EDUCATION FROM DERMATOLOGISTS: THE SIMULTANEOUSLY DEVELOPMENT OF 16 KERATINOCYTIC CANCERS AFTER USE OF METFORMIN IN COMBINATION WITH LOSARTAN/ HYDROCHLOROTHIAZIDE, METOPROLOL AND NIFEDIPINE- IMPORTANT LINKS TO DRUG RELATED (PHOTO)-NITROSO-CARCINOGENESIS AND ONCOPHARMACOGENESIS.

Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ˝betonate˝ concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ˝pure˝ Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.

Napex acupoint thread-embedding combined with metoprolol tartrate tablet for prophylactic treatment of migraine without aura: a randomized controlled trial. / æž•é¡¹éƒ¨åŸ‹çº¿æ³•è”åˆé ’çŸ³é ¸ç¾Žæ‰˜æ´›å°”ç‰‡é¢„é˜²æ€§æ²»ç–—æ— å ˆå †åå¤´ç—›ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the efficacy of napex acupoint thread-embedding combined with metoprolol tartrate tablet for prophylactic treatment of migraine without aura, and to compare its efficacy with simple napex acupoint thread-embedding and simple metoprolol tartrate tablet. METHODS: A total of 105 patients with migraine without aura were randomized into a combination group (35 cases, 5 cases dropped out), a thread-embedding group (35 cases, 4 cases dropped out) and a western medication group (35 cases, 2 cases dropped out). In the thread-embedding group, napex acupoint thread-embedding was applied at bilateral Fengchi (GB 20) and points of 1.5 cun nearby to the lower edge of spinous process of cervical 2. In the western medication group, metoprolol tartrate tablet was given orally, 12.5 mg a time, twice a day. In the combination group, napex acupoint thread-embedding combined with oral metoprolol tartrate tablet was delivered. The treatment of 8 weeks was required in the 3 groups. The days of headache attacks, frequency of headache attacks, headache severity (visual analogue scale [VAS] score) and the migraine specific quality of life questionnaire version 2.1 (MSQ) score were observed during baseline period (4 weeks before treatment to before treatment), observation period (1-4 weeks and 5-8 weeks in treatment) and follow-up period (1-4 weeks after treatment completion) respectively, the proportions of the days of headache attacks/frequency of headache attacks relieved by 50% were calculated, and the safety was evaluated in the 3 groups. RESULTS: During the observation period and the follow-up period, the days of headache attacks, frequency of headache attacks and headache VAS scores in the 3 groups were reduced compared with those of the baseline period (P<0.05). During the observation period and the follow-up period, the days of headache attacks and the frequency of headache attacks in the combination group were lower than those in the thread-embedding group and the western medication group (P<0.05); during the observation period (1-4 weeks in treatment), the headache VAS scores in the combination group and the thread-embedding group were lower than that in the western medication group (P<0.05); during the observation period (5-8 weeks in treatment) and the follow-up period, the headache VAS scores in the combination group were lower than those in the thread-embedding group and the western medication group (P<0.05). During the observation period and the follow-up period, the scores of role restriction, role prevention and emotion function of MSQ in the combination group were increased compared with those of the baseline period (P<0.05); during the observation period (5-8 weeks in treatment) and the follow-up period, the role prevention scores of MSQ in the thread-embedding group and the western medication group were increased compared with those of the baseline period (P<0.05); during the follow-up period, the emotion function scores of MSQ in the thread-embedding group and the western medication group were increased compared with those of the baseline period (P<0.05). During the observation period and the follow-up period, the scores of role restriction, role prevention and emotion function of MSQ in the combination group were higher than those in the thread-embedding group and the western medication group (P<0.05). There was no statistical difference in the proportions of the days of headache attacks/frequency of headache attacks relieved by 50% among the 3 groups (P>0.05), and there were no serious adverse reactions in the 3 groups. CONCLUSIONS: Napex acupoint thread-embedding combined with metoprolol tartrate tablet, simple napex acupoint thread-embedding and simple metoprolol tartrate tablet all can reduce the days of headache attacks and the frequency of headache attacks, relieve headache severity and improve the quality of life in patients with migraine without aura. Napex acupoint thread-embedding combined with metoprolol tartrate tablet has a better effect.

Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction.

