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Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)3 Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives. [ABSTRACT FROM AUTHOR]

Objective: Hypertensionis one of the most common chronic diseases, affecting more than 20% of the population. The side effects experienced due to antihypertensive medications, such as tiredness, muscle pain, and insomnia, are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSRs) and following differentiation of messages found in more than one patient. Methods: We conducted a retrospective analysis of the reported adverse drug reactions (ADRs) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) inhibitors, and sartans for the period 2017–2021. Each ICSR form was observed, and data for suspected medicine and type of adverse reaction was analyzed. Results: The total number of processed notifications for adverse drug reactions (ADRs) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29). Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on the Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusions: Cardiovascular medicines from the groups of ACE inhibitors, sartans, and statins have a high share of reported ADRs in the BDA system. Some of them are severe and need further investigation. [ABSTRACT FROM AUTHOR]

Objective: Hypertensionis one of the most common chronic diseases, affecting more than 20% of the population. The side effects experienced due to antihypertensive medications, such as tiredness, muscle pain, and insomnia, are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSRs) and following differentiation of messages found in more than one patient. Methods: We conducted a retrospective analysis of the reported adverse drug reactions (ADRs) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) inhibitors, and sartans for the period 2017–2021. Each ICSR form was observed, and data for suspected medicine and type of adverse reaction was analyzed. Results: The total number of processed notifications for adverse drug reactions (ADRs) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29). Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on the Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusions: Cardiovascular medicines from the groups of ACE inhibitors, sartans, and statins have a high share of reported ADRs in the BDA system. Some of them are severe and need further investigation.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N′-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension. [ABSTRACT FROM AUTHOR]

Adherence to treatment is understood as a complex model of the patient’s behavior in relation to their health, implemented in the degree of compliance of such behavior with respect to the recommendations received from the doctor regarding medications, self-control algorithms, diet and other lifestyle change measures. Adherence can be assessed by determining drug metabolites in body fluids (blood, urine) and using various questionnaires. At the same time, an important role in increasing adherence to therapy is assigned to the attending physician, without contact with which most patients make an independent decision to stop taking all or some of the prescribed drugs or to make an unreasonable correction of their dosages. Among the factors influencing the decrease in adherence to treatment of cardiac patients are the patient’s misunderstanding of their disease and the expected effects of therapy, fears of undesirable effects of therapy, a low level of motivation, a tendency towards forgetfulness and some others. Comorbidity and related polypharmacy also contribute to non-adherence, especially multiple drugs are prescribed simultaneously by various specialists — therapists, endocrinologists, urologists, neurologists, ophthalmologists. At the same time, there is a clear increase in undesirable consequences (repeated hospitalizations due to myocardial infarction and other cardiovascular events) in non-adherent patients 6 months after the previous coronary event and a significantly higher risk a year later. Increasing adherence to treatment is the task of medical workers, starting from the inpatient stage of treatment (clear recommendations noted in the discharge documents), followed by the support of outpatient doctors, explaining the need to take certain medications, and ending with monitoring the execution of medical prescriptions.

Six sartan substances including telmisartan, losartan, valsartan, irbesartan, olmesartan, and candesartan were selected in this work. A simple and sensitive liquid chromatography–tandem mass spectrometry method was developed and validated to simutaniously detect six drugs. Linearity, LOD, and LOQ were satisfied for routine quantitative and qualitative detection. The linearity ranged from 2 to 1000 ng/mL with the determination coefficient more than 0.98. The intra-day and inter-day precisions were all below 27.5%. All the recoveries were above 80%, and matrix effects were between 25 and 120%. Profiling detection of six sartan substances in human urine was also developed after administration. Irbesartan urinary metabolic pathway was firstly investigated by liquid chromatography quadruple time-of-flight mass spectrometry using full scan and targeted tandem mass spectrometry techniques. Fifteen urinary metabolites of irbesartan were identified and characterized, and ten of them were firstly reported. [ABSTRACT FROM AUTHOR]

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.

