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High concentration monoclonal antibody drug products represent a special segment of biopharmaceuticals. In contrast to other monoclonal antibody products, high concentration monoclonal antibodies are injected subcutaneously helping increase patient compliance and reduce the number of hospital patient visits. It is important to note that a high protein concentration (≥50 mg/mL) poses a challenge from a product development perspective. Colloidal properties, physical and chemical protein stability should be considered during formulation, primary packaging and manufacturing process development as well as optimization of other dosage form-related parameters. The aim of such development work is to obtain a drug product capable of maintaining appropriate protein structure throughout its shelf-life and ensure proper and accurate dosage upon administration.

Land Use and Land Cover Changes (LULCC) are interrelated with other global processes like global climate change, population growth, land degradation etc. Land use structure of a given area, region is adapted to the requirements of human society since the appearance of human beings. Land use structure is understood as the proportion of land use types orruring in a given area. The objective of the paper is to analyse land use changes in Lake Balaton catchment, Hungary and to present the role of changes of one ecosystem service, i.e. recreation and tourism by quantitative methods, based on spatial and statistical databases of land use and tourism in Lake Balaton catchment, Hungary between 1990 and 2012. The study area is a frequented touristic region of Hungary with variegated and beautiful landscape mosaics. The lake (595 km2) is exposed to various kinds of environmental impacts including agricultural activities and tourism. For the quantification of the Recreation and Ecotourism Ecosystem Service potential the Multi-Criteria Evaluation (MCE) method was applied. Land use changes between 1990 and 2012 were identified from the CORINE Land Cover Database and evaluated from ecological aspects and from the aspect of ecosystem services. The main changes include a continuous increase of the forest area and a remarkable on-going decrease of arable land. Soil erosion as the main land degradation process in the area endangering the quality of ecosystem services. The remarkable decrease of arable fields reduces erosion risk. Ecosystem services provided by each land use type were analysed. The main conclusion is that long term trend of land use changes is beneficial for ecosystem services.

Petra Hartmann,1 Edina Butt,2 Ágnes Fehér,1 Ágnes Lilla Szilágyi,1 Kurszán Dávid Jász,1 Boglárka Balázs,3 Mónika Bakonyi,3 Szilvia Berkó,3 Gábor Erős,4 Mihály Boros,1 Gyöngyi Horváth,5 Endre Varga,2 Erzsébet Csányi3 1Institute of Surgical Research, University of Szeged, Szeged, Hungary; 2Department of Traumatology, University of Szeged, Szeged, Hungary; 3Department of Pharmaceutical Technology, University of Szeged, Szeged, Hungary; 4Department of Pathology, University of Szeged, Szeged, Hungary; 5Department of Physiology, University of Szeged, Szeged, Hungary Purpose: Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL-1 in 230 μL volume) with that of an equivalent dose of oral (75 mg kg-1) and simple topical administration. Methods: Arthritis was induced with the injection of 2% λ-carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte–endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction. Results: EP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% λ-carrageenan and 4% kaolin injection. Increased leukocyte–endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia. Conclusion: The study provides evidence for the first time of the potent anti-inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration. Keywords: diclofenac, transdermal delivery, HPLC, intravital videomicroscopy

This study aimed to map water features using a Landsat image rather than traditional land cover. We involved the original bands, spectral indices and principal components (PCs) of a principal compo...

As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and used support vector machine to identify potentially effective drugs in our model disease, psoriasis. Using this method, we screened about 1,500 marketed and investigational substances, identified 51 drugs that were potentially effective, and selected three of them for experimental confirmation. All drugs inhibited tumor necrosis factor alpha-induced nuclear factor kappa B activity in vitro, suggesting they might be effective for treating psoriasis in humans. Additionally, these drugs significantly inhibited imiquimod-induced ear thickening and inflammation in the mouse model of the disease. All results suggest high prediction performance for the algorithm.

Szilvia Berkó,1,* Kálmán F Szűcs,2,* Boglárka Balázs,1,3 Erzsébet Csányi,1 Gábor Varju,4 Anita Sztojkov-Ivanov,2 Mária Budai-Szűcs,1 Judit Bóta,2 Róbert Gáspár2 1Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 2Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 3Gedeon Richter Plc., Budapest, 4Dr Derm Clinic of Anti-Aging Dermatology, Aesthetic Laser and Plastic Surgery, Budapest, Hungary *These authors contributed equally tothis work Purpose: Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods: The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results: Both intravenously and EP-administered neostigmine (0.2–66.7 µg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 µg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion: The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. Keywords: transdermal, electroporation, neostigmine, smooth muscle, contraction, plasma level

The aim of this work was to compare the penetration enhancer effect of newly developed sucrose myristate with the generally used sucrose laurate. Hydrogel formulations containing sucrose esters (SEs) were prepared and the model drug was Ibuprofen (IBU), which has oral side effects, so applying it in a transdermal system could be useful. We evaluated the effect of SE hydrogel formulations on the skin by the noninvasive in vivo test and examined their concentration dependent influence on the penetration of IBU through a synthetic membrane (in vitro) by the Franz cell method. The results indicated that sucrose myristate incorporated into hydrogel moistures the skin well and lastingly and showed a better drug penetration enhancing effect at a much lower concentration compared to sucrose laurate. Our results revealed that sucrose myristate could be a promising and effective penetration enhancer in the pharmaceutical field.

