Zagreb, Croatia
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Erceg M.,PLIVA Inc | Vertzoni M.,National and Kapodistrian University of Athens | Ceric H.,PLIVA Inc | Dumic M.,University of Rijeka | And 2 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2012

In this study, we evaluated the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM). DB, DM, and doxazosin hydrochloride (DH) were prepared and characterized. In vitro data were collected in various media, including human aspirates. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HCl pH 1.8. Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HCl pH 1.6 is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modeling procedures, the cumulative doxazosin profile in plasma was simulated and the 0-2 h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in pure aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure. Partial AUCs were used for evaluating early exposure after DB and DM administration in 4 dogs. Early exposure was significantly higher after administration of DM to dogs. Dogs are not appropriate for evaluating differences in early exposure after DB and DM administrations. © 2011 Elsevier B.V. All rights reserved.

Kwokal A.,PLIVA Inc | Cavuzic D.,PLIVA Inc | Roberts K.J.,University of Leeds
Crystal Growth and Design | Year: 2013

Crystallization of entacapone (E-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5- nitrophenyl) propenamide) in acetone solution at the 500 mL scale using a self-assembled layer of the host material on Au(111) as a seeding template was studied and monitored using attenuated total reflectance (ATR)-UV-vis spectroscopy and focused beam reflectance measurement (FBRM). The data reveal that the template promotes crystal growth at lower supersaturations and at an increased rate when compared to experiments carried out without the template. Crystals prepared using the template are also found to have superior properties compared to crystals produced without the template. Notably, use of the template produces crystals with a much narrower size distribution, greatly increased perfection and a more equant crystal morphology. These observations are consistent with the template providing a sympathetic surface for the promotion of crystallization through an analogous mechanism to that associated with conventional seeding, but with the added advantage of conferring a well-ordered, easily reproducible and more robust process. © 2013 American Chemical Society.

Kwokal A.,PLIVA Inc | Roberts K.J.,University of Leeds
CrystEngComm | Year: 2014

The ability to direct the surface crystallisation of different polymorphs of entacapone by tuning the electrochemical potential of Au(100) templates is demonstrated. Under quiescent conditions, without polarization (at open circuit potential), entacapone crystallises in its stable form A on the template surface and concomitantly in its metastable form D in the bulk solution. When Au(100) is negatively polarized (-150 mV), form D is still formed in the bulk solution but the metastable form α is found to crystallise at the edges of the template. Both crystals of form A and α were observed to grow epitaxially over the Au template surface. The electrochemical templating effect is consistent with the polarisation changing the structure of the initially adsorbed layers of supersaturated solution at the template surface which directs the nuclei formation and the subsequent crystal growth processes. This study demonstrates, for the first time, the direction of polymorphic form using a low field polarized nucleation template. © 2014 the Partner Organisations.

Orsolic N.,University of Zagreb | Car N.,PLIVA Inc
Tumor Biology | Year: 2014

Nephrotoxicity, hepatotoxicity, myelosuppression, and genotoxicity are the major limitation for the clinical use of cisplatin as an anti-tumoural drug. Hyperthermia enhances the clastogenicity of cisplatin. In addition, hyperthermia is a promising approach for cancer therapy because it not only kills cancer cells directly, but also activates anti-cancer immunity as an indirect effect. The aim of this study was to determine whether preventive treatment with quercetin (QU) can reduce cisplatin-induced DNA damage in liver, kidney and blood cells and whether QU has the potential to serve as a beneficial supplement before cisplatin hyperthermal intraperitoneal chemotherapy (HIPEC) in order to gain immunomodulatory responses of mice to the tumor. Preventive treatment of mice with QU (50 mg kg-1) had a protective effect on cisplatin-induced DNA damage in normal cells, except kidney cells, in both normothermic and hyperthermic conditions without interfering with the antitumor efficacy of the combined regimen. Immunostimulation by QU is stressed as an important factor in the tumor-inhibiting effect of hyperthermia in addition to the well known selective heat killing of neoplastic cells. In conclusion, these results suggested that preventive treatment with QU could protect the blood, liver and kidney cells of mice against HIPEC-induced injury and increase survival of mice by improving the antitumor adaptive immunity with hyperthermia. © 2014 International Society of Oncology and BioMarkers (ISOBM).

Milovac N.,University of Zagreb | Juretic D.,University of Zagreb | Kusic H.,University of Zagreb | Dermadi J.,PLIVA Inc | Bozic A.L.,University of Zagreb
Industrial and Engineering Chemistry Research | Year: 2014

The UV/H2O2 process was applied for the degradation of aromatic carboxylic acids (ACAs). Benzoic acid, salicylic acid, gentisic acid, and gallic acid are chosen as typical water pollutants representing ACAs with the increased number of hydroxyl groups. The effect of the structural characteristics of ACAs and UV/H2O2 process parameters on their degradation kinetics was investigated by a statistical/empirical approach employing the design of experiments and response surface methodology. Different optimal conditions for maximal degradation rates were established, while degradation rates followed the decreasing order benzoic acid > salicylic acid > gentisic acid > gallic acid with the increasing number of hydroxyl groups. The inversed order was established in the case of mineralization kinetics. Structurally influenced degradation pathways of studied ACAs, with the shared sequence related to the preferable hydroxylation position at the benzene ring, are reflected in the observed changes in the biodegradability and toxicity toward Vibrio fischeri during UV/H2O2 treatment. © 2014 American Chemical Society.

