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OBJECTIVES: Biopharmaceuticals improved the prognosis and quality of life of patients with chronic diseases. The aim of our study was to analyse the total reported suspected adverse drug reactions (ADR) and ADRs of reference biologicals and their biosimilars in Slovakia. METHODS: Using data from the State Institute for Drug Control database, we analysed the trends of suspected ADR submitted between 2001-2017 including the registered biosimilars and their reference biologicals: erythropoietin, filgrastim and infliximab. RESULTS: Severe suspected ADR represented 42.95 % from all the reported cases (n=13,462) over the time period 2006-2017 and 54.98 % over 2015-2017 respectively. Reports from 2015-2017 were further analysed. From 4,364 cases, 27 were associated with infliximab and one with erythropoietin. 75 % of these ADR were severe including one death. The difference between the suspected ADR for infliximab reference biological compared to the biosimilar was not statistically significant (p=0.171) after adjustment to the number of prescribed drug units. CONCLUSION: We did not find any evidence of increased risks associated with biosimilars compared to reference biologics. The spontaneous reporting system represents an inexpensive tool of reporting ADRs and should be utilized more frequently by health professionals, but even more importantly, by patients (Tab. 3, Fig. 2, Ref. 30). [ABSTRACT FROM AUTHOR]

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene Nfe2l2 , on the expression of selected NFR2-mediated gene expressions in the heart, and on vascular function. Rats were exposed to chronic crowding, DMF treatment (30 mg/kg/day, p.o.), or a combination of both for six weeks. Blood pressure (BP) was measured non-invasively, gene expressions were analysed using RT-qPCR, and vascular function was assessed by measuring noradrenaline (NA)-induced vasoconstriction and endothelium-dependent and -independent relaxations in the femoral arteries using a wire myograph. Chronic stress increased BP, Nfe2l2 expression, and NA-induced vasoconstriction, though it did not affect relaxation responses nor the left heart ventricle-to-body weight (LHV/BW) ratio. DMF elevated Nfe2l2 expression (as the main effect) in the heart but did not alter BP and vascular functions vs. control when administered alone. Interestingly, DMF increased the LHV/BW ratio, supposedly due to reductive stress induced by continuous NRF2 activation. When combined with stress, DMF treatment prevented stress-induced hypertension and mitigated NA-induced vasoconstriction without altering relaxation functions. In addition, the combination of stress and DMF increased Tnf and Nos2 expression and the expressions of several genes involved in iron metabolism. In conclusion, these findings suggest that DMF can prevent chronic stress-induced hypertension by reducing vascular contractility. Moreover, DMF itself may produce reductive stress in the heart and induce inflammation when combined with stress. This indicates a need for the careful consideration of long-term DMF treatment considering its impact on the heart.

Identifying alterations caused by aging could be an important tool for improving the diagnosis of cardiovascular diseases. Changes in vascular tone regulation involve various mechanisms, like NO synthase activity, activity of the sympathetic nervous system, production of prostaglandin, endothelium-dependent relaxing, and contracting factors, etc. Surprisingly, Ca 2+ -dependent Cl - channels (CaCCs) are involved in all alterations of the vascular tone regulation mentioned above. Furthermore, we discuss these mechanisms in the context of ontogenetic development and aging. The molecular and electrophysiological mechanisms of CaCCs activation on the cell membrane of the vascular smooth muscle cells (VSMC) and endothelium are explained, as well as the age-dependent changes that imply the activation or inhibition of CaCCs. In conclusion, due to the diverse intracellular concentration of chloride in VSMC and endothelial cells, the activation of CaCCs depends, in part, on intracellular Ca 2+ concentration, and, in part, on voltage, leading to fine adjustments of vascular tone. The activation of CaCCs declines during ontogenetic development and aging. This decline in the activation of CaCCs involves a decrease in protein level, the impairment of Ca 2+ influx, and probably other alterations in vascular tone regulation.

