The toxicological analysis of lead impurities in traditional herbal medicinal product with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) from pharmacies in Poland: the impurity profile and comprehensive toxicological risk assessment.

Traditional herbal medicinal products (THMP) with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) are very popular among the European population. The idea of our study was the toxicological analysis of lead impurities in THMP with Thymi herba obtained from Polish pharmacies. For this purpose, we prepared the impurity profiles and comprehensive toxicological risk assessment. The Pb impurity profiles show lead impurities in all samples investigated (in the range: 2.15-6.99 µg/L). The estimations of Pb impurities in the single dose (32.25-105.01 ng/single dose) and in the daily dose (64.50-210.00 ng/day) were based on the posology recommended by the manufacturers. All the results obtained meet the standards of the ICH Q3D (R1) guideline on elemental impurities according to the levels of Pb. It can be concluded that all investigated THMPs with Thymi herba available in Poland should not represent any health risk to adults.

The Control and Comprehensive Safety Assessment of Heavy Metal Impurities (As, Pb, and Cd) in Green Tea Camellia sinensis (L.) Samples (Infusions) Available in Poland.

Tea is the world's most common drink after water, and the world's annual sales exceed $43 billion, of which more than $11 billion is green tea (Camellia sinensis (L.)). Increasing evidence continues to show that green tea consumption and its ingredients have a variety of potential health benefits. The aim of the study was to control and assess the toxicological risk (TRA) of three heavy metals (As, Pb, and Cd) in infusions of green tea (n = 12) from Polish markets. We applied the method of inductive coupled plasma mass spectrometry (ICP-MS) to determine the selected heavy metal and designed a specific toxicological risk assessment with three crucial tiers. The first tier of our strategy was to determine the elements investigated (heavy metal impurities, µg/L). The second step was to estimate the weekly intake of green tea infusions (µg/week) based on weekly consumption. The third tier was to estimate the weekly intake per weight (µg/L/week/bw), based on the average weekly intake of green tea infusion per adult compared to the provisional weekly intake (PTWI) established by the FAO/WHO Joint Food Additives Expert Committee (JECFA). The levels of the investigated heavy metals occur at different levels in all of the investigated green tea infusions. The heavy metal profile indicated that As (0.0721-10.585 µg/L), Pb (0.386-1.695 µg/L), and Cd (0.126-0.346 µg/L) were present in all samples. Basic analysis of general content shows that As (average = 0.325 µg/L) was at a level similar to Cd (average = 0.214 µg/L). Surprisingly, the Pb content (average 0.891 µg/L) was approximately 2.75-4 times higher than that of As and Cd, respectively. The application of our proposed safety assessment methodology (three tiers) provides satisfactory results for regulatory purposes. The evaluation of the investigated heavy metals in all products analysed from green tea samples (infusions) showed that there were no health hazards to consumers due to weekly exposure. The results indicated that after drinking green tea infusions from Polish markets, the amount of investigated elements in weekly doses does not represent any health risks to consumers.

Protective Role of Myricetin and Fisetin Against Nephrotoxicity Caused by Lead Acetate Exposure through Up-regulation of Nrf2/HO-1 Signalling Pathway.

The effect of various flavonoids against oxidative stress and inflammation caused by lead exposure has been investigated. However, the protective effects of myricetin (MYC) and fisetin (FST), which are known to have potent antioxidant properties, against nephrotoxicity caused by exposure to lead acetate (LA), the water-soluble form of lead, have not been investigated. Our study investigated the protective role of these flavonoids against LA intoxication-induced nephrotoxicity. In our study, 42 male rats were used. The rats were randomly selected and divided into 6 groups. These groups were: control, LA (100 g/kg), LA + MYC (100 mg/kg), LA + MYC (200 mg/kg), LA + FST (100 mg/kg) and LA + FST (200 mg/kg). All chemicals were administered daily by gavage for 28 days. According to the experimental protocol, the animals were sacrificed and their kidney tissues were isolated. Serum biochemical parameters, histological examinations, levels of several trace elements, oxidative stress and inflammatory parameters at both biochemical and molecular levels in kidney tissues were examined. After LA administration, tissue lead levels increased and zinc levels decreased. This situation was reversed by MYC and FST treatment. Oxidative stress and inflammatory response were increased in the kidney tissue of LA-treated rats and renal function was impaired. It was observed that both doses of MYC and high dose of FST could prevent nephrotoxicity. Oral administration of both doses of MYC and high dose FST ameliorated the changes in biochemical, oxidative and inflammatory parameters. Restoration of normal renal tissue architecture was also demonstrated by histological studies. MYC and FST were found to have promising biological activity against LA-induced nephrotoxicity, acting by attenuating inflammation and oxidative stress and improving antioxidant status.

