The search for effective coronavirus disease (COVID-19) therapy has attracted a great deal of scientific interest due to its unprecedented health care system overload worldwide. We have carried out a study to investigate the in silico effects of the most abundant pomegranate peel extract constituents on the multi-step process of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization in the host cells. Binding affinities and interactions of ellagic acid, gallic acid, punicalagin and punicalin were studied on four selected protein targets with a significant and confirmed role in the process of the entry of virus into a host cell. The protein targets used in this study were: SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease 2. The results showed that the constituents of pomegranate peel extracts, namely punicalagin and punicalin had very promising potential for significant interactions with the selected protein targets and were therefore deemed good candidates for further in vitro and in vivo evaluation.

Cancer and heart diseases are the leading causes of morbidity and mortality in many countries worldwide. Using chemotherapy and targeted therapies has led to an improvement in cancer survival rates and, unfortunately, higher cardiac adverse side effects – cardiotoxicity (Leong et al., 2019). Antineoplastic medicines have improved overall survival and progression-free survival to the oncological patients (Jemal et al., 2011; Varricchi et al., 2019). Mentioned medicines can be associated with several side effects, including cardiovascular toxicity. The National Cancer Institute defines cardiotoxicity in very general terms as “toxicity that affects the heart” (www.cancer.gov/dictionary/). Cardiotoxicity can develop in a subacute, acute, or chronic manner (Albini et al., 2018). Mitochondria are central targets for antineoplastic medicineinduced cardiovascular toxicity (Varricchi et al., 2019). Antineoplastic-related cardiovascular toxicities have been presented in many countries especially North American and European (Leong et al., 2019). Reported results from western countries are showed that the incidence rate of cancer treatment-induced cardiotoxicity is related with several chemotherapy and targeted therapies: anthracycline (0.9%–57%), cyclophosphamide (2%–28%), trastuzumab (0%– 28%) and bevacizumab (1.7%–10.9%) (Leong et al., 2019). The Agency for medicines and medical devices of Bosnia and Herzegovina (ALMBIH) was established by the Law on Drugs and Medical Devices ("Official Gazette of B&H, No. 58/08") as an authorized body for medicines and medical devices produced and used in B&H. In 2019. ALMBIH has become full member of Uppsala Monitoring Centre – World Health Organization. The aim of this work was to investigate the cardiovascular toxicity of antineoplastic medicines in Bosnia and Herzegovina.

Introduction While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. Methodology A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. Results The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. Conclusion The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

Aim To compare individual case safety reports (ICSR) rates and characteristics between Croatia, Serbia, Montenegro, and Bosnia and Herzegovina (B&H). Methods This retrospective pharmacoepidemiological study used the data from ICSR received by the Agency for Medicines and Medical Devices in B&H in 2011-2016. The number, characteristics, and sources of reports, suspected drugs, and patient characteristics were analyzed. The results were compared with the publicly available data from Croatia, Serbia, and Montenegro. Results The number of reported adverse drug reactions per one million of inhabitants was lowest in B&H and highest in Croatia. There were significant differences in reporter characteristics, sources of reports, and the percentage of missing data in ICSR, while the Anatomical Therapeutic Chemical product classes, patient’s sex, and adverse drug reaction System Organ Classes were similar. Conclusion Despite the historical and geographical vicinity of B&H and its neighboring countries, there were significant differences in indicators of pharmacovigilance development.

O,O’ -diethyl- (S,S) -ethylenediamine- N,N’ -di-2-(3-cyclohexyl)propanoate (DE-EDCP) is novel substance with cytotoxic activity in human leukemic cells. The aim of this study has been to predict in vivo bioavailability of the DE-EDCP and its potential metabolite (S,S) -ethylenediamine- N,N’ -di-2-(3-cyclohexyl)propanoic acid (EDCP) by in vitro characterization which includes determination of lipophilicity and passive membrane permeability. There has also been evaluated inter-laboratory reproducibility of the bio-analytical method which was previously developed and validated for non-clinical study of the DE-EDCP and EDCP. Distribution coefficient n-octanol/water was 1.68 and 0.03, and apparent permeability coefficient was 4 × 10–4 cm/s and 20 × 10–4 cm/s, for the DE-EDCP and EDCP, respectively. Observed results have shown that the DE-EDCP is more lipophilic with better membrane retention, but the EDCP has better pass through the membrane. Also, there has been demonstrated a reproducibility and robustness of the proposed bio-analytical method.