Racane L.,University of Zagreb | Mihalic Z.,University of Zagreb | Ceric H.,PLIVA Inc | Popovic J.,Ruder Boskovic Institute | Tralic-Kulenovic V.,University of Zagreb
Dyes and Pigments | Year: 2013

The efficient synthesis, 1H and 13C NMR characterization, crystal and molecular structure, DFT calculations of 6-[(2-hydroxy-1-naphthyl)diazenyl]-2-methylbenzothiazole, as well as DFT calculations of 6-[(2-hydroxy-1-naphthyl)diazenyl]benzothiazole, are reported. Single-crystal X-ray diffraction data show that crystals of the azo dye derived from 2-methylbenzothiazole is principally composed of the hydrazone form. 2D NMR techniques (COSY, HMQC and HMBC) were used to assign 1H and 13C chemical shifts for each azo dye in DMSO and CHCl3 solution. Azo-hydrazone tautomerism of the dyes was investigated jointly by 13C NMR and DFT calculations. All three approaches show that in solution the equilibrium is only slightly shifted towards the hydrazone form. The very good agreement between the three differently obtained equilibrium constants suggest M06-2X/6-311+G(d,p)-SMD as the level of theory of choice for quantum-mechanical calculations of these and similar compounds in solution. © 2012 Elsevier Ltd. All rights reserved.

Leksic E.,PLIVA Inc | Pavlovic G.,University of Zagreb | Mestrovic E.,PLIVA Inc
Crystal Growth and Design | Year: 2012

Four novel lamotrigine cocrystals, namely, 1:1 lamotrigine:phthalimide (1), 1:1:1 lamotrigine:pyromellitic diimide:DMF (2), 2:1:0.64 lamotrigine:caffeine: 3-pentanone (3), and 1:1 lamotrigine:isophthaldehyde (4), were discovered using a combined hot-stage thermomicroscopy and differential-scanning calorimetry screening technique. The utilized cocrystal screening method is rapid, requires the use of small amounts of material, and is highly suitable for compounds that are prone to solvate formation. The structurally characterized cocrystals were prepared in an attempt to develop lamotrigine cocrystals based on cocrystal formers involving carbonyl and amide functional groups. The prepared cocrystals are sustained by N-H(amide)•••N(pyridyl), N-H(amino) •••O(amide), and N-H(amino)•••O(carbonyl) hydrogen bonds. © 2012 American Chemical Society.

A new azithromycin-based series of antibacterial macrolones is reported, which features the use of a 4′-ester linked glycin for tethering the quinolone side chain to the macrolide scaffold. Among the analogs prepared, compounds 9e and 22f with a quinolon-6-yl moiety were found to have potent and well-balanced activity against clinically important respiratory tract pathogens, including erythromycin-susceptible and MLSB resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. In addition, potential lead compounds 9e and 22f demonstrated outstanding levels of activity against Moraxella catarrhalis and inducibly MLSB resistant Staphylococcus aureus. The best member of this series 22f rivals or exceeds, in potency, some of the most active ketolide antibacterial agents known today, such as telithromycin and cethromycin. © 2016 Elsevier Ltd. All rights reserved.

Pavlovic D.,PLIVA Inc | Pavlovic D.,Bar - Ilan University | Mutak S.,PLIVA Inc
ACS Medicinal Chemistry Letters | Year: 2011

A series of novel C-4″-substituted azithromycins was synthesized and evaluated for in vitro antibacterial activity against a panel of representative erythromycin-susceptible and macrolide-lincosamide-streptogramin (MLS) resistant pathogens. In summary, azithromycin and quinolone substructures merged in a mutually SAR-compatible design gave rise to a new class of antimicrobials with an improved spectrum and potency over azithromycin. Prototypical analogues 7f and 8f display an improved potency versus azithromycin against Gram-positive and fastidious Gram-negative pathogens. In particular, these new leads maintain activity against MLS-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. In addition, they represent an improvement over telithromycin (1) and cethromycin (2) against the fastidious Gram-negative pathogen Haemophilus influenzae. © 2011 American Chemical Society.

Pavlovic D.,PLIVA Inc | Mutak S.,PLIVA Inc
Journal of Medicinal Chemistry | Year: 2010

A series of novel 6-O-substituted 8a-aza-8a-homoerythromycin A ketolides was synthesized and evaluated for in vitro antibacterial activity. Key strategic elements of the synthesis include the base-induced E-Z isomerization of 3-O-descladinosyl-6-O-allylerythromycin A 9(E)-oxime followed by ring-expanding reaction of the resulting 9(Z)-oxime via Beckmann rearrangement. The ketolides showed potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLSB) resistant Gram-positive and fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display in vitro activity comparable to telithromycin and cethromycin. © 2010 American Chemical Society.

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