BACKGROUND: Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system antagonists. METHODS: In a parallel-group, open-label trial performed at 45 centers in Sweden, Estonia, and New Zealand, we randomly assigned patients with an acute myocardial infarction who had undergone coronary angiography and had a left ventricular ejection fraction of at least 50% to receive either long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker treatment. The primary end point was a composite of death from any cause or new myocardial infarction. RESULTS: From September 2017 through May 2023, a total of 5020 patients were enrolled (95.4% of whom were from Sweden). The median follow-up was 3.5 years (interquartile range, 2.2 to 4.7). A primary end-point event occurred in 199 of 2508 patients (7.9%) in the beta-blocker group and in 208 of 2512 patients (8.3%) in the no-beta-blocker group (hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P = 0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points (death from any cause, 3.9% in the beta-blocker group and 4.1% in the no-beta-blocker group; death from cardiovascular causes, 1.5% and 1.3%, respectively; myocardial infarction, 4.5% and 4.7%; hospitalization for atrial fibrillation, 1.1% and 1.4%; and hospitalization for heart failure, 0.8% and 0.9%). With regard to safety end points, hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no-beta-blocker group; hospitalization for asthma or chronic obstructive pulmonary disease in 0.6% and 0.6%, respectively; and hospitalization for stroke in 1.4% and 1.8%. CONCLUSIONS: Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.).

Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug.

To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.

[Deep eutectic solvents synergistic with carboxymethyl -ß-cyclodextrin on the improvement of chiral separation of metoprolol by capillary electrophoresis].

The physical and chemical properties of chiral drugs are very similar. However, their pharmacological and toxicological effects vary significantly. For example, one enantiomer may have favorable properties whereas the other may be ineffective or even have toxic side effects. Hence, exploring innovative strategies to improve enantiomeric resolution is of great importance. Metoprolol (MET) is a ß-receptor blocker used to treat hypertension, stable angina pectoris, and supraventricular tachyarrhythmia. Establishing chiral separation and analysis methods of MET enantiomers is important for enhancing the quality of chiral drugs. Capillary electrophoresis (CE) has the advantages of a small sample size, simple operation, high separation efficiency, and many alternative modes; therefore it is widely used in the field of chiral drug separation. The chiral selectors commonly used for CE-based chiral separation include cyclodextrin (CD) and its derivatives, polysaccharides, proteins, and macrocyclic antibiotics. CD is one of the most commonly used and effective chiral selectors for CE. The relatively hydrophobic structure inside the cavity and the relatively hydrophilic structure outside the cavity of CD enable it and chiral molecules to form inclusion compounds with different binding constants, thus achieving chiral separation. However, the use of CD alone as a chiral selector does not always yield satisfactory separation results. Hence, the addition of other additives, such as ionic liquids and deep eutectic solvents (DESs) to assist CD-based chiral separation systems has received extensive attention. Previous studies on the enantiomeric separation of MET by CE have focused on the addition of CD and its derivatives alone for separation. Few studies have been conducted on the synergistic addition of auxiliary additives to CD to improve the enantiomeric resolution of MET. In this study, three DESs, namely, choline chloride-D-glucose, choline chloride-D-fructose, and lactate-D-glucose, were used for the CE-based chiral separation of MET for the first time, and the synergistic effect of the DESs on the separation of MET enantiomers by CD-based capillary zone electrophoresis was speculated. For this purpose, an uncoated fused silica capillary with inner diameter of 50 µm, total length of 50 cm and effective length of 41.5 cm was used as the separation column. First, the effects of CD type, CD concentration, buffer pH, and buffer concentration on MET separation were investigated, and the optimal conditions (15 mmol/L carboxymethyl-ß-cyclodextrin (CM-ß-CD), pH=3.0, and 40 mmol/L phosphate buffer) were obtained. Other CE conditions were as follows: UV detection at 230 nm, applied voltage of 25 kV. All operations were carried out at 20 ℃. Next, three types of DESs were prepared as auxiliary additives via a mixed-heating method. The DESs were mixed in a 50 mL round-bottomed flask at a certain molar ratio and then heated in a water bath at 80 ℃ for 3 h until a clear and transparent liquid was obtained. The effects of different DESs and their mass fraction on chiral separation were subsequently studied. The optimal choline chloride-D-fructose mass fraction was ultimately determined to be 1.5%. The resolution of MET increased from 1.30 without DES to 2.61 with 1.5% choline chloride-D-fructose, thereby achieving baseline separation. Finally, the separation effect and mechanism were speculated. The MET chiral separation method established in this study is of great significance for improving the quality of chiral compounds and ensuring the safety and effectiveness of clinical drugs. Furthermore, it may be useful in the research and development of CE-based chiral separation techniques using CD derivatives with DESs.

