In recent years, the field of analytical chemistry has witnessed a notable shift towards the adoption of greener chromatographic methods, aiming to minimize the environmental impact. An effective strategy involves substituting conventional harmful organic solvents with environmentally friendly alternatives, reducing the use of hazardous chemicals that contribute to environmental concerns. However, separating drug substances without the use of buffers and organic solvents presence is a big challenge. To overcome this challenge, a combination of quality-by-design (QbD) and green analytical chemistry (GAC) was employed in this study for method development. A high-performance liquid chromatography (HPLC) method was successfully developed and validated for the simultaneous determination of Nebivolol hydrochloride, Telmisartan, Valsartan, and Amlodipine besylate. The method utilized a mobile phase composed of a mixture of 0.1 % formic acid in water (pH: 2.5) and ethanol. A regular octadecyl silica (ODS) column was employed, and UV detection at 220 nm was utilized. The method exhibited linearity within the concentration range of 25-75 μg/mL for Telmisartan and 150-450 μg/mL for Nebivolol Hydrochloride, Valsartan, and Amlodipine besylate and the correlation coefficient was greater than 0.999 for all the analytes. Limits of detection (LOD) and quantification (LOQ) were determined as 0.01 and 0.04 μg/mL for Telmisartan, 0.06 and 0.20 μg/mL for Nebivolol Hydrochloride, 0.08 and 0.25 μg/mL for Amlodipine besylate, and 0.14 and 0.46 μg/mL for Valsartan, respectively. The developed method underwent thorough validation, encompassing various parameters such as linearity, accuracy, precision, LOD, LOQ, robustness, and ruggedness. The mean recovery values were observed to range between 98.86 % and 99.89 %. The accuracy demonstrated was consistently above 98.98 % for both intra-day and inter-day precisions were with the relative standard deviations less than 2 %. To establish its robustness, a quality-by-design-based experimental design (DoE) approach was implemented. Additionally, the method\'s environmental friendliness was evaluated using the Analytical Greenness metric (AGREE) an analytical eco scale, both confirming its alignment with sustainable practices and reduced ecological impact. The sustainability of the solvent used in the current study was evaluated by Green Solvents Selecting Tool (GSST) Further, the developed method greenness was evaluated with the green analytical tools such as Analytical method greenness score (AMGS) and using the recently released White Analytical Chemistry (WAC) using RGB assessment tool. By employing this greener approach to chromatography method, this study contributes to the ongoing efforts in analytical chemistry to promote sustainable practices and minimize the environmental footprint of analytical methods.

OBJECTIVE: The Action To promote brain HEalth iN Adults study aimed to determine the feasibility and applicability of recruitment using home blood pressure (BP) monitoring, routine blood biochemistry and videoconference measures of cognition, in adults at high risk of dementia.
METHODS: A decentralised double-blind, placebo-controlled, randomised feasibility trial with a four-stage screening process.
METHODS: Conducted with participants online in the state of New South Wales, Australia.
METHODS: Participants were aged 50-70 years with moderately elevated BP (systolic >120 and <160 mm Hg or diastolic >80 and <95 mm Hg) and ≥1 additional enrichment risk factor of monotherapy treatment of hypertension, diabetes mellitus, elevated low-density lipoprotein cholesterol, obesity, current smoking or a first degree relative with dementia, which indicated an elevated risk for future cognitive decline.
METHODS: Triple Pill (active antihypertensive treatment of telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg) or placebo Triple Pill (blinded study capsules).
METHODS: Primary outcome was feasibility of the study expressed as the percentage of participants randomised from those who were screened. Secondary outcomes were the applicability of videoconference measures of cognition and the overall trial, tolerability of the Triple Pill, safety outcomes and medication adherence.
RESULTS: The proportion (95% CI) of patients randomised to those screened was 5% (2%-10%). The applicability of the trial expressed as percentage of those who completed all remote assessments over the number of randomised participants was 67% (95% CI 05 to 22%). There were no serious adverse events or withdrawals from treatment. All participants adhered to study medication, except for one person who had two capsules left at the end of the study period.
CONCLUSIONS: The feasibility of this decentralised trial on BP lowering in patients at high risk for dementia is low. However, the applicability of remote assessments of cognitive function is acceptable.
BACKGROUND: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000121864.

Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.

