Bojan Stanimirov

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases.

BACKGROUND The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases. DATA SOURCES Detailed and comprehensive search of PubMed and Scopus databases was carried out for original and review articles. RESULTS Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, cholesterol gallstone disease, intestinal diseases and both hepatocellular and colorectal carcinoma. CONCLUSION Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also systemic diseases.

An Insight on Differences in Availability and Reimbursement of Orphan Medicines Among Serbia, Bulgaria and Sweden

ABSTRACT In the European Union (EU), rare diseases are defined as life-threatening or chronically debilitating diseases with prevalence lower than five in 10,000 inhabitants. Although individually rare, together, rare diseases affect a significant part of the population (27–36 million people in the EU). Therefore, patient access to orphan medicines is receiving increasing political attention in the EU. In order to assess the differences in availability of reimbursed orphan medicines among Serbia, Bulgaria and Sweden, National Reimbursement Lists were reviewed and identified orphan medicines were crossed with the List of orphan drugs in Europe, published in July 2011, available from Orphanet. The analysis of regulatory traits was based mainly on a review of the official documents setting out legislation regarding rare diseases and orphan medicines in the studied countries. Only 6.5% (4 out of 61) of the authorised orphan medicines in Europe with prior orphan designation and 25.0% (17 out of 68) without prior orphan designation were available and reimbursed in Serbia. In the Bulgarian Positive Drug List 44.3% (27 out of 61) of the drugs with prior orphan designation and 50.0% (34 out of 68) without prior orphan designation were identified. The share of reimbursed orphan medicines was the highest in Sweden among the observed countries—52.5% (32 out of 61) of the medicines with orphan designation and 60.3% (41 out of 61) without prior orphan designation. According to the first level of the ATC Classification System, most of the reimbursed orphan medicines in the three studied countries belonged to the group L: “Antineoplastic and immunomodulating agents”, while the most common indications for authorised and reimbursed orphan medicines were “Neoplasms” (C00-D48), with 19 available orphan drugs in Serbia, 26 in Sweden and 31 in Bulgaria. Inequities in the access to orphan medicines among Serbia, Bulgaria and Sweden may be explained by the differences in the approaches for registration, pricing and reimbursement of orphan medicines. The low share of reimbursed orphan drugs in Serbia may be due to incomplete compliance with EU legislation and existence of domestic procedure for authorisation as well. The EU legislation and policy on treatment of rare diseases obviously facilitate the penetration of orphan drugs on the EU market, but apparently there is also considerable budget impact on the availability of reimbursed orphan medicines.

Potential Applications of Gliclazide in Treating Type 1 Diabetes Mellitus: Formulation with Bile Acids and Probiotics

Abstract A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM.

The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes

Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug–drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects. However, the testing of the role of metabolites in CYP inhibition is still not routinely performed during the process of drug development, although the evaluation of time-dependent CYP inhibition during the clinical candidate selection process may provide information on possible effects of metabolites in CYP inhibition. Due to large number of compounds to be tested in the early stages of drug discovery, the experimental approaches for assessment of CYP-mediated metabolic profiles are particularly resource demanding. Consequently, a large number of in silico or computational tools have been developed as useful complement to experimental approaches. In summary, circulating metabolites may be recognized as significant CYP inhibitors. Current data may suggest the need for an optimized effort to characterize the inhibitory potential of parent drugs metabolites on CYP, as well as the necessity to develop the advanced in vitro models that would allow a better quantitative predictive value of in vivo studies.

The influence of bile salts on the distribution of simvastatin in the octanol/buffer system

Abstract Introduction: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability. Methods: LogD values of SVA and SVL with or without bile salts were measured by liquid–liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes. Results: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results. Conclusions: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.

Remarkably lower consumption of antidepressants in Serbia in comparison with Finland

Background Depression is an important health problem worldwide due to significant disability that it causes, reduction of quality of life, loss of work days, and even suicide. The aim of our survey was to evaluate the overall utilization and pattern of use of antidepressants in Serbia in a comparison with Finland in 2010 and to propose appropriate interventions in Serbia on the basis of the results obtained.

Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles

Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability. Besides, bile acids may withstand the gastrointestinal impediments and aid in the transporter-mediated absorption of physically complexed or chemically conjugated drug molecules. These biomolecules may increase the drug bioavailability also at submicellar levels by increasing the solubility and dissolution rate of non-polar drugs or through the partition into the membrane and increase of membrane fluidity and permeability. Most bile acid-induced effects are mediated by the nuclear receptors that activate transcriptional networks, which then affect the expression of a number of target genes, including those for membrane transport proteins, affecting the bioavailability of a number of drugs. Besides micellar solubilization, there are many other types of interactions between bile acids and drug molecules, which can influence the drug transport across the biological membranes. Most common drug-bile salt interaction is ion-pairing and the formed complexes may have either higher or lower polarity compared to the drug molecule itself. Furthermore, the hydroxyl and carboxyl groups of bile acids can be utilized for the covalent conjugation of drugs, which changes their physicochemical and pharmacokinetic properties. Bile acids can be utilized in the formulation of conventional dosage forms, but also of novel micellar, vesicular and polymer-based therapeutic systems. The availability of bile acids, along with their simple derivatization procedures, turn them into attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs, biomolecules and vaccines. Although toxic properties of hydrophobic bile acids have been described, their side effects are mostly produced when present in supraphysiological concentrations. Besides, minor structural modifications of natural bile acids may lead to the creation of bile acid derivatives with the reduced toxicity and preserved absorption-enhancing activity.

