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The aim of the study was to get detailed insight into the antibiotic consumption trends in the three year period (2016-2018) in Kocani Hospital, to identify the most often prescribed antibiotics and to determine whether the treatment of given diagnosis was in accordance with the official guidelines. The survey covered all pediatric and infant patients admitted to the pediatric ward. Patients’ data included gender, age, diagnosis, antibiotic used and doses. The majority of admitted patients were in the age group of 0-1 (27.48%, 25.94% and 30.77% for 2016, 2017 and 2018, accordingly) followed by age group of 1-2 years (20.86%, 22,0% and 23.83% for 2016, 2017 and 2018, consequently) and 2-3 years (16.06%, 16.1% and 14.63% for 2016, 2017 and 2018, consequently) .The most frequent diagnosis was acute tonsillitis which was determined in ~21% of patients, pneumonia without complications in ~18% and acute bronchitis in ~16% of patients in the period 2016-2018. Results from conducted survey identified high prescription rate and use of antibiotics predominantly ceftriaxone (82.58%, 81.05% and 50.85% in 2016, 2017 and 2018, respectively) contrary to official recommendations and evidences based on clinical data for treatment of the diagnoses in question. So, it is foreseeable to conclude that there is urgent need for restrictive and educational measures i.e. to strength the surveillance and monitoring of antibiotic prescription and usage and hence to promote awareness for rational use of antibiotics on all health-care levels. Key words: antibiotic prescription, antibiotic consumption, pediatric wards, annual report

Airway infections are a key component of cystic fibrosis (CF) lung disease. The approach to common pathogens such as Pseudomonas aeruginosa or Staphilococcus aureus is guided by a significant evidence base, but the treatment of other infections is significant challenge to pharmacotherapy teams. Here we present a specific approach to treatment of chronic infections with non-tuberculous mycobacteria (NTM) anaerobic bacteria and fungi in a 25 year old patient with CF and severely decreased lung function. Also, allergic bronchopulmonary aspegillosis (ABPA) was diagnosed in the patient. Key words: cystic fibrosis, non-tuberculous mycobacteria, allergic bronchopulmonary aspegillosis, antibiotics, systemic steroids

Hyperphosphatemia (HP) in patients with chronic kidney disease (CKD) leads to complications such as renal osteodistrophy, cardiovascular calcification and hemodynamic abnormalities, all of them having a serious impact on the survival rate and quality of life. Also, HP is a key pathogenic factor in the development of secondary hyperparathyroidism (SHPT) in CKD. Having in regard the significance of controlling serum phosphorus levels (Pi), in this paper, the needs and obstacles to successful pharmacological management of HP in CKD are presented, with an overview of major classes of phosphate binders (PBs) and other drugs affecting Pi level, such as active vitamin D sterols and calcimimetics (CMs). In addition, their effects on progression of cardiovascular calcification and bone health are elaborated. In this regard, a PubMed search was carried out to capture all abstracts and articles relevant to the topic of CKD, HP and mineral metabolism, bone disorders and vascular/valvular calcification (VC), published from January 2007 to August 2017. The search was limited to English language, with the search terms including drug name AND hyperphosphatemia or cardiovascular calcification or bone disorder. Comparative studies, clinical studies/trials and meta-analyses related to different classes/representatives of PBs, vitamin D analogues and CMs were reviewed and research data related to their efficacy and safety compared. Keywords: chronic kidney disease, hyperphosphatemia, phosphate binders, active vitamin D sterols, calcimimetics, bone disorders, cardiovascular calcification