This study aimed to develop a sensitive and simple liquid chromatography-tandem mass spectrometry for the simultaneous determination of organic azido impurities (AZBC, AZBT, and AZTT) in sartan active pharmaceutical ingredients and drug products. The method employed a HALO C8 column for chromatographic separation using gradient elution, with a mobile phase composed of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Quantification of analytes was achieved using a triple quadrupole mass spectrometer, operating in multiple reaction monitoring mode with positive electrospray ionization. The method was fully validated following the ICH Q2 (R1) guideline, and the validation parameters met the criteria for specificity, carryover, and robustness. The developed method was found to be sufficiently sensitive, with LOD and LOQ below the acceptable limits of azido impurities in pharmaceuticals as per the ICH M7 guideline. The assay had dynamic ranges of 1.00–20.00 ng/mg for AZBC and 0.10–15.00 ng/mg for AZBT and AZTT in sartans. In conclusion, the established method was effectively utilized for determining azido impurities in sartan active pharmaceutical ingredients and drug products, achieving high accuracy and precision.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N′-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

[Display omitted] Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N -nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed. [ABSTRACT FROM AUTHOR]

The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20 years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particularly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical “tips” with respect to handling N-nitrosamines chemical assessments. [ABSTRACT FROM AUTHOR]

Nitrosamines are compounds that have a harmful effect on the organisms of animals and humans. The first information about their teratogenic, mutagenic, and genotoxic effects appeared in the mid-twentieth century. The source of nitrosamines in the human environment are, among others, cold cuts, processed meat, drinking water, tobacco smoke, and some plastics. The discovery of the presence of nitrosamines in some medicinal products was received with great concern in 2018. The first group of drugs in which the presence of carcinogenic compounds was proven were sartans (valsartan, losartan, and irbesartan), and then also metformin, ranitidine, nizatidine, rifapentin, and rifampicin. Some of the medicinal products on the market were discontinued, and after the presence of nitrosamines was confirmed, they were withdrawn. Then, the investigations on the cause of the presence of such harmful compounds in the drugs were carried out. It turned out that in the case of three medicinal substances from the group of sartans, nitrosamines were impurities from the synthesis process, formed in the stage of tetrazole ring formation from organic or inorganic azides. In the case of macrolide antibiotics from the ansamycin group, nitrosamines were also process-related impurities, and in the case of metformin, ranitidine and nizatidine, they turned out to be degradation products of medicinal compounds. When it was discovered that nitrosamines could be present in some drugs used in the treatment of hypertension for over 5 years, that is from the last modification of the synthesis by the manufacturer of the drug substance, retrospective observational studies were carried out, in which the level of cancer risk associated with taking contaminated preparations was established. Analytical methods for the determination of nitrosamines in medicinal substances and medicinal products based on liquid or gas chromatography coupled with mass spectrometry have been developed. Moreover, testing procedures and stringent guidelines for the content of nitrosamines were introduced to the 10th edition of the European Pharmacopoeia to guarantee the appropriate quality of drugs, ensuring safe therapy.

This research introduces a novel approach for detecting sartan antihypertensive drug adulteration in herbal oral liquids using cotton fiber-supported liquid extraction (CF-SLE) combined with high-performance liquid chromatography-fluorescence detection (HPLC-FLD). Optimal extraction parameters were determined through systematic method development, establishing a sample solution with a pH of 3.0, using 200 mg of cotton fiber, ethyl acetate as the extraction solvent, and a solvent volume of 4 mL. These conditions demonstrated robust extraction efficiency and were further validated for precision and accuracy, with intra- and inter-day relative standard deviations consistently below 7.5 % and relative recoveries ranging from 88.5 % to 106.1 %. The method exhibited excellent linearity for sartans, with R² values greater than 0.993 across a concentration range of 10–2000 ng/mL. Detection limits were effectively established in the range of 2.6–3.1 ng/mL, indicating that the method's sensitivity is adequate for the intended screening purposes. This validated method was then applied to real sample analysis, confirming its potential for routine use in detecting illegal additives within complex herbal matrices, thereby ensuring consumer safety and supporting regulatory compliance. • A new CF-SLE-HPLC-FLD method for detecting sartan adulteration was developed. • Sustainable cotton fiber was employed, achieving high extraction efficiency. • Excellent linearity and sensitivity were obtained (detection limits: 2.6–3.1 ng/mL). • Validated method showed high precision (RSDs < 7.5 %) and recoveries (88.5 %-106.1 %). • The method can effectively screen for illegal additives in complex herbal oral liquids. [ABSTRACT FROM AUTHOR]