Design of Experimental Approach for Development of Rapid High Performance Liquid Chromatographic Process for Simultaneous Estimation of Metoprolol, Telmisartan, and Amlodipine from Formulation: Greenness and Whiteness Evaluation.

The design of an experimental approach, the Box-Behnken design, was implemented to optimize the chromatographic condition to develop a rapid HPLC procedure for quantification of a ternary mixture of metoprolol (MET), telmisartan (TEL), and amlodipine (AML) from the formulation. The perturbation plots, contour, and 3D response surface pictures were developed to study the impact of each variable on the analytes' retention time and the probable interaction between the parameters with fewer chromatographic runs. The optimized HPLC method separated the three analytes within 5 min with excellent selectivity and peak shape on a Zorbax C18 HPLC column using acetonitrile and phosphate buffer (20 mM, pH 5.8) with isocratic elution at a 1.1 mL/min flowrate. A wavelength 230 nm was utilized to monitor the elute. The validation of proposed method demonstrated a wide linearity range of 10-200 µg/mL for MET and TEL and 5-50 µg/mL for AML along with an excellent correlation coefficient. The correctness of the HPLC approach was further confirmed by excellent recovery of the added amount of analytes utilizing the standard addition technique. The recommended HPLC approach was employed safely for quality assurance of the formulation, because the evaluation of the method's greenness and whiteness confirmed the environmentally friendly nature of the approach.

Development of a hollow fiber-liquid phase microextraction method using tissue culture oil for the extraction of free metoprolol from plasma samples.

In this research, a method known as a hollow fiber-liquid-phase microextraction was employed to extract and concentrate free metoprolol from plasma samples. The extracted analyte was subsequently determined using high-performance liquid chromatography coupled with a diode-array detector. Several parameters, including hollow fiber length, sonication time, extraction temperature, and salt addition, were investigated and optimized to enhance extraction efficiency. After extracting the analyte under optimum conditions from plasma samples, the enrichment factor and extraction recovery were 50 and 86 %, respectively. Moreover, the method exhibited detection and quantification limits of 0.41 and 1.30 ng mL-1, respectively. The analysis of real samples demonstrated satisfactory relative recoveries in the range of 91-99 %.

Modulation of cAMP/cGMP signaling as prevention of congenital heart defects in Pde2A deficient embryos: a matter of oxidative stress.

Phosphodiesterase 2A (Pde2A) is a dual-specific PDE that breaks down both cAMP and cGMP cyclic nucleotides. We recently highlighted a direct relationship between Pde2A impairment, a consequent increase of cAMP, and the appearance of mouse congenital heart defects (CHDs). Here we aimed to characterize the pathways involved in the development of CHDs and in their prevention by pharmacological approaches targeting cAMP and cGMP signaling. Transcriptome analysis revealed a modulation of more than 500 genes affecting biological processes involved in the immune system, cardiomyocyte development and contractility, angiogenesis, transcription, and oxidative stress in hearts from Pde2A-/- embryos. Metoprolol and H89 pharmacological administration prevented heart dilatation and hypertabeculation in Pde2A-/- embryos. Metoprolol was also able to partially impede heart septum defect and oxidative stress at tissue and molecular levels. Amelioration of cardiac defects was also observed by using the antioxidant NAC, indicating oxidative stress as one of the molecular mechanisms underpinning the CHDs. In addition, Sildenafil treatment recovered cardiac defects suggesting the requirement of cAMP/cGMP nucleotides balance for the correct heart development.

Drought impact on pharmaceuticals in surface waters in Europe: Case study for the Rhine and Elbe basins.

