Dermal bioavailability of antiinflammatory drugs from sugar emulsifier stabilized bases: comparative application of in vitro / in vivo characterization methods

Uvod Aktuelna farmakoekonomska situacija ima za posledicu čest nedostatak lekova u potrebnim dozama/jačinama, a za neke lekovite supstance nisu odabrani pogodni nosači. Značaj primene odgovarajućeg vehikuluma/podloge naročito je izražen u slučaju lekova koji se primenjuju na koži. Ova grupa lekova podložna je i uticajima koji dolaze iz kozmetičke industrije, a odnose se na zadovoljavajući izgled, teksturu i senzorne karakteristike nosača, što se direktno reflektuje u kojoj meri će se pacijenti pridržavati propisanoj terapiji. Nedostatak lekova na tržištu može se prevazići izradom lekova u apoteci čime se, čak i u zemljama sa veoma razvijenom farmaceutskom industrijom, ponovo potencira značaj znanja i veština farmaceuta u ex tempore izradi lekova. Iz tog razloga, prepoznata je potreba za inoviranjem sastava takvih lekova, pre svega uvođenjem formulacija sa savremenim farmaceutskim ekscipijensima. S druge strane, ostaje otvoreno pitanje procene dermalne raspoloživosti ovakvih lekova, s obzirom da regulatorno prihvaćene metode nisu univerzalno primenljive (poput ograničene primenljivosti vazokonstriktornog testa na lekove iz grupe kortikosteroida) ili se smatraju neracionalnim u fazi razvoja formulacije (podrazumevaju značajna ulaganja i veliki broj ispitanika). Cilj istraživanja Cilj istraživanja ove disertacije bio je razvoj formulacije, fizičkohemijska i biofarmaceutska karakterizacija emulzionih sistema (podloga) stabilizovanih prirodnim mešanim emulgatorom tipa alkil poliglukozida (APG), sastava cetostearil glukozid i cetostearil alkohol, koji je od skora sertificiran kao farmaceutski ekscipijens. Razvijene formulacije poslužile su kao modeli za razvoj i optimizaciju protokola metode sa adhezivnim trakama (tape stripping metode) kao perspektivne in vivo tehnike za ispitivanje penetracije lekova kroz kožu, uz sprovođenje korelacije datih rezultata sa onim dobijenim prihvaćenim in vitro i in vivo metodama kroz nekoliko studija slučaja (ketoprofen, diklofenak dietilamin i hidrokortizon kao model lekovite supstance sa antiinflamatornim delovanjem, različitih fizičkohemijskih karakteristika)...Introduction Current pharmacoeconomic situation has resulted in a frequent shortage in certain drug doses/strengths or suitable dosage forms. The importance of the appropriate choice of the vehicle/base is especially emphasized in case of topical drugs. These are prone to influences stemming from the cosmetic industry, relating to satisfactory appearance, texture and sensorial properties of the carrier, which directly reflects patient adherence. Such drug deficiencies may be overcome through compounding practice in pharmacies which is, even in countries with highly developed pharmaceutical industry, reevaluating the importance of pharmacist’s knowledge and skills in extemporaneous drug preparation. Therefore, there is a need to innovate the composition of such drugs, particularly via introduction of formulations based on novel pharmaceutical excipients. On the other hand, the issue of dermal bioavailability assessment of these drugs remains, considering the regulatory accepted methods are not universally applicable (use of the skin blanching assay is limited to corticosteroid drugs) or their use is irrational in the formulation development phase (require substantial funds and a large number of volunteers). Aim The aim of this work was the development, physicochemical and biopharmaceutical characterization of emulsion systems (bases) stabilized with naturalorigin mixed alkyl polyglucoside (APG) emulsifier comprising cetostearyl glucoside and cetostearyl alcohol, recently given a status of pharmaceutical excipient. These formulations served as models for development and optimization of the tape stripping method protocol that could serve as a prospective in vivo technique for skin penetration studies, along with correlation of the obtained results with those provided through the acknowledged in vitro and in vivo methods via several case-studies (ketoprofen, diclofenac diethylamine and hydrocortisone as anti-inflammatory model drugs with diverse physicochemical characteristics). Methods Experimental work was organized in three phases: 1) With the aim of assessing physical stability and colloidal structure of the model bases stabilized with the sugar emulsifier, a comprehensive characterization was performed using polarization microscopy, pH and conductivity measurements, saturation concentration of model drugs, continual rheology, differential scanning calorimetry, thermogravimetric analysis, in vitro screening of model drugs liberation profiles, assessing the safety profiles of model bases: in vitro – citotoxicity assay and in vivo – non-invasive skin bioengineering techniques..