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as “bisartans” is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2+ domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681–686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric “warhead” of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

Nitrosamine impurities have been classified as probable human carcinogens for decades. These impurities were reported in water, food, tobacco, pesticides, and plastics but received attention in mid-2018 when N-nitrosodimethylamine (NDMA) was reported in valsartan drug products. Subsequently, it was revealed that several small molecule and complex nitrosamine impurities can form in any active pharmaceutical ingredient (API) or drug product in which secondary or tertiary amines are present (as API or as impurities) along with a nitrosating agent. Consequently, regulators have provided several guidelines for the risk assessment of nitrosamine formation during manufacturing, storage, or from contaminated supply chains. This has led to a demand for validated analytical methods that quantify N-nitrosamine impurities in pharmaceutical products. In this study, a highly sensitive and robust analytical method was developed and validated for quantitatively determining up to 15 small nitrosamines at low levels (0.01 ppm) in sartan drug substances. The study also suggests that this method can be extended not only to corresponding sartan drug products but could also be used as a generic screening method to test a variety of drug substances, and drug products with the minimum required optimization of method conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

A number of studies have now been conducted confirming the relationship between arterial hypertension (AH) and nonalcoholic fatty liver disease (NAFLD). It has been proved that the presence of AH increases or provokes the development of NAFLD. A study of telmisartan effectiveness in combination with atorvastatin and ursodeoxycholic acid (UDCA) in patients with AH and NAFLD was carried out in this article. Material and methods. The study included 39 patients diagnosed with arterial hypertension in combination with NAFLD, who were treated with a combination of drugs: Telmisartan, Atorvastatin and UDCA for 12 weeks. The comparison group consisted of 33 patients with NAFLD who received basic NAFLD therapy without telmisartan and atorvastatin. The study analyzed the efficacy of the prescription of this combination on the clinical condition of patients with AH combined with NAFLD, their hemodynamic parameters, the levels of blood lipid spectrum, IL-6, leptin, adiponectin, and the dynamics of echocardiographic and ultrasonographic parameters. Results and discussion. It has been revealed, that application of telmisartan, atorvastatin and UZHK combination for 12 weeks significantly reduced BP levels to the target values, improved hemodynamic indexes, led to reduction of atherogenic components of blood lipid spectrum. And also prescription of this combination decreased IL-6 and leptin levels, increased adiponectin content, which contributed to improvement of the general state of patients, decrease in the severity of clinical and functional manifestations of NAFLD.

In the current study, a feasible and sensitive liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) method was developed and validated for the determination of eight nitrosamines in Sartan active pharmaceutical ingredients (APIs). The proposed LC-APCI-MS/MS method was validated as per regulatory guidelines. The limit of detection and limit of quantification was found to be in the range of 0.32–1.58 ng/mL, 1.09–4.74 ng/mL, and the recovery was in the range of 86.4–109.6% for Sartan APIs, and 82.1–114.1% for Sartan final products, respectively. The calibration curves of all nitrosamines in the concentration range of 2–100 ng/mL were carried out, and the coefficient of determination (R2) was found to be in the range of 0.9990–0.9999. The robustness of the present method was within the acceptance (

The potential of targeting the Renin-Angiotensin-Aldosterone System (RAAS) as a treatment for the coronavirus disease 2019 (COVID-19) is currently under investigation. One way to combat this disease involves the repurposing of angiotensin receptor blockers (ARBs), which are antihypertensive drugs, because they bind to angiotensin-converting enzyme 2 (ACE2), which in turn interacts with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. However, there has been no in silico analysis of the potential toxicity risks associated with the use of these drugs for the treatment of COVID-19. To address this, a network-based bioinformatics methodology was used to investigate the potential side effects of known Food and Drug Administration (FDA)-approved antihypertensive drugs, Sartans. This involved identifying the human proteins targeted by these drugs, their first neighbors, and any drugs that bind to them using publicly available experimentally supported data, and subsequently constructing proteomes and protein–drug interactomes. This methodology was also applied to Pfizer’s Paxlovid, an antiviral drug approved by the FDA for emergency use in mild-to-moderate COVID-19 treatment. The study compares the results for both drug categories and examines the potential for off-target effects, undesirable involvement in various biological processes and diseases, possible drug interactions, and the potential reduction in drug efficiency resulting from proteoform identification.