This study aimed to elucidate the impact of variations in liver enzyme activity, particularly CYP3A4, on the metabolism of furmonertinib. An in vitro enzyme incubation system was established for furmonertinib using liver microsomes and recombinant CYP3A4 baculosomes, with analytes detected by LC-MS/MS. The pharmacokinetic characteristics of furmonertinib were studied in vivo using Sprague-Dawley rats. It was found that telmisartan significantly inhibited the metabolism of furmonertinib, as demonstrated by a significant increase in the AUC of furmonertinib when co-administered with telmisartan, compared to the furmonertinib-alone group. Mechanistically, it was noncompetitive in rat liver microsomes, while it was mixed competitive and noncompetitive in human liver microsomes and CYP3A4. Considering the genetic polymorphism of CYP3A4, the study further investigated its effect on the kinetics of furmonertinib. The results showed that compared to CYP3A4.1, CYP3A4.29 had significantly increased activity in catalyzing furmonertinib, whereas CYP3A4.7, 9, 10, 12, 13, 14, 18, 23, 33, and 34 showed markedly decreased activity. The inhibitory activity of telmisartan varied in CYP3A4.1 and CYP3A4.18, with IC50 values of 8.56 ± 0.90 μM and 27.48 ± 3.52 μM, respectively. The key loci affecting the inhibitory effect were identified as ARG105, ILE301, ALA370, and LEU373. Collectively, these data would provide a reference for the quantitative application of furmonertinib.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Microplastics have emerged as pervasive pollutants in aquatic environments, and their interaction with organic contaminants poses a significant environmental challenge. This study aimed to explore the adsorption of micropollutants onto microplastics in a river, examining different plastic materials and the effect of aging on adsorption capacity. Microplastics (low-density polyethylene (LDPE), polyethylene terephthalate (PET), and polyvinyl chloride (PVC)) were introduced into a river stream, and a comprehensive analysis involving 297 organic pollutants was conducted. Passive samplers were deployed to monitor micropollutant presence in the river. Sixty-four analytes were identified in the river flow, with telmisartan being the most prevalent. Nonaged PVC showed the highest telmisartan concentration at 279 ng/g (168 ng/m2 regarding the microplastic surface), while aged PVC exhibited a fourfold decrease. Conversely, aged LDPE preferentially adsorbed metoprolol and tramadol, with concentrations increasing 12- and 3-fold, respectively, compared to nonaged LDPE. Azithromycin and clarithromycin, positively charged compounds, exhibited higher sorption to PET microplastics, regardless of aging. Diclofenac showed higher concentrations on nonaged PVC compared to aged PVC. Aging induced structural changes in microplastics, including color alterations, smaller particle production, and increased specific surface area. These changes influenced micropollutant adsorption, with hydrophobicity, dissociation constants, and the ionic form of pollutants being key factors. Aged microplastics generally showed different sorption properties. A comparison of microplastics and control sand particles indicated preferential micropollutant sorption to microplastics, underscoring their role as vectors for contaminant transport in aquatic ecosystems. Analysis of river sediment emphasized the significance of contact time in pollutant accumulation. Overall, this study provides insights into the complex interactions between microplastics and organic pollutants under environmental conditions and contributes to a better understanding of the fate and behavior of these two types of contaminants in aquatic ecosystems.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 μM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

The study explores anticancer potential of telmisartan (TS) loaded lipid nanocarriers (TLNs) in glioma cells as a potential repurposing nanomodality along with estimation of drug availability at rat brain. Experimental TLNs were produced by previously reported method and characterized.In vitroanticancer efficacy of experimental TLNs was estimated by MTT, confocal microscopy, and FACs analysis in glioma cells. Plasma and brain pharmacokinetic (PK) parameters were also analysed by LCMS/MS. Spherical, nanosized, homogenous, unilamellar, TLNs were reported having desirable drug loading (9.5% ± 0.6%), negative zeta potential and sustained TS release tendency. FITC-TLNs were sufficiently internalized into U87MG cells line within 0.5 h incubation period. IC50for TLNs was considerably higher than free TS in the tested glioma cell lines. Further, TLNs induced superior apoptotic effect in U87MG cells than TS. PK (plasma/brain) data depicted higher AUC,Vss, MRT with lower Cltfor TLNs suggesting improved bioavailability,in vivoresidence and sustained drug availability than free TS administration. Docking studies rationalizedin vitro/in vivoresults as preferably higher binding affinity (docking score:12.4) was detected for TS with glioma proteins. Further,in vivostudies in glioma bearing xenograft model is underway for futuristic clinical validation of TLNs.

Angiotensin II (ANG II) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high-resolution renal arterial (RA) impedance. This study examines the effects of ANG II and its type 1 receptor blocker telmisartan (TELM) on RA impedance. In baroreflex-deactivated rats, we measured RA pressure (Pr) and blood flow (Fr) during random ventricular pacing to induce pressure fluctuation at three different mean Pr (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from Fr to Pr. The RA impedance was found to align with a three-element Windkessel model consisting of proximal (Rp) and distal (Rd) resistance and compliance (C). Our study showed Rd reflected the composite characteristics of afferent and efferent arterioles. Rd increased with increasing Pr under the baseline condition with a slope of 1.03 ± 0.21 (× 10-1) min·mL-1. ANG II significantly increased the slope by 0.72 ± 0.29 (× 10-1) min·mL-1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10-1) mmHg·min·mL-1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10-1) mmHg·min·mL-1, whereas it did not affect the slope. In contrast, Rp was less sensitive than Rd to ANG II or TELM, suggesting Rp may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANG II on the dynamics of the renal vasculature.NEW & NOTEWORTHY This present method of quantifying high-resolution renal arterial impedance could contribute to elucidating the characteristics of renal vasculature influenced by physiological mechanisms, renal diseases, or pharmacological effects. The present findings help construct a lumped-parameter renal hemodynamic model that reflects the influence of angiotensin II.

With aging population increasing globally, the use of pharmaceutically active compounds is rising. The cardiovascular drug telmisartan has been widely detected in various environmental compartments, including biota, surface waters, and sewage treatment plant effluents at concentrations ranging from ng/L to μg/L levels. This study evaluated the effects of telmisartan on the microcrustacean Daphnia magna at a wide range of concentrations (0.35, 0.70, 1.40, 500, and 1000 μg/L) and revealed significant ecotoxicological implications of this drug, even at environmentally relevant concentration. Acute exposure to telmisartan (1.40, 500, and 1000 μg/L) resulted in a notable decrease in heart rate, while chronic exposure accelerated the time to the first brood by 3 days and reduced neonate body size. Molecular investigations revealed marked downregulation of vitellogenin genes (Vtg1 and Vtg2). Non-monotonic dose responses were observed for gene expression, early-stage body length, and the total number of offspring produced, while the heart rate and time to the first brood showed clear concentration-dependent responses. These findings highlight the potential risks, notably to reproductive capacity, associated with exposure to telmisartan in environmentally relevant concentration, suggesting the need for further studies on the potential long-term ecological consequences.