Agency for Medicinal Products and Medical Devices

Zagreb, Croatia

Agency for Medicinal Products and Medical Devices

Zagreb, Croatia
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Luterotti S.,University of Zagreb | Kordic T.V.,Agency for Medicinal Products and Medical Devices | Dodig S.,Srebrnjak Childrens Hospital
Acta Pharmaceutica | Year: 2015

In an attempt to provide a reliable status of metal ions in children, new methods of analysis of children's sera are proposed. New flame atomic-absorption spectrometric (FAAS) methods are simple, cost-and time-effective and, above all, labor-, reagent-and sample-saving. Two methods were suggested: method A for simultaneous determination of Cu and Zn from 5-fold diluted sera, and method B, for assaying zinc alone in 10-fold diluted samples. Both methods are based on a single-step sample pretreatment (deproteinization with 3 mol dm-3 HCl). Method A uses a single-step calibration with a mixed standard. The main advantage of method B is an additional reduction in sample consumption. Both methods were fully validated against reference methods. Accuracy, sensitivity and precision have proven them to be comparable to the reference methods in terms of analytical performance, and applicable to analyses of children's sera. © 2015 Svjetlana Luterotti et al.


Luterotti S.,University of Zagreb | Kordic T.V.,Agency for Medicinal Products and Medical Devices | Letoja I.Z.,Srebrnjak Childrens Hospital | Dodig S.,Srebrnjak Childrens Hospital
Acta Pharmaceutica | Year: 2015

Newly introduced methods of assaying simultaneously copper and zinc and zinc alone in serum by flame atomic-absorption spectrometry are simple and economical, especially in saving the consumption of serum material. Along with biochemical parameters, they have been successfully applied to diagnostics/prognostics of tuberculosis in children, through analyses of sera from pediatric patients with lung tuberculosis or suspected tuberculosis, enabling the follow-up of therapeutic efficiency. The prognostic strength of Cu and Cu/Zn ratio together with C-reactive protein, complement components C3 and C4, and erythrocyte sedimentation rate have been documented. © 2015 Svjetlana Luterotti et al.


Tomic S.,Agency for Medicinal Products and Medical Devices | Sucic A.F.,Agency for Medicinal Products and Medical Devices | Martinac A.I.,Agency for Medicinal Products and Medical Devices
Regulatory Toxicology and Pharmacology | Year: 2010

European legislation for medicines places the emphasis on an assessment of quality, safety and efficacy during the procedure for the granting of marketing authorisations for medicines, in order to protect patient health. The integrated European regulatory system involves the participation of a network of experts from the agencies of the member states that takes part in the European procedures for the authorisation of medicines. On the way to full membership in the EU, candidate countries and potential candidates have to transpose and implement the European directives for medicinal products; they must also strengthen their scientific and administrative capacities. Croatia acquired good experience in implementing the simplified marketing authorisation procedure for medicines authorised in the EU pursuant to the New Collaboration Agreement between Drug Regulatory Authorities in Central and East European Countries (nCADREAC), which helps it to exchange information and prepare for the implementation of European procedures. However, there are still some provisions to transpose before actual full membership, and also dossier upgrading, in which the marketing authorisation holder has to harmonise its documentation about a medicinal product with the requirements of the directives, if a product already on the market was not previously approved in line with current European legislation. Collaboration with the European Medicines Agency (EMA) through an Instrument for Pre-Accession (IPA) provides candidate countries and potential candidates the opportunity for education and training in some regulatory activities as well as the participation of their representatives as observers in some EMA committees and working groups. Some characteristics of the national regulatory frameworks of the countries of South East Europe in their efforts to achieve harmonisation with EU legislation are presented in this paper. © 2010 Elsevier Inc.


