Momir Mikov - Academia.edu (original) (raw)

Papers by Momir Mikov

Scientific Reports, 2021

Acta Scientiae Veterinariae, Mar 19, 2018

Background: Multiple resistances to antibiotics are an emergent problem worldwide. Scientists int... more Background: Multiple resistances to antibiotics are an emergent problem worldwide. Scientists intensively search for new substances with the antimicrobial potential or the mode to restore the activity of old-generation antibiotics. Ampicillin is the antibiotic with the expanded range of antimicrobial activity, but its use has decreased due to the poor absorption and highly developed resistance. In vivo studies showed that ampicillin has better absorption and bioavailability if combined with bile acid salts. The aim of this study was to examine antimicrobial effects of ampicillin alone and its combination with semisynthetic monoketocholic acid salt (MKH) in vitro. Materials, Methods & Results: In this study, commercial preparation of ampicillin and sodium salt of 3α,7α-dihydroxy-12oxo-5β-cholanate were used. Their effects were evaluated on Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium), obtained from urine specimens of dogs with clinically manifested cystitis. The first two investigated strains were ampicillin-sensitive, while E. faecium was resistant to ampicillin. Modified macrodilution method according to Clinical and Laboratory Standards Institute Guidelines (M7-A8) was performed. Bacterial suspension equivalent to 0.5 McFarland was prepared in saline, compared to the standard (Biomerieux) ad oculi. The density was checked spectrophotometrically at a wavelength of 625 nm and adjusted if necessary to the desired absorbance from 0.08 to 0.1. The resultant suspension was diluted 1:100 and inoculated in test tubes. Number of bacteria was counted on Petri plates using dilutions from 10-3 to 10-7 in order to obtain valid and countable plates. One hundred microliters of appropriate dilutions were aseptically plated in triplicate onto nutrient agar. Plates were incubated on 37°C for 72 h, under aerobic conditions. The number of colony forming units (CFU) was determined by direct counting. As a valid for enumeration, we took plates with 30 to 300 CFU. Percentage of killed bacteria for ampicillin was from 69.33-95.19% for E. coli, 87.12-96.92% for E. faecalis and 7.20-33.30% for E. faecium. Ampicillin applied in the combination with MKH killed 99.99% to 100% of E. coli, 94.59% to 99.91% of E. faecalis and 31.73% to 64.76% of E. faecium. Mean percentage of killed bacteria for ampicillin was 81.93% for E. coli, 91.64% for E. faecalis, and 18.13% for E. faecium, while in combination with MKH percentage was 99.96% for E. coli, 98.23% for E. faecalis and 47.54% for E. faecium. Discussion: Results are presented as pharmacological minimal inhibitory concentration (MIC) values. Ampicillin was applied at the concentration higher than the therapeutic one, which could explain high MIC values for E. coli and E. faecalis. The combination of ampicillin with MKH showed the best improvement of antimicrobial effect on E. faecium (Δ = 29.41%), isolate that was resistant to ampicillin when applied alone. In all the investigated isolates, the combinations with MKH were more effective than ampicillin administered alone. It seems that MKH demonstrates a synergistic antimicrobial activity with ampicillin in vitro, which considerably decreases MIC values for all investigated isolates. These results implicate that MKH could restore the previous activity of ampicillin against some bacteria, which could be a significant benefit for clinical practice.

Scientific Reports, Nov 11, 2021

Microencapsulation represents a process that can create targeted, controlled release kinetics of ... more 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,7αdihydroxy-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 < 0.05 and p < 0.01), which indicates that basil has hypoglycemic and antihyperglycemic effects. Microvesicles, as a pharmaceutical-technological formulation, substantially enhance the hypolipidemic action of basil extract with MKC acid. Microencapsulation can improve efficiency of drug loading and key manufacturing parameters, thus potentiating new avenues for pharmaceuticals as therapeutics in the healthcare markets worldwide. The new formulation systems created via microencapsulation technology control pharmacokinetics, pharmacodynamics, immunogenicity, nonspecific toxicity, and drug efficacy, and represent an interdisciplinary approach that combines polymer science, pharmaceuticals, bioconjugate chemistry, and molecular biology 1,2. The main rationale behind novel drug delivery systems and encapsulation technologies is to avoid all the disadvantages of traditional drug transport in the body 3. Many new carriers for drug delivery and targeting are developed to minimize drug degradation, drug loss, to prevent drug side effects, and to increase drug bioavailability 4,5 Microencapsulation is a process that enables prolonged drug release and reduced side effects 4,6-8. When using herbal medicines, many components are destroyed due to the low pH in the stomach, while others can be metabolized in the liver before reaching the site of action. Consequently, the therapeutic effect will be absent if the compound of interest degrades preliminarily or is extensively metabolized previously. Natural components are metabolized much faster and easier in the body, so they cause fewer side effects compared to synthetic components 1. As a result, the pharmaceutical industry is increasingly interested in herbal preparations. Herbal medications are often insoluble, so incorporating them into alginate microvesicles increases their bioavailability. Soluble plant materials can also be incorporated into microparticles to increase the bioavailability 9. The lack of appropriate drug formulations can represent the problem related to the control of the blood glucose levels 10. Moreover, a knowledge of the pharmacokinetics and pharmacodynamics of antidiabetic medicines

