural cause of death. Quantitative toxicological analysis showed that levomepromazine, promethazine, dextromethorphan, estazolam, clomipramine, risperidone, and flunitrazepam concentrations in femoral blood were 0.750 μg/mL, 0.701 μg/mL, 0.332 μ/mL, 0.390 μg/mL, 0.216 μg/mL, 0.031 μg/mL, and 0.002 μg/mL, respectively, along with a blood ethanol level of 377 mg/dL. Conclusion. We concluded that the cause of death was the interaction between ethanol and multiple psychotropic drugs. Pharmacokinetic drug interactions due to the CYPs inhibition should be considered in the evaluation of toxicity in poisoning cases involving multiple drugs. [ABSTRACT FROM AUTHOR]

Background/Aim. The treatment of chronic myeloid leukemia (CML) has changed dramatically with the advent of targeted therapies. This study aimed to assess the efficacy of generic imatinib in CML patients treated in our center. Methods. The study was retrospective. It included 101 patients diagnosed with CML - chronic phase (CP). The patients were divided into two groups. Group 1 included 55 patients initially treated with branded imatinib and then switched to generic imatinib. Group 2 consisted of 46 newly diagnosed patients who received only generic imatinib from the beginning of therapy. Results. The patients were treated with branded imatinib for the mean of 42 months (range 6-132 months) before switching to generic imatinib. Treatment with generic imatinib lasted for 25 months on average (range 3-66 months). A quarter of the patients from the group 1 lost their cytogenetic response after being switched to generic imatinib, but without signs of transformation to acute leukemia. The patients treated with branded imatinib had a significantly longer event-free survival (EFS) and failure-free survival (FFS) (log-rank p = 0.01 and p = 0.03, respectively). These results could have been influenced by frequent changes of the brand and dosage formulation of generic imatinib. Conclusions. Our study showed a significantly longer EFS and FFS in the patients who were initially treated with branded imatinib, compared to those treated with generic imatinib only. These results provide useful information, but have to be interpreted within the context of the crossover study. [ABSTRACT FROM AUTHOR]

Background/Aim. Kidney tumors account for 2-3% of all tumors. Renal cell carcinoma (RCC) is the tenth most common malignancy. Sunitinib is used as the first treatment line in patients with a good and intermediate prognosis. The aim of this study was to analyze the risk factors, frequency, and adverse drug reactions (ADRs) of sunitinib in patients with metastatic RCC. Methods. The retrospective study included 170 patients treated at the Clinic for Oncology of the Clinical Center of Montenegro, Urology Clinic of the Clinical Center of Serbia, and Clinic for Oncology of the Clinical Center Niš. As a data source, we used patient medical histories and/or electronic patient records. ADRs were characterized by using Rawlins and Thompson classification. Each ADRs severity was assessed in accordance with the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. Results. ADRs of sunitinib occurred in 152 (89.4%) patients. ADRs were 89% type A and 11% type C. Disorders of the blood and lymphatic system, gastrointestinal disorders, and disorders of the skin and subcutaneous tissue were the most common manifestations of ADRs of sunitinib. Causality assessment was most commonly classified as certain (60%). Serious ADRs occurred in 4.5% of patients. Most patients recovered without consequences. The most common manifestations of ADRs were: leukopenia, hypothyroidism, thrombocytopenia, diarrhea, stomatitis, asthenia, and hypertension. All ADRs were expected. The number of concomitant medications and the duration of therapy proved to be the most significant risk factors for ADR to sunitinib. Conclusion. Our study shows that the incidence of ADRs of sunitinib in patients with kidney cancer is high. The ADRs were mostly moderate and mild in intensity and occurred as a consequence of the pharmacological action of the drug. It is necessary to conduct continuous education of medical oncologists in the field of monitoring safe drug use, as well as patients on sunitinib therapy, in order to improve their awareness of the sunitinib ADRs and the risk factors that lead to them, with the aim of reducing their frequency. [ABSTRACT FROM AUTHOR]

