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Ilijas M.,Galapagos Research Center Ltd | Malnar I.,Galapagos Research Center Ltd | Malnar I.,Croatian Agency for Medicinal Products and Medical Devices | Gabelica Markovic V.,Galapagos Research Center Ltd | Stepanic V.,Ruder Boskovic Institute
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

Physicochemical properties provide reliable guidance in optimization of pharmacological efficiency and ADME profile of small chemical compounds. Their high-throughput determination is regularly based on application of HPLC techniques. In this study CHI and CHI IAM of 32 4-hydroxycoumarin analogs were measured by HPLC with methanol gradient at pHs 2.8 and 7.0. Results were analyzed by PCA in terms of computed descriptors in order to identify space for optimization of their phospholipids affinity and lipophilicity for which predictive software failed to produce reliable estimations. The chromatographic behavior of studied 4-hydroxycoumarins was typical of acidic compounds. The CHI2.8, CHI7.0, CHI IAM2.8 and CHI IAM7.0 values were all considerably cross-correlated in accordance with their prevailing lipophilic character. Structure-retention relationship (SRR) analysis furthermore revealed that H-bond accepting capacity and dipolar interactions with methanol generally shorten their retention times. However, deviations from the linear trends were noticed for R3/R5-substituted derivatives able to form intramolecular contacts with the 4-O(H) group and characterized by more uniform electron density at 2-O and 4-O atoms and quite different acidity/H-bond donating capacity than the rest of derivatives. Thus, CHI and CHI IAM determinations and SRR analysis are fast and efficiently pointed to ways of modifying biological activities of 4-hydroxycoumarins. © 2012 Elsevier B.V.


Brozovic A.,Ruder Boskovic Institute | Vukovic L.,Ruder Boskovic Institute | Polancac D.S.,Galapagos Research Center Ltd. | Arany I.,University of Mississippi Medical Center | And 6 more authors.
PLoS ONE | Year: 2013

The major obstacle of successful tumor treatment with carboplatin (CBP) is the development of drug resistance. In the present study, we found that following treatment with CBP the amount of platinum which enters the human laryngeal carcinoma (HEp2)-derived CBP-resistant (7T) cells is reduced relative to the parental HEp2. As a consequence, the formation of reactive oxidative species (ROS) is reduced, the induction of endoplasmic reticulum (ER) stress is diminished, the amount of inter- and intrastrand cross-links is lower, and the induction of apoptosis is depressed. In HEp2 cells, ROS scavenger tempol, inhibitor of ER stress salubrinal, as well as gene silencing of ER stress marker CCAAT/enhancer-binding protein (CHOP) increases their survival and renders them as resistant to CBP as 7T cell subline but did not influence the survival of 7T cells. Our results suggest that in HEp2 cells CBP-induced ROS is a stimulus for ER stress. To the contrary, despite the ability of CBP to induce formation of ROS and activate ER stress in 7T cells, the cell death mechanism in 7T cells is independent of ROS induction and activation of ER stress. The novel signaling pathway of CBP-driven toxicity that was found in the HEp2 cell line, i.e. increased ROS formation and induction of ER stress, may be predictive for therapeutic response of epithelial cancer cells to CBP-based therapy. © 2013 Brozovic et al.


Kosol S.,University of Graz | Schrank E.,University of Graz | Krajacic M.B.,Galapagos Research Center Ltd. | Wagner G.E.,University of Graz | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2012

Interactions of macrolide antibiotics with biological membranes contribute to their bioavailability but are also involved in the formation of phospholipidosis, which is caused by the inhibition of phospholipase A 1 activity. We determined the interaction strength and localization of macrolide antibiotics with membrane-mimetics. Macrolides bind to membrane-mimetics with the positively charged amino groups being close to the micelle surface and thereby protect the lipids from being degraded by phospholipase A 1 rather than inhibiting the enzyme. © 2012 American Chemical Society.


Dumitrescu T.P.,University of North Carolina at Chapel Hill | Dumitrescu T.P.,Research Triangle Park | Anic-Milic T.,Research Center Zagreb Ltd. | Anic-Milic T.,Galapagos Research Center Ltd. | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ~2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and C b, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.). Copyright © 2013, American Society for Microbiology.


