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

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

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles

Reduction of the Inflammatory Responses against Alginate-Poly-L-Lysine Microcapsules by Anti-Biofouling Surfaces of PEG-b-PLL Diblock Copolymers

Large-scale application of alginate-poly-L-lysine (alginate-PLL) capsules used for microencapsulation of living cells is hampered by varying degrees of success, caused by tissue responses against the capsules in the host. A major cause is proinflammatory PLL which is applied at the surface to provide semipermeable properties and immunoprotection. In this study, we investigated whether application of poly(ethylene glycol)-block-poly(L-lysine hydrochloride) diblock copolymers (PEG-b-PLL) can reduce the responses against PLL on alginate-matrices. The application of PEG-b-PLL was studied in two manners: (i) as a substitute for PLL or (ii) as an anti-biofouling layer on top of a proinflammatory, but immunoprotective, semipermeable alginate-PLL100 membrane. Transmission FTIR was applied to monitor the binding of PEG-b-PLL. When applied as a substitute for PLL, strong host responses in mice were observed. These responses were caused by insufficient binding of the PLL block of the diblock copolymers confirmed by FTIR. When PEG-b-PLL was applied as an anti-biofouling layer on top of PLL100 the responses in mice were severely reduced. Building an effective anti-biofouling layer required 50 hours as confirmed by FTIR, immunocytochemistry and XPS. Our study provides new insight in the binding requirements of polyamino acids necessary to provide an immunoprotective membrane. Furthermore, we present a relatively simple method to mask proinflammatory components on the surface of microcapsules to reduce host responses. Finally, but most importantly, our study illustrates the importance of combining physicochemical and biological methods to understand the complex interactions at the capsules' surface that determine the success or failure of microcapsules applicable for cell-encapsulation