The effect of a 10-day-long treatment with taxifolin (TAX, 20 mg/kg/day p.o.) was investigated on spontaneously hypertensive rats (SHRs) with a focus on the vascular functions of isolated femoral arteries and thoracic aortas. TAX reduced blood pressure in SHRs. In femoral arteries, TAX increased acetylcholine-induced relaxation, reduced the maximal NA-induced contraction, and reduced acetylcholine-induced endothelium-dependent contraction (EDC); however, TAX had no effect on the vascular reactivity of isolated thoracic aortas. In addition, TAX elevated the total nitric oxide synthase (NOS) activity and iNOS protein expression but reduced cyclooxygenase-2 (COX2) protein expression in the tissue of the abdominal aorta without changes in Nos2 and Ptgs2 gene expressions. TAX also increased the gene expression of the anti-inflammatory interleukin-10 ( Il10 ). In addition, in vitro studies showed that TAX has both electron donor and H atom donor properties. However, TAX failed to reduce superoxide production in the tissue of the abdominal aorta after oral administration. In conclusion, our results show that a decrease in the blood pressure in TAX-treated SHRs might be attributed to improved endothelium-dependent relaxation and reduced endothelium-dependent contraction. In addition, the results suggest that the effect of TAX on blood pressure regulation also involves the attenuation of COX2-mediated pro-inflammation and elevation of anti-inflammatory pathways.

Introduction: The COVID-19 pandemic has resulted in more than 6.5 million deaths worldwide yet. Vaccination against the SARS-CoV-2 virus is a reliable way out of the pandemic, however, vaccination rate reaches only 58% in the Slovak Republic. Concerns about the adverse reactions of vaccines are one of the reasons for the low vaccination rate. Objective: The aim of our analysis was to review reported suspicions of adverse reactions (ARs) of registered COVID-19 vaccines (Comirnaty, Vaxzevria, Spikevax), which State Institute for Drug Control received from healthcare professionals and patients in the period from 1 January 2021 to 31 May 2021. Methods: Data were collected from the State Institute for Drug Control database, a retrospective analysis was carried out focusing on trends in the number of all reports of suspicions of adverse reactions sent to the State Institute for Drug Control during the previously mentioned period. We analysed the Retrieved data were analysed with the usage of descriptive statistics and comparison to historical data on drug adverse reactions in Slovakia was performed. Results : During the evaluation period, 5,763 reported suspicions of adverse reactions were analysed, overall, there was a significant ( p < 0.0001) increase in the number of reported adverse reactions fivefold. 93% of ARs ( n = 5,346) were reported for COVID-19 vaccines. In comparison of the extentof all adverse reactions, there is clearly a statistically significant difference between all types of vaccines administered at that time ( p ≤ 0.0001). No statistically significant difference ( p ≤ 0.238) was identified between Spikevax and Comirnaty in the proportion of serious adverse reactions. However, a significantly higher ( p ≤ 0.00001) proportion of reported suspicions of serious adverse reactions was observed after the administration of Vaxzevria. Conclusion: This is the first analysis conducted in Slovakia aimed to reported adverse reactions in relation to the administration of COVID-19 vaccines. The rate of spontaneously reported suspected adverse reactions has been insufficient in the past for a long time; during the period from January to May 2021 the reporting rate increased due active calls for adverse reactions reporting. In concordance with European data, Vaxzevria had a significantly higher ratio of reported suspicions of serious adverse reactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lassanova, Lassan, Liskova, Tesar and Cicova.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1-7 (Ang 1-7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1-7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.

We investigate the distribution and biological effects of polyethylene glycol (PEG)-coated magnetite (Fe 3 O 4 @PEG) nanoparticles (~30 nm core size, ~51 nm hydrodynamic size, 2 mg Fe/kg/day, intravenously, for two days) in the aorta and liver of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Fe 3 O 4 @PEG had no effect on open-field behaviour but reduced the blood pressure (BP) of Fe 3 O 4 @PEG-treated SHR (SHRu) significantly, compared to both Fe 3 O 4 @PEG-treated WKY (WKYu) and saline-treated control SHR (SHRc). The Fe 3 O 4 @PEG content was significantly elevated in the aorta and liver of SHRu vs. WKYu. Nitric oxide synthase (NOS) activity was unaltered in the aorta, but significantly increased in the liver of SHRu vs. SHRc. In the aorta, Fe 3 O 4 @PEG treatment increased eNOS, iNOS, NRF2 , and DMT1 gene expression (considered main effects). In the liver, Fe 3 O 4 @PEG significantly elevated eNOS and iNOS gene expression in SHRu vs. SHRc, as well as DMT1 and FTH1 gene expression (considered main effects). Noradrenaline-induced contractions of the femoral arteries were elevated, while endothelium-dependent contractions were reduced in SHRu vs. SHRc. No differences were found in these parameters in WKY rats. In conclusion, the results indicated that the altered haemodynamics in SHR affect the tissue distribution and selected biological effects of Fe 3 O 4 @PEG in the vasculature and liver, suggesting that caution should be taken when using iron oxide nanoparticles in hypertensive subjects.

