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Bats are known to inhabit both caves and open space areas. Bulgaria is among the Еuropean countries with the highest number of bat species. The species found in the country are distributed over a wide area. They range from the Pyrenees and the British Isles to the Pacific region and the Far East. Many bat species are carriers of potential human pathogens. Bats play an important role in agriculture and act as a biological pest crop control agent. Bulgarian bat ecosystem comprises temperate climate and a wide range of abiotic factors, including humidity, darkness, sunlight, and temperature variations. The metabolism of bats and their body temperature vary significantly between the period of activity and the hibernation. Fluctuations in body temperature can potentially impact host microbiome biodiversity. Temperature variations may induce a high level of microbial mutagenesis. Additionally,the existence in large, mixed-species colonies, togeteher with a relatively long individual lifespan (4 – 16 years) and extensive travel distances, enhances the likelihood of encountering multiple pathogens in a single host organism. This, in turn, facilitates genetic variations and re-combinations among those microbial pathogens, thereby raising their potential to breach species barriers. In this review, we summarized and analyzed the available scientific information concerning the potential microbial human pathogens associated with bats, alongside with our preliminary data on the biodiversity of bats blood microbiome. Future research should focus on bats as both pathogens carriers and dynamic models for predicting emerging and re-emerging zoonotic diseases.

Background. Oxidative stress and inflammation are closely related pathophysiological processes, both occurring in type 2 diabetes mellitus (T2DM). In addition to the standard treatment of T2DM, a potential strategy has been focused on the use of bile acids (BAs) as an additional treatment. Ursodeoxycholic acid (UDCA), as the first BA used in humans, improves glucose and lipid metabolism and attenuates oxidative stress. The aim of this study was to evaluate the potential metabolic, anti-inflammatory, and antioxidative effects of UDCA in patients with T2DM. Methods. This prospective, double-blind, placebo-controlled clinical study included 60 patients with T2DM, randomly allocated to receive UDCA or placebo. Subjects were treated with 500 mg tablets of UDCA or placebo administered three times per day (total dose of 1500 mg/day) for eight weeks. Two study visits, at the beginning (F0) and at the end (F1) of the study, included the interview, anthropometric and clinical measurements, and biochemical analyses. Results. UDCA treatment showed a significant reduction in body mass index (p=0.024) and in diastolic blood pressure (p=0.033), compared to placebo. In addition, there was a statistically significant difference in waist circumference in the UDCA group before and after treatment (p

Infestation of the road-killed hedgehogs (Erinaceus roumanicus) with Ixodes ticks in some parts of Upper Thracian Plain (Bulgaria) was investigated. A total of 5 tick species from 3 genera were identified.

The use of the gene pool of wild relatives, which have a significant reserve of genetic diversity, is of immediate interest for breeding common wheat. The creation and use of synthetic forms as “bridges” is an effective method of transferring valuable genetic material from wild relatives to cultivated wheat. For this purpose, genome addition, genome substitution and recombinant “secondary” synthetic forms have been created in the P.P. Lukyanenko National Center of Grain. The synthetic recombination form RS5 (BBAASDt ), in which the third genome consists of chromosomes of Aegilops speltoides (S) and Aegilops tauschii (Dt ), was obtained from crossing the synthetic forms Avrodes (BBAASS) and M.it./Ae. tauschii (BBAADt Dt ), in which the D genome from Ae. tauschii was added to the BBAA genomes of the durum wheat cultivar Mutico italicum. Introgression lines resistant to leaf rust, yellow rust and powdery mildew have been obtained from backcrosses with the susceptible common wheat cultivars Krasnodarskaya 99, Rostislav and Zhirovka. Twelve resistant lines that additionally have high technological characteristics of grain and flour have been selected. The cytological study (С-banding) has revealed chromosomal modifications in 6 of 8 lines under study. The rearrangements mainly affected the chromosomes of the D genome, 1D, 3D, 4D, 6D and 7D. It was found that in most cases the genetic material from the synthetic form RS5 in the studied lines was represented by substituted chromosomes from Ae. tauschii. In line 5791p17, the substitution of chromosomes 6D from Ae. tauschii and 7D from Ae. speltoides was revealed. Substitutions 4D(4Dt ), 6D(6Dt ) from Ae. tauschii and 7D(7S) from Ae. speltoides were obtained for the first time. Molecular analysis of 12 lines did not reveal effective leaf rust resistance genes, presumably present in synthetic forms of M.it./Ae. tauschii and Avrodes. It is assumed that the lines may carry previously unidentified genes for fungal disease resistance, in particular for resistance to leaf rust, from Ae. tauschii and Ae. speltoides.

