Leki przeciwnadciśnieniowe a skażenie rakotwórczymi nitrozoaminami

At the end of June 2018 small amounts of highly carcinogenic N–nitrosamine — N–nitrosodimethylamine (NDMA) contaminations were found in some of the angiotensin II receptor AT1 antagonists (sartans) used to treat arterial hypertension. By July 2019, four N–nitrosamine impurities had been identified in sartans: NDMA, N–nitrosodiethylamine, N‑nitrosodiisopropylamine and N-nitroso-N-methyl-4-aminobutyric acid. Seven manufacturers of three contaminated active substances (valsartan, losartan and irbesartan) from China, India and Mexico had also been identified. These compounds had infiltrated the active pharmaceutical ingredients probably as a consequence of ill-considered synthesis modifications. The number of people who have been prescribed contaminated valsartan alone is estimated at around 20 million worldwide. This paper discusses the role of sartans in medicine in the context of the physiological significance of the renin–angiotensin–aldosterone system as well as the role of tetrazole moiety in the mechanism of sartans receptor activity. The synthesis of tetrazole moiety and its modifications have been characterized as possible causes of the appearance of nitrosamine impurities in sartans. The toxicological properties of nitrosamines are also briefly outlined. The fact that nitrosamines had been entering medicines for at least five years without the knowledge of the authorities responsible for the safety of medicines has exposed a gross malfunctioning of the system intended to guarantee the safety of medicinal products. The valsartan scandal has forced changes to some drug regulations, in particular the requirements for analytical procedures.At the end of June 2018 small amounts of highly carcinogenic N–nitrosamine — N–nitrosodimethylamine (NDMA) contaminations were found in some of the angiotensin II receptor AT1 antagonists (sartans) used to treat arterial hypertension. By July 2019, four N–nitrosamine impurities had been identified in sartans: NDMA, N–nitrosodiethylamine, N‑nitrosodiisopropylamine and N-nitroso-N-methyl-4-aminobutyric acid. Seven manufacturers of three contaminated active substances (valsartan, losartan and irbesartan) from China, India and Mexico had also been identified. These compounds had infiltrated the active pharmaceutical ingredients probably as a consequence of ill-considered synthesis modifications. The number of people who have been prescribed contaminated valsartan alone is estimated at around 20 million worldwide. This paper discusses the role of sartans in medicine in the context of the physiological significance of the renin–angiotensin–aldosterone system as well as the role of tetrazole moiety in the mechanism of sartans receptor activity. The synthesis of tetrazole moiety and its modifications have been characterized as possible causes of the appearance of nitrosamine impurities in sartans. The toxicological properties of nitrosamines are also briefly outlined. The fact that nitrosamines had been entering medicines for at least five years without the knowledge of the authorities responsible for the safety of medicines has exposed a gross malfunctioning of the system intended to guarantee the safety of medicinal products. The valsartan scandal has forced changes to some drug regulations, in particular the requirements for analytical procedures

Acute Valproic Acid Intoxication: An Attempt at Estimating the Correlation Between Serum Level and Clinical Manifestations

We investigated the association between serum valproic acid (VPA) levels and clinical conditions in patients after acute intoxication with this drug. We performed a retrospective study of cases of VPA intoxications hospitalized in Toxicology Unit in Cracow in 2 years of observation. The study included 26 patients (age: 35.69 ± 12.93 years). In all patients, the VPA plasma level was higher than the therapeutic range, mean ± SD: 275.32 ± 135.97 μg/ml. About half of poisoned patients described in this report were treated with VPA prior to the poisoning. We noted four cases of mixed VPA intoxications with ethanol. Acute pulmonary failure was observed in two persons. The mean hospital stay for all patients was 4.69 days. This analysis demonstrates that increased serum VPA levels, in acute intoxication with this drug, were associated with the severity of poisoning — in PSS (P = 0.019) and in Matthews coma scale (P = 0.022), diastolic pressure (P = 0.022) and length of stay in hospital (P = 0.001). No correlation was detected between the serum VPA concentration and the heart rate and systolic blood pressure. In persons treated with VPA earlier, the course of poisoning was less severe, although these results were not statistically significant