The sympathetic nerve activity (SNA) is augmented in hypertension. SNA is regulated by neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) activity in hypothalamic paraventricular nuclei (PVN) and/or brainstem rostral ventrolateral medulla. High nNOS or eNOS activity within these brain regions lowers the SNA, whereas low cerebral nNOS and/or eNOS activity causes SNA augmentation. We hypothesize that the decreased cerebral nNOS/eNOS activity, which allows the enhancement of SNA, leads to the augmentation of renal eNOS/nNOS activity. Similarly, when the cerebral nNOS/eNOS activity is increased and SNA is suppressed, the renal eNOS/nNOS activity is suppressed as well. The activation of endothelial alpha(2)-adrenoceptors, may be a possible mechanism involved in the proposed regulation. Another possible mechanism might be based on nitric oxide, which acts as a neurotransmitter that tonically activates afferent renal nerves, leading to a decreased nNOS activity in PVN. Furthermore, the importance of the renal nNOS/eNOSactivity during renal denervation is discussed. In conclusion, the presented hypothesis describes the dual organ-specific role of eNOS/nNOS activity in blood pressure regulation and suggests possible connection between cerebral NOS and renal NOS via activation or inhibition of SNA, which is an innovative idea in the concept of pathophysiology of hypertension.

Various studies have shown that certain flavonoids, flavonoid-containing plant extracts, and foods can improve human health. Experimental studies showed that flavonoids have the capacity to alter physiological processes as well as cellular and molecular mechanisms associated with their antioxidant properties. An important function of flavonoids was determined in the cardiovascular system, namely their capacity to lower blood pressure and to improve endothelial function. (-)-Epicatechin and taxifolin are two flavonoids with notable antihypertensive effects and multiple beneficial actions in the cardiovascular system, but they also possess antiviral effects, which may be of particular importance in the ongoing pandemic situation. Thus, this review is focused on the current knowledge of (-)-epicatechin as well as (+)-taxifolin and/or (-)-taxifolin-modified biological action and underlining molecular mechanisms determined in preclinical studies, which are relevant not only to the treatment of hypertension per se but may provide additional antiviral benefits that could be relevant to the treatment of hypertensive subjects with SARS-CoV-2 infection.

Objectives: Biopharmaceuticals improved the prognosis and quality of life of patients with chronic diseases. The aim of our study was to analyse the total reported suspected adverse drug reactions (ADR) and ADRs of reference biologicals and their biosimilars in Slovakia., Methods: Using data from the State Institute for Drug Control database, we analysed the trends of suspected ADR submitted between 2001-2017 including the registered biosimilars and their reference biologicals: erythropoietin, filgrastim and infliximab., Results: Severe suspected ADR represented 42.95 % from all the reported cases (n=13,462) over the time period 2006-2017 and 54.98 % over 2015-2017 respectively. Reports from 2015-2017 were further analysed. From 4,364 cases, 27 were associated with infliximab and one with erythropoietin. 75 % of these ADR were severe including one death. The difference between the suspected ADR for infliximab reference biological compared to the biosimilar was not statistically significant (p=0.171) after adjustment to the number of prescribed drug units., Conclusion: We did not find any evidence of increased risks associated with biosimilars compared to reference biologics. The spontaneous reporting system represents an inexpensive tool of reporting ADRs and should be utilized more frequently by health professionals, but even more importantly, by patients (Tab. 3, Fig. 2, Ref. 30). Text in PDF www.elis.sk Keywords: adverse drug reaction, spontaneous reporting, biopharmaceuticals, biosimilars, infliximab.

[This corrects the article DOI: 10.1155/2014/289361.].