Abstract Microencapsulation represents a process that can create targeted, controlled release kinetics of drugs, thus optimizing therapeutic efficacy. Our group has investigated the impact of this technology on Wistar rats to determine pharmacological efficacy of basil extracts. Animals were treated with water extract of Ocimum basilicum in microvesicles and with combination of basil extracts and 3α,7α-dihydroxy-12-keto-5-cholanate, also known as 12-monoketocholic acid (MKC) acid in microvesicles for 7 days. Alloxan was used to induce hyperglycemia. Pharmacological effects on glycemia were evaluated by measuring blood glucose levels in alloxan-induced diabetic rats. Microvesicles were prepared using the Büchi-based microencapsulating system developed in our lab. The dose of basil extract that was orally administered in rats was 200 mg/kg and the dose of MKC acid was 4 mg/kg as per established protocols. A seven-day treatment with basil aqueous extract, as well as a combination of basil and MKC acid extract in the pharmaceutical formulation, led to a statistically significant reduction in the blood glucose concentration of animals with alloxan-induced hyperglycemia compared to pre-treatment values (p

Armin Mooranian,1,2 Thomas Foster,1,2 Corina M Ionescu,1,2 Louise Carey,1,2 Daniel Walker,1,2 Melissa Jones,1,2 Susbin Raj Wagle,1,2 Bozica Kovacevic,1,2 Jacqueline Chester,1,2 Edan Johnstone,1,2 Jafri Kuthubutheen,3 Daniel Brown,4 Marcus D Atlas,2 Momir Mikov,5 Hani Al-Salami1,2 1The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia; 2Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia; 3Fiona Stanley Hospital, Perth, WA, Australia; 4Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia; 5Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, 21101, SerbiaCorrespondence: Hani Al-SalamiHearing Therapeutics, Biotechnology and Pharmaceutical Sciences, Curtin University, Bentley, Perth, 6102, WA, AustraliaTel +61 8 9266 9816Fax + 61 8 9266 2769Email hani.al-salami@curtin.edu.auIntroduction: In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs.Methods: Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug’s main target being pancreatic beta-cells, the formulations’ effects on cell viability, functions and inflammatory profiles were also investigated.Results and Conclusions: CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.Keywords: microencapsulation, diabetes mellitus, Glyceryl monooleate, Eudragit, chenodeoxycholic acid

The pathogen transmitting Aedes albopictus mosquito is spreading rapidly in Europe, putting millions of humans and animals at risk. This species is well-established in Albania since its first detection in 1979. The sterile insect technique (SIT) is increasingly gaining momentum worldwide as a component of area-wide-integrated pest management. However, estimating how the sterile males will perform in the field and the size of target populations is crucial for better decision-making, designing and elaborating appropriate SIT pilot trials, and subsequent large-scale release strategies. A mark-release-recapture (MRR) experiment was carried out in Albania within a highly urbanized area in the city of Tirana. The radio-sterilized adults of Ae. albopictus Albania strain males were transported by plane from Centro Agricoltura Ambiente (CAA) mass-production facility (Bologna, Italy), where they were reared. In Albania, sterile males were sugar-fed, marked with fluorescent powder, and released. The aim of this study was to estimate, under field conditions, their dispersal capacity, probability of daily survival and competitiveness, and the size of the target population. In addition, two adult mosquito collection methods were also evaluated: BG-Sentinel traps baited with BG-Lure and CO2, (BGS) versus human landing catch (HLC). The overall recapture rates did not differ significantly between the two methods (2.36% and 1.57% of the total male released were recaptured respectively by BGS and HLC), suggesting a similar trapping efficiency under these conditions. Sterile males traveled a mean distance of 93.85 ± 42.58 m and dispersed up to 258 m. Moreover, they were observed living in the field up to 15 days after release with an average life expectancy of 4.26 ± 0.80 days. Whether mosquitoes were marked with green, blue, yellow, or pink, released at 3.00 p.m. or 6.00 p.m., there was no significant difference in the recapture, dispersal, and survival rates in the field. The Fried competitiveness index was estimated at 0.28. This mark-release-recapture study provided important data for better decision-making and planning before moving to pilot SIT trials in Albania. Moreover, it also showed that both BG-traps and HLC were successful in monitoring adult mosquitoes and provided similar estimations of the main entomological parameters needed.

Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.

Despite the growing number of new drugs approved for the treatment of inflammatory bowel disease (IBD), the long-term clinical use of thiopurine therapy and the well-known properties of conventional drugs including azathioprine have made their place in IBD therapy extremely valuable. Despite the fact that thiopurine S-methyltransferase (TPMT) polymorphism has been recognized as a major cause of the interindividual variability in the azathioprine response, recent evidence suggests that there might be some yet unknown causes which complicate dosing strategies causing either failure of therapy or toxicity. Increasing evidence suggests that gut microbiota, with its ability to release microbial enzymes, affects the pharmacokinetics of numerous drugs and subsequently drastically alters clinical effectiveness. Azathioprine, as an orally administered drug which has a complex metabolic pathway, is the prime illustrative candidate for such microbial metabolism of drugs. Comprehensive databases on microbial drug-metabolizing enzymes have not yet been generated. This study provides insights into the current evidence on microbiota-mediated metabolism of azathioprine and systematically accumulates findings of bacteria that possess enzymes required for the azathioprine biotransformation. Additionally, it proposes concepts for the identification of gut bacteria species responsible for the metabolism of azathioprine that could aid in the prediction of dose-response effects, complementing pharmacogenetic approaches already applied in the optimization of thiopurine therapy of IBD. It would be of great importance to elucidate to what extent microbiota-mediated metabolism of azathioprine contributes to the drug outcomes in IBD patients which could facilitate the clinical implementation of novel tools for personalized thiopurine treatment of IBD.

Introduction/Objective. Pain is often an underrecognized entity in children with cerebral palsy. The aim of this study was to determine whether there are differences in pain self-perception between children with cerebral palsy and their caregivers. Methods. This retrospective study included 70 children with cerebral palsy and 70 of their caregivers, treated at the Institute of Child and Youth Health Care of Vojvodina, Serbia. Pain intensity ratings on the Visual Analog Scale (VAS) provided by children and/or their caregivers were analyzed. Results. The research involved 70 children with cerebral palsy and the same number of their caregivers. While only 43 (61.4%) of these children were testable, all 70 caregivers participated. Pain was reported by 19 (44.2%) children and 42 (60%) caregivers, while 17 (39.5%) children suffered from musculoskeletal pain, which was noted by 39 (55.7%) caregivers. Average caregiver rating for musculoskeletal pain for children at Level V, I and III on the Gross Motor Function Classification System (GMFCS) was 6.20 ± 2.10, 2.67 ± 2.18, and 2.50 ± 2, respectively. Average self- and caregiver-reported VAS rating for headache/stomachache was 2.73 ± 1.86 and 2.35 ± 1.49, respectively (p > 0.05). Statistically significant differences were noted in the musculoskeletal pain VAS scores provided by the caregivers for children at different GMFCS levels (p < 0.01). Conclusion. Although no differences in pain perception between children with cerebral palsy and their caregivers have been established, in children with the most severe level of motor disability, caregivers report a statistically higher level of musculoskeletal pain.

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 non-compartmental 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.

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Background/Aim: Cardiac arrest (CA) is a leading cause of mortality in the last forty years worldwide. Immediately initiated cardiopulmonary resuscitation (CPR) improves chances for survival. Aim of this study was to determine the efficiency of the Emergency medical service (EMS) dispatch centre in the absence of the uniform emergency medical dispatch assessment protocols in the management of cardiac arrest. Methods: The retrospective and observational study was conducted in Institute for Emergency Medical Service Novi Sad (IEMS Novi Sad) Serbia during a one-year follow-up. The study included patients with out-of-hospital cardiac arrests who underwent CPR. Results: EMS teams of the IEMS Novi Sad had 198 CPRs in the follow-up period. In 142 (71.72 %) calls, the EMS dispatcher got information that the patient was unconscious. The reported reaction time I by the dispatchers for the unconscious patients was 1.37 ± 1.27 minutes, actual duration of the conversation between the dispatcher and a caller - was longer: 138.21 ± 103.02 seconds (p < 0.001). The average conversation time with a caller was 61.37 ± 31.13 seconds. In 6 (4.22 %) cases, the EMS team was dispatched to a patient before the phone call was terminated. At the moment of arrival, all patients were unconscious, 194 (94.37 %) were pulseless, while the remaining 8 (5.63 %) experienced cardiac arrest during the examination. The cardiac arrest was witnessed by a layman in 120 (84.51 %) cases and CPR was initiated by bystanders, before the arrival of the EMS team, only in 13 (10.83 %) patients. Twenty-seven (19.01 %) patients arrived in a hospital with vital signs. Conclusion: The absence of the uniform EMS dispatch assessment protocols for the triage of incoming calls and phone assisted CPR for lay rescuers decreases the survival rate of patients with cardiac arrest.