Leki przeciwnadciśnieniowe a skażenie rakotwórczymi nitrozoaminami

At the end of June 2018 small amounts of highly carcinogenic N–nitrosamine — N–nitrosodimethylamine (NDMA) contaminations were found in some of the angiotensin II receptor AT1 antagonists (sartans) used to treat arterial hypertension. By July 2019, four N–nitrosamine impurities had been identified in sartans: NDMA, N–nitrosodiethylamine, N‑nitrosodiisopropylamine and N-nitroso-N-methyl-4-aminobutyric acid. Seven manufacturers of three contaminated active substances (valsartan, losartan and irbesartan) from China, India and Mexico had also been identified. These compounds had infiltrated the active pharmaceutical ingredients probably as a consequence of ill-considered synthesis modifications. The number of people who have been prescribed contaminated valsartan alone is estimated at around 20 million worldwide. This paper discusses the role of sartans in medicine in the context of the physiological significance of the renin–angiotensin–aldosterone system as well as the role of tetrazole moiety in the mechanism of sartans receptor activity. The synthesis of tetrazole moiety and its modifications have been characterized as possible causes of the appearance of nitrosamine impurities in sartans. The toxicological properties of nitrosamines are also briefly outlined. The fact that nitrosamines had been entering medicines for at least five years without the knowledge of the authorities responsible for the safety of medicines has exposed a gross malfunctioning of the system intended to guarantee the safety of medicinal products. The valsartan scandal has forced changes to some drug regulations, in particular the requirements for analytical procedures.Pod koniec czerwca 2018 roku w niektórych lekach z grupy antagonistów receptora AT1 dla angiotensyny II (sartanów) stosowanych w nadciśnieniu tętniczym wykryto niewielkie ilości silnie rakotwórczego zanieczyszczenia N–nitrozodimetyloaminą (NDMA) z grupy N–nitrozoamin. Do lipca 2019 roku zidentyfikowano łącznie cztery N–nitrozoaminy stanowiące zanieczyszczenia sartanów — NDMA, N–nitrozodietyloaminę, N–nitrozodiizopropyloaminę oraz kwas N‑nitrozo-N‑metylo-4‑aminomasłowy, a także siedmiu wytwórców trzech skażonych substancji czynnych (walsartanu, losartanu, irbesartanu) pochodzących z Chin, Indii oraz Meksyku. Związki te przedostawały się do produktów leczniczych prawdopodobnie wskutek nieprzemyślanych modyfikacji syntezy. Liczbę osób, którym przepisano sam skażony walsartan, w skali światowej szacuje się na około 20 milionów. W pracy omówiono miejsce sartanów w leczeniu w kontekście fizjologicznego znaczenia układu renina–angiotensyna–aldosteron oraz rolę ugrupowania tetrazolowego w mechanizmie ich działania receptorowego. Scharakteryzowano syntezę ugrupowania tetrazolowego oraz jej modyfikacje jako możliwe przyczyny pojawienia się zanieczyszczeń nitrozoaminowych w sartanach. Pokrótce przedstawiono także toksykologiczne właściwości nitrozoamin. Fakt, że związki te przedostawały się do leków przez co najmniej 5 lat niewykryte i bez wiedzy organów odpowiedzialnych za bezpieczeństwo leków, obnażył rażące niedostosowanie do rzeczywistości systemu mającego gwarantować bezpieczeństwo produktów leczniczych. Dlatego „afera walsartanowa” wymusiła zmiany niektórych regulacji dotyczących leków, zwłaszcza wymagania dotyczące procedur analitycznych

Patients who buy acetylsalicylic acid in Polish pharmacies — population characteristics and description of medical problem