Vojnosanitetski Pregled, 2018

Scripta medica, May 3, 2018

Introduction: Based on the international drug regulatory requirements, all generic pharmaceutical... more 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 significant 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.

Materials Science and Engineering: C

Biomaterials, 2022

The role of endogenous bile acids as lipid stabilizers aiding uptake of lipophilic nutrients via ... more The role of endogenous bile acids as lipid stabilizers aiding uptake of lipophilic nutrients via micelle formation and saponification effects is well documented and precedes their growing applications in pharmaceutical sciences. Their utility stems from their unique physico-chemical profile and ability to modulate immune cell signalling pathways. It has been shown that bile acids alter specific receptor-mediated pathways of cellular respiration and metabolism, providing potential clinical therapies for cardio-metabolic disorders such as diabetes mellitus, hypercholesterolemia, and heart disease. Additionally, some bile acids exert profound anti-oxidant, anti-inflammatory and immunosuppressant properties, and are effective at reducing blood pressure and alleviating hypertension. Their unique amphoteric properties and proven ability as permeability enhancers make them a desirable pharmaceutical excipient. When incorporated with various carbohydrates, polymers, hydrogels and/or polyelectrolytes to form micro- or nano-capsules, they provide enhanced thermodynamic, osmotic and structural stability, and cater for controlled delivery via specific tissue targeting, pH dependant release and temperature guided sol-gel complexation. Additionally, due to their immunosuppressant properties, they enhance the immunogenicity of encapsulated cells, increasing the feasibility of bioartificial organs as transplantable therapeutics. This review explores existing and future applications of bile acids and provides a synopsis of their role in advanced, novel therapeutic delivery systems.

Objective: To develop and validate a high-performance liquid chromatographic method (HPLC) for th... more Objective: To develop and validate a high-performance liquid chromatographic method (HPLC) for the determination of nifedipine (NFD) concentration in rat plasma. Methods: 1.5 mol of sodium hydroxide solution was added to each plasma sample, followed by the addition of an extraction solvent based on nhexane and dichloromethane (70: 30, v/v). The organic layer was transferred and evaporated to dryness under nitrogen flow. The residue was reconstituted with 0.5 mol of acetic acid, followed by the addition of n-hexane. After centrifuging the mixture, the supernatant organic layer of nhexane was discarded, and the aqueous solution was injected onto the HPLC using A Phenomenex Luna-C18 reversed phase analytical column (250 x 4.6 mm, 5 µm). The mobile phase consisted of 0.01 mol aqueous ammonium formate: methanol: acetonitrile (55: 43: 2, v/v) with pH adjusted to 4.9 using formic acid. The flow rate was 0.8 ml/min; UV detector set at 235 nm and the samples were quantified using the peak ar...

Dissolution Technologies, 2020

This study aimed to compare the different physical parameters and dissolution profiles of 10 year... more This study aimed to compare the different physical parameters and dissolution profiles of 10 years-expired with nonexpired lamotrigine (LTG) immediate-release tablet formulations. Dissolution tests were conducted using a validated high-performance liquid chromatography method. Dissolution characteristics of the tablet formulations were evaluated at three points spanning the physiological pH range (pH 1.2, pH 4.5, pH 6.8). Physical characteristics of LTG tablets were determined according to the European Pharmacopoeia. The dissolution profile comparison was carried out using model-independent (statistical) and model-dependent (kinetic) methods to provide detailed information about dissolution data. The t-test was applied to investigate differences between expired and non-expired tablets, and the differences were considered statistically significant if p ≤ 0.05. The results demonstrated no statistical differences in physical characteristics between expired and non-expired tablets; however, there were differences in the dissolution profiles, which could cause different pharmacokinetic profiles. The results of this investigation showed that the drug content did not change significantly. Therefore, the lower dissolution rate for expired LTG tablets is due to an interaction of LTG with one or more excipients in the tablet formulation during aging.

Zbornik Matice srpske za prirodne nauke, 2019

Urinary tract infections (UTI) are one of the most common infectious diseases, primarily caused b... more 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.

Current Pharmaceutical Design, 2019

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which open... more Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in co...