A series of new (S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate esters has shown cytotoxic activity towards human leukemic cell lines. The aim of this study was to develop and validate a bioanalytical method for quantification of (S,S)-O,O-diethyl-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate dihydrochlorides (DE-EDCP) and its metabolite, substituted propanoic acid (EDCP), in mouse serum by ultra high-performance liquid chromatography—tandem mass spectrometry (UHPLC—MS/MS). Structural analog, derivative of 1,3-propanediamine, was used as an internal standard (IS). Sample preparation employed protein precipitation by acetonitrile and subsequent centrifugation. Optimal UHPLC separation conditions were set to achieve simultaneous determination of both compounds in a short run time of 6 min. Additionally, the selected reaction monitoring (SRM) mode developed in this method allowed a highly sensitive, accurate, and precise identification of compounds of interest. The lower limit of quantitation (...

Introduction/Objective: The efficacy and safety of bevacizumab (BEV) in combination with capecitabin and irinotecan in first-line therapy of patients with metastatic colorectal cancer (mCRC) were studied. In order to improve safety and efficacy of chemotherapy, as well as to reduce adverse reactions to a minimum, doses of active agents applied were changed in relation to previously employed schedules. Methods: Patients with histologically documented mCRC who have not previously received chemotherapy or had received adjuvant or neoadjuvant chemotherapy, which ended 6 months before capecitabin treatment (1000 mg/m2 per os from 2nd to 8th day of each cycle), irinotecan (175 mg/m2 every 2 weeks), plus bevacizumab (5 mg/kg i.v. every 2 weeks) were observed. Results: The study, conducted as a prospective one included 35 patients of both sexes. Overall response rate (ORR) of 28.6%, partial response (PR) of 28.6%, progressive disease (PD) of 28.6% and stable disease (SD) of 42.8% were found. Progression-free survival (PFS) of the patients analyzed was 11.3 months (95% CL: 9.1 - 12.9) while overall survival (OS) of the patients included was 25.2 months (95% CL: 17.4 - 28.4 months) and 117 adverse effects were recorded in 24 patients. Alopecia, nausea and vomiting, hemorrhage, hand-foot syndrome, diarrhea, abdominal pain, proteinuria, and hypertension (51.4%, 37.1%, 37.1%, 25.7%, 22.8%, 20.0%, 20.0% and 17.1%, respectively) were most frequently observed adverse effects. Conclusion(s): The results of this clinical trial support and recommend the use of bevacizumab plus capecitabin and irinotecan in the doses and schedule applied throughout this study as first-line treatment of mCRC patients.

Introduction/Objective: The efficacy and safety of bevacizumab (BEV) in combination with capecitabin and irinotecan in first-line therapy of patients with metastatic colorectal cancer (mCRC) were studied. In order to improve safety and efficacy of chemotherapy, as well as to reduce adverse reactions to a minimum, doses of active agents applied were changed in relation to previously employed schedules. Methods: Patients with histologically documented mCRC who have not previously received chemotherapy or had received adjuvant or neoadjuvant chemotherapy, which ended 6 months before capecitabin treatment (1000 mg/m2 per os from 2nd to 8th day of each cycle), irinotecan (175 mg/m2 every 2 weeks), plus bevacizumab (5 mg/kg i.v. every 2 weeks) were observed. Results: The study, conducted as a prospective one included 35 patients of both sexes. Overall response rate (ORR) of 28.6%, partial response (PR) of 28.6%, progressive disease (PD) of 28.6% and stable disease (SD) of 42.8% were found. Progression-free survival (PFS) of the patients analyzed was 11.3 months (95% CL: 9.1 - 12.9) while overall survival (OS) of the patients included was 25.2 months (95% CL: 17.4 - 28.4 months) and 117 adverse effects were recorded in 24 patients. Alopecia, nausea and vomiting, hemorrhage, hand-foot syndrome, diarrhea, abdominal pain, proteinuria, and hypertension (51.4%, 37.1%, 37.1%, 25.7%, 22.8%, 20.0%, 20.0% and 17.1%, respectively) were most frequently observed adverse effects. Conclusion(s): The results of this clinical trial support and recommend the use of bevacizumab plus capecitabin and irinotecan in the doses and schedule applied throughout this study as first-line treatment of mCRC patients.

Nimesulide belongs to the group of semi-selective COX-2 inhibitors, widely used in solid oral formulations. In the present work the influence of surfactants among other drug excipients, as well as particle size of the active substance and the effects of medium pH on the dissolution rate of nimesulide from solid pharmaceutical forms. For that purpose, four different preparations containing 100 mg nimesulide per tablet and available in the market of Bosnia and Herzegovina (labeled here as A, B, C and D) were studied. The test for the assessment of dissolution profiles of the formulations was performed in surfactant-free dissolution medium pH 7.5. The dissolution profiles were compared by calculating difference (f1), and similarity (f2) factors. The increasing dissolution medium pH value from 7.5 to 7.75 resulted in a significant increase of nimesulide dissolution rate from the examined formulations. Also, the results showed that particle size affects to a great extent the dissolution rate and the best results were achieved with micronized nimesulide. The presence of the surfactants among the other excipients expressed a negligible effect on the dissolution profile.