Background/Aim. Drug utilisation monitoring could identify drug-related problems and hence improve the awareness of irrational drug use. The objective of this study was to analyse the drug utilisation patterns in a rehabilitation hospital over the period 2011-2016. Methods. The Anatomic Therapeutic Chemical classification/Defined Daily Dose (ATC/DDD) methodology was used to monitor the drug utilisation expressed as a number of DDD per 100 patient-days (HPD). The values of DDDs were obtained from the World Health Organisation (WHO) Collaborating Centre for Drug Statistics Methodology. Utilisation trends were analysed by means of the Compound Aggregate Growth Rate (CAGR), which is defined as an average annual change rate of some value during the period of interest. Results. The number of patient-days increased during the six years period; the CAGR being1.8% annually. At the same time, the total number of dispensed DDDs as well as the number of DDD/HPD decreased with the CAGR of -2.0% and -3.7% respectively. The average drug cost per patient-day varied from BAM 1.38 in 2013 to 0.95 in 2016; the CAGR being -1.8%. The most utilised drugs belonged to the ATC groups C, A, B, M and N and they contributed to an average of 77% of all drugs used each year. On the top of the list of most utilised drugs were: hydroxocobalamin, thioctic acid, enalapril, diclofenac, amlodipine, acetylsalicylic acid, pantoprazole, paracetamol and bromazepam. Conclusions. The overall drug utilisation in the hospital was modest and almost equal in 2016 compared to 2011. Besides the leading consumption of vitamin B12 and thioctic acid, this study points out some interesting prescribing patterns, such as predominant use of diclofenac over ibuprofen, and overuse of proton pump inhibitors. There is a need for educative interventions among physicians in order to improve their prescribing practice. [ABSTRACT FROM AUTHOR]

Background/Aim. The reactivation of the varicella zoster virus results in herpes zoster. Acyclovir is currently recommended over 7 to 10 days for herpes zoster treatment and should be started within 72 hours of rash eruption. This study analyses whether a therapy delay and/or shorter courses of treatment are associated with adverse outcomes. Methods. We identified 292 patients treated at the Clinic for Infectious and Tropical Diseases in Belgrade for herpes zoster in a five-years period. The data on these patients were analyzed using the descriptive statistics, the χ² test, the Mann-Whitney U-test and the multiple logistic regression analysis. Results. The average time from rash eruption to the first dose of acyclovir was 4.07 ± 2.64 days. The patients received acyclovir for 6.83 ± 2.45 days. Seventy-one patients had disseminated herpes zoster, 100 had cranial nerve involvement, 86 had complications other than postherpetic neuralgia and one patient died. In cases where therapy was delayed there was no significant association with complications (χ² = 0.031; p = 0.86). Our logistic regression model was not able to predict who was treated less than 7 days. An association between the HZ complications and abbreviated acyclovir regimens was not demonstrated (χ² = 1.109; p = 0.326). We conducted the PubMed search on February 1st, 2017 and found no proof for the need to apply at least 7 days of acyclovir therapy for herpes zoster in the studies that have been published so far. Conclusion. We were unable to prove an association between therapy delay and unfavorable outcomes. The same was true for shorter than recommended acyclovir courses. [ABSTRACT FROM AUTHOR]

Background/Aim. There are several questionnaires for measuring intensity of nausea after drug administration, but they are either too settings specific (like those measuring chemotherapy-induced nausea), or they were not properly tested for reliability and validity. The aim of this study was to develop and validate a reliable instrument that can measure drug-induced nausea. Methods. The cross-sectional study for assessing reliability and validity of a questionnaire was performed. The questionnaire with 5 items and answers according to the Likert's scale was developed during two brainstorming sessions of the research team. Its reliability, validity and temporal stability were tested on the sample of 128 outpatients taking iron salts orally. Results. The final version of the Drug-Induced Nausea Scale (DINS) with 5 items showed excellent reliability, both when rated by the investigators (Cronbach's alpha 0.892) and by the patients themselves (Cronbach's alpha 0.897). It was temporally stable, and both divergent and convergent validity tests had very good results. Factorial analysis revealed only one factor, which means that the whole scale is measuring only one phenomenon, intensity of nausea, as was originally intended. Conclusion. The DINS is reliable and valid instrument for measuring intensity of drug-induced nausea. Identification of patients with high intensity of druginduced nausea by this questionnaire will help prescribers to decide whether the therapy should be stopped or the patient switched to less emetogenic therapy. [ABSTRACT FROM AUTHOR]