(1) Background: The influence of different factors on balance in adolescence is assessed by conducting functional balance tests that examine its different components. (2) Materials and methods: The study sample comprised 110 healthy adolescents of both sexes, aged 12–18 years. Single Leg Stance with Eyes Open (SLS-EO) and Eyes Closed (SLS-EC) tests were conducted to evaluate static balance, whereas the Functional Reach Test (FRT) and Lateral Reach Test (LRT) were performed to establish functional stability limits. The influence of sex, age, demographic factors, anthropometric characteristics, participation in sports activities, and trunk extensor muscle endurance (Biering–Sorensen test) on balance performance was determined through correlational and univariate linear regression analyses. (3) Results: Older age (Beta [β] = 0.247; 95% CI [0.75, 5.20]; p < 0.01) and better trunk extensor muscle endurance (β = 0.224; 95% CI [0.015, 0.13]; p < 0.05) were significant predictors of the SLS-EO results, while younger age (β = −0.219; 95% CI [−1.32, −0.11]; p < 0.05) and higher muscle percentage (β = 0.237; 95% CI [0.06, 0.48]; p < 0.05) emerged as significant predictors of LRT performance, and greater bone mass was a significant predictor of FRT results (β = 0.444; 95% CI [3.62, 8.17]; p < 0.01). However, none of the independent variables was a statistically significant predictor of the SLS-EC results. (4) Conclusions: The current study found that age, trunk extensor muscle endurance, muscle percentage, and bone mass are significant predictors of different balance components, suggesting that balance is task-specific. [ABSTRACT FROM AUTHOR]

Abstract Background Sand flies (Diptera: Psychodidae) are medically important vectors of human and veterinary disease-causing agents. Among these, the genus Leishmania (Kinetoplastida: Trypanosomatidae), and phleboviruses are of utmost importance. Despite such significance, updated information about sand fly fauna is missing for Balkan countries where both sand flies and autochtonous leishmaniases are historically present and recently re-emerging. Therefore, a review of historical data on sand fly species composition and distribution in the region was followed by a large-scale entomological survey in eight Balkan countries to provide a recent update on local sand fly fauna. Methods The literature search involved the period 1910–2019. The entomological survey was conducted at 1189 sampling stations in eight countries (Bulgaria, Bosnia and Herzegovina, Croatia, Kosovo, Montenegro, North Macedonia, Serbia and Slovenia), covering 49 settlements and 358 sampling sites between June and October in the years 2014 and 2016, accumulating 130 sampling days. We performed a total of 1189 trapping nights at these stations using two types of traps (light and CO2 attraction traps) in each location. Sampling was performed with a minimal duration of 6 (Montenegro) and a maximal of 47 days (Serbia) between 0–1000 m.a.s.l. Collected sand flies were morphologically identified. Results In total, 8490 sand fly specimens were collected. Morphological identification showed presence of 14 species belonging to genera Phlebotomus and Sergentomyia. Historical data were critically reviewed and updated with our recent findings. Six species were identified in Bosnia and Herzegovina (2 new records), 5 in Montenegro (2 new records), 5 in Croatia (2 new records), 9 in Bulgaria (5 new records), 11 in North Macedonia (1 new record), 10 in Serbia (no new records), 9 in Kosovo (3 new records) and 4 in Slovenia (no new records). Conclusions This study presents results of the first integrated sand fly fauna survey of such scale for the Balkan region, providing first data on sand fly populations for four countries in the study area and presenting new species records for six countries and updated species lists for all surveyed countries. Our findings demonstrate presence of proven and suspected vectors of several Leishmania species.

