•Metallacrowns and azametallacrowns as versatile functional materials for catalysis, luminescence, magnetism and sorption.•Challenges in the development of multifunctional metallacrown-based ...materials are described.
Metallacrowns (MCs) obtained by changing the CCO fragments of organic crown ethers on MNO or MNN units have been developed extensively in the past few decades. A vast array of unique MCs with diverse structural patterns and accessible topologies can provide non-trivial functional properties. This review describes the applications of MCs in catalysis, luminescence, and magnetism. Examples of porous lattices based on MCs as secondary building units are also discussed, including their thermal stability, sorption properties, and applications in the separation or exchange of cations or anions.
Aims
To evaluate the efficacy and safety of mirabegron in children and adolescents (aged 3 to <18 years) with neurogenic detrusor overactivity (NDO) using clean intermittent catheterization.
Methods
...In this open‐label, multicenter, baseline‐controlled, Phase III study (NCT02751931), participants received once‐daily mirabegron at an adult dose equivalent of 25 mg. Dose was increased to 50 mg equivalent unless there were safety/tolerability concerns. The primary efficacy endpoint was change from baseline to Week 24 in maximum cystometric capacity (MCC). Secondary urodynamic assessments, Pediatric Incontinence Questionnaire (PIN‐Q), Patient Global Impression of Severity (PGI‐S), Clinician Global Impression of Change (CGI‐C), and Acceptability questionnaires were included.
Results
Overall, 86 participants (55 aged 3 to <12 years, 31 aged 12 to <18 years) received treatment; 68 were included in efficacy assessments. A statistically significant increase in MCC from baseline to Week 24 was observed (87.20 ml, 95% confidence interval: 66.07, 108.33; p < .001); this increase was apparent from Week 4. Significant increases in bladder compliance, bladder volume until first detrusor contraction, average volume per catheterization, maximum daytime catheterized volume and number of dry days per week. Significant decreases in detrusor pressure and number of leakage episodes per day were also observed. Significant improvement in PGI‐S but not PIN‐Q was observed. Most participants reported their condition had either much or very much improved using the CGI‐C. Mirabegron was well tolerated in this population with a profile aligned with that in adults.
Conclusions
Mirabegron was effective and well‐tolerated in the treatment of pediatric patients with NDO.
The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of ...infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction.
In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine.
Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.
An increasing body of data indicates that a reduction of ticagrelor maintenance dose (MD) in stabilized patients might improve ticagrelor's safety profile and adherence to the treatment. The aim of ...this review was to discuss the rationale and summarize the current pharmacodynamic and clinical outcomes-based evidence from reduced MD of ticagrelor in patients with coronary artery disease (CAD).
A narrative systematic review based on a literature search using the PubMed database from its inception through to June 2020. A search strategy included a combination of relevant search terms regarding ticagrelor reduced MD. The pre-determined inclusion criteria were: (1) randomized or observational trials; (2) presentation of clinical or pharmacodynamic results; (3) evaluation of any ticagrelor MD below 90 mg BID in patients with CAD.
Studies evaluating the following ticagrelor reduced MD have been identified: 90 mg QD, 60 mg BID, 60 mg QD, 45 mg BID, 22.5 mg BID. Majority of trials assessing doses <60 mg BID were performed in Asian patients only. Antiplatelet effect of ticagrelor in CAD decreases with the dose, however even reduced MDs provide sufficient platelet inhibition, which is greater than in clopidogrel-treated patients. De-escalation of ticagrelor dose shows a propensity towards a reduced rate of bleeding and non-bleeding adverse events.
Ticagrelor doses below 90 mg BID generally show an acceptable profile of platelet inhibition. The number of studies reporting clinical outcomes in CAD patients receiving reduced MD of ticagrelor are limited, however available results indicate that in a stable setting this strategy offers improved safety with preserved efficacy in the prevention of thrombotic events.