Mirosevic Skvrce N.,Agency for Medicinal Products and Medical Devices | Bozina N.,University of Zagreb | Zibar L.,Clinical Hospital Osijek | Barisic I.,University of Zagreb | And 2 more authors.
Pharmacogenomics | Year: 2013

Aim: To investigate whether an association exists between fluvastatin-induced adverse drug reactions (ADRs) and polymorphisms in genes encoding the metabolizing enzyme CYP2C9 and the drug transporter ABCG2 in renal transplant recipients (RTRs). Materials & methods: Fifty-two RTRs that experienced fluvastatin ADRs and 52 controls matched for age, gender, dose of fluvastatin and immunosuppressive use were enrolled in the study. Genotyping for CYP2C9*2, *3 and ABCG2 421C>A variants was performed by real-time PCR. Results: CYP2C9 homozygous and heterozygous mutant allele (*2 or *3) carriers had 2.5-times greater odds of developing adverse effects (χ2 = 4.370; degrees of freedom = 1; p = 0.037; φ = 0.21, odds ratio [OR]: 2.44; 95% CI: 1.05-5.71). Patients who were the carriers of at least one mutant CYP2C9 allele (*2 or *3) and who were receiving CYP2C9 inhibitors, had more than six-times greater odds of having adverse effects than those without the inhibitor included in their therapy (p = 0.027; OR: 6.59; 95% CI: 1.24-35.08). Patients with ABCG2 421CA or AA (taken together) had almost four-times greater odds of developing adverse effects than those with ABCG2 421CC genotype (χ2 = 6.190; degrees of freedom = 1; p = 0.013; φ = 0.24, OR: 3.81; 95% CI: 1.27-11.45). Patients with A allele had 2.75-times (95% CI: 1.02-7.40) greater odds of developing adverse effects than those with C allele. Conclusion: Our preliminary data demonstrate an association between fluvastatin-induced ADRs in RTRs and genetic variants in the CYP2C9 and ABCG2 genes. Original submitted 25 February 2013; Revision submitted 15 July 201. © 2013 Future Medicine Ltd.


Hafner A.,University of Zagreb | Lovric J.,University of Zagreb | Lako G.P.,Agency for Medicinal Products and Medical Devices | Pepic I.,University of Zagreb
International Journal of Nanomedicine | Year: 2014

The application of nanotechnology in areas of drug delivery and therapy (ie, nanotherapeutics) is envisioned to have a great impact on public health. The ability of nanotherapeutics to provide targeted drug delivery, improve drug solubility, extend drug half- life, improve a drug's therapeutic index, and reduce a drug's immunogenicity has resulted in the potential to revolutionize the treatment of many diseases. In this paper, we review the liposome-, nanocrystal-virosome polymer therapeutic-, nanoemulsion-, and nanoparticle- based approaches to nanotherapeutics, which represent the most successful and commercialized categories within the field of nanomedicine. We discuss the regulatory pathway and initiatives endeavoring to ensure the safe and timely clinical translation of emerging nanotherapeutics and realization of health care benefits. Emerging trends are expected to confirm that this nano-concept can exert a macro-impact on patient benefits, treatment options, and the EU economy. © 2014 Hafner et al.


Plazonic A.,Agency for Medicinal Products and Medical Devices | Males Z.,University of Zagreb | Mornar A.,University of Zagreb | Nigovic B.,University of Zagreb | Kujundzic N.,University of Zagreb
Chemistry of Natural Compounds | Year: 2011

The water extract of burr parsley (Caucalis platycarpos L.) showed remarkable antitumor activity in rats and mice. Phenolic compounds, including phenolic acids and flavonoids, are considered to be the major bioactive compounds. The aim of this work was to develop a reverse phase HPLC-DAD method for the simultaneous quantification of flavonoid aglycones and phenolic acids, and an HPLC-DAD-MS/MS method for structural characterization of phenolic compounds, obtained after hydrolysis of C. platycarpos methanolic extract. Caffeic acid was the predominant phenolic acid, and luteolin was the predominant flavonoid aglycone. The optimized and validated method for the determination of the five phenolic acids and four flavonoid aglycones ensured reliable results and could be used for the quality control of raw plant material. © 2011 Springer Science+Business Media, Inc.