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1–7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells. [ABSTRACT FROM AUTHOR]

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE's protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE's ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19. [ABSTRACT FROM AUTHOR]

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N -nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of "supersartans", called "bisartans", bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of "supersartans" referred to herein as "bisartans", bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: During the 2019 Coronavirus pandemic (COVID-19), a concern emerged regarding a possible correlation between the severe form of SARS-CoV-2 infection and administration of ACE-Inhibitors (ACE-I) and Sartans (ARB), since long-term use of these drugs may potentially result in an adaptive response with up-regulation of the ACE 2 receptor. Given the crucial role of ACE2, being the main target for virus entry into the cell, the potential consequences of ACE2 up-regulation have been a source of debate. The aim of this retrospective cohort study on COVID-19-positive patients who died is to investigate whether previous long-term exposure to ACE-I and/or ARB was associated with higher mortality due to COVID-19 infection, compared to all other types of drug treatment. Methods: We analysed the clinical and demographic data of 615 patients hospitalized for COVID-19 at the two hospitals of the Vasta Area n.5, between March 2020 and April 2021. Among them, 86 patients, treated with ACE-Is and/0 ARBs for about 12 months, died during hospitalization following a diagnosis of acute respiratory failure. Several quantitative and qualitative variables were recorded for all patients by reading their medical records. Results: The logistic model showed that the variables that increase mortality are age and comorbid diseases. There were no demonstrable mortality effects with ACE-I and ARB intake. Conclusions: The apparent increase in morbidity in patients with COVID-19 who received long-term treatment with ACE-I or ARB is not due to the drugs themselves, but to the conditions associated with their use. [ABSTRACT FROM AUTHOR]

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In the present study, the uptake and metabolization of the sartan drug telmisartan by a series of plants was investigated. Thereby for seven potential metabolites, modifications on the telmisartan molecule such as hydroxylation and/or glycosylation could be tentatively identified. For two additional signals detected at accurate masses m/z 777.3107 and m/z 793.3096, no suggestions for molecular formulas could be made. Further investigations employing garden cress (Lepidium sativum) as a model plant were conducted. This was done in order to develop an analytical method allowing the detection of these substances also under environmentally relevant conditions. For this reason, the knowledge achieved from treatment of the plants with rather high concentrations of the parent drug (10 mg L−1) was compared with results obtained when using solutions containing telmisartan in the μg - ng L−1 range. Thereby the parent drug and up to three tentative drug-related metabolites could still be detected. Finally cress was cultivated in water taken from a local waste water treatment plant effluent containing 90 ng L−1 of telmisartan and harvested and the cress roots were extracted. In this extract, next to the parent drug one major metabolite, namely telmisartan-glucose could be identified. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) is a receptor for the spike protein of SARS-COV-2 that allows viral binding and entry and is expressed on the surface of several pulmonary and non-pulmonary cell types, with induction of a "cytokine storm" upon binding. Other cell types present the receptor and can be infected, including cardiac, renal, intestinal, and endothelial cells. High ACE2 levels protect from inflammation. Despite the relevance of ACE2 levels in COVID-19 pathogenesis, experimental studies to comprehensively address the question of ACE2 regulations are still limited. A relevant observation from the clinic is that, besides the pro-inflammatory cytokines, such as IL-6 and IL-1β, the anti-inflammatory cytokine IL-10 is also elevated in worse prognosis patients. This could represent somehow a "danger signal", an alarmin from the host organism, given the immuno-regulatory properties of the cytokine. Here, we investigated whether IL-10 could increase ACE2 expression in the lung-derived Calu-3 cell line. We provided preliminary evidence of ACE2 mRNA increase in cells of lung origin in vitro , following IL-10 treatment. Endothelial cell infection by SARS-COV-2 is associated with vasculitis, thromboembolism, and disseminated intravascular coagulation. We confirmed ACE2 expression enhancement by IL-10 treatment also on endothelial cells. The sartans (olmesartan and losartan) showed non-statistically significant ACE2 modulation in Calu-3 and endothelial cells, as compared to untreated control cells. We observed that the antidiabetic biguanide metformin, a putative anti-inflammatory agent, also upregulates ACE2 expression in Calu-3 and endothelial cells. We hypothesized that IL-10 could be a danger signal, and its elevation could possibly represent a feedback mechanism fighting inflammation. Although further confirmatory studies are required, inducing IL-10 upregulation could be clinically relevant in COVID-19-associated acute respiratory distress syndrome (ARDS) and vasculitis, by reinforcing ACE2 levels. [ABSTRACT FROM AUTHOR]

