Agency for Medicinal Products and Medical Devices

Zagreb, Croatia

Agency for Medicinal Products and Medical Devices

Zagreb, Croatia

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Orsolic N.,University of Zagreb | Bevanda M.,Clinical Hospital Mostar | Kujundi N.,University of Zagreb | Plazonic A.,Agency for Medicinal Products and Medical Devices | And 2 more authors.
Planta Medica | Year: 2010

The presence of peritoneal carcinomatosis arising from gastrointestinal and gynecologic tumors is associated with a poor prognosis. Animal models of peritoneal carcinomatosis are important in the evaluation of new treatment modalities. The purpose of this study was to investigate the effect of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in an animal model of induced peritoneal carcinomatosis in the mouse. For induction of peritoneal carcinomatosis, cells from transplantable mammary carcinoma (MCa) were implanted intraperitoneally in CBA mice. Seven or 3 days before implantation of MCa cells (5×103) the mice were injected with lyophilized water extract from Caucalis platycarpos L. (CPL; 200mgkg 1) into the abdominal cavity. Immediately after implantation of MCa cells in the abdominal cavity, mice were treated two times with 2mL of saline that was heated either at 37°C or 43°C (hyperthermal treatment) and cytostatics (doxorubicin 20mgkg1, cisplatin 10mgkg1, mitomycin 5mgkg1, 5-FU 150mgkg1). We followed the survival of animals and the side effects appearing with different forms of treatment. CPL increased the life span of mice with peritoneal carcinomatosis without hyperthermal treatment (ILS%=32.55%) but showed no effect on the life span of mice with hyperthermal treatment (ILS%=1.44). Combined treatment with CPL and cytostatics (CIS, DOX, and MIT) significantly affected the development of peritoneal carcinomatosis and increased the survival of mice (ILS% 37°C=144.17, 415.46, and 124.13, ILS% 43°C=311.42, 200.74, and 138.33, respectively). However, intraperitoneal chemotherapy with 5-FU alone resulted in greater survival time of mice than the treatment with 5-FU + CPL. Results suggest the synergistic effect of hyperthermia, chemotherapy, and immunotherapy. CPL significantly increases the antitumor activity of the hyperthermic chemotherapy and the survival rate of mice with peritoneal carcinomatosis. The stimulative effect of CPL on immunomodulation may be a possible mechanism which protects mice from developing peritoneal carcinomatosis and reduces the side effects of chemotherapy, increasing the life span of mice. © Georg Thieme Verlag KG Stuttgart · New York.


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.


PubMed | University of Zagreb and Agency for Medicinal Products and Medical Devices
Type: Journal Article | Journal: Archives of medical research | Year: 2015

Patients with certain types of stroke need urgent anticoagulation and it is extremely important for them to achieve fast and stable anticoagulant effect and receive individualized treatment during the initiation of warfarin therapy.We conducted a prospective study among 210 acute stroke patients who had an indication for anticoagulation and compared the impact of CYP2C9 and VKORC1 genotype-guided warfarin dosing (PhG) with fixed dosing (NPhG) on anticoagulation control and clinical outcome between groups.PhG achieved target INR values earlier, i.e., on average in 4.2 (4.1-4.7, 95% CI) days compared to NPhG (5.2 days [4.7-6.4, 95% CI]) (p = 0.0009), spent a higher percentage of time in the therapeutic INR range (76.3% [74.7-78.5, 95% CI] vs. 67.1% [64.5-69.6, 95% CI] in NPhG), and spent less time overdosed (INR > 3.1) (PhG 0.4 [0.1-0.7, 95% CI], NPhG 1.7 [1.1-2.3, 95% CI] days; p >0.000). PhG reached stable maintenance dose faster (10 [9.9-10.7, 95% CI] vs. 13.9 [13.3-14.7, 95% CI] days in controls; p = 0.0049) and had a better clinical outcome in relation to neurological deficit on admission as compared to NPhG.We confirmed that warfarin therapy with genotype-guided dosing instead of fixed dosing reduces the time required for stabilization and improves anticoagulant control with better clinical outcome in early stages of warfarin therapy introduction among acute stroke patients, which is essential for clinical practice.


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.


PubMed | University of Split and Agency for Medicinal Products and Medical Devices
Type: | Journal: Therapeutics and clinical risk management | Year: 2015

The increased consumption of analgesics has been documented worldwide during the last 2 decades. The aim of the study was to examine the trends in opioid and nonopioid analgesic consumption in Croatia between 2007 and 2013.Data on opioid consumption were extracted from the database of the national authority. All opioid and nonopioid analgesics were included in the analysis. Data were presented as defined daily doses per 1,000 inhabitants per day. Adequacy of opioid consumption was calculated using adequacy of consumption measure.During the examined 7-year period, the total consumption and total cost of all analgesics in Croatia showed continuous increase. In the M01A group (anti-inflammatory and antirheumatic products, nonsteroids), ibuprofen had an exponential increasing trend, and in 2011, it overtook diclofenac consumption. Ibuprofen and diclofenac had the highest consumption also in the M02A group of topical products for joint and muscular pain. Tramadol was by far the most consumed type of opioids (N02A group) and paracetamol in the group of other analgesics and antipyretics (N02B). The adequacy of consumption measure value was 0.19, indicating that Croatia is a country with a low opioid consumption.Between 2007 and 2013, both consumption of analgesics and their cost in Croatia had an increasing trend. Comparisons with data from other countries, based on the published literature, indicate that analgesic consumption in Croatia is still relatively low. Calculation of the adequacy of opioid consumption indicated that Croatia is a country with low opioid consumption. Further studies are necessary for establishing whether current analgesic consumption in Croatia corresponds to patient needs.


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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