Phenylketonuria (PKU) is a metabolic and genetic disorder caused by a phenylalanine hydroxylase (PAH) gene deficiency that raises Phe levels in organs. Dietary therapy involves an elimination diet ...and Phe-free items, which may alter microbiota. The study examined the oral and intestinal microbiomes of a 63-year-old PKU patient and a control man, living in rural areas. iSeq100 (Illumina) sequenced the stool and oral 16S rRNA gene V3-V4 region. PKU guts had more Firmicutes and fewer Bacteroidetes than control. Clostridia predominated in PKU, while Bacteroidia dominated in control. Oral Bacteroidetes. Firmicutes, Proteobacteria, and Fusobacteria phyla were similar in both men. The microbiome may differ from those fed a Phe-free diet from birth due to late diagnosis and treatment of PKU. Due to the age of the 63-year-old patient's and late therapy, the results differ from earlier studies. No study has compared an older PKU patient's gut and oral microbiomes.
In this study, novel single nucleotide polymorphisms (SNPs) were found in the 5′-regulatory regions (promoters) of the bovine glucose transporter (GT) genes SLC2A12 and SLC5A1. These polymorphisms ...were shown to associate with certain milk production traits in HF cows, including milk yield, milk composition, and somatic cell count. It was shown that the SNP g.-671C > G (NC_037336.1: g.72224078C > G) in the SLC2A12 gene could be an effective marker of cattle production traits and that genotypes CC and CG are associated with the best productivity. The polymorphisms found in the SLC5A1 gene promoter also influenced milk production traits in HF cows, albeit to a lesser extent, and we propose that these polymorphisms could be useful as genetic markers for milk production traits in marker-assisted selection (MAS); however, this must be confirmed on larger populations of cattle. In addition, the presence of polymorphisms within promoter regions appears to affect the expression of GT genes in the cow mammary gland and modify transcription factor (TF) binding capacity.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
High platelet reactivity (HPR) is a risk factor for stent thrombosis, a potentially lethal complication of percutaneous coronary intervention. HPR is also associated with increased risk of myocardial ...infarction and death in invasively-treated patients with acute coronary syndrome (ACS). HPR occurs even in ACS patients treated with ticagrelor, a state-of-the-art antiplatelet agent, especially during the first hours of treatment. Patient-level pharmacodynamic data obtained from 102 ACS subjects enrolled in two prospective, pharmacodynamic trials were analysed in order to identify clinical features related with increased odds of on-ticagrelor HPR during the first two hours after ticagrelor loading dose in ACS patients. Presence of ST-segment elevation myocardial infarction (versus non-ST-segment elevation ACS) and morphine co-administration were the strongest predictors of HPR at 1 and 2 hours after ticagrelor loading dose according to linear regression analyses, multiple backward stepwise logistic regression analyses and generalized estimating equation model. By pinpointing simple to recognize clinical features, the results of this study facilitate identification of ACS patients who have the highest odds of HPR during the initial phase of treatment with ticagrelor, and who could potentially benefit from alternative treatment strategies.
Increasing attention has been recently devoted to 89Zr(IV) and 68Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a ...deep investigation is presented on Ga(III) and Zr(IV) complexes with a series of tri-(H 3 L1, H 3 L3, H 3 L4 and desferrioxamine E, DFOE) and tetrahydroxamate (H 4 L2) ligands. Herein, we describe the rational design and synthesis of two cyclic complexing agents (H 3 L1 and H 4 L2) bearing three and four hydroxamate chelating groups, respectively. The ligand structures allow us to take advantage of the macrocyclic effect; the H 4 L2 chelator contains an additional side amino group available for a possible further conjugation with a biomolecule. The thermodynamic stability of Ga(III) and Zr(IV) complexes in solution has been measured using a combination of potentiometric and pH-dependent UV–vis titrations, on the basis of metal–metal competition. The Zr(IV)-H 4 L2 complex is characterized by one of the highest formation constants reported to date for a tetrahydroxamate zirconium chelate (log β = 45.9, pZr = 37.0), although the complex-stability increase derived from the introduction of the fourth hydroxamate binding unit is lower than that predicted by theoretical calculations. Solution studies on Ga(III) complexes revealed that H 3 L1 and H 4 L2 are stronger chelators in comparison to DFOB. The complex stability obtained with the new ligands is also compared with that previously reported for other hydroxamate ligands. In addition to increasing the library of the thermodynamic stability data of Ga(III) and Zr(IV) complexes, the present work allows new insights into Ga(III) and Zr(IV) coordination chemistry and thermodynamics and broadens the selection of available chelators for 68Ga(III) and 89Zr(IV).