The Toxicological Analysis and Toxicological Risk Assessment of Chosen Elemental Impurities (Ag, Au, Co, Cr, Cs, Li, Mo, Se, and Sr) in Green Tea (Camellia sinensis (L.)) Infusions.

Our study's objective is to evaluate the potential health effects of elemental impurities (Ag, Au, Co, Cr, Cs, Li, Mo, Se, and Sr) found in green tea infusions (Camellia sinensis (L.)). The ICP-MS-based methodology was employed for elemental analysis and a detailed health risk evaluation based on weekly consumption (µg/L of infusion/week). The provisional tolerable weekly intake (PTWI), established by the Joint FAO Expert Committee on infusion/week/month based on existing literature data, was then compared to the subjects with data from the available literature. The exposure of the study items to Co ranged from 0.07904 to 0.85421 µg/day. On the contrary, the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines state that the established permitted daily exposure PDE (oral exposure) for Co is 50 µg/day. The PDE of lithium is around 560 µg/day, and according to our study, the estimated daily exposure of the evaluated products to Li fell between 0.0185 and 0.7170 µg/day. Our research also revealed modest concentrations of Cs (0.399-2.654 µg/L), Mo (0.0113-0.107 µg/L), and Sr (9.848-22.331 µg/L) in infusions. The recognized PDE for molybdenum is approximately 3400 µg/day. Only two samples contained silver, and when considering daily consumption, the predicted daily exposure to Ag is between 4.4994 and 0.03122 µg/day. The amounts of all evaluated elements in a daily dose of green tea infusions should not harm the consumer's health. Further considerations should take aspects, such as constant change and environmental pollution, into account.

The Toxicological Risk Assessment of Dermal Exposure of Patients Exposed to Lead and Cadmium Due to Application of Ointments with Marjoram Herb Extract (Majoranae herbae extractum).

Potential heavy metal impurities (HMI) in pharmaceuticals/pharmaceutical products/drugs based on plant raw materials (e.g., herbs) are an important problem in the pharmaceutical industry; however, there is a lack of scientific articles on the comprehensive toxicological risk assessment of HMI in ointment applied dermally. To make the appropriate toxicological risk assessment, we consider: (1) the raw results of the levels of lead and cadmium in the ointments (metal per kg of mass), (2) one-time administration of the applied ointment, (3) daily exposure of Pb and Cd in the applied ointments according to the maximum daily dose of applied pharmaceuticals, including transcutaneous penetration, (4) human health risk assessment based on the USEPA model, and 5) the margin of exposure (MoE). The raw results indicated that lead (7.05-101.78 µg/kg) and cadmium (0.32-0.81 µg/kg) were present in all samples. The levels of analyzed HMI (independently of the producer and declared composition) were similar. Pb and Cd contamination associated with daily doses met the standards of the ICH Q3D (R2) guide on elemental impurities in pharmaceuticals, including the cutaneous route of administration. Taking into account the daily amount of lead and cadmium (ointment, ug/day) the results were satisfactory, confirming the safety of marjoram herb extract ointments available in Polish pharmacies according to the ICH guideline Q3D (R2) on elemental impurities. The HQ values obtained for Pb and Cd in all samples were less than 1; therefore, exposure to these HMI would not cause a health risk based on the USEPA model strategy. Furthermore, the obtained values of MoE for Pb and Cd in ointments were above 100, so exposure to these elements would not cause a health risk based on the MoE-based strategy. The original contribution of this work is that this is the first study on the triple approach strategy to evaluate the safety of heavy metal impurities in traditional herbal medicinal products applied dermally in solid form (ointments with marjoram herb extract). The research is novel and has not been previously published; The proposed procedure includes transcutaneous penetration of heavy metal (Pb and Cd) impurities described for the first time in the literature.

Lead impurities in traditional herbal medicinal products with Plantago lanceolata L., folium (Ribwort Plantain leaves) available in Polish pharmacies - toxicological risk assessment for adults.

