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Portale naukowe

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Laboratorium

PRACA NAUKOWA
SCIENCE

Obecnie moja praca naukowa w Instytucie Nauk Medycznych Uniwersytetu Rzeszowskiego oraz zainteresowania naukowe koncentrują się na problemach praktycznych (zastosowanie na potrzeby przemysłu) w zakresie toksykologii regulacyjnej, w szczególności:

  • toksykologiczna ocena ryzyka zdrowotnego zanieczyszczeń metalicznych w lekach oraz produktach specjalnego przeznaczenia medycznego na potrzeby farmakoterapii żywieniowej;

  • procedury i strategie wyznaczania wartości współczynnika PDE na potrzeby przemysłu farmaceutycznego;

  • ocena bezpieczeństwa (safety assessment) oraz toksykologiczna ocena ryzyka (TRA, toxicological risk assessment) produktów konsumenckich (leków, produktów kosmetycznych, suplementów diety, produktów żywnościowych, wyrobów medycznych):

    • koncepcje TTC oraz iTTC;

    • problematyka ilościowej ekstrapolacji w TRA w odniesieniu do: 

      • QIVIVE (Quantitative In Vitro to In Vivo Extrapolation), 

      • ISIVIVE (In Silico In Vitro In Vivo Extrapolation) / in vivitrosi (in vivo, in vitro and in silico).

    • NGRA (next generation risk assessment) - ocena ryzyka następnej/nowej generacji jako zmiana paradygmatu klasycznej toksykologicznej oceny ryzyka;

    • zastosowanie nowych podejść metodologicznych NAM (New Approach Methodologies) do rozwiązywania złożonych toksykologicznych punktów końcowych w odniesieniu do:

      • IATA (Integrated Approaches for Testing and Assessment, tj. zintegrowanych podejść do badania i oceny);

      • ITS (Integrated Testing Strategies, tj. zintegrowanych strategii badania);

      • DA (Defined Approaches, tj. zdefiniowane podejścia).

    • toksykologiczna ocena ryzyka (TRA) uwzględniająca:

      • specyficzne punkty końcowe (endpoints);

      • MoA (Mode of Action, sposoby działania);

      • PoT (Pathways of Toxicity, ścieżki toksyczności);

      • AOP (Adverse Outcome Pathway, ścieżki niekorzystnych skutków);

    • zastosowanie modeli toksykokinetycznych bazujących na fizjologii (physiologically-based toxicokinetic, PBTK) w NGRA

    • organ-on-chip na potrzeby toksykologii regulacyjnej.

Współpraca naukowa

Pracownia Biopierwiastków
kierownik: dr hab. Mirosław Krośniak
Wydział Farmaceutyczny

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Wybrane publikacje

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Toxics, 2022, 10(4), 188; 
https://doi.org/10.3390/toxics10040188

K. Jurowski, M. Krosniak

The level of potentially toxic elements (PTE) in phyto-pharmaceuticals can be a potential threat to human health through the food chain. The traditional herbal medicinal products (THMPs) with the marshmallow root (Althaea officinalis L., radix), which we can find in European pharmacies, are widely used among the European population. However, recently, voices have been heard in the public about alleged PTE occurrence. In this article, the levels of Pb and Cd impurities were measured in samples of THMPs with marshmallow root available in Polish pharmacies (n = 10). Our proposed toxicological approach was based on two important issues. The first was PTE levels (Pb: 1.60–6.80 μg/L and Cd: 0.80–3.81 μg/L presented as raw results) in comparison with the permissible limit set by FAO/WHO for medicinal herbs (10,000 µg/kg for Pb and 300 µg/kg for Cd) and also ICH Q3D guidelines (0.5 μg/g for Pb and also Cd). The second was the estimation of exposure of investigated PTE in a single dose and daily dose for each THMP. It should be noted that the content of analyzed heavy metals in a single dose of analyzed products was very low, and hence is not a threat for patients. The obtained daily intake of heavy metals impurities in comparison with PDE values confirms the safety of all analyzed phytopharmaceuticals (all of the samples meet the standards of the ICH Q3D guideline). It can be summarized that each of the analyzed THMP with marshmallow root available in Poland are safe for the patients. Based on literature review, this article is the first study about heavy metals impurities level in final THMPs with A. officinalis L., radix (marshmallow root) available in European pharmacies

Kamil Jurowski, Maria Fołta, Barbara Tatar, Mehmet Berkoz, Mirosław Krośniak 

Essential elements like Cu, Mn and Zn are extremely important for herbs’ growth and physiological functions; however, from a toxicological point of view, the exposure of these elements (as essential elemental impurities) can exhibit potential harmful effects for patients. In Europe, very popular are ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products for adjunctively in rhinitis (runny nose). Based on posology of ointments with Marjoram herb extract, the exposure to these elemental impurities may be high during long-term use. Hence, the aim of this article is the health risk assessment of essential elemental impurities (Cu, Mn and Zn) through the dermal exposure of ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products applied adjunctively in rhinitis available in Polish pharmacies. The investigated essential elements were determined by well-validated methodology (R > 0.997, recoveries, LOD and LOQ values were acceptable) based on flame atomic absorption spectrometry (FAAS). Our results indicated that all analysed herbal medicinal products with Marjoram herb extract available in Polish pharmacies contain relatively low levels of essential element impurities, i.e. Cu (0.14–0.49 mg/kg), Mn (0.31–2.57 mg/kg) and Zn (0.73–3.19 mg/kg). The estimated exposure of the investigated elemental impurities confirms the safety of all products. To the best of our knowledge, the study about Cu, Mn and Zn contents in HMPs with Majoranae herbae extractum is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view due to ICH Q3D elemental impurity guideline for pharmaceuticals.

