EFFICACY AND SAFETY OF LOW-DOSE VERSUS STANDARD-DOSE ALTEPLASE REGIMENS IN PATIENTS WITH ACUTE ISCHAEMIC STROKE

Background: The use of intravenous recombinant tissue plasminogen activator, alteplase, at a dose of 0.9 mg/kg is an effective treatment for patients with acute ischaemic stroke; this dose is also associated with high intracerebral haemorrhage rates. The aim of this study was to evaluate whether the low-dose alteplase treatment is as effective and safe as the standard-dose regimen. Subjects and methods: This was a retrospective, single-centre study, and data were collected from the Hospital Stroke Registry. Based on the severity of stroke and the risk of intracerebral haemorrhage, patients were divided into two groups according to the alteplase doses given; the low-dose (0.6 mg/kg) group (n=45) and the standard-dose (0.9 mg/kg) group (n=165). Ninety-day outcomes measured as modified Rankin score and National Institute for Health Stroke Scale (NIHSS) score, as well as symptomatic intracerebral haemorrhage and mortality rates were analysed. Results: The standard-dose group had a slightly more favourable outcome (Rankin score 0-2) at 90 days after alteplase treatment than the low-dose group (64.24% vs. 53.33%), but the difference was not significant. The total intracerebral haemorrhage rate and mortality rate at 90 days were higher in the standard-dose group than in the low-dose group (21.2% vs. 13.3% and 6.1% vs. 0.0%, respectively), but these differences were not statistically significant. Conclusion: The low-dose alteplase treatment applied to the patients with high intracerebral haemorrhage risk had comparable efficacy and safety profile to the standard-dose regimen

EFFICACY AND SAFETY OF LOW-DOSE VERSUS STANDARD-DOSE ALTEPLASE REGIMENS IN PATIENTS WITH ACUTE ISCHAEMIC STROKE

Background: The use of intravenous recombinant tissue plasminogen activator, alteplase, at a dose of 0.9 mg/kg is an effective treatment for patients with acute ischaemic stroke; this dose is also associated with high intracerebral haemorrhage rates. The aim of this study was to evaluate whether the low-dose alteplase treatment is as effective and safe as the standard-dose regimen. Subjects and methods: This was a retrospective, single-centre study, and data were collected from the Hospital Stroke Registry. Based on the severity of stroke and the risk of intracerebral haemorrhage, patients were divided into two groups according to the alteplase doses given; the low-dose (0.6 mg/kg) group (n=45) and the standard-dose (0.9 mg/kg) group (n=165). Ninety-day outcomes measured as modified Rankin score and National Institute for Health Stroke Scale (NIHSS) score, as well as symptomatic intracerebral haemorrhage and mortality rates were analysed. Results: The standard-dose group had a slightly more favourable outcome (Rankin score 0-2) at 90 days after alteplase treatment than the low-dose group (64.24% vs. 53.33%), but the difference was not significant. The total intracerebral haemorrhage rate and mortality rate at 90 days were higher in the standard-dose group than in the low-dose group (21.2% vs. 13.3% and 6.1% vs. 0.0%, respectively), but these differences were not statistically significant. Conclusion: The low-dose alteplase treatment applied to the patients with high intracerebral haemorrhage risk had comparable efficacy and safety profile to the standard-dose regimen

Pharmacists’ clinical knowledge and practice in the safe use of contraceptives: real knowledge vs. self-perception and the implications

Background: Pharmacists are often the first healthcare professionals that patients contact with their illnesses and requests for medical information, which is enhanced following the recent COVID-19 pandemic. Community pharmacists are expected and required to possess a broad spectrum of knowledge and skills. Self-assessment of these competencies is needed for their self-improvement. Purpose of the study: To assess pharmacists’ clinical knowledge and practice in the safe use of contraceptives, and to compare the scores obtained by external observation with pharmacists’ self-assessment of their knowledge as well as investigate the significance of preceptorship experiences. Contraceptives was chosen as the subject area in view of high rates of abortions as a means of contraception in Bosnia and Herzegovina. Methods: A questionnaire approach was used. The questionnaire included the following: the first domain contained two case scenarios (safe use of contraceptives), which evaluated clinical knowledge, a second domain in which pharmacists self-assessed their knowledge to resolve cases from the first domain and a third domain that measured the demographics of pharmacists (including experience in preceptorship). Dispensing practice was evaluated in the second domain. The questionnaires were distributed to a convenient sample of 100 pharmacists at the Annual Meeting of Bosnia and Herzegovina Pharmacists. The results were presented as counts (%). The groups (preceptors and non-preceptors) were compared using Mann-Whitney U test, paired assessments were analyzed by Wilcoxon signed-rank test and Spearman’s correlation was used to assess the correlation between variables. Results: Of the 100 pharmacists invited to participate, 84 completed the questionnaire (84 % response rate). There was no agreement between pharmacists’ real knowledge (average score - case 1: 2.71, case 2: 3.3) and their self-assessment (average score - case 1: 3.77, case 2: 3.91). There was no statistically significant difference in the actual knowledge of pharmacists (experienced/non-experienced in precepting), while the difference in the self-assessment was significant between these two groups. Conclusion: Pharmacists appear to overrate themselves, which leads to self-enhancement bias, in which the experience in precepting has some influence. Pharmacists’ capability in performing an objective self-assessment of their clinical knowledge needs to be carefully studied in the future to fully benefit patients