Traditional herbal medicinal products (THMP) with Plantago lanceolata L., folium (Ribwort Plantain Leaves) are well-known and very popular among the European population. The aim of our study was the toxicological risk assessment for adults of Pb impurities in THMP with Plantago lanceolata L. obtained from pharmacies in Poland. The estimations of Pb impurities in the single dose (22.1 - 50.7 ng/single dose) and in the daily dose (ng/day) were based on the worst-case scenario (WCS), i.e. based on the posology recommended by manufacturers. The estimated daily exposure (ng/day) meets the standards of the ICH Q3D (R1) guideline on elemental impurities (5.0 µg/day) according to the Pb levels (all results were below 250 ng/day). It can be concluded that all investigated THMPs with Plantago lanceolata L., folium available in pharmacies from Poland should not represent any health risk to the adults.

The Toxicological Safety Assessment of Heavy Metal Impurities (As, Pb, and Cd) in Mint Tea Infusions (Mentha piperita L.) Available in Polish Markets.

Mint tea (Mentha piperita L.) is one of the most widely consumed single infusion herbal teas (infusion) around the world; however, impurities and pollutants can pose a potential health risk to human health during tea drinking. The idea of this study was the comprehensive toxicological risk assessment (TRA) of three heavy metals (As, Pb, and Cd) in mint tea infusions (Mentha piperita L.; n = 17) available in Polish markets. We applied an inductively coupled plasma mass spectrometry (ICP-MS)-based methodology for the determination of the chosen heavy metals and designed a specific TRA approach. The first step in our TRA was the determination of the elements investigated (heavy metal impurity profile, µg/L of infusion). The second step was the estimation of the weekly intake (µg/L of infusion/week) based on the weekly consumption of tea. The third step was the estimation of the weekly intake per body weight (µg/L of infusion/week/bw) based on the weekly consumption of tea per adult person compared to the Provisional Tolerable Weekly Intake (PTWI) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). The level of investigated heavy metals occurs in all of the investigated mint tea infusions but at a relatively low level. The heavy metal profile indicated presence of As (0.36-1.254 µg/L), Pb (0.47-1.24 µg/L), and Cd (0.17-0.40 µg/L) in all the samples investigated. The basic analysis of the general content shows that As levels (mean = 0.70 µg/L) were very similar to the Pb levels (mean = 0.72 µg/L). The Cd content (mean = 0.21 µg/L) was approximately 3.5 times lower than the As and Pb levels. TRA provides satisfactory results for regulatory purposes. TRA for the elements investigated in the analyzed products indicated that there was no health hazard to consumers for weekly exposure. The results indicated that the levels of investigated elements in daily doses should not represent any health hazard to the consumer after drinking mini tea infusions from products available in Polish markets. This well-designed TRA methodology was useful and important for regulatory toxicology purposes.

Cadmium impurities in traditional herbal medicinal products with Thymi herba available in Polish pharmacies - short communication: the level of Cd impurities and comprehensive toxicological risk assessment.

Traditional herbal medicinal products (THMP) with Thymi herba are very popular as OTC among the European population. The aim of this article was the toxicological risk assessment (TRA) of Cd impurities in THMP with Thymi herba from Polish pharmacies. The estimations of Cd impurities in the single dose (1.10-12.90 µg/single dose) and in the daily dose (ng/day) were based on the worst-case scenario (WC), i.e. based on the dosage indicated in the community herbal monograph on Thymus vulgaris L. and Thymus zygis L., herba by the European Medicines Agency (EMA). The estimated daily exposure (ng/day) meets the standards of the ICH Q3D (R1) guideline (5.0 µg/day) according to the Cd levels (all results were below 40 ng/day). It can be concluded that all THMPs analysed with Thymi herba from Polish pharmacies should not represent any health risk to the human health.

Antioxidant and anti-inflammatory effect of olive leaf extract treatment in diabetic rat brain.

OBJECTIVES: Olive (Olea europaea L.) plays a promising role in pharmaceutical, nutraceutical, and cosmetic production. On the other hand, olive leaf is widely used in folk medicine due to its antihyperglycemic activity. For this aim, possible effects of olive leaf extract (OLE) in the brain tissue of streptozotocin-induced diabetic rats were investigated. METHODS: A total of 28 male rats were divided into four equal groups as control, diabetic (single dose of 45 mg/kg streptozotocin, i.p.), OLE (500 mg/kg/day), and diabetic + OLE groups. The study was terminated 21 days after the diabetes model was formed. At the end of the study, all the animals were sacrificed and blood and brain tissues were isolated. Relative brain weights, complete blood count, blood glycated hemoglobin, serum glucose, total protein, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, insulin, gonadal hormone levels, production and messenger ribonucleic acid (mRNA) levels of proinflammatory cytokines and mediators, total thiol, total oxidative stress, and total antioxidant status levels and fatty acid composition in brain tissue were measured in all study groups. RESULTS: In diabetic rats, relative brain weight and serum insulin level decreased, glycated hemoglobin, oxidative stress, production and mRNA level of proinflammatory cytokines and mediators increased, hyperglycemia, hypercholesterolemia and hypertriglyceridemia, degraded fatty acid composition, anemia, leukopenia, and thrombocytopenia occurred. After OLE treatment, a remarkable improvement in most of these parameters, except gonadal hormones, has been observed in diabetic rats. CONCLUSIONS: This study suggests that olive leaf can be a precious neuroprotective agent in diabetes.