Brothers of women with polycystic ovary syndrome (PCOS) were found to be at increased risk for cardiometabolic disorders. This risk may be exacerbated by concurrent poorly controlled hypertension. Angiotensin II receptor blockers are the most frequently used antihypertensive drugs. The aim of the present study was to compare blood pressure‐lowering and pleiotropic effects of telmisartan between male siblings of PCOS probands and unrelated men. The study included 2 age‐, blood pressure‐, and mass index‐matched groups of men with grade 1 hypertension: 24 brothers of women with PCOS (group A) and 26 brothers of healthy women (group B). All subjects were treated with telmisartan (80 mg daily). Blood pressure, glucose homeostasis markers, and plasma lipids, as well as plasma levels of total testosterone, bioavailable testosterone, androstenedione, uric acid, high‐sensitivity C‐reactive protein (hsCRP), homocysteine, fibrinogen, and 25‐hydroxyvitamin D were measured before and after 12 weeks of therapy. At entry, there were between‐group differences in the degree of insulin resistance, plasma levels of high‐density lipoprotein‐cholesterol, triglycerides, calculated bioavailable testosterone, androstenedione, hsCRP, and 25‐hydroxyvitamin D. Although telmisartan reduced blood pressure in both study groups, this effect was stronger in group B. Irrespective of the study group, the drug improved insulin sensitivity and reduced circulating levels of uric acid and homocysteine, but these effects were more pronounced in group B than group A. Only in group B, telmisartan decreased hsCRP and fibrinogen, as well as increased 25‐hydroxyvitamin D. The obtained results suggest that hypertensive male relatives of PCOS probands may gain less benefit from telmisartan treatment than unrelated hypertensive men. [ABSTRACT FROM AUTHOR]

The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence. Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens. Regulators first became aware of the presence of nitrosamines in EU medicines in 2018, with reports of detection of N-nitroso-dimethylamine (NDMA) in valsartan from one manufacturer. A subsequent EU review of all valsartan medicines was triggered by the European Medicines Agency (EMA) and was later extended to other angiotensin receptor blockers/sartans. A separate review was also started for ranitidine medicines. This was followed by an EU-wide examination of the risk of presence of nitrosamines in all human medicines. This article reflects on the investigation of the EU regulatory network into the presence of nitrosamines and the scientific knowledge informing recommendations for developers on how to limit nitrosamines in medicines.

A rapid, synchronized liquid chromatographic method was established for the estimation of hydrochlorothiazide (HCZ), amlodipine (AMD), olmesartan (OLM), telmisartan (TEL), and irbesartan (IRB) in binary and ternary coformulations using the same chromatographic conditions. Five analytes were separated on a Zorbax C18 column using isocratic elution with a mobile phase consisting of acetonitrile, methanol, and 20 mM phosphate buffer (pH 3.5) in a ratio of 45:20:35% v/v. The analytes were detected at a wavelength of 230 nm at ambient temperature. Furthermore, the proposed liquid chromatographic procedure was validated for linearity, precision, accuracy, stability, and robustness using an experimental design. Analytes were separated with good resolution within 3.5 min. Analytes showed good linearity in a concentration satisfactory to analyze the different ratios of these analytes in the formulations. Pareto charts showed that the flow rate and mobile phase composition have a significant effect on the peak area of analytes and hence need to be carefully controlled, however, the method is robust. Finally, the different formulations consisting of HCZ, AMD, OLM, TEL, and IRB in different ratios were analyzed with high accuracy using an optimized HPLC method and compared with reported methods. Furthermore, the reported HPLC procedure is simple, rapid, and accurate and therefore can used for regular quality control of binary and ternary formulations using the same stationary and mobile phase. [ABSTRACT FROM AUTHOR]