In vitro anticancer evaluation of novel triphenyltin(IV) compounds with some N-acetyl-S-naphthoquinonylcysteine derivatives

Triphenyltin(IV) compounds with naphthoquinone derivatives containing N-acetylcysteine, N-acetyl-S-(3,4-dihydro-3,4-dioxo-1-naphthyl)cysteine (1,2-NQC), 1, and N-acetyl-S-(1,4-dihydro-1,4-dioxo-2-naphthyl)cysteine (1,4-NQC), 2, were synthesized and characterized by elemental microanalysis, IR, multinuclear (H-1, C-13, Sn-119) NMR spectroscopy as well as HR-ESI mass spectrometry. With the aim of in vitro anticancer activity determination of ligand precursors and novel synthesized organotin(IV) compounds against human cervix adenocarcinoma (HeLa), human colon carcinoma (HT-29) and melanoma carcinoma cell line (B16F10), MTT colorimetric assay method was applied. The results indicate that synthesized compounds exhibited remarkable antiproliferative activity toward all tested cell lines with IC50 in the range from 0.17 to 0.87 mu M. Complex 1 showed the greatest activity against HT-29 cells, with IC50 value of 0.21 +/- 0.01 mu M, 119 times better than cisplatin, while complex 2 demonstrated the highest activity toward HeLa cells, IC50 = 0.17 +/- 0.01 mu M, which is similar to 26 times better than cisplatin

Supplementary data for article: Pantelic, N.; Stanojkovic, T. P.; Zmejkovski, B. B.; Sabo, T. J.; Kaluerovic, G. N. In Vitro Anticancer Activity of Gold(III) Complexes with Some Esters of (S, S)-Ethylenediamine-N, N G2-Di-2-Propanoic Acid. European Journal of Medicinal Chemistry 2015, 90, 766–774. https://doi.org/10.1016/j.ejmech.2014.12.019

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.12.019]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1651

Izvori varijabilnosti osobina porasta i telesne razvijenosti bikova Simentalske rase u performans testu

To test the variability of traits of Simmental bulls in performance test, data of the Livestock - Veterinary Centres for Reproduction and Artificial Insemination of Velika Plana and Krnjača were used. In the analysis, data on 113 performance tested bulls born from 2008 to 2009 were used. The analysis included two sets of characteristics: body development traits and growth traits. The average body mass of calves entering the test was 195.75 kg, while the body mass at the end of the test was 476.50 kg, average daily gain in the test was 1138.69 g. Average values of body development traits measured at the end of the test, with 12 months of age were: height at withers 127.13 cm, chest circumference 179.42 cm, the chest depth 61.19 cm and body length 151.34 cm. The influence of their sires, the year and the Centre on the variability of traits was studied. The effect of age is present at a high level of statistical significance (p lt 0.01) for all traits that are registered at the end of the test, while the effect of the Centre was present in the variability of body mass at the end of the test, the daily gain in the test and the length of the body. The bulls-sires' influence was demonstrated (p lt 0.05) on the variability in body mass of calves entering the test.Za ispitivanje varijabilnosti osobina simentalskih bikova u performans testu iskorišćeni su podaci stočarsko-veterinarskog centra za reprodukciju i veštačko osemenjavanje iz Velike Plane i Krnjače. Za analizu su upotrebljeni podaci o 113 performans testiranih bikova rođenih u periodu od 2008 do 2009 godine. Analizom su obuhvaćene dve grupe osobina: osobine telesne razvijenosti i osobine porasta. Prosečna telesna masa sa kojom su telad ulazila u test iznosila je 195,75 kg, dok je telesna masa na kraju testa 476,50 kg, prosečan dnevni prirast u testu iznosio je 1138,69 g. Prosečne vrednosti osobina telesne razvijenosti merenim na kraju testa, sa 12 meseci uzrasta iznosile su: visina grebena 127.13 cm, obim grudi 179.42 cm, dubina grudi 61.19 cm i dužina trupa 151.34 cm. Analizirani su uticaj očeva, godine i centra na varijabilnost osobina. Efekat godine je prisutan na visokom nivou statističke značajnosti (p lt 0,01) za sve osobine koje se registruju na kraju testa, dok je efekat centra prisutan u varijabilnosti telesne mase na kraju testa, dnevnog prirasta u testu i dužini tela. Bikovi-očevi su ispoljili uticaj (p lt 0,05) na varijabilnost telesne mase sa kojom su telad ulazila u test