Background/Aim. The Professional System of Continuous Glucose Monitoring, the iPro®2 CGM System (Medtronic) is designed to be worn together with a glucose sensor with an electrode inserted into the subcutaneous tissue, up to 7 days, without insight into the current level of glycemia. After reading data from the iPro®2 device, a realistic picture of the glycemia movement during the period of wearing the device is obtained. The aim of the study was to examine whether objective measurement information collected through the use of professional continuous glucose monitoring (CGM) contribute to improved metabolic control in children with type 1 diabetes mellitus who are on the multiple daily insulin injections (MDI). Methods. The study was conducted on 24 patients (14 girls) aged 5 to 18 years, with an average age 12 ± 3.3 years, in the period from June to December 2016 in the Clinic of Pediatrics, University Clinical Center of the Republic of Srpska in Banja Luka. Glycated hemoglobin (HbA1c) was measured in the laboratory at the start of the trial and 3 months afterwards in order to determine the effect of wearing professional iPro®2 on metabolic control, and then three months later, to test for the long-lasting effects in the absence of iPro®2 monitoring. Results. The initial HbA1c was 7.78 ± 1.17% (min: 5.50%; max: 10.00%). After 3 months, HbA1c showed a statistically significant decrease to 7.34 ± 0.84% (min: 5.60%, max: 8.90%). At the six-month follow-up visit, without implementing professional CGM in the meantime, a significant increase in HbA1c was reached, with the average value of 7.68% ± 0.83% (min: 5.50%, max: 9.10%). Conclusion. This study shows that carrying a professional CGM for 7 days per month, 3 months continuously is associated with certain improvement of metabolic control in children with diabetes who are on MDI without increasing risks of hypoglicemia. [ABSTRACT FROM AUTHOR]

Background/Aim. Drug-drug interactions involving antimicrobials present important and often unrecognized complications of pharmacotherapy which can be prevented. The aim of the present study was to identify the frequency and type of potential drug-antimicrobial agent interactions among outpatients and to define recommendations for their management. Methods. Crosssectional prescription database study was conducted. The analysis randomly included 823 patients who visited Health Center Novi Sad over 1-month period (November 1-30, 2011) and had prescribed ≥ 2 drugs where at least one drug was antimicrobial agent for systemic use. All interacting drug combinations involving antimicrobials were identified according to Drug Interaction Facts. Additionally, based on the compendium, potential interactions were classified into categories: pharmacological mechanisms, potential clinical outcomes and management advice. Results. Overall, 88 potential clinically significant drug-antimicrobial agent interactions were identified among 69 (8.4%) exposed outpatients [the mean age 61.7 years (SD ± 15.4); the mean number of prescribed drugs 7.5 (SD ± 2.9); 56.5% females]. The most common identified potential interacting pairs were benzodiazepines undergoing oxidative metabolism and clarithromycin or erythromycin, and aminophylline and ciprofloxacin. In 83.0% of all cases underlying mechanism was pharmacokinetic involving primary inhibition of metabolic pathways mediated by CYP3A4 and CYP1A2 isoenzymes. Excessive sedation (22.7%), cardiotoxicity (20.5%), miscellaneous aminophylline adverse effects (13.6%), and bleeding (10.2%) were the most frequently implicated potential clinical outcomes. Risk for adverse interactions could be managed by close monitoring of simultaneous administration of drugs (37.5%), different risk-modifyng strategies (31.8%), and avoiding combinations (30.7%). Conclusion. Among outpatients, there was common potential for clinically significant interactions involving antimicrobials. Information based on the results of the present study could be integrated in existing computerized physician order entry system in the Health Center as a form of clinical support. [ABSTRACT FROM AUTHOR]