• Modelling of micropollutant degradation by ozonation in reverse osmosis concentrate. • Assessment of bromate formation during ozonation of RO concentrate. • X-ray contrast media treatment in RO concentrate by UV/persulfate oxidation. • Determination of sulfateradical and hydroxyl radical reaction rate constants of irbesartan and candesartan. This study investigated the elimination of pharmaceuticals, corrosion inhibitors, x-ray contrast media and perfluorinated compounds from reverse osmosis concentrates during ozonation and UV/persulfate processes. Second-order rate constants for the reactions of candesartan, irbesartan, methyl-benzotriazole, and chloro‑benzotriazole with sulfate radical (SO 4 ·−) were determined for the first time. Experiments were conducted in buffered pure water, in buffered water added with the matrix substituents chloride, carbonate, NOM, and reverse osmosis concentrate with spiked micropollutants (MP). UV/persulfate eliminated all MP to a higher extent than ozonation in RO concentrates due to the higher yield of oxidative species and photolytic degradation. Compounds with electron-rich moieties such as carbamazepine, diclofenac, metoprolol, and sulfamethoxazole were completely eliminated with small ozone doses (< 0.5 mg O 3 / mg DOC) and with a small fluence (< 5000 J m−2) in UV/persulfate processes. Photosensitive compounds with high reactivity towards hydroxyl radicals (·OH) and SO 4 ·− like the x-ray contrast media Iopamidol, Iohexol, and Amidotrizoic acid were successfully eliminated with a reasonable fluence in UV/persulfate, whereas these compounds persist in ozonation at common ozone dosages. However, much higher fluences and ozone dosages were required for the least reactive compounds like the class of benzotriazoles. Comparing the application of both oxidative processes to the RO concentrate, ozonation has the disadvantage of forming bromate. The energy input of both processes strongly depends on the target compounds to be eliminated. For the elimination of compounds such as sulfamethoxazole, ozonation is a feasible technique, whereas UV/persulfate is better suited for the elimination of recalcitrant compounds such as x-ray contrast media. In general, oxidative process treatment of RO concentrate could be applied to partly abate micropollutants before discharge. [Display omitted] [ABSTRACT FROM AUTHOR]

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE’s protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE’s ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.

A hydrophobic gadolinium-based magnetic ionic liquid (MIL) was investigated for the first time as an extraction solvent in dispersive liquid–liquid microextraction (DLLME). The tested MIL was composed of trihexyl(tetradecyl)phosphonium cations and paramagnetic gadolinium chloride anions. The prepared MIL showed low water miscibility, reasonable viscosity, markedly high magnetic susceptibility, adequate chemical stability, low UV background, and compatibility with reversed-phase HPLC solvents. These features resulted in a more efficient extraction than the corresponding iron or manganese analogues. Accordingly, the overall method sensitivity and reproducibility were improved, and the analysis time was reduced. The applicability of the proposed MIL was examined through the microextraction of four sartan antihypertensive drugs from aqueous samples followed by reversed-phase HPLC with UV detection at 240 nm. The DLLME procedures were optimized for disperser solvent type, MIL mass, disperser solvent volume, as well as acid, base, and salt addition. The limits of quantitation (LOQs) obtained with the analysis of 1.2-mL samples after DLLME and HPLC were 80, 30, 40, and 160 ng/mL for azilsartan medoxomil, irbesartan, telmisartan, and valsartan, respectively. Correlation coefficients were greater than 0.9988 and RSD values were in the range of 2.48–4.07%. Under the optimized microextraction conditions and using a 5-mL sample volume, enrichment factors were raised from about 40 for all sartans using a 1.2-mL sample to 175, 176, 169, and 103 for azilsartan medoxomil, irbesartan, valsartan, and telmisartan, respectively. The relative extraction recoveries for the studied sartans in river water varied from 82.5 to 101.48% at a spiked concentration of 0.5 μg/mL for telmisartan and irbesartan and 1 μg/mL for azilsartan medoxomil and valsartan. [ABSTRACT FROM AUTHOR]