The Control of Novel and Traditional Elemental Impurities: Ag, Au, Co, Cs, Li, Mo, Se, Sr, and V in Mint Tea Infusions (Peppermint, Mentha piperita L.) Available in Poland: A Health Risk Assessment.

The purpose of our studies is the evaluation of the health risks of the novel elemental impurities (Ag, Au, Co, Cs, Li, Mo, Se, Sr, and V) in mint tea infusions (Mentha piperita L.) available in Poland. For this purpose, we applied ICP-MS-based methodology for content analysis (elemental profile and µg/L of the infusion) and also the specific health risk assessment for a comprehensive assessment. Our strategy was based on weekly intake (µg/L of infusion/week) considering weekly tea consumption. Then, based on the weekly consumption of tea per adult, individuals were compared to the Temporary Tolerated Weekly Intake (PTWI) designated by the Joint FAO Expert Committee on Food Additives (JECFA), and the weekly consumption per body weight (µg/L of infusion/week/bw) was estimated. Daily exposure to Co in the tested products is in a range of 0.093-0.238 µg/day. In comparison, the established PDE (oral exposure) for Co by the ICH guideline (the ICH guideline Q3D (R1), 2019) is 50 µg/day. For lithium, PDE is approximately 560 µg/day and, in our study, the estimated daily exposure for Li in investigated products is in a range of 0.226-2.41 µg/day. Our studies found also low levels of Cs (in a range of 0.0598-0.195 µg/L), Mo (in a range of 0.663-3.261 µg/L), and Sr (0.223-65.842 µg/L) in infusions. For Molybdenum, the established PDE is approximately 3400 µg/day. There are no documents about Sr and Co in the Joint FAO/WHO Expert Committee on Food Additives (JECFA) database and the ICH guideline Q3D (R1). In the case of V, the established PDE is 120 µg/day, and the level of V in analyzed infusions is in a range of 0.284-0.702 µg/L. Silver and gold were present only in a few samples, and the estimated daily exposure for Ag is approximately 0.04575 µg/day for product A and approximately 0.1885 µg/day for product O, except for Au, which is in a range of 0.000356-0.114 µg/L. The estimated daily exposure for Ag is 167 µg/day and, for Au, it is in a range of 8.9 × 105-0.0285 µg/day. It can be concluded that levels of all investigated elements (novel and also traditional elemental impurities) in the daily dose should not threaten the consumer's health after consuming mint tea infusions.

The Human Health Risk Assessment of Heavy Metals Impurities (Cd and Pb) in Herbal Medicinal Products as Menthae piperitae tinctura (Mentha × piperita L., folium) Available in Pharmacies from Poland.

Appropriate human health risk assessment (HHRA) is 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 herbal medicinal products (HMP) as Menthae piperitae tinctura (Mentha × piperita L., folium) available in Polish pharmacies. These phytopharmaceuticals registered in EU are very common and usually applied 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 (2) additionally margin of exposure (MoE)-based concept to cover also specific population groups. Raw results shows that Cd and Pb were present in all analyzed HMP with Mentha × piperita L., folium (PTM1-PTM10) available in Polish pharmacies. In all samples, Cd impurities (in the range: 0.305-0.506 µg/L) were greatly lower than Pb impurities (in the range: 1.122-4.4921 µg/L). The HHRA of Cd and Pb impurities considering ICH Q3D R1 guideline-based approach made it possible to conclude that all results were below the permissible limit set 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 confirm all samples safety. The second approach, an MoE-based strategy, indicated that the obtained values of MoE for Cd and Pb in 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 our knowledge, this article is the first study about heavy metals impurities level in final HMPs as Menthae piperitae tinctura (Mentha × piperita L., folium) available in Polish pharmacies.