Background/Aim. Under the current financial crisis in Greece, an effort has been made by the Greek health authorities to encourage generic prescribing, in order to lower medicinal cost. The purpose of this work was to study antipsychotics use, and to calculate utilization of generics in antipsychotics sales in a sample from the medicines market of Thessaloniki, the second largest city in Greece. Methods. A sample of antipsychotics registered sales was collected using the new Electronic Health Records that have been applied in pharmacies during the last years in Greece. The sample corresponded to a small amount of sales from the market of Thessaloniki during the period July 2014--June 2015, including only community and no hospital sales. All brand names (prototype and generics) of antipsychotics and their relative ratios in the sales were estimated, and the percentage of generics in the sale of each medicine was calculated. The amount of medicines was estimated in Defined Daily Doses (DDDs) of the reference/prototype drug and its generics. Results. Olanzapine, quetiapine, haloperidol and risperidone sales corresponded to 77% of total antipsychotics sales with percentages of sales 25%, 19%, 19% and 14% respectively. The percentage of sales of other antipsychotics was 7% for amisulpride, 6% for aripiprazole, 4% for ziprasidone and 3% for clozapine. Generic use corresponded to 41% of total sales of antipsychotic drugs (10.884 DDDs out of 26.433 DDDs). Concerning second generation antipsychotics, generic use was high for amisulpride, olanzapine, risperidone and quetiapine. Conclusion. In the study sample, second generation antipsychotics corresponded to 78% of sales in the community of Thessaloniki. Haloperidol utilization was also notable. Considering Greek practices, the percentage of generics in antipsychotics sales was very high even for some of the newest antipsychotics. [ABSTRACT FROM AUTHOR]

Background/Aim. Tacrolimus concentration-dose ratio as a potential therapeutic drug monitoring strategy was suggested to be used for the patients subjected to renal transplantation. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio, suggested to be used as a therapeutic drug monitoring strategy and the polymorphisms of genes encoding the most important enzymes, such as CYP3A5 and CYP3A4, as well as the transporter P-glycoprotein, for its metabolism and elimination. Methods. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 RealTime PCR System by assessing allelic discrimination based on TaqMan® methodology. Results. Patients (n = 13) who were treated with less than 2 mg of tacrolimus/day (0.024 ± 0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/mL/mg/kg. In this group, 84.62% patients had CYP3A5 *3*3 allele. All of these patients had CYP3A4 *1*1/*1*1B allele. Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant, while 69.23% of our patients had CC and CT gene variants. Conclusion. Tacrolimus concentration-dose ratio greater than 150 ng/mL/mg/kg is cut-off value in patients subjected to renal transplantation which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein. [ABSTRACT FROM AUTHOR]

Background/Aim. Carbapenem resistance has escalated in medically important enterobacteria such as Klebsiella pneumoniae and Escherichia coli worldwide. Multidrug-resistant strains represent an important source of concern as effective therapeutic options of infections they cause are limited or none. There were no comprehensive studies considering the presence of carbapenemase production in enterobacteria in Serbia so far. The aim of the study was to determine carbapenemase production in hospital isolates of multidrug-resistant K. pneumoniae and E. coli in Serbia. Methods. Strains of K. pneumoniae and E. coli resistant to at least one carbapenem (imipenem, meropenem, ertapenem) were collected from November 2013 to May 2014. Isolates were obtained from clinical samples of patients treated in 14 hospitals in Serbia. Carbapenem resistance was confirmed using phenotypic tests and polymerase chain reaction (PCR) in National Reference Laboratory for Registration and Surveillance of Antimicrobial Resistance of Bacterial Strains in Novi Sad. Results. Of 129 collected strains, 121 (93.8%) were K. pneumoniae and 8 (6.2%) were E. coli. Seventy (54.3%) strains were obtained from urine, 26 (20.2%) from blood, 19 (14.7%) from wound secretions and 14 (10.9%) from lower respiratory tract secretions. Carbapenemase genes were detected in 58 (45%) isolates. The gene bla New Delhi-metallo-beta-lactamases (blaNDM) was found in 33 (27.3%) K. pneumoniae, bla oxacillinases-48 (blaOXA-48) in 10 (8.3%), bla K. pneumonia carbapenemase (blaKPC) in 1 (0.8%), and 7 (5.4%) strains harbored both blaOXA-48 and blaNDM. Seven E. coli harbored blaNDM gene. Conclusion. In Serbia, the most common type of carbapenemase in both multidrug-resistant K. pneumoniae and E. coli is NDM. Co-production of OXA-48 and NDM was found in K. pneumoniae. To our knowledge, KPC production was detected for the first time in Serbia. [ABSTRACT FROM AUTHOR]