Hydrological droughts are expected to increase in frequency and severity in many regions due to climate change. Over the last two decades, several droughts occurred in Europe, including the 2018-drought, which showed major adverse impacts for nature and different sectoral uses (e.g. irrigation, drinking water). While drought impacts on water quantity are well studied, little understanding exists on the impacts on water quality, particularly regarding pharmaceutical concentrations in surface waters. This study investigates the impact of the 2018-drought on concentrations of four selected pharmaceuticals (carbamazepine, sulfamethoxazole, diclofenac and metoprolol) in surface waters in Europe, with a major focus on the Elbe and Rhine rivers. Monitoring data were analysed for the period of 2010-2020 to estimate the spatiotemporal patterns of pharmaceuticals and assess the concentration responses in rivers during the 2018-drought compared to reference years. Our results indicate an overall deterioration in water quality, which can be attributed to the extremely low flow and higher water temperatures (∼ + 1.5 °C and + 2.0 °C in Elbe and Rhine, respectively) during the 2018-drought. Our results show an increase in the concentrations of carbamazepine, sulfamethoxazole, and metoprolol, but reduced concentrations of diclofenac during the 2018-drought. Significant increases in carbamazepine concentrations (+45 %) were observed at 3/6 monitoring stations in the upstream part of the Elbe, which was mainly attributed to less dilution of chemical loads from wastewater treatment plants under drought conditions. However, reduced diclofenac concentrations could be attributed to increased degradation processes under higher water temperatures (R2 = 0.60). Moreover, the rainfed-dominated Elbe exhibited more severe water quality deterioration than the snowmelt-dominated Rhine river, as the Elbe's reduction in dilution capacity was larger. Our findings highlight the need to account for the impacts of climate change and associated increases in droughts in water quality management plans, to improve the provision of water of good quality for ecosystems and sectoral needs.

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug-Drug Interaction with Metoprolol.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in Cmax and area under curve of plasma metoprolol in rats.

Evaluation of in vitro dissolution profiles of modified-release metoprolol succinate tablets crushed using mortar and pestle technique.

PURPOSE: Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach. METHODS: Dissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV-vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f2) and difference (f1) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R2adj). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes. RESULTS: The dissolution profiles were not similar at pH 4.5 (f2=45.43, f1=18.97) and pH 6.8 (f2=31.47, f1=32.94). CT best fitted with Higuchi (pH 1.2: R2adj=0.9990), Weibull (pH 4.5: R2adj=0.9884), and Korsmeyer-Peppas (pH 6.8: R2adj=0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R2adj=0.9986), logistic (pH 4.5: R2adj=0.9839) and first-order (pH 6.8: R2adj=0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p=0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets. CONCLUSION: Crushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube.

Co-release of cytokines after drug-eluting stent implantation in acute myocardial infarction patients with PCI.

Acute Myocardial Infarction (AMI) after Percutaneous Coronary Intervention (PCI) often requires stent implantation leading to cardiovascular injury and cytokine release. Stent implantation induces cytokines production including TNFα, Hs-CRP, IL-1ß, IL2 receptor, IL6, IL8, and IL10, but their co-release is not extensively established. In 311 PCI patients with Drug-Eluting Stent (DES) implantation, we statistically evaluate the correlation of these cytokines release in various clinical conditions, stent numbers, and medications. We observed that TNFα is moderately correlated with IL-1ß (r2 = 0.59, p = 0.001) in diabetic PCI patients. Similarly, in NSTEMI (Non-ST Segment Elevation) patients, TNFα is strongly correlated with both IL-1ß (r2 = 0.97, p = 0.001) and IL8 (r2 = 0.82, p = 0.001). In CAD (Coronary Artery Disease)-diagnosed patients TNFα is highly correlated (r2 = 0.84, p = 0.0001) with IL8 release but not with IL-1ß. In patients with an increased number of stents, Hs-CRP is significantly coupled with IL8 > 5 pg/ml (t-statistic = 4.5, p < 0.0001). Inflammatory suppressor drugs are correlated as TNFα and IL8 are better suppressed by Metoprolol 23.75 (r2 = 0.58, p < 0.0001) than by Metoprolol 11.87 (r2 = 0.80, p = 0.5306). Increased TNFα and IL-1ß are better suppressed by the antiplatelet drug Brilinta (r2 = 0.30, p < 0.0001) but not with Clopidogrel (r2 = 0.87, p < 0.0001). ACI/ARB Valsartan 80 (r2 = 0.43, p = 0.0011) should be preferred over Benazepril 5.0 (r2 = 0.9291, p < 0.0001) or Olmesartan (r2 = 0.90, p = 0.0001). Thus, the co-release of IL-1ß, IL8 with TNFα, or only IL8 with TNFα could be a better predictor for the outcome of stent implantation in NSTEMI and CAD-diagnosed AMI patients respectively. Cytokine suppressive medications should be chosen carefully to inhibit further cardiovascular damage.