Objective: to study the level of volitional self-regulation and emotional burnout in male sambo-athletes who underwent sports injuries of various degrees of severity. Materials and methods: 60 male sambo-athletes were examined. They were divided into 3 groups of 20 people in each group based on types of sports injuries. Results: significantly (p=0.001) lower level of volitional self-regulation was found in the third group who underwent more injuries (total scale: Q1=6,0; Me=8,0; Q3=10,0; «perseverance»: Q1=5,0; Me=5,5; Q3=8,0; «self-control»: Q1=4,0; Me=4,5; Q3=5,0). More pronounced emotional burnout occured in athletes who had more injuries (Q1=64,5; Me=69,0; Q3=71,0; p=0,001). Inadequate emotional response and emotional and moral disorientation was leveled down with aggravation of the severity of injuries (Q1=25,0; Me=44,0; Q3=61,0; p=0,039). Adaptation systems strain is manifested by a marked emotional exhaustion and decrease in volitional self-regulation with an increase in the number of injuries. Conclusions: if incidence and severity of injuries increases in sambo-athletes the level of volitional self-regulation reduces and emotional burnout occurs, which is characterized by the stress of the system of psychological adaptation.

Bile acids (BAs) are amphiphilic compounds and of recently have demonstrated wide range of formulation stabilizing effects. A recent study showed that primary un-metabolised bile acids (PUBAs) have β-cell protective effects, and synergistic antidiabetic effects when combined with antioxidant and anti-inflammatory drugs, such as probucol (PB). Thus, this study aimed to design and test microcapsules containing a PUBA incorporated with PB and an alginate-Eudragit matrix.Six types of microcapsules were developed without (control) or with (test) PUBA, and tested for internal and external features and β-cell protective effects.The incorporation of PB-alginate-Eudragit with PUBA produced stable microcapsules but did not exert consistent positive effects on cell viability in the hyperglycaemic state, which suggests that PUBA in alginate-Eudragit matrices did not exhibit synergistic effects with PB nor exerted antidiabetic effects. Keywords: Probucol, Microencapsulation, Eudragit, Alginate, Oral delivery, Diabetes mellitus

Introduction/Aim Carbon monoxide (CO) is a gas produced by incomplete combustion of carbon compounds and is a leading cause of poising throughout the world. The objective of this paper is to analyze 5 cases of acute carbon monoxide poisoning in petroleum industry workers, occupying a shared accommodation and to present diagnostic, therapeutic and preventive measures. Case report the workers had to be treated by the emergency medical service during the night for health problems arising from carbon monoxide inhalation from a faulty installation. Venous blood samples were collected to measure the concentration of carboxyhemoglobin (COHb) and gas analyses were done upon admission and 120 minutes later. They were treated with parenteral therapy and oxygen by mask, and they made a complete recovery. Conclusion Faulty installation of a gas-powered heating system caused acute carbon monoxide poisoning in 5 people occupying the space. After 120 minutes in a closed environment, the carbon monoxide concentration was high enough to cause a significant increase of COHb in the venous blood. Prompt diagnosis and adequate therapy are crucial to ensure a favorable treatment outcome. Preventive measures, such as educating workers and introducing health and safety measures into the work environment are extremely important in preventing accidents such as these.

Armin Mooranian,1 Nassim Zamani,1 Momir Mikov,2 Svetlana Goločorbin-Kon,3 Goran Stojanovic,4 Frank Arfuso,5 Bozica Kovacevic,1 Hani Al-Salami1 1Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, Western Australia, Australia; 2Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia; 3Department of Pharmacy, University of Novi Sad, Novi Sad, Serbia; 4Faculty of Technical Sciences, University of Novi Sad, Novi Sad, Serbia; 5Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, AustraliaCorrespondence: Hani Al-SalamiBiotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, AustraliaTel + 61 8 9266 9816Fax + 61 8 9266 2769Email hani.al-salami@curtin.edu.auIntroduction: Recent formulation and microencapsulation studies of probucol (PB) using the polymer sodium alginate (SA) and bile acids have shown promising results but PB stability, and pharmacology profiles remain suboptimal. This study aimed to investigate novel polymers for the nano and micro encapsulation of PB, with the anti-inflammatory bile acid ursodeoxycholic acid (UDCA).Material and methods: Six formulations using three types of polymers were investigated with and without UDCA. The polymers were NM30D, RL30D, and RS30D and they were mixed with SA and PB at set ratios and microencapsulated using oscillating-voltage-mediated nozzle technology coupled with ionic gelation. The microcapsules were examined for physical and biological effects using pancreatic β-cells.Results and discussion: UDCA addition did not adversely affect the morphology and physical features of the microcapsules. Despite thermal stability remaining unchanged, bile acid incorporation did enhance the electrokinetic stability of the formulation system for NM30D and RL30D polymers. Mechanical stability remained similar in all groups. Enhanced uptake of PB from the microcapsule by pancreatic β-cells was only seen with NM30D-UDCA-intercalated microcapsules and this effect was sustained at both glucose levels of 5.5 and 35.5 mM.Conclusion: UDCA addition enhanced PB delivery and biological effects in a formulation-dependent manner.Keywords: probucol, microencapsulation, NM30D, ursodeoxycholic acid, diabetes, oxidative stress