Background Glycerol is known to possess anti-irritant and hydrating properties and previous studies suggested that xylitol may also have similar effects. Objective Our aim was to study whether different concentrations of these polyols restore skin barrier function and soothe inflammation in sodium lauryl sulphate (SLS)-induced acute irritation. Methods The experiments were performed on male SKH-1 hairless mice. The skin of the dorsal region was exposed to SLS (5%) for 3 h alone or together with 5% or 10% of glycerol respectively. Further two groups received xylitol solutions (8.26% and 16.52% respectively) using the same osmolarities, which were equivalent to those of the glycerol treatments. The control group was treated with purified water. Transepidermal water loss (TEWL) and skin hydration were determined. Microcirculatory parameters of inflammation were observed by means of intravital videomicroscopy (IVM). Furthermore, accumulation of neutrophil granulocytes and lymphocytes, the expression of inflammatory cytokines and SLS penetration were assessed, as well. Results Treatment with the 10% of glycerol and both concentrations of xylitol inhibited the SLS-induced elevation of TEWL and moderated the irritant-induced increase in dermal blood flow and in the number of leucocyte-endothelial interactions. All concentrations of the applied polyols improved hydration and prevented the accumulation of lymphocytes near the treatment site. At the mRNA level, neither glycerol nor xylitol influenced the expression of interleukin-1 alpha. However, expression of interleukin-1 beta was significantly decreased by the 10% glycerol treatment, while expression of tumour necrosis factor-alpha decreased upon the same treatment, as well as in response to xylitol. Higher polyol treatments decreased the SLS penetration to the deeper layers of the stratum corneum. Conclusion Both of the analysed polyols exert considerable anti-irritant and anti-inflammatory properties, but the effective concentration of xylitol is lower than that of glycerol.

Since 2013, the EU FP7 research project “IQmulus” encourages the participation of the whole scientific community as well as specific user groups in the IQmulus Processing Contest (IQPC). This year, IQPC 2015 consists of three processing tasks (tracks), from which “Water detection and classification on multi-source remote sensing and terrain data” is introduced in the present paper. This processing track addresses a particular problem in the field of big data processing and management with the objective of simulating a realistic remote sensing application scenario. The main focus is on the detection of water surfaces (natural waters, flood, inland excess water, other water-affected categories) using remotely sensed data. Multiple independent data sources are available and different tools could be used for data processing and evaluation. The main challenge is to identify the right combination of data and methods to solve the problem in the most efficient way. Although the first deadline for submitting track solutions has passed and the track has been successfully concluded, the track organizers decided to keep the possibility of result submission open to enable collecting a variety of approaches and solutions for this interesting problem.

A lamellar lyotropic liquid crystal genistein-based formulation (LLC-Gen) was prepared in order to increase the aqueous solubility of the lipophilic phytocompound genistein. The formulation was applied locally, in a murine model of melanoma, with or without electroporation. The results demonstrated that, when the formulation was applied by electroporation, the tumors appeared later. During the 21 days of the experiment, the LLC-Gen formulation decreased the tumor volume, the amount of melanin and the degree of erythema, but when electroporation was applied, all these parameters indicated a better prognosis even (lower tumor volume, amount of melanin and degree of erythema). Although hematoxylin–eosin (HE) staining confirmed the above events, application of the LLC-Gen formulation by electroporation did not lead to a significant effect in terms of the serum concentrations of the protein S100B and serum neuron specific enolase (NSE), or the tissue expression of the platelet-derived growth factor receptor β (PDGFRβ) antibody.

Psoriasis is a T lymphocyte-mediated inflammatory disorder that affects the skin. A number of studies have demonstrated the occurrence of lipid alterations in psoriatic skin, resulting in a highly perturbed stratum corneum (SC). Relatively little attention has been paid to the protein conformation of the SC. In this study, the attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum of the untreated psoriatic patients' unharmed SC was obtained after tape stripping. We focused on the amide-I band components in order to establish whether there are any protein alterations in the intact areas of psoriatic skin. Fourier self-deconvolution (FSD) of the amide-I band was followed by curve-fitting to generate the underlying components. Integration of band areas provided an estimate of the secondary structure. The results indicated decreases in all amide-I band components, the peak at 1660 cm − 1 revealing the most dramatic change. This peak is characteristic of the turn structure in the protein chain. The decrease is marked in the case of the β-sheet structure at 1630 cm − 1 too. This ATR-FTIR imaging is a rapid and simple noninvasive method, promotes a better understanding of the disease, and would be helpful in following the treatment.