Bioremediation of rapid sand filters for removal of organic micropollutants during drinking water production.

Rapid sand filtration (RSF) is used during drinking water production for removal of particles, possible harmful microorganisms, organic material and inorganic compounds such as iron, manganese, ammonium and methane. However, RSF can also be used for removal of certain organic micropollutants (OMPs). In this study, it was investigated if OMP removal in columns packed with sand from full scale RSFs could be stimulated by bioaugmentation (i.e. inoculating RSFs with sand from another RSF) and/or biostimulation (i.e. addition of nutrients, vitamins and trace-elements that stimulate microbial growth). The results showed that removal of PFOA, carbamazepine, 1-H benzotriazole, amidotrizoate and iopamidol in the columns was low (< 20 %). Propranolol and diclofenac removal was higher (50-60 %) and propranolol removal likely occurred via sorption processes, whereas for diclofenac it was unclear if removal was a combination of physical-chemical and biological processes. Moreover, bioaugmentation and biostimulation resulted in 99 % removal of gabapentin and metoprolol after 38 days and 99 % removal of acesulfame after 52 days of incubation. The bioaugmented column without biostimulation showed 99 % removal for gabapentin and metoprolol after 52 days, and for acesulfame after 80 days. In contrast, the non-bioaugmented column did not remove gabapentin, removed < 40 % metoprolol and showed 99 % removal of acesulfame only after 80 days of incubation. Removal of these OMPs was negatively correlated with ammonium oxidation and the absolute abundance of ammonia-oxidizing bacteria. 16S rRNA gene sequencing showed that OMP removal of acesulfame, gabapentin and metoprolol was positively correlated to the relative abundance of specific bacterial genera that harbor species with a heterotrophic and aerobic or denitrifying metabolism. These results show that bioaugmentation of RSF can be successful for OMP removal, where biostimulation can accelerate this removal.

Nutrimetric Validation of Solanidine as Dietary-Derived CYP2D6 Activity Marker In Vivo.

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day.

Which should you choose for post operative atrial fibrillation, carvedilol or metoprolol? A systemic review and meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention. METHODS: We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes. RESULTS: In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001]. CONCLUSION: In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.

Pharmacokinetics and bioequivalence of two metoprolol succinate extended release tablets in healthy Chinese subjects under fasting and fed conditions.

AIMS: The aims of this study were to evaluate and compare the pharmacokinetic profiles and establish bioequivalence of test and reference metoprolol succinate extended-release (ER) tablets in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: Subjects were randomly assigned to either the fasting or the fed group and also to one of the two treatment sequences (test-reference or reference-test), according to which they received a single 47.5-mg dose of the test or reference metoprolol ER tablet in the study periods. During each period, blood samples were collected at pre-dose and at intervals up to 48 hours after dosing. Plasma concentrations of metoprolol were determined by liquid chromatography. The safety of both ER tablets was monitored throughout the study. RESULTS: 60 subjects were enrolled and all completed the study, with 30 participants each in the fasting and fed groups. In both groups, the 90% confidence intervals for AUC0-48h, AUC0-inf, and Cmax were within the acceptable bioequivalence range (80 - 125%). There were no significant differences in adverse event (AE) reporting between the subjects receiving test or reference ER tablet. No serious AEs occurred during the study period. CONCLUSION: The test metoprolol ER tablet was bioequivalent to the reference metoprolol ER tablet (Betaloc ZOK) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.

Intravenous Diltiazem Versus Metoprolol in Acute Rate Control of Atrial Fibrillation/Flutter and Rapid Ventricular Response: A Meta-Analysis of Randomized and Observational Studies.