Wstęp. Celem badania była charakterystyka pacjentów nabywających w ogólnodostępnych aptekach preparaty kwasu acetylosalicylowego (ASA) rekomendowanego w dawkach kardiologicznych, a także jej powiązanie z próbą stratyfikacji grup ryzyka tych osób. Materiał i metody. Wykorzystano wystandaryzowane ankiety w formie elektronicznej skierowane do pacjentów zgłaszających się do aptek. Wywiad przeprowadzali farmaceuci lub technicy farmaceutyczni. Wyniki. Badanie objęło 532 pacjentów, którzy kupili preparat ASA dla siebie. Większość z nich nie przybyła wcześniej incydentów sercowo-naczyniowych, zaś decyzja o rozpoczęciu leczenia stanowiła wynik rekomendacji profesjonalisty medycznego. Odsetek osób, które kierowały się reklamą mediach, był znacznie mniejszy i kształtował się na poziomie około 20%. Wnioski. Sugeruje się, że w kontekście stosowania preparatów ASA w dawkach kardiologicznych największe znaczenie nadal mają wskazania objęte profilaktyką pierwotną. Obserwacja ta implikuje konieczność wykonywania dodatkowych badań diagnostycznych w tej grupie pacjentów, jak również wskazuje na rolę lekarzy i farmaceutów w procesie monito­rowania farmakoterapii.Introduction. The aim of our study was to characterize patients in Poland who buy in pharmacies over-the-counter formulations of acetylsalicylic acid (ASA) in doses recommended by cardiologists as well as to attempt a risk stratification of this population. Material and methods. We used standardized electronic questionnaires addressed to patients coming to pharmacies. Patients were interviewed by pharmacists or pharmacy technicians. Results. The survey included 532 patients who bought ASA drug for themselves. Most of them have not previously had any cardiovascular events, and the decision to start ASA was the result of a medical professional’s recommendation. The percentage of people who were motivated by mass media advertising was much smaller, at approximately 20%. Conclusions. It is suggested that the most important indications for use of ASA in cardiologic doses are those concerning primary prevention. This observation warrants performing further diagnostic work-up, and points out to the role of physicians and pharmacists in therapy monitoring

Znaczenie glikoproteiny PCSK9 w farmakoterapii hipercholesterolemii rodzinnej

It has been shown that subtilisin-like proprotein convertase expression seems to be strongly correlatedwith low-density lipoprotein (LDL)-receptors decreased on the cells surface. Consequently , it contri -butes to increase of coronary incidents risks. Currently, the protein inhibition is therefore one of the mostpromising therapeutic strategy which can be used in the treatment of familiar hypercholesterolemia. Apartfrom small-molecule lead compounds, the high-affinity protein binding ligands are some of monoclonalantibodies. The preliminary studies suggest that SAR236553/REGN726, J16 and mAb1 reduce significantlyLDL cholesterol and can be used in the combination with statins. Moreover , in case of patients takinghydroxy-methylglutaryl coenzyme A inhibitors, the administration of AMG145 is not related with a highrisk of some adverse drug reactions (especially myopathy).Wykazano, że nadmierna ekspresja konwertazy proproteinowej jest silnie skorelowana ze zmniejszonągęstością receptorów lipoprotein o niskiej gęstości (LDL) na powierzchni komórek, a tym samym przyczyniasię do wzrostu ryzyka wystąpienia incydentów wieńcowych. Inhibicja białka jest więc obiecującąstrategią terapeutyczną między w terapii innymi hipercholesterolemii rodzinnej. Oprócz związków drobnocząsteczkowychduże powinowactwo do białka wykazują liczne przeciwciała monoklonalne. Wstępnewyniki badań sugerują, że SAR236553/REGN726, J16 i mAb1 nie tylko istotnie zmniejszają stężenie cholesterolufrakcji LDL, ale można je również wykorzystać w leczeniu skojarzonym ze statynami. Co więcej,zastosowanie niektórych z nich (AMG145) pozwala na znaczne obniżenie ryzyka wystąpienia miopatiiu chorych przyjmujących wcześniej inhibitory reduktazy 3-hydroksy-3-metyloglutarylo-koenzymu A

Epidemiological Study of Acute Poisoning for Antiepileptic Drugs: A 2-Year Retrospective Study in Cracow, Poland