The Toxicological Assessment of Content and Exposure of Heavy Metals (Pb and Cd) in Traditional Herbal Medicinal Products with Marshmallow Root (Althaea officinalis L., radix) from Polish Pharmacies.

The level of potentially toxic elements (PTE) in phytopharmaceuticals 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.

The Comprehensive Toxicological Assessment of Total Chromium Impurities in Traditional Herbal Medicinal Product with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) Available in Pharmacies in Poland: Short Communication.

Scientific reports about elemental impurities in final pharmaceutical products are essential from a regulatory point of view; unfortunately, there is a lack of studies about this important toxicological topic. The aim of our short communication was determination of total Cr impurities in traditional herbal medicinal products (THMP) with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) available in Polish pharmacies (n = 6, because only six manufacturers produce this kind of pharmaceutical products in Poland). The total content of Cr impurities was determined by atomic absorption spectrometry using electrothermal atomization (ETAAS). Applied comprehensive toxicological risk assessment was based on three main tiers: Tier 1, the comparison of raw results as total Cr impurities profile (metal per L of THMP) with ICH Q3D guideline standards; Tier 2, the estimation of total Cr exposure with a single dose; and Tier 3, the estimation of total Cr daily exposure. We confirmed that total Cr impurities were present in all analyzed THMP with thymi herba (the observed level was below 6.0 µg/L). Total Cr concentration in a single dose can be deceptively high in comparison to the raw results but is not a threat to patients (20.15-63.45 ng/single dose). Moreover, the estimation of total Cr daily exposure shows that all analyzed THMP are characterized by daily dose (40.30-181.41 ng/day) below PDE value (10,700 mg/day); hence, all products meet the standards of ICH Q3D elemental impurities guideline.

The Level of Cadmium Impurities in Traditional Herbal Medicinal Products with Plantago lanceolata L., folium (Ribwort Plantain Leaves) Available in Polish Pharmacies - Comprehensive Toxicological Risk Assessment Including Regulatory Point of View and ICH Q3D Elemental Impurities Guideline.

Plantago lanceolata L., folium (ribwort plantain) is an active pharmaceutical ingredient in traditional herbal medicinal products (THMP) available in pharmacies as a demulcent for the symptomatic treatment of oral or pharyngeal irritations and associated dry cough. This kind of THMP is widely applied among the European population; however, recently, voices have been heard in the public about alleged cadmium impurities. The idea of our study was a comprehensive risk assessment of the Cd impurity exposure and its effect on human health. Our assessment strategy was based on regulatory aspects (raw results versus limits set by FAO/WHO for herbal medicines) and toxicological risk assessment approach based on ICH Q3D guideline for elemental impurities in final pharmaceutical products. The cadmium was determined by electrothermal atomization atomic absorption spectrometry based on our previously described methodology. Obtained results show that all analysed THMP with P. lanceolata L., folium available in the Polish pharmacies contain cadmium impurities, but at a very low level (ranged 0.73 - 20.6 µg/L). The content of Cd in a single dose (ng/single dose) is also very low and is not a threat to patients. The estimated maximum daily exposure (ng/day) of Cd based on the 'worst-case scenario' (maximum concentrations by oral administration) meets the standards of ICH Q3D guideline (all results were below oral permitted daily exposure; PDE for Cd, i.e. < 5.0 µg/day). It can be concluded that all analysed samples of THMP with P. lanceolata L., folium should not represent any health hazard to the patients due to cadmium levels. To the best of our knowledge, this is the first study about Cd impurity level in THMP with P. lanceolata L., folium (ribwort plantain leaves) available in European pharmacies.

The Health Risk Assessment of Essential Elemental Impurities (Cu, Mn and Zn) Through the Dermal Exposure of Herbal Ointment Extracted from Marjoram Herb (Majoranae herbae extractum).

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.

The Toxicological Risk Assessment of Cu, Mn, and Zn as Essential Elemental Impurities in Herbal Medicinal Products with Valerian Root (Valeriana officinalis L., radix) Available in Polish Pharmacies.