Background/Aim. Urinary tract infections (UTIs) are among the most common infections in outpatients. The aim of this study was to define the causative agents of urinary tract infections and their resistance to antimicrobial drugs in the urban area of central Serbia, as well as to evaluate eventual differences associated with age and gender of the patients. Methods. This retrospective study analysed data taken from routine, consecutively collected urine cultures of outpatients with symptomatic UTIs, collected from the Department of Microbiology, Institute of Public Health in Kragujevac, Serbia, from January 2009 to December 2013. Results. There were 71,905 urine cultures, and 24,713 (34.37%) of them were positive for bacterial pathogens. The most common pathogen was Escherichia coli (E. coli) (56.56%), followed by Klebsiella spp. (16.20%), Proteus spp. (14.68%), Enterococcus spp. (5.29%) and Pseudomonas aeruginosa (3.74%). E. coli and Enterococcus spp. isolation rates were lower in males ≥ 60 years old (23.71% and 4.87%, respectively), while Klebsiella spp. was more prevalent in this group (32.06%). The most common causative agents isolated from 15-29 years old male patients were Enterococcus spp. and Pseudomonas aeruginosa (13.28% each). Among women, the isolation rate of E.coli was high in all age groups (around 70%). Proteus spp. was frequently isolated from females ≤ 14 years old (13.27%), while Klebsiella spp. was the most frequent in the oldest age female group (10.99%). Conclusion. Choice of antibiotics for treatment of UTIs should be governed not only by the local resistance patterns, but also by gender and age of patients. [ABSTRACT FROM AUTHOR]

Background/Aim. Bacillus cereus (B. cereus) usually ingested by food can cause two types of diseases: vomiting due to the presence of emetic toxin and diarrheal syndrome, due to the presence of diarrheal toxins. Systemic manifestations can also occur. The severe forms of disease demand antibiotic treatmant. The aim of this study was to determine the differences in antibiotic susceptibility and β-lactamase activity of B. cereus isolates from stools of humans, food and environment. Methods. Identification of B. cereus was performed with selective medium, classical biochemical test and polymerase chain reaction (PCR) with primers specific for bal gene. Thirty isolates from each group were analysed for antibiotic susceptibility using the diskdiffusion assay. Production of β-lactamase was determined by cefinase test, and double-disc method. Results. All strains identified as B. cereus using classical biochemical test, yielded 533 bp fragment with PCR. Isolates from all the three groups were susceptible to imipenem, vancomycin, and erythromycin. All isolates were susceptible to ciprofloxacin but one from the environment. A statistically significant difference between the groups was confirmed to tetracycline and trimethoprimsulphamethoxazole sensitivity. A total of 28/30 (93.33%) samples from the foods and 25/30 (83.33%) samples from environment were approved sensitive to tetracycline, while 10/30 (33.33%) isolates from stools were sensitive. Opposite to this result, high susceptibility to trimethoprim-sulphamethoxazole was shown in samples from stools (100%), while isolates from foods (63.33%) and from environment (70%) had low susceptibility. All samples produced β-lactamases. Conclusion. The strains of B. cereus from all the three groups showed high rate of sensitivity to most tested antibiotics, except to tetracycline in samples from human stool and to trimethoprimsulphamethoxazole in samples from food and environment. The production of β-lactamases was confirmed in all the strains. [ABSTRACT FROM AUTHOR]