Technology and Health Care, 2019

In the last decade, the attention of the scientific community has been focused on bile acids and ... more In the last decade, the attention of the scientific community has been focused on bile acids and their salts as systems for the transportation of drugs; specifically their role as carriers and integration into nanomedicine. Bile acids can play a critical role as drug carriers in the form of chemical conjugates, complexation, mixed micelles formation as well as stabilized bile acid liposomes (bilosomes). The unique molecular structure and interaction of these amphiphilic-steroidal compounds make them an interesting subject of research. This review is based on literature research in order to emphasize the importance of bile acids and their salts as absorption modulators in order to improve therapeutic potentials of low bioavailability drugs.

Pharmaceutical Development and Technology, 2019

Bile acid-polymer-probucol microparticles: protective effect on pancreatic β-cells

Frontiers in Pharmacology, 2019

Cervical cancer can be cured, because it has a long preinvasive period. Early diagnosis and treat... more Cervical cancer can be cured, because it has a long preinvasive period. Early diagnosis and treatment of cervical cancer at women are crucial for reducing of rate mortality. Today, there are many methods for detecting premalignant lesions and one of them is a conventional Papanicolaou test. Cervical cancer develops through a series of changes in the epithelium called cervical intraepithelial neoplasia (CIN). The biological and genetic characteristics of the cells at cancer in situ are irreversibly altered and abnormal cells have the potential to metastasize to others anatomical regions. Infection with human Papillomavirus, which is transmitted sexually, is considered the main cause and represent the necessary, but not the only factor for the development of cervical cancer. Types of high risk human Papillomavirus are often associated with invasive cervical cancer. The carcinogenic types of HPV 16 and 18 are responsible for 70% of cervical cancer and about 50% of CIN 3. Primary prevention of cervical cancer is aimed at reducing incidence, control of causes and risk factors. In this scientific work, in addition to explaining the various treatments necessary for the treatment of cervical carcinoma, we were discussed about the anticancer effects of the synthetic derivative of ursodeoxycholic acid, such as HS-1183, and synthetic derivatives of chenodeoxycholic acid such as HS-1199 and HS-1200. Also, the effects of bile acid complexes with metals such as platinum, zinc, nickel, and copper were considered in the effective treatment of cervical cancer. KEY POINTS • Lymphogenic spreading of cervical cancer occurs relatively early in the regional lymph nodes, while this sort of progression of cervical cancer is rarer in the juxtaregional (paraaortic), mediastinal and supraclavicular nodes. • Clinically proven supraclavicular metastases are not a rarity. In stages IIb and IIIa with metastases in paraaortal nodes occur a 20% metastases at the neck lymph nodes. • Hematogenic metastases are relatively rare and occur in the posterior phase. Distant metastases are detected in the lungs and liver. • Preinvasive and microinvasive stages of cervical cancer are without symptoms. With deeper invasion of the strome, certain clinical symptoms such as prolonged

Dose-Response, 2019

Purpose: To determine whether severe hypoalbuminemia (<25 mg/L) has a significant effect on se... more Purpose: To determine whether severe hypoalbuminemia (<25 mg/L) has a significant effect on serum levels of vancomycin and whether it can effect vancomycin dosage regimen and the loading dose administration. Material and Methods: Prospective, cohort, and a single-center study included 61 patients whose vancomycin serum levels were measured in steady state. Vancomycin trough levels ( C min) that were in the range 15 to 20 µg/mL were considered therapeutic and trough levels higher than 15 µg/mL were considered potentially nephrotoxic. Results: In the group of patients with severe hypoalbuminemia, C min was significantly higher compared to the those with nonsevere hypoalbuminemia (>25 mg/L; 23.04 [19.14] vs 13.28 [11.28], P = .01). In the group of patients who received the vancomycin loading dose of 2 g, C min was significantly higher in patients with severe hypoalbuminemia compared to the patients with nonsevere hypoalbuminemia (34.52 [25.93] vs 15.37 [10.48], P = .04). Conclusi...