Ljubas D.,University of Zagreb | Curkovic L.,University of Zagreb | Marinovic V.,Forensic Science Center Ivan Vucetic | Bacic I.,Forensic Science Center Ivan Vucetic | Tavcar B.,Galapagos Research Center Ltd.
Reaction Kinetics, Mechanisms and Catalysis | Year: 2015

Two nanostructured sol–gel TiO2 films were prepared on a glass substrate by means of the dip-coating technique with titanium (IV) isopropoxide as a precursor with and without the addition of polyethylene glycol (PEG) as a structure-directing agent. The synthesized films were characterized by using thermal gravimetry, differential scanning calorimetry, micro-Raman spectroscopy, and atomic force microscopy (AFM). Results of the AFM analysis revealed that both films are nanostructured and that the TiO2 film prepared with the addition of PEG has higher values of roughness. The photocatalytic activity of the films was evaluated by the photocatalytic degradation of the methyl orange monoazo dye and the congo red diazo dye with predominant radiation wavelengths of 365 nm (UV-A) and 254 nm (UV-C). The effects of temperature (17.5, 25 and 35 °C) on the film stability and on the degradation process were also followed. The TiO2 film created with the addition of PEG showed heightened photoactivity at all reaction temperatures and higher degradation rates of both dyes were observed with the UV-C than with the UV-A radiation. In some cases, the total decolorization process was complete in 90 or 120 min, but the total mineralization of the dye solutions was not achieved after 120 min. The TiO2 films were stable at all three temperatures after more than 50 working hours. The degradation processes of dyes were monitored by means of the UV/VIS spectrophotometry and the liquid chromatography mass spectrometry together with the total organic carbon. © 2015 Akadémiai Kiadó, Budapest, Hungary


Gregorek A.C.,University of Zagreb | Gornik K.C.,University of Zagreb | Polancec D.S.,Galapagos Research Center Ltd. | Dabelic S.,University of Zagreb
Biochemical Genetics | Year: 2013

Abdominal aortic aneurysm (AAA) is a complex genetic disorder caused by the interplay of genetic and environmental risk factors. The number of (GT) n repeats in the heme oxygenase-1 (HO-1) gene promoter modulates transcription of this enzyme, which might have anti-inflammatory, antioxidant, antiapoptotic, and antiproliferative effect. The distribution of alleles and genotypes in Croatian individuals genotyped for the (GT) n HO-1 polymorphism was similar to that in other European populations. Frequency of the short (S) alleles (GT < 25) was higher in AAA patients (41.9%) than in non-AAA individuals (28.2%, p = 0.0026) because there were more SL heterozygotes among the AAA patients. The SL genotype appeared to increase the risk for AAA, but the increase was not statistically significant after adjustment for age, sex, smoking, hypertension, and hyperlipidemia (OR = 1.53, 95% CI 0.90-3.09, p = 0.062). These findings contradict those of the only other study performed so far on the association of (GT) n HO-1 polymorphism and AAA. © 2013 Springer Science+Business Media New York.


Litvic M.,BELUPO Pharmaceuticals Inc. | Regovic M.,BELUPO Pharmaceuticals Inc. | Smic K.,BELUPO Pharmaceuticals Inc. | Lovric M.,BELUPO Pharmaceuticals Inc. | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Mo(VI) and Mo(V) salts both react selectively with Hantzsch esters to produce substitute pyridines in good-to-excellent yield (75-99%). The remarkable reactivity and selectivity of MoOCl4 under reflux of acetonitrile and MoCl5 in dichloromethane at room temperature encouraged us to propose that molybdenum-containing enzymes (such as xanthine or aldehyde oxidase) also participate to some degree in the metabolism of 1,4-dihydropyridine drugs in the liver analogous to NADH in the respiratory chain. © 2012 Elsevier Ltd. All rights reserved.