Background: Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid., Research Design and Methods: Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries., Results: Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%-80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2)., Conclusion: This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

Background/Aims: The peptide hormone angiotensin II (ATII) plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT1), the stimulation of which induces an increase in cytosolic [Ca2+] and calmodulin activation. Ca2+-bound (activated) calmodulin stimulates the activity of the Na+/ H+ exchanger isoform 1 (NHE1); and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT1 receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT1 mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3) cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca2+] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT1 and the angiotensin II receptor type 2 (AT2). Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca2+/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT1 was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT2 inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT1 antagonists (sartans) in hypertensive cancer patients should therefore be given critical consideration.

Clinical and pharmacological characteristics of elderly patients hospitalized for bleeding and in-hospital mortality according to bleeding type are barely described. Retrospective cohort study of 13,496 consecutive patients admitted to internal medicine wards. Clinical characteristics, comorbidities and pharmacological treatments were collected for each patient. Predictors of in-hospital mortality were investigated. Overall, 531 (3.9%) patients were admitted for bleeding: 189 clinically relevant non-major bleeding, 106 cerebral and 236 major non-cerebral (95.8% gastrointestinal (GI)). Among 106 cerebral bleedings, 28.3% and 24.5% were typical and atypical intracranial, respectively, and 47.2% were subdural haemorrhages. Most of patients with GI bleeding presented with anaemia (90.7%). A similar rate of GI bleeding was found in aspirin-treated patients taking or not proton pump inhibitors (PPI). In-hospital mortality was 9.98%. Age ≥80 years (odds ratio (OR) 2.513, p=.005), cerebral bleeding (OR 5.373, p<.001), eGFR <30 ml/min/m2 (OR 2.388, p=.035) and COPD (OR 2.362, p=.024) were positively associated with mortality, while ACE inhibitors/ARBs use was negatively associated (OR 0.383, p=.028). The most frequent type of major haemorrhage was GI bleeding, which was not modified by the use of PPI in patients taking aspirin. Cerebral bleeding increased all-cause death, which was lower in ACE inhibitors/ARBs users. Gastrointestinal (GI) bleeding was the most common reason for hospital admission. The rate of GI bleeding was similar in patients on aspirin using or not PPI. Cerebral bleeding increased in-hospital mortality, which was lower in patients taking ACE inhibitors/ARBs. [ABSTRACT FROM AUTHOR]

The chronic extension of heart and blood-vessel walls due to hypertension leads to metabolic disorders in their interstitial matrix. To assess involutive and hypertensive changes in the cardiac and vascular interstitial matrix and to assess the their potential correction with Valsartan and Veroshpiron, 30 normotensive elderly women and 30 patients of the same age with stage-II arterial hypertension (AH) have been examined. Echocardiography and Doppler cardiography were carried out, the volume fraction of interstitial collagen (VFIC) in the myocardium and cardiovascular conjugation (CVC) was measured, and the serum concentrations of systemic collagenogenesis markers were determined. In elderly patients with AH, a higher intensity of LV myocardial fibrosis was found with a statistically significant increase in VFIC as compared to the patients with normal tension. This was due to the increased activity of fibrosis markers. A decrease in their levels was observed after antihypertensive therapy, which proved the antifibrotic effect of the therapy. [ABSTRACT FROM AUTHOR]

