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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.

Abstract Background The prime significance of species belonging to the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) is their ability to transmit viruses such as bluetongue virus (BTV) to wild and domestic ruminants. Prior to 1998, BTV was considered exotic in Europe, but according to recent history of its outbreaks, it has become endemic in southern and eastern European countries circulating beyond its expected historical limits, into the Balkan region. The wind-borne long-distance dispersal of Culicoides spp. over water bodies and local spreading between farms emphasize the necessity of filling in the information gaps regarding vector species distribution. In most Balkan countries, data on Culicoides fauna and species distribution are lacking, or information is old and scarce. Results During this study, 8586 specimens belonging to 41 species were collected. We present the first faunistic data on Culicoides species in the former Yugoslav Republic of Macedonia (FYROM), Kosovo, Montenegro and Serbia. For other countries (Bosnia and Herzegovina, Bulgaria and Croatia), all historical records were compiled for the first time and then expanded with our findings to various extents. In all countries, confirmed or suspected BTV vector species belonging to the subgenera Avaritia and Culicoides were collected. The total number of species sampled during our field collections was 20 in Bosnia and Herzegovina (15 new records), 10 in Bulgaria (2 new records), 10 in Croatia (5 new records), 13 in FYROM, 9 in Kosovo, 15 in Montenegro, and 28 in Serbia. Of these, 14 species were registered for the first time in this part of the Balkans. Conclusions This paper provides the first data about Culicoides fauna in FYROM, Kosovo, Montenegro and Serbia, as well as new records and an update on the checklists for Bosnia and Herzegovina, Bulgaria and Croatia. These findings provide preliminary insights into the routes of BTV introduction and spreading within the Balkans, and present a valuable contribution to further research related to Culicoides-borne diseases in Europe.

Background: This retrospective analysis assessed all recorded malaria cases in Bulgaria after 1965, when the country was certified as malaria-free by the World Health Organization (WHO), and evaluated the readiness of the public health system to interrupt an outbreak of local transmission in case of infection importation. Methods: The cases were analyzed according to causative species; geographic origin of the imported case; and the citizenship, age, and gender of the infected individuals. Results: In the 50-year study period (1966–2015), there were a total of 3011 cases of malaria imported to Bulgaria from different regions of the world. The majority of the cases originating in Africa were caused by Plasmodium falciparum (65.5%), while most of these originating in Asia were caused by P. vivax (80.9%). The potential season for malaria transmission in Bulgaria is from April to October, and 58.5% of the malaria cases were imported during that time of the year. Conclusions: The increasing movement of people to and from areas endemic for malaria requires the health authorities of countries with appropriate conditions for reintroduction to conduct enhanced measures for surveillance and control of this potentially deadly disease. Keywords: Local transmission, Reintroduction, Surveillance, Control

The synthetic forms of Triticum miguschovae (GGAADD), Triticum palmovae (AbAbDD), T. durum (M. it.)/Ae. Tauschii (BBAADD) and the introgressive lines of common wheat created on their basis were evaluated for resistance to leaf rust. All synthetic forms have a high resis­tance to leaf rust. Twenty-two lines of common wheatresistant to leaf rust with genetic material from T. miguschovae, 10 lines with genetic material from T. du­rum (M. it.)/Ae. tauschii and 4 lines obtained on the basis of T. palmovae were identified. A screening with the use of molecular markers for the presence of leaf rust resistance genes Lr21, Lr26, Lr32, Lr39 was done. The GDM35 marker linked to the Lr39 gene was identified in the synthetic forms. Molecular markers Lr21F/R and BARC135 linked to the genes Lr21 and Lr32, respectively, were not identified. Resistance to leaf rust in lines 729, 1555, 2203, 2289, 2295, 2296, 4155, 4171, obtained on the basis of T. miguschovae, lines 3261, 3265, obtained on the basis of T. palmovae, and in line 4141 with the genetic material from T. durum (M. it.)/Ae. Tauschii is controlled by the presence of the Lr39 gene. The SCM9 marker indicating the presence of translocation of 1BL.1RS with the Lr26 gene was detected in 15 lines obtained on the basis of T. miguschovae, in 2 lines with genetic material from T. durum (M. it.)/Ae. tauschii, and in 1 line created on the basis of T. palmovae. Lines 729, 1555, 2203, 2289, 2295, 2296, 4155, 4171 obtained with the participation of T. miguschovae and line 3261 with the participation of T. palmovae carry a combination of genes (Lr39+Lr26).