Recent initiatives in the Republic of Srpska to enhance appropriate use of antibiotics in ambulatory care : their influence and implications

Introduction:There are increasing concerns world-wide with growing rates of antibiotic resistance necessitating urgent action. There have been a number of initiatives in the Republic of Srpska in recent years to address this and improve rational antibiotic prescribing and dispensing despite limited resources to fund multiple initiatives. Objective: Analyse antibiotic utilization patterns in the Republic of Srpska following these multiple initiatives as a basis for developing future programmes in the Republic if needed. Methods: Observational retrospective study of total outpatient antibiotic utilization from 2010 to 2015, based on data obtained from the Public Health Institute, alongside documentation of ongoing initiatives to influence utilization. The quality of antibiotic utilisation principally assessed according to ESAC, ECDC and WHO quality indicators and DU 90% (the drug utilization 90%) profile as well as versus neighbouring countries. Results: Following multiple initiatives, antibiotic utilization remained relatively stable in the Republic at 15.6 DIDs to 18.4 DIDs, with a decreasing trend in recent years, with rates comparable or lower than neighbouring countries. Amoxicillin and the penicillins accounted for 29%-40% and 50% of total utilization, respectively. Overall, limited utilization of co-amoxiclav (7% - 11%), cephalosporins, macrolides and quinolones, as well as low use of third and fourth generation cephalosporins versus first and second cephalosporins. However, increasing utilization of co-amoxiclav and azithromycin, as well as higher rates of quinolone utilization compared to some countries, was seen. Conclusions: Multiple interventions in the Republic of Srpska in recent years have resulted in one of the lowest utilisation of antibiotics when compared with similar countries, acting as an exemplar to others. However, there are some concerns with current utilisation of co-amoxiclav and azithromycin which are being addressed. This will be the subject of future research activities

Recent initiatives in the Republic of Srpska to enhance appropriate use of antibiotics in ambulatory care : their influence and implications

Introduction:There are increasing concerns world-wide with growing rates of antibiotic resistance necessitating urgent action. There have been a number of initiatives in the Republic of Srpska in recent years to address this and improve rational antibiotic prescribing and dispensing despite limited resources to fund multiple initiatives. Objective: Analyse antibiotic utilization patterns in the Republic of Srpska following these multiple initiatives as a basis for developing future programmes in the Republic if needed. Methods: Observational retrospective study of total outpatient antibiotic utilization from 2010 to 2015, based on data obtained from the Public Health Institute, alongside documentation of ongoing initiatives to influence utilization. The quality of antibiotic utilisation principally assessed according to ESAC, ECDC and WHO quality indicators and DU 90% (the drug utilization 90%) profile as well as versus neighbouring countries. Results: Following multiple initiatives, antibiotic utilization remained relatively stable in the Republic at 15.6 DIDs to 18.4 DIDs, with a decreasing trend in recent years, with rates comparable or lower than neighbouring countries. Amoxicillin and the penicillins accounted for 29%-40% and 50% of total utilization, respectively. Overall, limited utilization of co-amoxiclav (7% - 11%), cephalosporins, macrolides and quinolones, as well as low use of third and fourth generation cephalosporins versus first and second cephalosporins. However, increasing utilization of co-amoxiclav and azithromycin, as well as higher rates of quinolone utilization compared to some countries, was seen. Conclusions: Multiple interventions in the Republic of Srpska in recent years have resulted in one of the lowest utilisation of antibiotics when compared with similar countries, acting as an exemplar to others. However, there are some concerns with current utilisation of co-amoxiclav and azithromycin which are being addressed. This will be the subject of future research activities

Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway

Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL

In Silico and In Vitro Studies of Alchemilla viridiflora Rothm-Polyphenols' Potential for Inhibition of SARS-CoV-2 Internalization

Since the outbreak of the COVID-19 pandemic, it has been obvious that virus infection poses a serious threat to human health on a global scale. Certain plants, particularly those rich in polyphe- nols, have been found to be effective antiviral agents. The effectiveness of Alchemilla viridiflora Rothm. (Rosaceae) methanol extract to prevent contact between virus spike (S)-glycoprotein and angiotensin- converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors was investigated. In vitro results revealed that the tested samples inhibited 50% of virus-receptor binding interactions in doses of 0.18 and 0.22 mg/mL for NRP1 and ACE2, respectively. Molecular docking studies revealed that the compounds from A. viridiflora ellagitannins class had a higher affinity for binding with S-glycoprotein whilst flavonoid compounds more significantly interacted with the NRP1 receptor. Quercetin 3-(6”-ferulylglucoside) and pentagalloylglucose were two compounds with the highest exhibited interfering potential for selected target receptors, with binding energies of −8.035 (S-glycoprotein) and −7.685 kcal/mol (NRP1), respectively. Furthermore, computational studies on other SARS-CoV-2 strains resulting from mutations in the original wild strain (V483A, N501Y-K417N-E484K, N501Y, N439K, L452R-T478K, K417N, G476S, F456L, E484K) revealed that virus internalization activity was maintained, but with different single compound contributions

Polypharmacy among the elderly in the Republic of Srpska : extent and implications for the future

Prescribing of medicines is a fundamental component of care for the elderly. However, increasing concern with polypharmacy and its impact on morbidity, mortality and costs. Analyze long-term prescription use and the prevalence of polypharmacy in the elderly in the Republic of Srpska. Subsequently use the findings to suggest potential future measures. Retrospective study of all elderly patients 2005 to 2010 stratified by age group (3 groups), sex and long term medicine use. Polypharmacy (5 or more medicines) increased from 1.4% of the elderly taking medicines long term to 3.6% by 2010, with 53.6% of elderly taking 2 or more medicines long term. Most prevalent diseases were cardiovascular diseases and diabetes. Most prescriptions were in accordance with recent guidelines. However, concern with appreciable prescribing of digoxin and aminophylline. Whilst polypharmacy rates low in the Republic, increasing rates are a concern. Further studies are planned

Prevalencija pet farmakološki najznačajnijih CYP2C9 i CYP2C19 alelenih varijanti u populaciji Republike Srpske u Bosni i Hercegovini

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RTPCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants – 16.2 and 20.4 %, respectively – nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.Citokrom P450 (CYP) visokopolimorfna je superobitelj enzima s ključnom ulogom u metabolizmu lijekova, masnih kiselina, steroida i ksenobiotika. U okviru spomenute skupine enzimi CYP2C9 i CYP2C19 prepoznati su kao klinički važni jer sudjeluju u prvoj fazi metabolizma lijekova te mogu dovesti do neadekvatnoga terapijskog odgovora, toksičnosti i pojave određenih bolesti. Cilj istraživanja je bio odrediti genotipove i prevalenciju alela u 216 nasumice odabranih zdravih ispitanika u populaciji Republike Srpske (Bosna i Hercegovina), te rezultate usporediti s drugim populacijama. Genotipovi enzima CYP2C9 i CYP2C19 određeni su metodom lančane reakcije polimeraze u realnom vremenu (eng. real-time PCR). Prema protokolu proizvođača, korištene su Taqman početnice i probe (engl. Taqman SNP genotyping assay). Kod CYP2C9, učestalosti alela *2 i *3 su 13,6 odnosno 7,4 %. Od 216 sudionika, njih četvero (1,86 %) spori su metabolizatori, a većina njih (62,03 %) normalni metabolizatori. Što se tiče CYP2C19, učestalosti alela *2 i *17 su 16,2 odnosno 20,4 %. Od ukupnoga broja sudionika, njih devet (4,17 %) spori su metabolizatori, njih 57 (26,39 %) brzi metabolizatori, a devet je sudionika (4,17 %) okarakterizirano kao ultrabrzi metabolizatori. U usporedbi s podatcima o učestalosti genotipova i alelnih varijanti CYP2C9 i CYP2C19 u drugim europskim populacijama, dobiveni rezultati pokazali su veliku sličnost. Rezultati ovog istraživanja upućuju da bi određene terapije trebale uzeti u obzir utvrđene fenotipove CYP2C9 i CYP2C19 prilikom procjene individualnih rizika i dobrobiti primjene