BACKGROUND: Atrial fibrillation (AF) and/or atrial flutter (AFL) with rapid ventricular response (RVR) is a condition that often requires urgent treatment. Although guidelines have recommendations regarding chronic rate control therapy, recommendations on the best choice for acute heart rate (HR) control in RVR are unclear. METHODS: A systematic search across multiple databases was performed for studies evaluating the outcome of HR control (defined as HR less than 110 bpm and/or 20% decrease from baseline HR). Included studies evaluated AF and/or AFL with RVR in a hospital setting, with direct comparison between intravenous (IV) diltiazem and metoprolol and excluded cardiac surgery and catheter ablation patients. Hypotension (defined as systolic blood pressure less than 90 mmHg) was measured as a secondary outcome. Two authors performed full-text article review and extracted data, with a third author mediating disagreements. Random effects models utilizing inverse variance weighting were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the I2 test. RESULTS: A total of 563 unique titles were identified through the systematic search, of which 16 studies (7 randomized and 9 observational) were included. In our primary analysis of HR control by study type, IV diltiazem was found to be more effective than IV metoprolol for HR control in randomized trials (OR 4.75, 95% CI 2.50-9.04 with I2 = 14%); however, this was not found for observational studies (OR 1.26, 95% CI 0.89-1.80 with I2 = 55%). In an analysis of observational studies, there were no significant differences between the two drugs in odds of hypotension (OR 1.12, 95% CI 0.51-2.45 with I2 = 18%). CONCLUSION: While there was a trend toward improved HR control with IV diltiazem compared with IV metoprolol in randomized trials, this was not seen in observational studies, and there was no observed difference in hypotension between the two drugs.

Effect of Carvedilol Versus Metoprolol on Contrast-Induced Nephropathy in Patients with Acute Coronary Syndrome Undergoing Percutaneous Intervention Therapy.

Carvedilol can inhibit inflammation, vasoconstriction, and oxidative stress, which play important roles in the development and progression of contrast-induced nephropathy (CIN). To the best of our knowledge, no studies have investigated the potential effect of carvedilol on the prevalence of CIN after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). The present study aimed to determine whether carvedilol use is associated with the development of CIN. A total of 319 patients (mean age, 59.2 ± 12.4 years; 77.7% male) with ACS who underwent urgent PCI at our institution between May 2019 and May 2022 were included prospectively. Overall, 100 and 219 patients were assigned to the carvedilol and metoprolol groups, respectively. The prevalence of CIN was significantly lower in the carvedilol group (6.0%) than in the metoprolol group (18.3%; P = .003). Multivariate analysis revealed that carvedilol use (odds ratio [OR] .250, 95% confidence interval [CI] .092-.677, P = .006), amount of contrast agent (OR 1.004, 95% CI 1.000-1.008, P = .031), and admission estimated glomerular filtration rate (OR .978, 95% CI 0.960-.995, P = .014) were independently associated with the development of CIN. The use of carvedilol may be a promising option for the prevention of CIN in patients with ACS undergoing urgent PCI.

Influence of Weight and Body Size on the Pharmacokinetics of Heart Failure Pharmacotherapy: A Systematic Review.

OBJECTIVE: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. DATA SOURCES: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. STUDY SELECTION AND DATA EXTRACTION: Articles written in English or French related to the aim of our study were retained for analysis. DATA SYNTHESIS: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. CONCLUSION: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.

Removal of emerging micropollutants from nanofiltration retentate of municipal wastewater within biological fixed-bed reactors under nitrifying and denitrifying conditions.

Municipal water resource recovery facilities are not designed to eliminate micropollutants, leading to many pollutants entering the aquatic environment. Within this study, as part of the project MicroStop, the biological treatment of nanofiltration effluent (retentate) under pure aerobic (without nitrification) as well as nitrifying and denitrifying conditions has been investigated for micropollutant elimination. A potential of further biotransformation under increased hydraulic retention time (HRT) of 14 days was shown. Under both HRT of 7 and 14 days, eliminations below LOQ were achieved in the aerated bioreactor for gabapentin, iomeprol, and metoprolol, reaching > 95%, > 69 to > 92%, and > 72%, respectively. The reduction of diclofenac was positively influenced by longer HRT leading to an elimination of up to 67%. Sulfamethoxazole was reduced under denitrification, but accumulated under aeration, resulting in fluctuating results and an overall elimination of 78% under 14 days HRT. PRACTITIONER POINTS: The micropollutant elimination in fixed-bed bioreactors of highly concentrated nanofiltration retentate was studied. Pure aerobic (without nitrification), nitrifying, and denitrifying conditions were investigated under hydraulic retention times (HRT) of 7 and 14 days. Higher initial pollutant concentrations enhanced the biological degradability in attached growth for substances being moderately degradable in activated sludge systems. 4A potential of further biological micropollutant elimination was shown for gabapentin, iomeprol, metoprolol, and diclofenac.