Lactobacillus casei 01 was co-encapsulated with the prebiotic oligofructose-enriched inulin at different concentrations to investigate the efficiency of the prebiotic for improving the probiotic viability. Prebiotic effect on the probiotic survival under microencapsulation conditions by spray- and freeze-drying and storage stability of encapsulated living cells at 4 °C during period of 8 weeks was evaluated. Adhesiveness of L. casei 01 loaded microparticles to pig mucin was investigated in vitro to estimate the role of microencapsulation for improving the cell adhesion ability. The microparticles produced with 3% w/w oligofructose-enriched inulin showed higher initial count, while oligofructose-enriched inulin applied at 1.5% w/w resulted in better protection of L. casei 01 under storage conditions. Further, it has been observed significantly increased pig mucin binding to microparticles compared to free probiotic cells in buffer solutions simulating GI conditions, during 24 h incubation. Hence, cell microencapsulation beside enhanced viability may allow prolonged residence time of the probiotic cells in the lower intestine through excellent muco-adhesive properties of the encapsulating materials. The results suggest synbiotic chitosan-Ca-alginate microparticles as convenient delivery system capable to ensure effective cell concentration in the lower intestine where probiotic colonization is dominant.

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.

In our previous work Box-Behnken experimental design was applied for formulation optimization of the thermoreversible mucoadhesive in situ vaginal hydrogels with propolis and optimized batches were identified. Optimized batches of bioartificial polymer hybrid composites (chitosan, Lutrol® F-127 and Lutrol® F-68 mixture)) (CP1, CP2, CP3) were prepared using so-called cold method. Formulation P3 (chitosan free) was prepared in order to evaluate the effect of chitosan on the physico-chemical and biopharmaceutical properties of the polymer hybrid composites (gels). The pH values of the gels were 4-4.5. The gelation temperature for all formulations was in a range of 29-33 o C. Total flavonoids content was above 95%. Increase in concentration of Lutrol® F-127 and Lutrol® F-68/Lutrol® F-127 ratio lead to a higher viscosity values and slower gel erosion/dissolution. The presence of chitosan increased gel viscosity and hence slow-down erossion/dissoluiton. Propolis release rate was the highest in P3 which released propolis within 5 h, corresponding to time of complete erosion. The same correlation between erosion process and drug release rate was observed in CP1-CP3, where prolonged propolis release for more than 10 h was achieved. Microbiological quality was in accordance with the requirements of Ph. Eur. 7. All formulations demonstrated adequate stability at 5 ± 3 °C during 6 months. Based on overall results it can be anticipated that bioartificial blended bioinspired polymer hybrid composites for propolis vaginal delivery could represent intelligent delivery systems with physicochemical and biopharmaceutical properties in favor or efficacious and safe therapy of vaginal infections.

Polymer hybrid composites for propolis vaginal delivery were developed and optimized in term of gelling temperature (Tg) using experimental design studies. Formulation of intelligent delivery system, with in situ gelling and controlled release properties, was carried out by bioartificial blending of chitosan and poloxamers, Lutrol F127 and Lutrol F68. Response-surface, Box-Behnken, experimental design was applied for determination of key factors influencing Tg. Influence of Lutrol F127 concentration, Lutrol F68/Lutrol F127 mass ratio and volume of simulated vaginal fluid was evaluated. Derived correlations enabled formulation optimization in term of Tg (32 °C). The model was cross-validated. Confirmation report and relative error percent of predicted and experimental values were obtained.

Simple, automated SPE procedure combined with fast LC-MS/MS chromatographic separation resulted in obtaining high-throughput LC-MS/MS method for determination of indapamide in serum. The SPE procedure was performed on polymeric mixed-mode sorbent and the analytes were quantitated using electrospray ionization in positive mode. The recovery of indapamide and internal standard were 89.25- 90.36% and 79.10%, respectively. Experimentally it was confirmed that the matrix effect had a negligible effect of ionization efficiency. The validation data showed that the proposed method provides accurate and reproducible results in range of 0.50-50 ng/mL. In addition, a comparison was made between the method for determination of indapamide in serum and in blood (develop in our previously work) regarding the extraction procedure and matrix effect.