Mutagenic and teratogenic pyrrolizidine alkaloids (PAs) have been identified in several plant species. The industrially most important PA-containing plant is Symphytum officinale (common comfrey). The application of its root is restricted in several countries due to its PA content. In medicines, the daily alkaloid quantity and duration of treatment may be limited even in case of topical application. Due to the confirmed good absorption of PAs from the gastrointestinal tract, the prohibition of oral use is justified, however the limitation of external application is not supported by relevant data. Penetration experiments on human skin are not available to be a rational basis for limitation. The aim of our work was to carry out pharmacokinetic studies on the diffusion and penetration of lycopsamine (a main PA of comfrey) from a Symphytum product through a synthetic membrane and human skin. Investigations were carried out on vertical Franz diffusion cell and lycopsamine was quantified by a validated LC-MS method. The amount of lycopsamine diffused through a synthetic membrane varied between 0.11% and 0.72% (within 24 h). On human epidermis, the rate of penetration was lower (0.04–0.22%). Our results may contribute to the more realistic toxicological assessment of externally applied PA-containing products.

The remote sensing techniques provide a great possibility to analyze the environmental processes inlocal or global scale. Landsat images with their 30 m resolution are suitable among others for landcover mapping and change monitoring. In this study three spectral indices (NDVI, NDWI, MNDWI) wereinvestigated from the aspect of land cover types: water body (W); plough land (PL); forest (F); vineyard(V); grassland (GL) and built-up areas (BU) using Landsat-7 ETM+ data. The range, the dissimilaritiesand the correlation of spectral indices were examined. In BU – GL – F categories similar NDVI valueswere calculated, but the other land cover types differed significantly. The water related indices (NDWI,MNDWI) were more effective (especially the MNDWI) to enhance water features, but the values of othercategories ranged from narrower interval. Weak correlation were found among the indices due to thedifferences caused by the water land cover class. Statistically, most land cover types differed from eachother, but in several cases similarities can be found when delineating vegetation with various watercontent. MNDWI was found as the most effective in highlighting water bodies.

In. Fonetikai olvasókönyv. Egyetemi e-jegyzet. ed. Judit Bóna, ELTE Fonetikai Tanszék, Budapest, 2016.

The aim of the present work was the optimization of the transdermal delivery of a lyotropic liquid crystal genistein-based formulation (LLC-GEN). LLC was chosen as medium in view of the poor solubility of GEN in water. Membrane diffusion and penetration studies were carried out with a Franz diffusion cell, through a synthetic membrane in vitro, a chick chorioallantoic membrane ex ovo, and ex vivo excised human epidermis. Thereafter, LLC-GEN was combined with electroporation (EP) to enhance the transdermal drug delivery. The synergistic effect of EP was verified by in vivo ATR-FTIR and ex vivo Raman spectroscopy on hairless mouse skin.