Životna proizvodnja visokomlečnih krava

Lifetime milk production is a key success factor in fulfilling the production potential of high-yielding cows. Lifetime milk production traits are pronouncedly variable. The life expectancy and the length of productive life of dairy cows are repeatedly limiting factors for improving lifetime milk production. Lifetime milk production is greatly depended on age at first calving and the number of lactations during productive life. Previous researches have implied there are real chances for improving the lifetime milk production of high-yielding cows. The goal of this research was to investigate the significance of key systematic factors on the lifetime production of high-yielding Black-and-White cows. The animals included in the sample had different share of Holstein genes. The researchers determined systematic factors that caused some significant phenotypic variations of the investigated trait. The average lifetime milk production was 25,002.66±7,755.39 kg. When observed by cow genotypes, the mean values of the lifetime milk production varied from 27,061.37 kg ( (lt) 58% HF) and 24,761.26 kg (58-73% HF) to 23,185.36 kg (>73% HF). The differences in lifetime milk production determined among the animals were due to a highly significant (p≤0.01) impact of the bulls - the sires of the cows and the year of culling; the impact of the class of HF genes was significant (p≤0.05), whereas the impact of the reason for culling was non-significant (p>0.05).Osobine životne proizvodnje visokomlečnih krava imaju veliki ekonomski značaj. Crno-bela goveda imaju značajan genetski potencijal za proizvodnju mleka. Visokoproizvodne krave crno-bele rase izložene su tokom produktivnog veka velikom broju složenih uticaja koji intenzivno deluju na nivo relizacije njihovog genetskog potencijala. Uslovi sredine često nisu u saglasnosti sa potrebama ove visokomlečne rase goveda. Povećanjem učešća gena holštajn-frizijske rase, tokom procesa oplemenjivanja evropskog tipa crno-belih goveda, došlo je do povećanja prinosa mleka. Dosadašnja istraživanja ukazuju na mogućnost za značajnije povećanje životne produktivnosti crno-belih krava. Poznavanje broja i nivoa uticaja faktora sredine, na životnu proizvodnju visokomlečnih krava, važno je zbog njihovog uključivanja u model. U skladu sa značajem pojedinih sistematskih faktora u okviru istraživanja je obavljena njihova objektivna procena. Cilj rada je bio da se primenom odgovarajuće metodologije ispita značajnost razlika, u ostvarenoj životnoj proizvodnji mleka kod visokoproizvodnih crno-belih krava, preko najvažnijih sistematskih uticaja. Prosečna životna proizvodnja mleka iznosila je 25002.66±7755.39 kg litara. Posmatrano po genotipovima krava prosečne vrednosti životne proizvodnje mleka iznosile su 27061.37 kg ( (lt) 58% HF), 24761.26 kg (58-73% HF) i 23185.36 kg (> 73% HF). Utvrđene razlike između grla u pogledu ostvarenog nivoa životne proizvodnje mleka nastale su kao posledica visoko značajnog uticaja (P≤0.01) bikova-očeva krava i godine izlučenja krava, klasa HF gena krava imala je značajan uticaj (p≤0.05), dok razlog izlučenja nije imao značajan uticaj (P>0.05)