An incident of sartan medicine contamination was notified by Europe in June 2018. The contaminant was identified as a probable carcinogenic nitrosamine and the recalls of sartan medicines were soon made. Since then, more nitrosamine contaminants in sartan medicines were reported. To broaden the applicability and variety in nitrosamine determination, a multi-analyte method is required. In this study, a feasible and sensitive multi-analyte LC-MS/MS method for determination of 12 nitrosamines in sartans was established, where the active pharmaceutical ingredients and final products merchandised in Taiwan were also examined. Chromatographic separation was achieved on an Xselect® HSS T3 column (15 cm x 3 mm i.d., 3.5 mm) with gradient elution using mobile phase A consisting of 0.1% formic acid in water and mobile phase B consisting of 0.1% formic acid in acetonitrile/methanol (2:8). Validation of the proposed method was also carried out. The limit of detection and limit of quantification for 12 nitrosamines were 20 ng/g and 50 ng/g, respectively. The intra-day and inter-day recoveries of nitrosamines were among 80e120% with precision of 20% for most nitrosamines within sartans matrices. The method was successfully established and applied to authentic samples which a total of 98 positive samples containing 5 distinct nitrosamines, including N-nitrosodiethylamine, N-nitrosodimethylamine, N-nitroso-N-methyl-4-aminobutyric acid, N-nitrosomorpholine and Nnitrosopiperidine, were detected from 557 authentic samples. [ABSTRACT FROM AUTHOR]

Aims: Polypharmacy is one of the most typical features of geriatrics. Unreliable drug usage belongs to its risks, among others. One way of reducing this risk is to integrate more drugs into one tablet (polypill). Nowadays this could be done especially in cardiovascular medicine. Real world data from the health care provided in Slovakia, which would reflect the potential for switching from more tabs with one drug towards the polypill in seniors, are almost unknown. Methods: We used the "Slovak Audit of atrial FIbrillation Study" (SAFIS) data (3 706 patients, average age 80.5 years) and evaluated how frequently patients had the combination of an angiotensin converting enzyme inhibitor (ACEI) or an AT1-receptor for angiotensin II inhibitor (ARB) and a diuretic, an ACEI/ARB and a betablocker (BB), an ACEI/ARB and a statin or at least 3 out of these 4 drug groups at discharge. Results: The average number of recommended drugs was 9.1 at discharge. A diuretic, BB, statin or ACEI/ARB was recommended in 68.9, 64.1, 31.9 and 52.4% of patients respectively. Simultaneous treatment with a diuretic and an ACEI/ARB, BB and an ACEI/ARB, statin and an ACEI/ARB was recommended in 37.9, 36.2, and 19.7% patients respectively. The frequency of these co-treatments was typically higher than 40% in 65-79 yrs. old, declining with age moderately, but staying above 20% even in the oldest (90 yrs. and older) for combinations of an ACEI/ARB with a diuretic or a BB. At least 3 drugs from the groups ACEI/ARB, BB, diuretics, statins were recommended in 38.6% of patients. Conclusion: The potential for the reduction of the number of daily used tablets with their integration in a polypill is really high in seniors. [ABSTRACT FROM AUTHOR]

Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.

A rapid, synchronized liquid chromatographic method was established for the estimation of hydrochlorothiazide (HCZ), amlodipine (AMD), olmesartan (OLM), telmisartan (TEL), and irbesartan (IRB) in binary and ternary coformulations using the same chromatographic conditions. Five analytes were separated on a Zorbax C18 column using isocratic elution with a mobile phase consisting of acetonitrile, methanol, and 20 mM phosphate buffer (pH 3.5) in a ratio of 45:20:35% v/v. The analytes were detected at a wavelength of 230 nm at ambient temperature. Furthermore, the proposed liquid chromatographic procedure was validated for linearity, precision, accuracy, stability, and robustness using an experimental design. Analytes were separated with good resolution within 3.5 min. Analytes showed good linearity in a concentration satisfactory to analyze the different ratios of these analytes in the formulations. Pareto charts showed that the flow rate and mobile phase composition have a significant effect on the peak area of analytes and hence need to be carefully controlled, however, the method is robust. Finally, the different formulations consisting of HCZ, AMD, OLM, TEL, and IRB in different ratios were analyzed with high accuracy using an optimized HPLC method and compared with reported methods. Furthermore, the reported HPLC procedure is simple, rapid, and accurate and therefore can used for regular quality control of binary and ternary formulations using the same stationary and mobile phase.