causes of cardiovascular morbidity and mortality and more than a half of all health insurance expenditures for reimbursed medicines are allocated to antihypertensive drugs in Serbia. The aim of this study was to identify the antihypertensive drug utilization patterns among hypertensive outpatients in the city of Novi Sad, Serbia, determine the adherence to clinical guidelines and address the economic aspects of current prescribing practices. Methods. This retrospective observational study was conducted in Novi Sad over a period of six months. The data on the number of packages, size their, and retail price of antihypertensives issued on prescription in outpatients with the diagnosis of essential arterial hypertension was collected from all state-owned pharmacies in Novi Sad. Drug consumption was analyzed using the Anatomical Therapeutic Chemical (ATC)/ defined daily dose (DDD) methodology. Results. Total consumption of antihypertensives issued on prescription over a 6-month period in the city of Novi sad, Serbia was 283.48 DDD per 1,000 inhabitans per day (DID). Angiotensin converting enzyme inhibitors (ACEi) were most commonly prescribed drugs, and were used 3 times more often than calcium channel blockers and 5 times more than beta-blockers. The consumption of diuretics and angiotensin receptor antagonists was low within all the groups of outpatients. Both national and international guidelines state superiority and effectiveness of diuretics in treatment of hypertension in the elderly, but their consumption was unreasonable low despite the fact that over 70% of all antihypertensive drugs in the city of Novi Sad were dispensed in people aged > 60. The use of more expensive ACEi was observed despite the guidelines deeming all the drugs of this class equally effective in treatment of hypertension. Conclusion. Large differences in utilization of different groups of antihypertensive agents were noted in this study. Underutilization of valuable, efficacious, and cost-effective thiazide diuretics and overuse of expensive ACE inhibitors is unjustifiable. There is a potential for large savings with switching to low-price ACEi, modeling the practice of Scandinavian countries. [ABSTRACT FROM AUTHOR]

Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppressive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/ dose (C/D) ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872) of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC) were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD) per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine) while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster elimination of tacrolimus in the females was also seen, with the exception of the doses > 0.25 mg/kg. Tacrolimus exposure in the pantoprazole-treated patients was significantly less expressed, while in patients treated with CCB amplodipine the tacrolimus C/D ratio was significantly higher in comparison with the patients not treated with them. [ABSTRACT FROM AUTHOR]

Life as we know it heavily relies on biological catalysis, in fact, in a very nonromantic version of it, life could be considered as a series of chemical reactions, regulated by the guarding principles of thermodynamics. In ancient times, a beating heart was a good sign of vitality, however, to me, it is actually the presence of active enzymes that counts... Though we do not usually pay attention, the history of enzymology is as old as humanity itself, and dates back to the ancient times. This paper is dedicated to these early moments of this remarkable science that touched our lives in the past and will make life a lot more efficient for humanity in the future. There was almost always a delicate, fundamentally essential relationship between mankind and the enzymes. Challenged by a very alien and hostile Nature full of predators, prehistoric men soon discovered the medicinal properties of the plants, through trial and error. In fact, they accidently discovered the enzyme inhibitors and thus, in crude terms, kindled a sparkling area of research. These plant-derivatives that acted as enzyme inhibitors helped prehistoric men in their pursuit of survival and protection from predators; in hunting and fishing... Later in history, while the underlying purposes of survival and increasing the quality of life stayed intact, the ways and means of enzymology experienced a massive transformation, as the 'trial and error' methodology of the ancients is now replaced with rational scientific theories. [ABSTRACT FROM AUTHOR]

Explanation the topic The pharmaceutical activity is the activity of public or social and special interest, because it is a direct function of health care. Topic positioning and discussion The aim of this paper is to highlight the importance of ensuring the quality of pharmaceutical substances that supplies hospitals, which are used for production of galenic and magistral drugs. Conclusion Compliance with national legislation, as well as establishing compliance prescribed by the European legislation in the field of drug development is binding. Therefore, all manufacturers of drugs and/or active pharmaceutical ingredients must apply quality standards prescribed by the European Pharmacopoeia in order to develop, manufacture and sales of medicines. When it comes to the quality of pharmaceutical ingredients for the production of drugs in the pharmacy, pharmacies especially in residential institutions in our country is permanently done by harmonizing national legislation in order to improve conditions for the preparation and production of galenic drugs in terms of inpatient health institutions performed in a manner that is prescribed by international regulations. This requires the adaptation of institutions, including fundamental changes in competence as national professional and administrative and regulatory rules that apply to state- and private sectors. [ABSTRACT FROM AUTHOR]