Figure 1. — kopia.tif

Biological Trace Element, 2022, 200: 1981–1987;
https://doi.org/10.1007/s12011-021-02842-8

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Biological Trace Element, 2022, 200:1965-1971
https://doi.org/10.1007/s12011-021-02798-9

Kamil Jurowski, Maria Fołta, Barbara Tatar, Mehmet Berkoz, Mirosław Krośniak 

For elemental impurities that have been studied for transcutaneous absorption, the available data are rarely suitable for proper toxicological risk assessment — there are multiple factors that can influence this dermal absorption. Hence, in our studies, we applied generic and conservative approach — cutaneous permitted daily exposure (CPDE) described in International Conference on Harmonisation’s Q3D Guideline on Elemental Impurities (ICH Q3D). The aim of this article is toxicological risk assessment (TRA) of dermal exposure of patients exposed to nickel and chromium due to application of ointments with Marjoram herb extract (Majoranae herbae extractum) available in Polish pharmacies (n = 5, because only five manufacturers produce this kind of pharmaceutical products in Poland). To make the appropriate TRA approach, we considered (1) raw results (metal per kg of ointment), (2) one-time administration of applied ointments, and (3) daily exposure versus CPDE. Due to the fact the concentrations of Ni generally present in cutaneous products as impurities are not considered sufficient to induce sensitization, the cutaneous and transcutaneous concentration limits (CTCLs) approach was applied for this element assessment. The toxicological analysis was carried out using microwave-assisted wet digestion with concentrated nitric acid and electrothermal atomization atomic absorption spectrometry. Our results show that the ointments with Marjoram herb extract from pharmacies in Poland represent a potential health hazard to patients; however, there may be a requirement for the monitoring of impurities of nickel in future. To the best of our knowledge, this paper is the first study about nickel and chromium content in ointments with Marjoram herb extract (Majoranae herbae extractum).

Kamil Jurowski, Maria Fołta, Barbara Tatar, Mehmet Berkoz, Mirosław Krośniak

lemental impurities (EIs) profiling in final pharmaceutical products is often not adequately treated, however it is crucial problem in pharmaceutical analysis by reason of the various regulatory authorities (like ICH Q3D guideline). EIs in pharmaceuticals may arise from numerous sources of which the herbal ingredients are not a frequent subject of pharmaceutical analyses. However, based on number of traditional use registrations per year for herbal medicinal products (HMPs) in the EU, it can be stated that monocomponent HMPs are still very popular for use. Due to the high frequency of use, exposure to EIs from HMPs may be high during long-term use. The aim of our article was Ni and Cr impurities profiling of Valeriana officinalis L., radix (Valerian root) as an example of the HMP available in Polish pharmacies for the relief of mild nervous tension and sleep disorders. The choice of metals was justified by: (1) a single dose of Ni administered via oral route can induce dermatitis in nickel-sensitised individuals; (2) Cr is a very problematic element from toxicological point of view. Our results indicate that the standards of the ICH Q3D guideline are met for all EIs.

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Regulatory Toxicology and Pharmacology, 2021, 123: 104945
https://doi.org/10.1016/j.yrtph.2021.104945

Kamil Jurowski, Miroslaw Krosniak

Appropriate Human Health Risk Assessment (HHRA) is the desire in modern regulatory toxicology, especially for elemental impurity studies. The aim of this article is the comprehensive HHRA of two heavy metals impurities – Cd and Pb, in Traditional Herbal Medicinal Products (THMP) such as Menthae piperitae tinctura (Mentha x piperita L., folium) available in Polish pharmacies. These registered phytopharmaceuticals in the EU are very common and usually used OTC products by adults and also children/adolescents. For this purpose, we applied double regulatory approach, including: 1) requirements of ICH Q3D R1 guideline about elemental impurities and additionally Margin of Exposure (MoE)-based concept to cover also specific population groups. The raw results show that Cd and Pb were present in all THMPs analyzed with Mentha x piperita L., folium (PTM1 – PTM10) available in Polish pharmacies. In all samples, the impurities of Cd (in the range: 0.305 – 0.506 µg/L) were significantly lower than Pb impurities (in the range: 1.122 – 4.4921 µg/L).The HHRA of the impurities of Cd and Pb considering ICH Q3D R1 guideline-based approach made it possible to conclude that all results were below the permissible limit established by FAO/WHO for medicinal herbs and plants in different countries (300 µg/kg for Cd and 10,000 µg/kg for Pb). Additionally, the estimated daily intake of investigated elemental impurities compared to the PDE value confirms the safety of all samples. The second approach – MoE-based strategy indicated that the MoE values obtained values of MoE for Cd and Pb in the daily dose for each samples were above 10 000, hence exposure to these elemental impurities would not cause a health risk for all investigated population groups (children, adolescents and adults). To the best of our knowledge, this article is the first study on the level of heavy metal impurities level in final THMPs as Menthae piperitae tinctura (Mentha x piperita L., folium) available in Polish pharmacies.

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