The activation of Ca(2+)-dependent Cl(-) channels during norepinephrine-induced contraction of vascular smooth muscle was suggested to depolarize cell membrane and to increase Ca(2+) entry. Hypertension and ageing are associated with altered Ca(2+) handling including possible activation of Ca(2+)-dependent Cl(-) channels. Our study was aimed to determine Ca(2+)-dependent Cl(-) channels contribution to norepinephrine-induced contraction during hypertension and ageing. Norepinephrine-induced concentration-response curves of femoral arteries from 6- and 12-month-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were recorded using wire myograph. Pretreatment with Ca(2+)-dependent Cl- channel inhibitor indanyloxyacetic acid 94 [R(+)-IAA-94](IAA) attenuated norepinephrine-induced contraction in all groups, but relatively more in WKY than SHR arteries. The attenuation of norepinephrine-induced contraction after Ca(2+)-dependent Cl(-) channels blockade was partially reduced in 12-month-old WKY rats, but substantially diminished in 12-month-old SHR. IAA effect was enhanced after NO synthase inhibition but decreased by ageing. In 20-month-old WKY rats norepinephrine-induced contraction was not affected by IAA but was almost abolished after cyclooxygenase inhibition by indomethacin or niflumic acid. In conclusion, contribution of Ca(2+)-dependent Cl(-) channels to norepinephrine-induced contraction diminished with age, hypertension development, and/or NO synthesis inhibition. Ca(2+)-dependent Cl(-) channels are important for maintenance of normal vascular tone while their inactivation/closing might be a pathological mechanism.

Aim: The relationship of age and hypertension on endothelial dysfunction and increased responses to vasoconstrictor stimuli., Background: Hypertension is a disease accompanied by endothelial dysfunction and is characterized by an impaired vascular reactivity and enhanced activity of sympathetic nervous system., Materials and Methods: In our experiment, we used spontaneously hypertensive rats representing model of essential hypertension and the Wistar-Kyoto rats as normotensive strain. Femoral arteries of adult and aged rats were put into the chamber of Mulvany-Halpern isometric myograph. As the nutrient solution, the modified Krebs-Henseleit solution having temperature 37 °C and bubbled with O2 was used. After 30 minutes stabilization of blood vessels, a dose-dependent curve of norepinephrine response was recorded (concentrations 3x10-8 M, 10-7 M, 3x10-7 M, 10-6 M, 3x10-6 M, 10-5 M, 3x10-5 M, 10-4 M), followed by a dose-dependent curve of acetylcholine response (concentrations 3x10-8 M, 10-7 M, 3x10-7 M, 10-6 M, 3x10-6 M)., Results: Our experiments recorded an increased reactivity to contraction stimuli in spontaneously hypertensive animals. Vascular reactivity to norepinephrine at 5 month and 12 month old rats from the same group was not significantly affected. Our experiments on the other hand, did not record a reduced endothelium-dependent relaxation in hypertensive compared to normotensive animals, neither in different age groups., Conclusions: Increased norepinephrine-induced contraction occurs even before development of reduced acetylcholine-induced relaxation in SHR rats. We predict that in our experiment hypertension plays a bigger role in the development of endothelial dysfunction than aging (Fig. 2, Ref. 22).

HER2-positive status is associated with increased risk of central nervous system (CNS) metastases in breast cancer patients. Leptomeningeal carcinomatosis (LMC) represents a rare but disastrous manifestation of metastatic breast cancer (MBC) with limited treatment options and poor prognosis. Several case reports of intrathecal (i.t.) trastuzumab in the treatment of LCM were published so far. Usually, i.t. trastuzumab was administered in monotherapy or in combination with metothrexate. Herein, we report for the first time two patients with metastatic breast cancer and leptomeningeal carcinomatosis treated by intrathecal methotrexate (15 mg total dose) and cytarabine (24 mg total dose) with escalating dose of trastuzumab. We observed that up to 100 mg of trastuzumab can be safely administered intratecally with i.t. metothrexate and cytarabine. Both patients achieved good control of leptomeningeal disease for 13.5 and 6 months without significant toxicity. We suggest that i.t. trastuzumab with cytarabine and metothrexate is associated with promising benefit and warrant further investigation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Melatonin is suggested to be beneficial in several pathological conditions including arterial hypertension. One of the mechanisms proposed for its antihypertensive action is the protection against endothelial dysfunction. We investigated whether melatonin can accelerate the recovery from N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension after the cessation of L-NAME administration., Methods: Male adult Wistar rats (n=40) were randomized into 3 treated groups: 5-week L-NAME, 5-week L-NAME + 3-week vehicle, 5-week L-NAME + 3-week melatonin and into 2 age-matched control groups. The blood pressure was measured in the carotid artery. The NO-signalling was represented by NO-synthase activity and expression in the aorta and NO-mediated relaxations of femoral and mesenteric arteries. The endothelium-derived-constricting factor (EDCF)-signalling was represented by aortic cyclooxygenase-2 expression and femoral EDCF-mediated contractions. Oxidative load was determined in the aorta based on conjugated dienes concentration and inner diameter was measured in femoral arteries., Results: L-NAME caused hypertension, reduced NO-signalling and arterial diameter and increased oxidative load and EDCF-signalling. While the NO-signalling was restored spontaneously 3 weeks after L-NAME cessation, the EDCF-signalling, oxidative load and arterial remodeling were completely restored only when melatonin treatment was administered during the recovery period. The blood pressure regression was comparable between spontaneous and melatonin recovery., Conclusion: Although melatonin did not accelerate blood pressure reduction, it attenuated EDCF-contractions and oxidative load and enlarged arterial diameter. These effects may be beneficial for cardiovascular protection.