The toxicological risk assessment (TRA) of elemental impurities (EI) in especially herbal medicinal products (HMP) is a significant challenge for pharmaceutical industry. In Europe, very popular are traditional HMP with valerian root (Valeriana officinalis L., radix) for relief of mild symptoms of mental stress and to aid sleep. The aim of our unique article is the comprehensive TRA of Cu, Mn, and Zn as EI in HMP with V. officinalis L., radix available in Polish pharmacies. This article is a continuation of our previously conducted studies about TRA of heavy metals (Pb and Cd) in these same samples. Investigated elements were determined by flame atomic absorption spectrometry (F AAS). The values of the correlation coefficients (R > 0.998) confirm the linearity of the applied instrument for precision and accuracy of results. The recoveries, LOD and LOQ values were acceptable. Our results show that all investigated HMP with valerian root available in Polish pharmacies contain Cu (0.16-0.23 mg/L), Mn (0.11-0.76 mg/L), and Zn (0.22-0.48 mg/L) at a very low level. Based on our estimation of EI including single dose (µg/20 mL) and estimated daily intake (µg/day), our results confirm the safety of all pharmaceuticals. To the best of our knowledge, the Cu, Mn, and Zn impurity profile in HMP with V. officinalis L., radix is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view (ICH Q3D elemental impurities guideline for pharmaceuticals).

The Toxicological Risk Assessment of Lead and Cadmium in Valeriana officinalis L., radix (Valerian root) as Herbal Medicinal Product for the Relief of Mild Nervous Tension and Sleep Disorders Available in Polish Pharmacies.

Studies related to the toxicological risk assessment (TRA) of heavy metal impurities (HMIs) in pharmaceuticals are an important issue but there is a lack of refereed literature around the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product (HMP) for the relief of mild nervous tension and sleep disorders according to lead and cadmium impurities. The aim of the study was to estimate the TRA of lead and cadmium in Valeriana officinalis L., radix (Valerian root) as HMP (n = 5) available in Polish pharmacies. In the case of herbal pharmaceuticals, it is particularly important to control the level of HMIs accumulated during the plant's growth. Perhaps, the exposure for a single dose is not relevant; however, justification of our studies is a fact that herbal therapies are usually long term. Therefore, even small HMI doses as present in particular plant may accumulate in patient body over a long period of time. Levels of lead and cadmium were measured by electrothermal atomization atomic absorption spectrometry. The levels of lead and cadmium as HMIs (independently of the producer and declared composition) are quite similar. Our results are satisfactory, confirming the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product for the relief of mild nervous tension and sleep disorders available in Polish pharmacies according to ICH guideline Q3D. To the best of our knowledge, this paper is the first study about lead and cadmium content as HMIs in HMP containing Valeriana officinalis L., radix (Valerian root).

The Toxicological Risk Assessment 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.

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).

Ni and Cr impurities profile in Valeriana officinalis L., radix-based herbal medicinal product available in polish pharmacies due to ICH Q3D guideline.

Elemental 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.

Effect of long-term proton pump inhibitor therapy on complete blood count parameters and selected trace elements: a pilot study.

INTRODUCTION: Proton pump inhibitors (PPIs) are widely prescribed for several gastrointestinal conditions, often as long­term therapy. The effects of term PPI use have not been fully elucidated. OBJECTIVES: We aimed to determine the association between long­term PPI use and complete blood count parameters, particularly red blood cell (RBC) count, white blood cell (WBC) count, and hemoglobin concentrations, as well as serum levels of selected micronutrients such as selenium (Se), iron (Fe), copper (Cu), and zinc (Zn). PATIENTS AND METHODS: We enrolled 37 patients on long­ term PPI therapy (mean [SD] age, 57.1 [15.4] years) and 30 healthy controls (mean [SD] age, 39.3 [11.8] years). In each group, complete blood count, and serum Fe levels were performed, and serum Cu, Zn, and Se levels were measured using atomic absorption spectrometry. RESULTS: Red blood cell and WBC counts were lower in the PPI group compared with controls (mean [SD], 4.24 [0.55] ×106/µl vs 4.7 [0.4] ×106/µl; P <0.001 and 6.13 [1.44] ×103/µl vs 7.3 [1.28] ×103/µl; P <0.001, respectively). Hemoglobin and serum Fe concentrations were also lower in the PPI group (mean [SD], 12.5 [1.8] g /dl vs 14.3 [0.8] g /dl; P <0.001 and 16.3 [5.4] µmol/l vs 23.4 [2.7] µmol/l; P <0.001, respectively). Serum Zn and Cu concentrations were higher in PPI users than in controls. CONCLUSIONS: Long­term PPI therapy may reduce RBC and WBC counts as well as hemoglobin levels, leading to iron deficiency. It may also aff ect concentrations of some micronutrients, although the underlying mechanism of this association is not fully clear.