From a historical point of view, one can notice that the role of the pharmacists employed in community and hospital pharmacies became more complex. Today, they do not only supply, store, prepare and dispense medicines with ensured quality, but they also provide professional services based on the concept of pharmaceutical care and good pharmacy practice. In this paper, detailed review on the current legislative regulating the status and practice of the community and hospital pharmacies in some EU-member countries and in Macedonia is given. The implementation of the concept of pharmaceutical care and good pharmacy practice in selected EU member-countries, Great Britain, Germany and Slovenia, and in Croatia as a future EU member as well as in Macedonia is also discussed. In addition, set of recommendations for establishing the good pharmacy practice standards is prepared and presented. At the end, an attempt is made to establish a basis for development a modern Law on Pharmacy Practice in the Republic of Macedonia.

Viability of L. casei during fermentation in soymilk and freeze-dried soymilk; effect of cryoprotectant, rehydration and storage temperature The aim of the work was to investigate the behaviour of L. casei and the effect of sorbitol on its viability during fermentation in soymilk drink. Values for pH, ranging from 6.82 to 3.42 in the soymilk drink without sorbitol and from 6.74 to 3.41 in the drink with sorbitol were noted during 72 h of fermentation at 25oC. The corresponding values for titratable acidity ranged from 0.071% to 0.758% and from 0.073% to 0.761%, respectively. Soymilk was found to support the growth of L. casei with improvement in viability for 0.24 log at the end of fermentation when sorbitol was added. Survival of L. casei and the effectiveness of sorbitol in improving viability during freeze-drying, subsequent rehydration and during a 5-week period of storage under different temperatures were also investigated. After freeze-drying, L. casei exhibited a survival percent of approximately 46%. Sorbitol improved the viability of L. casei by 0.51 log immediately after freeze-drying and by 1.30 log and 0.47 log during five weeks of storage at 25oC and 4oC, respectively. Further study revealed that the freeze-dried fermented soymilk rehydrated at 45oC was optimum for the recovery of L. casei with improvement in recovery for 0.68 log when sorbitol was added. A higher percent of survival was noted when the dried soymilk was stored at 4oC than at 25oC with improved viability at the end of 5 weeks storage for approximately 6 log for drinks with and without sorbitol. Fermented dried soymilk with sorbitol afforded significant tolerance of L. casei to acid stress. Generally, a stable probiotic diary product was prepared in which the concentration of L. casei remained above therapeutic level of 107 cfu/ml.

Liposome dispersions and liposome gel formulations for topical administration were evaluated as modified release delivery systems for 5-fluorouracil. Drug substance has been entrapped in the internal aqueous compartment of liposomes during the preparation. The concentration of 5-fluorouracil in the hydration medium was varied and the effect on the liposome characteristics was considered. Liposome gel formulations were prepared by incorporation of liophylized liposomes into a structured vehicle of chitosan. The decrease of the amount of aqueous phase bearing total drug quantity (drug/aqueous phase ratio from 1:100, 1:60, 1:40) led to an increase of the percentage of liposome-entrapped drug, and decreased percentage of drug release, while particle size analysis showed no changes in vesicle size. Liposome gel formulations showed initially a higher drug release rate in comparision with liposome dispersions, which could be related to the release of “free” 5-fluorouracil, leaked from liposomes due to the process of liophylization. This was followed by slower release (after 1.5 hour) as a result of the influence of the viscosity of the gel matrix.

The effect of the buffer system on the stability of tetracaine hydrochloride in eyedrop formulation was evaluated. Eyedrop formulations containing tetracaine hydrochloride 0.5%(w/v) were prepared using different buffer systems (acetate, phosphate and borate buffer) under a constant pH of 5.4, and a buffer concentration of 0.06M. Long-term tests at 26 o C and accelerated stability tests at elevated temperature (45, 50, 60 o C) over a period of 168 days were carried out by following the macroscopic view, pH, sterility, content of tetracaine hydrochloride and detection of the degradation products. Also, values of the constant of degradation rate at different temperatures and t90% were calculated. The phosphate and acetate buffers provided satisfactory stability of tetracaine hydrochloride eyedrops, while borate buffer was not sufficient to maintain the pH value of the solution.