Background: Skin metastases are present in 1-9% of cancer patients. In rare cases, skin metastases can manifest as lesions with signs of inflammation and are diagnosed as inflammatory cutaneous metastases (ICM). ICM in lung cancer are extremely rare and often misdiagnosed., Patients and Methods: We report on a 55-year-old man with metastatic lung adenocarcinoma and bone metastases in the axial skeleton and left humerus diagnosed in August 2008. He underwent 6 cycles of palliative chemotherapy with cisplatin and gemcitabine, obtaining a minor response. Five months later, he experienced increasing pain in his left arm, with erythematous oedematous lesion with poorly defined margins and an inflammatory appearance. A diagnosis of skin infection was made and he was treated by antibiotic therapy without improvement., Results: Skin biopsy revealed skin infiltration by poorly differentiated carcinoma compatible with a primary lung tumour. He was started on second line therapy with docetaxel, however, the patient's status deteriorated rapidly and he died two months after the first appearance of ICM., Conclusion: Metastasis of lung carcinoma could be one of the causes of inflammatory skin lesions in cancer patients and these metastases should be considered in cancer patients with persisting cutaneous lesions with signs of inflammation and no response to antibiotic therapy.

Background: Although increasing attention has been given to the evaluation of use of potentially inappropriate medication in the older European Union (EU) member countries, information on this topic from Central and Eastern Europe is scarce., Objectives: The aims of the present study were: to identify risk factors enhancing the probability of use of potentially inappropriate medication in hospitalized older patients under the conditions of the Slovak healthcare system and to compare our results with previously published European studies., Methods: The evaluation was performed in 600 patients aged > or =65 years, hospitalized in a general hospital between 1 December 2003 and 31 March 2005. To identify the use of potentially inappropriate medication, the Beers 2003 criteria were applied. Particular socio-demographic and clinical characteristics, as well as comorbid medical conditions were evaluated among possible factors enhancing the probability of use of potentially inappropriate medication., Results: At least one potentially inappropriate medication was prescribed to 126 (21%) of 600 patients. Multivariate analysis identified polypharmacy [odds ratio (OR) 2.38; 95% confidence interval (CI): 1.50-3.79], depression (OR 2.03; 95% CI: 1.08-3.82), immobilization (OR 1.87; 95% CI: 1.16-3.00) and heart failure (OR 1.73; 95% CI: 1.13-2.64) as factors associated with an increased risk of use of inappropriate medication. In contrast, patients aged > or =75 years had a lower risk of being prescribed potentially inappropriate medication (OR 0.58; 95% CI: 0.39-0.88)., Conclusions: Polypharmacy, immobilization, heart failure and depression were documented as predictors of use of potentially inappropriate medication. In depressive patients, drugs other than antidepressants contributed to the extensive use of potentially inappropriate medication. The observed prevalence of use of potentially inappropriate medication in older hospitalized Slovak patients was lower than the prevalence previously documented in Poland and the Czech Republic, but higher than in Croatia and Turkey. The identified risk factors were consistent with previous findings from other parts of Europe.