Timocki medicinski glasnik, 2019

Sažetak: Teška trauma je vodeći uzrok mortaliteta i teškog stepena invaliditeta. Hitna medicinska... more Sažetak: Teška trauma je vodeći uzrok mortaliteta i teškog stepena invaliditeta. Hitna medicinska pomoć najčešće prva ostvaruje kontakt sa povređenom osobom, tako da od procene težine povrede zavisi dinamika definitivnog zbrinjavanja povređenog. Da bi se procenila težina povrede, neophodna je upotreba adekvatnog Trauma skora (TS). Najčešće korišćeni na prehospitalnom nivou je Revidirani trauma skor (RTS). Pregledom velikih indeksnih baza pronašli smo studije koje se bave upoređivanjem dugo korišćenog RTS skora sa novorazvijenim skorovima MGAP (Mechanism, Glasgow coma scale, Age, and arterial Pressure) i GAP (Glasgow coma scale, Age, and arterial Pressure). Analizom pet pronađenih studija došli smo do zaključka da su novorazvijeni skorovi jednostavniji za upotrebu, a pri tome imaju istu ili bolju trijažnu i prediktivnu vrednost ishoda trauma. Ključne reči: Trauma skor; Revidirani trauma skor; MGAP (Mechanism, Glasgow coma scale, Age, and arterial Pressure) skor; GAP (Glasgow coma scale, Age, and arterial Pressure) skor Summary: Context: Severe trauma is a leading cause of mortality and high-degree invalidity. Emergency Medical Services (EMS) are usually first-line responders to the traumatized persons and the management of traumatism and its dynamics depend on the accurate evaluation by the EMS providers. In order to evaluate the severity of injury, it is necessary to use the adequate trauma score (TS). The aim of this paper is to compare the most common prehospital scoring system RTS (Revised TS) with newly developed MGAP (Mechanism, Glasgow Coma Scale, Age and Arterial Pressure) and GAP (Glasgow Coma Scale, Age and Arterial Pressure), based on the published studies, in order to determine better triage and predictive value, i.e. the highest sensitivity and specificity. Methods: Our search through the large indexical data bases (Web of Science, Scopus, PubMed, Serbian Citation Index), completed on 01 May 2017, discovered numerous articles about trauma scores. Results: Prehospitally, most commonly used score is a RTS. After viewing large indexed data bases, we found studies comparing RTS with newly developed scores, such as MGAP and GAP. MGAP and GAP have better triage and predictive value than RTS. In addition to this, these scores are easier to use and calculate. In most cases, it is possible to calculate them retrospectively, which is not the case with RTS. Its importance is even more prominent in low and middle-income countries, where there are great differences in availability, quality and equipment between medical centres. Conclusions: After analyzing five studies, we concluded that new scores are easier to apply, with equal or improved triage and predictive values regarding the outcome of the trauma.

Praxis medica, 2018

Newly synthetized derivative of bile acid, sodium salt of 3α, 7α-dihydroxy-12-oxo 5β cholanic aci... more Newly synthetized derivative of bile acid, sodium salt of 3α, 7α-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<0.05). Distributionm of MKCh through animal organism depends on the way of application of the substance, which probably determines its caracterisation as the transport promotor of applied xenobiotics. HPLC has proved as aa relatively simple, fast and effective method for the determination of synthetic bile acid,MKCh in these biological materials. key words: bile acids and salts, HPLC method, intranasal and intravenous administration, rats

Therapeutic Delivery, 2019

Aim: Taurine-conjugated bile acids possess positive formulation-stabilization effects, which are ... more Aim: Taurine-conjugated bile acids possess positive formulation-stabilization effects, which are desirable in diabetes treatments. The taurine-conjugated bile acid, taurocholic acid (TCA), has shown promising formulation-stabilizing effects on the delivery of the antioxidant drug, probucol (PB), but success is limited due to its poor release profile. This study aimed to design new PB-TCA formulations using new polymers, and examine antioxidant and antidiabetic effects using β-cells for PB with or without TCA. Materials and methods: Different formulations using alginate-insoluble esters of polymethylacrylate polymers encapsulating PB and TCA were developed, microencapsulated and examined for stability and biological activity. Results: TCA addition to new PB matrices improved osmotic and mechanical properties, and this effect was dependent on polymethylacrylate composition and concentration. Conclusion: TCA can optimize the oral delivery of anti-diabetic compounds.

Phytotherapy Research, 2018

Pycnogenol® (PYC) has already being used as a food supplement and herbal medicine due to its pote... more Pycnogenol® (PYC) has already being used as a food supplement and herbal medicine due to its potent antioxidant properties. The aim of the present study was to examine the protective effect of PYC on acetaminophen‐induced acute liver injury in rats. The effect of PYC on acetaminophen‐induced hepatotoxicity in rats was examined by determining biochemical parameters, in vitro antioxidant activity, histological assessment, and oxidative status in liver homogenates. The best antioxidant properties were demonstrated in methanolic extracts. Seven‐day pretreatment with PYC suppressed elevation of CYP2E1 protein expression induced by administration of toxic dose of acetaminophen. PYC at 50 mg/kg showed the ability to significantly decrease malondialdehyde (MDA) level compared with the group received acetaminophen. Xanthine oxidase (XOD) enzyme activity was significantly elevated in acetaminophen‐treated group compared with control, whereas concomitant administration of PYC in a dose of 50 m...

Drug Testing and Analysis, 2017