The aim of this study was designed to examine the rate of occurrence of antiepileptic drug overdose in 2002 and 2012 in Cracow, Poland, and analyze the demographics and clinical features of the patients Antiepileptic drugs (AEDs) intoxication. A retrospective study included all the patients admitted in to the Toxicology Units in Cracow for AED intoxications in 2002 and in 2012. Patients were identified of discharge diagnoses (ICD-10). AED intoxication were 5.40% of the total admissions. Mean age of the patients was 35.88 ± 12.54 years. The female-to-male ratio was 1:1.7. The most frequent AED was carbamazepine (n = 140), followed by valproate (n = 31). The most frequent motivation was intentional intoxication (n = 166, 94.86%). Ethanol was coingested by 51 patients (29.14%). Most of the patients ingested other drugs (32%). Antiepileptic drugs intoxication accounted for only of 7.13% of all cases admitted to the abovementioned toxicology units in 2002 and 2012 in Cracow. Our studies show that most of the AED poisoning cases in those years were caused by drugs belonging to the old generation antiepileptic drugs, including carbamazepine and valproic acid. The majority of the intoxication cases was related to suicidal poisoning and commonest identified reason of self-intoxication were issues with self including attention-seeking behavior

Epidemiology and Risk Factors for Suicide Among Adult Patients with Epilepsy

Suicides constitute a serious public health issue worldwide. The number of suicide victims has been increasing over the years. Susceptibility to suicidal behaviour depends on the interaction of a number of factors. The reasons for taking a decision on committing suicide may objectively seem prosaic, and yet, according to the victim, cannot be resolved in any other way. Very often, it is the disease which is a risk factor for suicide. Suicidal thoughts, suicidal behaviours and suicide attempts as well as committed suicides occur far more frequently in epileptic patients than in the general population. There are many reasons for suicides committed by patients suffering from epilepsy. This paper presents basic data on epidemiology and risk factors of suicide attempts among patients with epilepsy. Risk factors in this group of patients include, inter alia, prior suicide attempts, co-morbidity of epilepsy with depression and other mental disorders, early onset (before 18 years of age), type and frequency of epileptic seizures and the use of anti-epileptic drugs, particularly in polytherapy

6-Acetyl-5-hydroxy-4,7-dimethylcoumarin derivatives : design, synthesis, modeling studies, 5-HT1A, 5-HT2A and D2 receptors affinity

Molecular docking studies using appropriate 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptors models were used to design sixteen new 5-hydroxycoumarin derivatives with piperazine moiety (3–18). The microwave radiation have been used to synthesize them and their structures have been confirmed using mass spectrometry, $^{1}$H and $^{13}$C NMR. All newly prepared derivatives were evaluated for their 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptor affinity. Seven of the synthesized derivatives showed very high affinities to 5-HT$_{1A}$ receptor (3–4.0 nM, 6–4.0 nM, 7–1.0 nM, 9–6.0 nM, 15–4.3 nM, 16–1.0 nM, 18–3.0 nM) and one of them showed high affinities to 5-HT$_{2A}$ receptor (16–8.0 nM). In the case of the D$_{2}$ receptor none of the tested derivatives showed high affinity. Compounds 7 and 16 were identified as potent antagonists of the 5-HT$_{1A}$ receptor as shown by the [35S]GTPcS binding assay but they didn’t show any antidepressant effect at the single dose tested (10 mg/kg) in the tail suspension tests

Wiedza kursantów ośrodków szkolenia kierowców odnośnie użycia automatycznego defibrylatora zewnętrznego (AED) w trakcie akcji ratunkowej = Students knowledge of driver training center on the use an Automated External Defibrillator (AED) during rescue