Bile Acids as Novel Pharmacological Agents: the Interplay between Gene Polymorphisms, Epigenetic Factors and Drug Response.

BACKGROUND The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging. METHODS The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome. RESULTS Most effects of bile acids are mediated by both nuclear and G protein-coupled receptors. Three natural bile acids have already been registered for the use in humans, but various semi-synthetic bile acid analogues with improved pharmacokinetic and pharmacodynamic properties have been developed, which opens up new avenues in pharmacotherapy. Many efforts have been made to evaluate the impact of nuclear receptors on inter-individual variation in responses to drugs, since nuclear receptors are significant mediators between environmental stimuli and pharmacokinetics. Genetic variation of bile acid-activated receptors is associated with both benign and malignant diseases, in terms of disease risk and severity, but also with pharmacokinetics and therapy outcome. Furthermore, the activity of these receptors may be masked or amplified by epigenetic modifications. CONCLUSION Both genetic and epigenetic factors may alter complex and intricate network of bile acid signaling pathways, contributing to the development of several metabolic and non-metabolic diseases and altered activities of drug-metabolizing enzymes and transporters. These polymorphisms and epigenetic modifications may also impact the effectiveness and pharmacokinetics of bile acid analogues, which must be taken into account during the development of these compounds as novel therapeutic agents.

Differences in the use of medicines for peptic ulcer and gastro-esophageal reflux disease between Serbia, Croatia and Sweden

Results The overall consumption of medicines from A02B subgroup in 2010 in Serbia was 22.9 DID, whereas in Croatia and Sweden was 32.8 DID and 48.6 DID, respectively. In Serbia, H2RAs accounted for 71.8% (16.5 DID) of medicines used within A02B subgroup, while in Croatia H2RAs accounted for 37.3% (12.2 DID) and in Sweden 2.2% (1.1 DID). In the same year, the utilization of PPIs in Serbia (6.5 DID) was more than three times lower than in Croatia (20.6 DID) and more than seven times lower than in Sweden (47.3 DID). The bulk of prescription (DU90%) was made up of 3 (out of 7) medicines in Serbia, 5 (out of 8) medicines in Croatia and 5 (out of 14) medicines in Sweden. The most frequently used medicine from the A02B subgroup in Serbia was ranitidine (56.0%, i.e. 12.8 DID), in Croatia pantoprazole (36.5%, i.e.12.0 DID) and in Sweden omeprazole (81.3%, i.e. 39.0 DID).

Considerable differences in the utilisation of antidiabetics between Serbia and Scandinavian countries

Background Diabetes mellitus is a major public health concern with devastating human, social and economic impact. It is increasing globally, affecting more than 180 million people worldwide. The objective of our study was to analyse the overall volume of use of antidiabetics in Serbia compared to Scandinavian countries (Sweden, Norway, Denmark), chosen for their rational and conservative prescription practice. Methods Data on consumption of antidiabetics (ATC group A10) in 2010 were extracted from the databases of the representative national authorities. Utilisation of these medicines was measured through the defined daily dose (DDD) unit and the results were expressed as DDD per 1000 inhabitants per day (DID). Results In 2010, antidiabetics were used at a similar rate in Serbia (47.3 DID) and Scandinavian countries (from 46.5 DID in Sweden to 47.67 DID in Norway), but the share of use of insulins (A10A) and oral antidiabetics (A10B) differed among the observed countries. The proportion of insulin in Serbia was 22.0% of all antidiabetics which is relatively low in comparison with Scandinavian countries (from 36.2% in Denmark to 50.8% in Sweden). Utilisation of long-acting insulins (A10AE) was much lower in Serbia (1.3 DID) compared to Scandinavian countries (range: 2.6–4.6 DID). The share of oral antidiabetics use also differed among these countries. In Serbia, sulfonylureas (A10BB), as a second-line treatment for type 2 diabetes, were used predominantly (55.6%) compared to metformin (44.1%). In Scandinavian countries, metformin, as preffered oral agent for type 2 diabetes and the only medicine from the biguanide class (A10BA), was used at a higher rate than in Serbia (from 51.2% in Denmark to 60.4% in Sweden). New medicinal products with effect on the incretin system (A10BH and A10BX) were also used at a higher rate in Scandinavian countries (range: 0.5–2.5 DID) in comparison to Serbia (0.002 DID). Conclusions