Markic J.,University of Split | Jeroncic A.,University of Split | Polancec D.,Galapagos Research Center Ltd. | Bosnjak N.,University of Split | And 3 more authors.
European Journal of Pediatrics | Year: 2013

Early recognition of serious bacterial infection (SBI) in children is essential for better treatment outcome. Flow cytometry analysis of neutrophil surface molecules has been more frequently utilized as a tool for diagnosis of infection. The infants (n = 105) under 6 months of age presenting to the pediatric emergency department with fever without apparent source who were hospitalized with suspicion of having SBI were enrolled in this prospective study. Sixty-nine infants were included into the training pool and were classified into bacterial or viral infection group. Validation pool consisted of 36 infants. The values of white blood cells counts, absolute neutrophil count (ANC), C-reactive protein (CRP), procalcitonin (PCT), neutrophil CD11b, CD15s and CD64 expression, and the percentage (%CD15s+) and absolute count (AC-CD15s+) of CD15s+ neutrophils were determined. In infants with SBI, %CD15s+ was 10.5 times more likely to be higher than the cut-off value. ANC, CRP, PCT, CD64, and AC-CD15s+ were also found as useful biomarkers for differentiation between bacterial and viral infection. The best fit multivariate logistic regression model included CRP, PCT, and %CD15s+ as strong predictors of SBI. The model's sensitivity (87 %) and specificity (83 %) indicated high model's accuracy. After validation on independent dataset, model's accuracy maintained high: 86 % sensitivity and 93 % specificity, confirming its reliability and supporting CRP, PCT, and %CD15s+ as real predictors. The findings of this study support assumption made in the literature on significance of CD15s in inflammation processes. Also, this study demonstrated for the first time that CD15s is potentially valuable biomarker of SBI in infants. © 2013 Springer-Verlag Berlin Heidelberg.


Ivetic Tkalcevic V.,Galapagos Research Center Ltd. | Hrvacic B.,Galapagos Research Center Ltd. | Bosnar M.,Galapagos Research Center Ltd. | Cuzic S.,Galapagos Research Center Ltd. | And 3 more authors.
Translational Research | Year: 2012

The murine model of cantharidin-induced ear inflammation was profiled in detail for its alignment with the human model and to explore the mechanism of anti-inflammatory activity of the macrolide antibiotics, clarithromycin and azithromycin. Ear swelling in CD1 mice persisted for 7 days, with peak intensity at 16 h after inflammation induction. As in humans, cantharidin (12.5 μg/ear) generated macrophage-inflammatory protein (MIP)-2, monocyte chemoattractant protein (MCP)-1, keratinocyte-derived chemokine (KC), interleukin (IL)-6, IL-1β, and myeloperoxidase (MPO) production, as well as neutrophil accumulation in mouse ear tissue. The tested macrolides, clarithromycin and azithromycin, administered orally (2 × 150 mg/kg) 0.5 h before and 5 h after cantharidin challenge, reduced MIP-2, MCP-1, KC, and MPO concentrations and thereby decreased ear swelling. Our results suggest that cantharidin-induced acute inflammation represents an excellent model for translational research of novel anti-inflammatories. © 2012 Mosby, Inc. All rights reserved.


Gabelica Markovic V.,Galapagos Research Center Ltd. | Mesic M.,Galapagos Research Center Ltd. | Alihodzic S.,Galapagos Research Center Ltd. | Kovacevic K.,Galapagos Research Center Ltd.
Kemija u industriji/Journal of Chemists and Chemical Engineers | Year: 2011

Galapagos Research Centre d. o. o., is a private research organization, active in the field of chemistry, biology, biomedicine, veterinary science and pharmacy. This article is devoted to the International Year of Chemistry; this review includes the areas of study undertaken by the chemists in the research centre. Also presented are the current techniques and technologies applied in the implementation of research and development projects. The main activities of chemists are directed to the synthesis of new organic compounds resulting in potentially new medicines, their subsequent identification, structural characterization, purification process, magnification (scale up), the applied analysis of biological materials (DMPK - Drug Metabolism and Pharmacokinetics) and the pharmaceutical development of preclinical candidates. Project teams at Galapagos incorporate researchers of all relevant professions to explore the potential of new medicines. These include chemists (chemical engineers and technologists), biologists, medical doctors, veterinarians and pharmacists. The ultimate goal of each of the projects is to establish an effective, well-defined preclinical candidate, which is further developed in other parts of the organization (Belgium, France, Great Britain), otherwise in the development laboratories of large partner organizations. This research article includes research and technology supported by concrete examples, and the results published in previous articles.

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