Short-term liquid storage of ram semen in various extenders

The aim of this study was to investigate the effects of three extenders on ram sperm quality after short-term liquid storage (24 hours’ holding time). The study included 20 crossbred rams (Pirot Pramenka x Wurttemberg x Ile de France), 12 months old. Animals were housed at the experimental sheep farm of the Institute for Animal Husbandry in Belgrade, Serbia. Semen was collected through electro ejaculation. The ejaculates were obtained from single services and routine field analysis of the semen was performed immediately after the collection. The semen was split and diluted with three extenders, namely Optidyl®, Andromed® and ultrahigh temperature processed (UHT) milk, in ratios of 1 : 50 or 1 : 100. The ejaculates were examined for sperm motility variables (sperm cell motility percentage, the progressive motility percentage, curvilinear velocity (VCL), straight line velocity (VSL), average path velocity (VAP), sperm linearity (LIN), straightness (STR), amplitude of lateral sperm head displacement (ALH), beat cross frequency (BCF) and circular tracks), and sperm morphology (live sperm percentage, percentage of normal sperm forms with intact acrosome, percentage of abnormal sperm forms and total damaged acrosome) by computer-assisted sperm analysis (CASA) and classic sperm cytology after supravital eosin/nigrosine/trypan blue staining, respectively. It was observed that the type of extender used in diluting ram semen is an important factor in the successful short-term liquid preservation (at 4 °C) of ram spermatozoa. In conclusion, this study showed that egg yolk (Optidyl) and soybean (Andromed)-based extenders gave better results of both sperm morphology and sperm motility parameters compared with UHT milk.Keywords: Diluents, morphology, motility, sper

Laser interactions with bundle fiber structures

Laser damages of materials are in research focus during the last decade. These terms can be understood as useful in the treatment of materials or in theoretical modeling of interactions of laser beams with the material. Also, they can be destructive when it comes to high power density where the nonlinear effects are present, too. In addition to the theory, many detailed experimental work is required for new optical components applications. The experiments with Nd 3+ : YAG laser (1.064 µm) with defined working regime and power densities and specifically developed optical fiber bundles are the subject of this paper. The fibers are developed in laboratory conditions for specific purposes. Also, commercial optical fiber bundle for dental use are presented and discussed as comparison with the same laser types

Design and In Vitro Biological Evaluation of a Novel Organotin(IV) Complex with 1-(4-Carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2,5-dione

A novel triphenyltin(IV) compound with 1-(4-carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2,5-dione was synthesized and characterized by IR, NMR spectroscopy, mass spectrometry, and elemental analysis. In vitro anticancer activity of ligand precursor and synthesized organotin(IV) compound was determined against tumor cell lines: human adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human breast cancer (MDA-MB-453), using microculture tetrazolium test (MTT) assay. The results indicate that complex exhibited very high antiproliferative activity against all tested cell lines with IC50 values in the range of 0.22 to 0.53 mu M. The highest activity organotin(IV) compound expressed against the HeLa cells (IC50=0.22 +/- 0.04 mu M). The ligand precursor did not show anticancer activity (IC50>200 mu M). Furthermore, fluorescence microscopy analysis of HeLa cells reveal that organotin(IV) complex induced apoptosis as a mode of cell death, which is consistent with the increase of cells in the sub-G1 phase

Influence of nuclear radiation and laser beams on optical fibers and components

The influence of nuclear radiation and particles has been the object of investigation for a long time. For new materials and systems the research should be continued. Human activities in various environments, including space, call for more detailed research. The role of fibers in contemporary communications, medicine, and industry increases. Fibers, their connections and fused optics components have one type of tasks - the transmission of information and power. The other type of tasks is reserved for fiber lasers: quantum generators and amplifiers. The third type of tasks is for fiber sensors, including high energy nuclear physics. In this paper we present some chosen topics in the mentioned areas as well as our experiments with nuclear radiation and laser beams to fiber and bulk materials of various nature (glass, polymer, metallic, etc.)