We were investigating the predictive value of RMI and ROMA indices in patients with ovarian tumors of uncertain dignity, in order to determine whether these methods are suitable for the early detection of ovarian malignancy. Our study included 162 patients treated at the Gynecological Department of the National Institute of Oncology (Budapest, Hungary). These patients were diagnosed with ovarian tumor of uncertain dignity, and were admitted to our Department with the purpose of gynecological surgery. Each of them had CA-125, HE4 blood tests and ultrasound scan in order to calculate RMI and ROMA indices and to study their effectiveness. In every case, the final type of surgery was determined by intraoperative frozen section examination results. Efficacy of RMI and ROMA indices was detected by the final histological examination taken from the same material that was sent for intraoperative frozen section. The sensitivity and specificity of RMI index was 82.0% and 85.1%, respectively, while ROMA index sensitivity and specificity was 88.5% and 72.3%. The results were better in postmenopausal women: RMI sensitivity had increased to 90.9% and specificity to 82.8%. ROMA index sensitivity reached 95.5% with a specificity of 60.7%. Thus premenopausal RMI sensitivity significantly decreased (58.8%), and specificity had surged (88.4%). In case of premenopausal ROMA results sensitivity had declined, though the results are much better than for RMI (70.6% vs. 58.8%), while specificity was 14% less than that of RMI (74.4% vs. 88.4%). According to our study, RMI and ROMA indices are good methods for identifying the dignity of malignant ovarian tumors. The sensitivity and specificity results are in accordance with international literature. Even though the premenopausal and postmenopausal values are different, RMI and ROMA tests complement each other and are excellent for predicting the dignity of a tumor. With the help of these indices 61 cases of malignancy were detected, which means that we have to operate only 3 patients in order to detect 1 case of malignancy.Az RMI- és a ROMA-index predikciós értékét vizsgáltuk bizonytalan dignitású adnexképlettel rendelkezõ betegekben, annak meghatározása érdekében, hogy e vizsgáló módszerek alkalmazásával hogyan lehetne a petefészek-daganatok korai felismerését elõsegíteni. Tanulmányunkba az Országos Onkológiai Intézet Nõgyógyászati Osztályán kezelt 162 beteget vontunk be. A betegeknél klinikai vizsgálattal bizonytalan dignitású adnexképletet találtunk, és valamennyi betegnél mûtéti megoldást terveztünk. Annak érdekében, hogy az RMI- és a ROMA-teszt mûködését értékelni tudjuk, minden betegben az adnexképlet felfedezésével egyidejûleg, a kivizsgálás részeként CA-125- és HE4-meghatározást, valamint ultrahangos vizsgálatot is végeztünk. Vizsgáltuk a betegek menopauzális státuszát, és a kapott értékek alapján végeztük az RMI és a ROMA kiszámítását. A mûtét végleges típusát az intraoperatív fagyasztásos szövettani vizsgálat eredménye határozta meg. Az RMI és ROMA hatékonyságának vizsgálatához a mûtéti preparátumból készült végleges szövettani vizsgálatok eredményeit használtuk. A vizsgálati eredmények alapján az RMI teljes anyagra vonatkoztatott szenzitivitása 82,0%, specificitása 85,1% volt, míg a ROMA esetében ugyanezen értékek 88,5%-nak és 72,3%-nak bizonyultak. Posztmenopauzában jobb szenzitivitási értékeket találtunk, RMI: 90,9%, ROMA: 95,5%, mindkét esetben kismértékben csökkent specificitás mellett, RMI: 82,8%, ROMA: 60,7%. Premenopauzában az RMI szenzitivitása jelentõsen csökkent (58,8%), míg a specificitása nõtt (88,4%). A ROMA esetében premenopauzában a szenzitivitás csökkenése szintén megfigyelhetõ, de a kapott érték lényegesen magasabb, mint az RMI esetében (70,6% vs. 58,8%), a specificitás viszont 14%-kal lett alacsonyabb, mint amit az RMI esetében mértünk (74,4% vs. 88,4%). Anyagunkban az adnexképlet dignitásának megítélésére használt RMI és ROMA predikciós vizsgálatok jól teljesítettek. A kapott szenzitivitási és specificitási értékek jól megfeleltek a nemzetközi adatoknak. Bár a két módszer teljesítménye különbözik premenopauzában, illetve posztmenopauzában, együttes alkalmazásuk jól kiegészíti egymást. A vizsgálatba bevont betegeink között 61 malignus folyamatot sikerült azonosítani, ami azt jelenti, hogy csak 3 beteget kellett megoperálni ahhoz, hogy egy malignus folyamat felismerésre kerüljön. Javasoljuk az RMI és ROMA döntéstámogató pontozásos rendszerek széleskörû alkalmazását, egyben a feltételezett malignus adnexképlettel rendelkezõ betegek centrumba irányítását.

The aim of this study was to investigate the behavior of promising penetration enhancers through the use of 2 different skin test systems. Hydrogel-based transdermal formulations were developed with ibuprofen as a nonsteroidal anti-inflammatory drug. Transcutol and sucrose esters were used as biocompatible penetration enhancers. The permeability measurements were performed with ex vivo Franz diffusion cell methods and a newly developed Skin Parallel Artificial Membrane Permeability Assays (PAMPA) model. Franz diffusion measurement is commonly used as a research tool in studies of diffusion through synthetic membranes in vitro or penetration through ex vivo human skin, whereas Skin PAMPA involves recently published artificial membrane-based technology for the fast prediction of skin penetration. It is a 96-well plate-based model with optimized artificial membrane structure containing free fatty acid, cholesterol, and synthetic ceramide analog compounds to mimic the stratum corneum barrier function. Transdermal preparations containing 2.64% of different sucrose esters and/or Transcutol and a constant (5%) of ibuprofen were investigated to determine the effects of these penetration enhancers. The study demonstrated the good correlation of the permeability data obtained through use of human skin membrane and the in vitro Skin PAMPA system. The Skin PAMPA artificial membrane serves as quick and relatively deep tool in the early stages of transdermal delivery systems, through which the enhancing efficacy of excipients can be screened so as to facilitate the choice of effective penetration components.