Background/Aim. Rhabdomyolysis (RM) is potentially lethal syndrome, but there are no enough published data on its frequency and characteristics in acute poisonings. The aim of this study was to determine the causes and severity of RM in acute poisonings. Methods. Patients hospital charts were retrospectively screened during a one-year period in order to identify patients with RM among 656 patients treated due to acute poisonings with different agents. All the patients with RM were selected. Entrance criterion was the value of creatine kinase (CK) over 250 U/L. The severity of RM was assessed according to the Poison Severity Score. The patients were divided into three groups: the first one with mild RM (CK from 250 to 1,500 U/L), the second with moderate RM (CK from 1,500 to 10,000 U/L) and the third with severe RM (CK greater than 10,000 U/L). Results. RM occurred in 125 (19%) of the patients with acute poisonings. It was mainly mild (61%), or moderate (36%), and only in 3% of the patients was severe RM. The incidence of RM was the highest in poisonings with opiates (41%), pesticides (38%), neurolep-tics (26%), anticonvulsants (26%), ethyl alcohol (20%), and gases (19%). Psychotropic agents were the most common causes of poisoning, and consequently of RM. Fatal outcomes were registered in 32 (25.60%) of all RM patients. The incidence of fatal outcomes in poisonings with mild, moderate and severe RM was 19.73%, 31.11% and 75%, respectively. Conclusion. RM syndrome occurs at a relatively high rate in acute poisonings. Although agent's toxicity is crucial for the outcome, severe RM and its complications may significantly influence the clinical course and prognosis of poisoning. Routine analysis of CK, as a relevant marker for RM may indicate the development of RM in acute poisoning and initiate prompt therapeutic measures in preventing acute renal failure as the most frequent consequence of extensive rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. The beginning of orphan drugs development. This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. Conclusion. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs. [ABSTRACT FROM AUTHOR]

Uvod: Primarni aldosteronizam (PA) predstavlja grupu poremećaja koja se odlikuje neadekvatnom i nesupresibilnom produk-cijom aldosterona. Prevalenca PAje rastuća u hipertenzivnoj populaciji. Zlatni standard za skrining PA, određivanje odnosa (ARR) aldosterona i plazma reninske aktivnosti (PRA) posturalno, pod uticajem je brojnih endogenih i egzogenih faktora. Testiranje u optimalnim uslovima nije uvek moguće. Cilj rada: Utvrditi kakav je uticaj antihipertenzivnih lekova i koncentra-cije kalijuma i natrijuma u krvi i urinu na vrednosti aldosterona i plazma reninsku aktivnost. Metod rada: U retrospektivnoj studiji analizirana je medicinska dokumentacija pacijenata primljenih na Odeljenje za bolesti štitaste žlezde u periodu 2009-2011. godine sa povećanim rizikom za primarni aldosteronizam. Kod svih pacijenata analizirani su telesna masa i visi-na, koncentracije natrijuma i kalijuma u serumu i urinu, koncentracije aldosterona u plazmi i PRA, podaci o lekovima u terapiji i pridruženim bolestima. Od statističkih metoda korišćeni su metodi deskriptivne sta-tistike, Studentov T test i jednostruka linearna povezanost. Rezultati: Od 137 pacijenata bilo je više pacijenata sa rezistentnom hipertenzijom (53,28%) nego sa tumorima nadbubrega (46,72%). Najviše pacijenata bilo je na terapiji kalcijumskim antagonistima. Terapija alfa adrenergičkim i kalcijumskim antagonistima ne utiče na ARR. Blokatori beta adrenergičkih receptora i ACE inhibitori mogu da utiču, a diuretici i vazodilatatori sigurno utiču. Dijabetes melitus može da nosi veći rizik od lažno negativnih rezultata. Natriureza je značajno povezana sa plazma aldosteronom i kalijumom u serumu. Plazma aldosteron i PRA značajno su povezani sa koncentracijama elektrolita u urinu. Zakljucak: Povećana prevalenca primarnog aldosteronizma nameće potrebu za preciznijom i boljom dijagnostikom. [ABSTRACT FROM AUTHOR]

A great number of drugs affect thyroid function by different mechanisms. A wide range of mechanisms include modifications to the hypopthlamo-pituitary axis, synthesis and secretion of thyroid homone by thyroid and change in thyroid hormone metabolism as well as their acitivities in tissue. A small subset of drugs including glucocorticoids, dopamine and dopamine agonists, somatostatine analogs and rexinoids cause suppression of TSH and central hypothyreoidism.This central hypothyroidism usually is not cllinically evident and its medical treatment is not necessery. Non-thyroidal illness syndrome (NTIS) also causes TSH suppression and central hypothyreoidism by complex mechanisms. It becomes clinically apparent if the treatment of NTIS is associated with using glucocorticoids and dopamine and then possibilities possibilities of treatment this hypothreoidism should be considered. Different mechanisams by which these drugs cause central hypothyreoidism and their clinial relevance were analysed in this review. [ABSTRACT FROM AUTHOR]