Background/Aim: Gliclazide is one of the most commonly prescribed oral anti-hyperglycaemic therapies in type 2 diabetes mellitus (T2D). Recently reported additional beneficial pharmacological properties of gliclazide, including immunomodulatory and anticoagulant activities, suggested its potential application in treatment of type 1 diabetes mellitus (T1D). However, following oral administration, gliclazide was shown to have poor and variable absorption directing research into development of novel pharmaceutical delivery systems of gliclazide suitable for T1D. Since bile acids have previously demonstrated stabilising and controlled-release effects on microcapsules, their use for preparation of microcapsules of gliclazide may lead to improvements in gliclazide release, absorption and antidiabetic effects. This investigation was aimed to evaluate drug absorption profiles and hypoglycaemic effects of alginate-based microcapsules of gliclazide, prepared together with or without cholic acid, in healthy rats. Methods: Thirty healthy Wistar rats with confirmed normal glucose blood concentration were allocated into five groups and administered with a single dose of either vehicle microcapsules, gliclazide in suspension, gliclazide microcapsules, gliclazide in suspension together with cholic acid or microencapsulated gliclazide in combination with cholic acid. Following respective gliclazide dose, blood was sampled over next 10 hours and blood glucose levels and gliclazide serum concentrations were measured. Results: This analysis demonstrated altered effects of different gliclazide formulations in healthy rats with the highest gliclazide absorption mirrored by the most profound hypoglycaemic effect being achieved after its oral administration as a suspension (p

Introduction: Despite the progress in breast cancer treatment, currently used methods are often aggressive and with low selectivity, thus inducing systemic toxicity while obtaining limited effect. The application of nanotechnologies is a promising novel technology, which could overcome these limitations. Corresponding section headings: Incorporation of the medication into a nanocarrier enables the administration of molecules with the suboptimal pharmacokinetic profiles if given as free agents. Furthermore, nanomedicine could improve the safety profile of currently used chemotherapeutics, by modifying pharmacokinetic properties and prolonging the half-life of the therapeutic. Most importantly, it provides a possibility of designing drug carriers with selective delivery to malignant cells, based on their characteristics. Conclusion: This advantage initiated an entirely new subset of targeted breast cancer therapy development, and has demonstrated favorable outcomes even in treatment of aggressive malignant types, metastatic developments, and multi-drug resistance.

Synthetic recombination form RS7 (BBAAUS), in which the first two genomes, A and B, originate from common wheat, and the third recombinant genome consists of Aegilops speltoides (S) and Ae. umbellulata (U) chromosomes, was obtained from crossing synthetic forms Avrodes (BBAASS) and Avrolata (BBAAUU). Resistant to leaf rust, yellow rust and powdery mildew, introgression lines have been obtained from backcrosses with the susceptible varieties of common wheat Krasnodarskaya 99, Fisht and Rostislav. PCR analysis showed the presence of amplification fragments with marker SCS421 specific for the Lr28 gene in the line 4991n17. The cytological study (С-banding and FISH) of 14 lines has revealed chromosomal modifications in 12 of them. In most cases, the lines carry translocations from Ae. speltoides, which were identified in chromosomes 1D, 2D, 3D, 2B, 4B, 5B and 7B. Also, lines with the substituted chromosomes 1S (1B), 4D (4S), 5D (5S) and 7D (7S) were identified. Lines that have genetic material from Ae. speltoides and Ae umbellulata at once were revealed. In the line 3379n14, translocations in the short arm of chromosome 7D from Ae. umbellulata and chromosomes 5BL, 1DL, 2DL from Ae. speltoides were revealed. The line 4626p16 presumably has a translocation on the long arm of chromosome 2D from Ae. umbellulata and the T7SS.7SL-7DL translocation from Ae. speltoides. The T1DS.1DL-1SL and T3DS.3DL-3SL translocations from Ae. speltoides, and T2DS.2DL-2UL and T7DL.7DS-7US from Ae. umbellulata have been obtained for the first time. These lines may carry previously unidentified disease resistance genes and, in particular, leaf rust resistance genes from Ae. speltoides and Ae. umbellulata.

