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ABSTRACT
In the present study, we performed gastropod analyses on loess–palaeosol sequences from northeast Armenia (Southern Caucasia) covering at least three glacial–interglacial cycles. The elaborated ecostratigraphy shows significant patterns of species composition related to the succession of pedocomplexes and loess, respectively. Pedocomplexes included species that can be associated with high‐grass to forest‐steppe biomes, indicating increased humidity for these sections compared to the loess layers. In contrast, loess layers that relate to glacial periods are associated with gastropod species of semidesert environments with shrub‐ and shortgrass‐steppes, indicating semiarid to arid conditions. Furthermore, the loess deposits do not show any evidence for cold‐adapted gastropod species. Therefore, we suggest that average July temperatures in the study area were above 10 °C, even during periods of loess deposition. Consequently, we propose that the limiting factor for tree growth during glacial periods was aridity, rather than temperature. In addition, we observe environmental differences between the various glacial times, with our results indicating a trend towards steadily increasing aridity in Southern Caucasia across the Middle to Late Pleistocene.
Seven new 1,2,3,4,5-pentathiepino[6,7-a]indolizines were synthesized in which the pentathiepine moieties bear an indolizine backbone that is derivatized from C–H to F-, Cl-, Br-, I-, NO2-, and CH3-substitutions, respectively, in a meta position relative to the aza group on the pyridine moiety. Their preparation took place via two common steps: (i) a Sonogashira coupling between (4-substituted) 2-bromo- or 2-chloropyridines and propynyl 3,3-diethylacetal, and (ii) a ring closing reaction mediated by a molybdenum oxo-bistetrasulfido complex and elemental sulfur. The latter simultaneously facilitates the 1,2,3,4,5-pentathiepino chain/ring- and indolizine ring-formations. The fluoro derivative was addressed with 2-bromo-5-aminopyridine as the starting material via a Sandmeyer reaction. The iodo derivative was obtained from 5-bromo-2-alkynylpiridine using a metal-assisted variation of the Finkelstein reaction. The requirement to explore different reaction conditions and the varied respective yields of the final products are discussed. The influence of the distinct substitutions on the pyridine moieties, their electronic structures, and respective chemical properties was investigated through a set of spectroscopic/analytical characterizations. Intriguingly, in all cases, the nitro-substituted derivative exhibited a distinct behavior compared to the six other investigated derivatives, which was also addressed computationally. All seven new pentathiepines were crystallized, and their respective molecular structures were determined using single crystal X-ray diffraction. These structures are compared and discussed as are their respective packing patterns.
Background
Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen.
Methods
This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients’ global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed.
Discussion
This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care.
Trial registration
ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680