Background/Aim. There is a high rate of schizophrenic patients who do not adhere to their prescribed therapy, despite the implementation of antipsychotic long-acting injections and the introduction of atypical antipsychotics. The aim of this study was to investigate the differences in sociodemo-graphic, clinical and medication adherence variables between the two groups of schizophrenic patients on maintenance therapy with depot antipsychotic fluphenazine decanoate and oral antipsychotics only as well as a correlation between the medication adherence and other examined variables. Methods. A total of 56 patients of both genders, aged < 60 years, with the diagnosis of schizophrenia (F20) (ICD-10, 1992) clinically stable for at least 6 months were introduced in this cross-sectional study. The patients from the depot group (n = 19) were on classical depot antipsychotic fluphenazine decanoate administering intramuscularly every 4 weeks (with or without oral antipsychotic augmentation) and the patients from the oral group (n = 37) were on oral therapy alone with classical or Atypical antipsychotics, either as monotherapy or combined. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Item G12 of the PANSS was used to assess insight into the illness. The patients completed the Medical Adherence Rating Scale (MARS) was used to assess adherence to the therapy. A higher MARS score indicates behavior [Medical Adherence Questionnaire (MAQ subscale)] and attitudes toward medication [Drug Attitude Inventory (DAI subscale)] that are more consistent with treatment adherence. The exclusion criteria were determined. The Pearson's χ² test was used to compare categorical variables, Student's t-test to compare continuous variables and Pearson's correlation to test the correlation significance; p = 0.05. Results. Significant between-group differences in age, illness duration, chlorpromazine equivalents, PANSS score and DAI subscore were found. Item G12 of the PANSS subscore and MARS score correlated significantly negatively. A significant positive correlation between receiving depot antipsychotic and DAI subscore as well as between illness duration and both DAI subscore and MARS score were also found. Conclusion. Schizophrenic patients on classical depot antipsychotic maintenance therapy might present subpopulation of patients with significantly longer illness duration, more favorable medication attitude and outcome in relation to those on oral antipsychotics alone. [ABSTRACT FROM AUTHOR]

Background/Aim. Hydrophilic matrix tablets represent the most commonly used oral dosage form. Carbomers used in the concentration of 10%-30% for preparation of matrix tablets, may significantly affect the profile of drug release due to the formation of hydrogel matrix tablets. The aim of this study was to compare the influence of different types of Carbopol® (carbomers in the pharmacopoeia) on the release rate of lithiumcarbonate and other pharmaceutical, technological, physical and chemical properties of the prepared formulations of matrix tablets. Methods. Three different formulations of matrix tablets were made according to direct compression method. The tablets were of the following composition: carbomer, lactose monohydrate, magnesium-stearate, lithium-carbonate in the proportion 75 : 120 : 5 : 300. The first formulation was made with Carbopol® 971P NF, the second one with Carbopol® 974 P NF and the third one with Carbopol® 71G NF. The quantity of lithium-carbonate was determined according to the BP 2009, pharmaceutical and tecnological properties were examined in accordance with the regulations of Ph. Jug. V, whereas the release rate of lithium-carbonate from the formulations was examined by the application of dissolution test, prescribed in the monography 'Lithium Carbonate Extended-Release Tablets' in USP 26. Results. The profile of lithium-carbonate release from matrix tablets with Carbopol® 974P NF entirely complies with the regulations of USP 26, whereas the values obtained from the analysis of matrix tablets with Carbopol® 971P NF and Carbopol® 71G NF were considerably lower than the prescribed ones. In all the investigated formulations the content of the drug, mass variation and tablet hardness comply with the regulations set in pharmacopoeia. Conclusion. In the formulation of matrix tablets with lithium-carbonate, by the application of carbomers in the concentration of 15%, with Carbopol ® 974 P NF a favourable lithium-carbonate release profile was achieved, whereas in the formulations with Carbopol® 971P NF and Carbopol® 71G NF, the release rate was significantly lower than that given in the USP 26 monography. [ABSTRACT FROM AUTHOR]