Up to 80% of COVID-19 survivors experience prolonged symptoms known as long COVID-19. The aim of this study was to evaluate the effects of a multidisciplinary rehabilitation program in patients with ...long COVID-19. The rehabilitation program was composed of physical training (aerobic, resistance, and breathing exercises), education, and group psychotherapy. After 6 weeks of rehabilitation in 97 patients with long COVID-19, body composition analysis revealed a significant decrease of abdominal fatty tissue (from 2.75 kg to 2.5 kg; p = 0.0086) with concomitant increase in skeletal muscle mass (from 23.2 kg to 24.2 kg; p = 0.0104). Almost 80% of participants reported dyspnea improvement assessed with the modified Medical Research Council scale. Patients’ physical capacity assessed with the 6 Minute Walking Test increased from 320 to 382.5 m (p < 0.0001), the number of repetitions in the 30 s Chair Stand Test improved from 13 to 16 (p < 0.0001), as well as physical fitness in the Short Physical Performance Battery Test from 14 to 16 (p < 0.0001). The impact of fatigue on everyday functioning was reduced in the Modified Fatigue Impact Scale from 37 to 27 (p < 0.0001). Cardiopulmonary exercise test did not show any change. The multidisciplinary rehabilitation program has improved body composition, dyspnea, fatigue and physical capacity in long COVID-19 patients.
Iron is a trace element required for normal performance of cellular processes. Because both the deficiency and excess of this metal are dangerous, its absorption, distribution and accumulation must ...be tightly regulated. Disturbances of iron homeostasis and an increase in its level may lead to overload and neurodegenerative diseases. Phlebotomy was for a long time the only way of removing excess iron. But since there are many possible disadvantages of this method, chelation therapy seems to be a logical approach to remove toxic levels of iron. In clinical use, there are three drugs: desferrioxamine, deferiprone and deferasirox. FBS0701, a novel oral iron chelator, is under clinical trials with very promising results. Developing novel iron-binding chelators is an urgent matter, not only for systemic iron overload, but also for neurodegenerative disorders, such as Parkinson's disease. Deferiprone is also used in clinical trials in Parkinson's disease. In neurodegenerative disorders the main goal is not only to remove iron from brain tissues, but also its redistribution in system. Few chelators are tested for their potential use in neurodegeneration, such as nonhalogeneted derivatives of clioquinol. Such compounds gave promising results in animal models of neurodegenerative diseases. Drugs of possible use in neurodegeneration must meet certain criteria. Their development includes the improvement in blood brain barrier permeability, low toxicity and the ability to prevent lipid peroxidation. One of the compounds satisfying these requirements is VK28. In rat models it was able to protect neurons in very low doses without significantly changing the iron level in liver or serum. Also iron chelators able to regulate activity of monoamine oxidase were tested. Polyphenols and flavonoids are able to prevent lipid peroxidation and demonstrate neuroprotective activity. While cancer does not involve true iron overload, neoplastic cells have a higher iron requirement and are especially prone to its depletion. It was shown, that desferrioxamine and deferasirox are antiproliferative agents active in several types of cancer. Very potent compounds with possible use as anticancer drugs are thiosemicarbazones. They are able to inhibit ribonucleotide reductase, an enzyme involved in DNA synthesis. Because the relationship between the development of overload / neurodegenerative disorders, or cancer, and iron are very complex, comprehension of the mechanisms involved in the regulation of iron homeostasis is a crucial factor in the development of new pharmacological strategies based on iron chelation. In view of various factors closely involved in pathogenesis of such diseases, designing multifunctional metal-chelators seems to be the most promising approach, but it requires a lot of effort. In this perspective, the review summarizes systemic iron homeostasis, and in brain and cancer cells, iron dysregulation in neurodegenerative disease and possible chelation strategies in the treatment of metal systemic overload, neurodegeneration and cancer.
PDF