Parasitic diseases are a significant part of the overall pathology registered in Bulgaria. It is essential to constantly improve the efficiency of the public health system in order to deal with autochthonous parasitic diseases

Background/Aim. Assessment of minor neurological dysfunction (MND) provides information about a child's neurological condition which helps to identify the vulnerability of the child to the development of motor impairment, difficulties in learning or behavioral disorders. The aim of this study was to determine differences in the prevalence of MND in children from the general population with respect to age (5 and 6 years old) and sex. Methods. The examination was carried out in a preschool institution in the city of Novi Sad, Serbia. The total sample included 120 children divided into two groups according to age: 60 children aged 5 (group A) and 60 children aged 6 years (group B). The children were recruited at three randomly selected kindergartens and approximately equal sex representation, randomly selected as well. The testing was done by the Touwen's test, modified by Hadders-Algra. The results were classified into three groups: the absence of MND, presence of simple MND (presence of one or two domains of dysfunction) and the presence of complex MND (presence of at least three domains of dysfunction). Results. Sixtyseven children out of 120 (55.8%) had a normal neurological condition, while 53 (44.2%) showed MND [49 (40.8%) simple, and 4 (3.4%) complex]. MND occurred more frequently in the youngest age group than in the older children (57% vs. 32%; p = 0.01). MND was also more frequent in boys than in girls, but this difference was not statistically significant. Conclusion. Our results show the importance of testing children at preschool age in order to detect potential neurological vulnerability and timely begin with the appropriate therapy.

Newly synthetized derivative of bile acid, sodium salto f 3 α, 7 α-dihydroxy-12-oxo 5β cholanic acid (monoketocholanate) expressed a good characteristic as intranasal transport enhancer of xenobiotics. The aim of our sudy was to explore if it has an influence on bile metabolism and to measure its concentration in blood and bile after intravenous and intranasal administration. The experiment was performed in vivo on adult male Wistar rats. The determination of monoketocholanate (MKCh) in rats blood and bile, was carried out by high-performance liquid chromatography (HPLC), on an HP ODS2 column, using methanol/acetonitrile/acetate buffer as mobile phase. Absorbances were measured at 210 nm. Blood samples were taken from the prepared right axillary artery in 0, 1, 5, 10, 20, 30, 60, 90, 120 and 180 minutes from the beginning of the experiment. Bile was collected in a half an hour intervals, during the three hour period. The results showed that MKCh changed the amount of excreted bile depending on the way of application. Intranasal application increased the bile volume and the MKCh concentration, both in blood and bile compared to the intravenous application (p

Introduction: Based on the international drug regulatory requirements, all generic pharmaceutical manufacturers are obliged to ensure that their generic products are similar or equivalent to the innovative brand. The quality of generic medicines should be comparable with the innovator brand and therefore interchangeable with the innovator. Based on the Biopharmaceutical Classification System (BCS), dissolution tests can be used as a replacement for in vivo studies for drugs that belong to the BCS class I. Dissolution tests are considered the most sensitive in vitro parameters that can be with the highest probability of correlation with in vivo bioavailability. The comparison of in vitro dissolution tests using similarity factor (f2) is very often used as the most important parameter that can reflect the existence of bioavailability. Aim of the Study: The aim of this study was to compare the physico-chemical characteristics of two amlodipine formulations made by the same manufacturer using the dissolution test and similarity factors to ascertain their in vitro similarity. Material and methods: Two different generic copies of amlodipine 5 mg tablets produced by the same pharmaceutical manufacturer were evaluated using pharmaceutical parameters such as: uniformity of active ingredient test, weight uniformity text, disintegration test, hardness test, tablet friability test, and in vitro dissolution test. Results: The results have shown that different salts and different manufacturing procedures do not have effect on in vitro equivalence of amlodipine tablets. The similarity factor (f2) at pH 4.5, 1.2 and 6.8 was 63.90, 53.87 and 57.57, respectively. Although these values demonstrated equivalence, statistically signifcant differences were found in the degree of dissolution rates of tablets formulation depending on time and pH values. The results of our study showed equivalence of dissolution profiles of different amlodipine formulations. Conclusion: The results of our study have shown that the equivalence of dissolution profiles exists, although there were statistical differences in some pharmaceutical parameters.