Staniszewska Anna, Korczak Anna, Juszczyk Grzegorz, Duda-Zalewska Aneta, Olejniczak Dominik, Dąbrowska-Bender Marta, Bujalska-Zadrożny Magdalena. Wiedza kursantów ośrodków szkolenia kierowców odnośnie użycia automatycznego defibrylatora zewnętrznego (AED) w trakcie akcji ratunkowej = Students knowledge of driver training center on the use an Automated External Defibrillator (AED) during rescue. Journal of Education, Health and Sport. 2015;5(5):67-75. ISSN 2391-8306. DOI: 10.5281/zenodo.17443http://ojs.ukw.edu.pl/index.php/johs/article/view/2015%3B5%285%29%3A67-75https://pbn.nauka.gov.pl/works/559145http://dx.doi.org/10.5281/zenodo.17443Formerly Journal of Health Sciences. ISSN 1429-9623 / 2300-665X. Archives 2011 – 2014 http://journal.rsw.edu.pl/index.php/JHS/issue/archive Deklaracja.Specyfika i zawartość merytoryczna czasopisma nie ulega zmianie.Zgodnie z informacją MNiSW z dnia 2 czerwca 2014 r., że w roku 2014 nie będzie przeprowadzana ocena czasopism naukowych; czasopismo o zmienionym tytule otrzymuje tyle samo punktów co na wykazie czasopism naukowych z dnia 31 grudnia 2014 r.The journal has had 5 points in Ministry of Science and Higher Education of Poland parametric evaluation. Part B item 1089. (31.12.2014).© The Author (s) 2015;This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland and Radom University in Radom, PolandOpen Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License(http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited.This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercialuse, distribution and reproduction in any medium, provided the work is properly cited.The authors declare that there is no conflict of interests regarding the publication of this paper.Received: 15.02.2015. Revised 27.04.2015. Accepted: 08.05.2015. Wiedza kursantów ośrodków szkolenia kierowców odnośnie użycia automatycznego defibrylatora zewnętrznego (AED) w trakcie akcji ratunkowejStudents knowledge of driver training center on the use an Automated External Defibrillator (AED) during rescue Anna Staniszewska1*, Anna Korczak2, Grzegorz Juszczyk3, Aneta Duda-Zalewska3, Dominik Olejniczak3, Marta Dąbrowska-Bender3, Magdalena Bujalska-Zadrożny4 1 Katedra i Zakład Farmakologii Doświadczalnej i Klinicznej WUM2 SPZOZ Warszawa Wawer3 Zakład Zdrowia Publicznego WUM4 Zakład Farmakodynamiki WUM *autor do korespondencji: dr n. med. Anna StaniszewskaKatedra i Zakład Farmakologii Doświadczalnej i Klinicznej WUMBanacha 1b, 02-097 Warszawa, tel: (22) 116-61-60, e-mail: [email protected] StreszczenieWstęp: Resuscytacja krążeniowo-oddechowa połączona z wczesną defibrylacją w ciągu 3-5 minut od utraty przytomności może dać efektywną reanimację w 49-75% przypadków, zaś każda minuta opóźnienia defibrylacji zmniejsza prawdopodobieństwo przeżycia poszkodowanego o 10-12%.Cel pracy: Praca miała na celu określenie stanu wiedzy przyszłych kierowców, jaką posiadają na temat automatycznych defibrylatorów zewnętrznych oraz ich użycia w trakcie akcji ratunkowej.Materiał i metoda: Badaniem objęto 200 osób, które wypełniły autorską ankietę na temat automatycznych defibrylatorów zewnętrznych. Badanie przeprowadzono na przełomie 2013 i 2014 roku. W badaniu wykorzystano metodę sondażu diagnostycznego, opartą na technice ankietowej z użyciem kwestionariusza ankiety stworzonej na potrzeby pracy. Do analizy j wyników posłużono się metodą statystyki opisowej.Wyniki i Wnioski: Na podstawie analizy odpowiedzi badanych na pytania ankiety stwierdzono, że wiedza kursantów na temat automatycznego defibrylatora zewnętrznego jest niedostateczna, zarówno pod względem znajomości działania AED,  jak i jego lokalizacji. Wyniki przeprowadzonego badania wskazują na konieczność przygotowania i wdrożenia programu edukacyjnego na temat automatycznego defibrylatora zewnętrznego. AbstractIntroduction: Resuscitation cardiopulmonary combined with early defibrillation within 3-5 minutes of unconsciousness can give effective resuscitation cardio-respiratory in 49-75% of cases and each minute of delay defibrillation reduces the probability of survival of the victim by 10-12%.Aim of the study. Evaluation of knowledge  about Automated External Defibrillator among the driver training centers students.Material and methods. A group of 200 person was enrolled in order to evaluate the knowledge  about Automated External Defibrillator by the special designed questionnaire.in late 2013 and 2014.The study used the method of diagnostic survey, questionnaire based on the technique of using a questionnaire survey of his own design. For the comparative analysis results are used by descriptive statistics.Results and conclusions. Results and conclusions. The knowledge about AED, among driver training centers students is inadequate. The results pointed at necessity of preparation and putting AED education program. Słowa kluczowe: wiedza, kursanci ośrodków szkolenia kierowców, automatyczny defibrylator zewnętrzny.Key words: knowledge, driver training centers students, Automated External Defibrillator