This article presents the results of a molecular marker-assisted study of allelic variants of Wx genes in common wheat (Triticum aestivum L.) lines. The study was carried out as part of the work on the transfer of null alleles of the genes Wx-A1, Wx-B1, and Wx-D1 to the varieties of soft wheat and creation of breeding material with modified activities of the main enzymes involved in amylose biosynthesis. The lines were obtained at the Department of Breeding and Seed Production of Wheat and Triticale, National Center of Grain named after P.P. Lukyanenko, by crossing mutant forms carrying inactive (null) alleles of genes Wx-A1, Wx-B1, and Wx-D1 with bread wheat cultivars. The molecular markers selected for the study allowed identification of valuable breeding material carrying both single null alleles of Wx genes and their combinations in its genome. A combination of two null alleles (Wx-A1b + Wx-D1b) was detected in 30 lines. The presence of three null alleles (Wx-A1b + Wx-B1b + Wx-D1b), which corresponded to fully Wx wheat, was found in one line. We selected 37 lines that combined the presence of the Wx-B1e allele with the Wx-A1b and Wx-D1b null alleles. The Wx-A1b + Wx-B1e combination was identified in 26 lines, and 24 lines carried the combination of alleles Wx-B1e + Wx-D1b. The mutant forms PI619381, PI619384, and PI619386 were identified as carriers of the functional Wx-B1e allele. The Wx-A1b and Wx-B1e alleles could have been transferred to the studied lines from the donors used or from the Starshina and Korotyshka varieties, respectively. The mutant forms used in the crosses are donors of the Wx-B1b and Wx-D1b alleles. The use of molecular markers chosen by us for identification of the allelic state of the Wx-A1, Wx-B1, and Wx-D1 genes can provide grounds for marker-assisted selection for this trait. Selected lines found to possess null alleles of the Wx genes are applicable in breeding programs aimed at the improvement of technological qualities of grain and raise of bread wheat varieties with modified starch properties.

Urinary tract infections (UTI) are one of the most common infectious diseases, primarily caused by bacteria present in the intestinum, affecting the entire urinary tract or only a part of it. If the urinary bladder and urethra are affected then they are considered “lower” urinary tract infections, and the affected kidneys and ureter are considered “upper” urinary tract infections. There is a division into uncomplicated and complicated UTIs. Approximately 15% of all prescribed antibiotics in the United States are prescribed as therapy of UTIs. The UTI data from other countries are similar. The costs incurred in the treatment of these infections are significant - in the United States, the direct costs of UTI treatments are estimated at $ 1.6 billion per year.

Gut micro flora represents a system of extensive metabolic capacity which is quite different when compared to other cells of body and organs. In recent times, there has been an evidence of very important role of gut cysteine conjugate beta-lyases in metabolism of cystein conjugates. A lot of studies are dedicated to exploration of the role of gut micro flora in formation of methylthio adducts from paracetamol in conventional mice and those treated with neomycin as our study. A highly significant reduction in urinary excretion of 3-methylthioparacetamol in group of neomycin-treated mice was confirmed as well its glucuronic acid and sulphate conjugates. Following the principal role of gut flora in the C-S cleavage of paracetamol l-3-cyctein it is clear that highest concentration of methylthio adducts from paracetamol are presented in pretreated mice.