Benkovic G.,Agency for Medicinal Products and Medical Devices | Skrlin A.,University of Zagreb | Madic T.,PLIVA Inc | Debeljak Z.,University of Zagreb | Medic-Saric M.,University of Zagreb
Electrophoresis | Year: 2014

Current methods for determination of impurities with different charge-to-volume ratio are limited especially in terms of sensitivity and precision. The main goal of this research was to establish a quantitative method for determination of impurities with charges differing from that of recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim) with superior precision and sensitivity compared to existing methods. A CZE method has been developed, optimized, and validated for a purity assessment of filgrastim in liquid pharmaceutical formulations. Optimal separation of filgrastim from the related impurities with different charges was achieved on a 50 μm id fused-silica capillary of a total length of 80.5 cm. A BGE that contains 100 mM phosphoric acid adjusted to pH 7.0 with triethanolamine was used. The applied voltage was 20 kV while the temperature was maintained at 25°C. UV detection was set to 200 nm. Method was validated in terms of selectivity/specificity, linearity, precision, LOD, LOQ, stability, and robustness. Linearity was observed in the concentration range of 6-600 μg/mL and the LOQ was determined to be 0.3% relative to the concentration of filgrastim of 0.6 mg/mL. Other validation parameters were also found to be acceptable; thus the method was successfully applied for a quantitative purity assessment of filgrastim in a finished drug product. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Vucic K.,Agency for Medicinal Products and Medical Devices | Jelicic Kadic A.,University of Split | Puljak L.,University of Split
Journal of Clinical Epidemiology | Year: 2015

Objectives To analyze whether protocols of Cochrane systematic reviews address data extraction from figures in included trials. Study Design and Setting Protocols of Cochrane systematic reviews published between May 2013 and May 2014 were screened by two authors independently, and the following data were collected: date of protocol publication, country of authors' origin, number of authors, number of affiliated institutions, Cochrane review group, whether the protocol contains description about data extraction from figures, method of data extraction from figures, and literature reference for a method of data extraction from figures. Results Among 589 protocols, 33 (5.6%) mentioned data extraction from figures in Methods section. Only one protocol specified that computer software will be used for data extraction from figures, one specifically indicated that data from figures will not be used, few stated estimation or approximation, whereas others did not provide any description of methodology for data extraction from figures. Conclusion Very few protocols of Cochrane systematic reviews mention data extraction from figures, and even when mentioned, methods for data extraction are unclear. Methodology for data extraction from figures should be incorporated into the Cochrane Handbook and new methodological standards for Cochrane systematic reviews. © 2015 Elsevier Inc. All rights reserved.


Jelicic Kadic A.,University of Split | Vucic K.,Agency for Medicinal Products and Medical Devices | Dosenovic S.,University of Split | Sapunar D.,University of Split | Puljak L.,University of Split
Journal of Clinical Epidemiology | Year: 2016

Objectives To compare speed and accuracy of graphical data extraction using manual estimation and open source software. Study Design and Setting Data points from eligible graphs/figures published in randomized controlled trials (RCTs) from 2009 to 2014 were extracted by two authors independently, both by manual estimation and with the Plot Digitizer, open source software. Corresponding authors of each RCT were contacted up to four times via e-mail to obtain exact numbers that were used to create graphs. Accuracy of each method was compared against the source data from which the original graphs were produced. Results Software data extraction was significantly faster, reducing time for extraction for 47%. Percent agreement between the two raters was 51% for manual and 53.5% for software data extraction. Percent agreement between the raters and original data was 66% vs. 75% for the first rater and 69% vs. 73% for the second rater, for manual and software extraction, respectively. Conclusions Data extraction from figures should be conducted using software, whereas manual estimation should be avoided. Using software for data extraction of data presented only in figures is faster and enables higher interrater reliability. © 2016 Elsevier Inc. All rights reserved.


Mirosevic Skvrce N.,Agency for Medicinal Products and Medical Devices
Croatian medical journal | Year: 2011

To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence. In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them. HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n=4) was significantly higher (P<0.001) than among the remaining reports (580 out of 1982; n=2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter. The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education.

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