Background/Aim. Children with cerebral palsy (CP) grow at a slower rate relative to their peers. Their body height, body weight and bone mineral density are significantly below those measured for healthy children of corresponding age. The aim of this work was to estimate bone mineral density in relation to the anthropometric parameters and the level of gross motor function in the children with cerebral palsy. Methods. This cross-sectional pilot study included 23 children with CP, aged 6 to 17 years, in whom the gross motor function level was estimated according to the Gross motor function classification system- expanded and revised (GMFCS-E&R), while the anthropometric parameters were established in relation to the developmental charts for healthy children as well as those pertaining to children with CP. Bone mineral density was measured by dual energy X-ray absorptiometry and the findings were interpreted in accordance with the International Society for Clinical Densitometry Official Positions of Adults & Pediatrics. Mean values with interquartile deviations, along with frequencies and percentages were the descriptive statistical measures employed in the analyses. Differences between groups were ascertained through the Kruskal-Wallis test. Results. Our sample of 23 children comprised of 56.5% boys and 43.5% girls, aged 13.00 ± 3.56 years, of whom 3/4 had a severe form of gross motor dysfunction (GMFCS-E&R levels IV and V). All subjects had lower bone density in both regions of interest [spinal Z-score -1.60 ± 1.40 standard devation (SD); hip Z-score -2.00 ± 3.00 SD], as well as lower anthropometric parameters [height Z-score -2.74 ± 4.28; body weight Z-score - 3.22 ± 6.96; body mass index (BMI) Z-score -2.64 ± 6.03]. In the observed sample, bone mineral density in the spine (p < 0.01) and the hip (p < 0.05) was reduced in all subjects, and all children had a lower body weight (p < 0.01) and the BMI (p < 0.01), but not body height, in relation to the existing developmental charts for the CP children adopted from the US. Children with the CP Level IV on the GMFCS-E&R had a significantly lower bone density (spinal Z-score -1.90 SD; hip Z-score -3.40 SD), with the reduction even more pronounced at level V (spinal Z-score -3.80 SD; hip Z-score -2.30 SD). Conclusion. A significantly lower bone mineral density as well as the decreased values of all observed anthropometric parameters, were noted in the children with CP. In the observed sample, bone mineral density in both spine and hip was reduced in all subjects, all of whom also had lower body weight and the BMI, but not body height compared to the existing developmental charts for the children with CP adopted from the US. The children with severe forms of CP (GMFCS-E&R levels IV and V) had significantly lower bone mineral density.

Bile acids (BA)s are known surfactants and well-documented to play a major role in food digestion and absorption. Recently, potential endocrinological and formulation-stabilisation effects of BAs have been explored and their pharmacological effects on supporting cell survival and functions have gained wide interest. Hence, this study aimed to explore the hyper-glycaemic dependent dose-effect of the BA chenodeoxycholic acid (CDCA) when encapsulated with pancreatic β-cells, allowing assessment of CDCA’s impacts when encapsulated. Four different concentrations of the BA were prepared, and viable cells were encapsulated and incubated for 2 days. Multiple analyses were carried out including confocal imaging, glucose-induced cellular mitochondrial viability indices, insulin production, inflammatory biomarker analyses and cellular bioenergetics measurements. There was a significant dose-effect with different concentrations of the BA, affecting cellular viability and antioxidant activities, cell functions and insulin release, inflammatory biomarkers, and cellular-bioenergetics at different oxidative stress levels. The results demonstrate that, when encapsulated, the BA CDCA exerts positive pharmacological effects at the cellular level, and such effects are concentration dependent.

A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA.

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic β-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules’ images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules’ thermal and chemical stability assays were also assessed to ascertain an association between capsules’ stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.

Clindamycin hydrochloride is a widely used antibiotic for topical use, but its main disadvantage is poor skin penetration. Therefore, new approaches in the development of clindamycin topical formulations are of great importance. We aimed to investigate the effects of the type of gelling agent (carbomer and sodium carmellose), and the type and concentration of bile acids as penetration enhancers (0.1% and 0.5% of cholic and deoxycholic acid), on clindamycin release rate and permeation in a cellulose membrane in vitro model. Eight clindamycin hydrogel formulations were prepared using a 23 full factorial design, and they were evaluated for physical appearance, pH, drug content, drug release, and permeability parameters. Although formulations with carbomer as the gelling agent exerted optimal sensory properties, carmellose sodium hydrogels had significantly higher release rates and permeation of clindamycin hydrochloride. The bile acid enhancement factors were higher in carbomer gels, and cholic acid exerted more pronounced permeation-enhancing effects. Since the differences in the permeation parameters of hydrogels containing cholic acid in different concentrations were insignificant, its addition in a lower concentration is more favorable. The hydrogel containing carmellose sodium as a gelling agent and 0.1% cholic acid as a penetration enhancer can be considered as the formulation of choice.

Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems. Such studies have demonstrated significantly enhanced delivery and safety of biguanides using nanocapsules. Enhanced delivery and safety have widened the potential applications of biguanides not only in diabetes but also in other disorders. Hence, this review aimed to explore biguanides’ pharmacokinetics, pharmacodynamics, and pharmaceutical applications in diabetes, as well as in other disorders.