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PURPOSE: Hypotension is common during anesthesia induction. However, minimal hemodynamic effects of remimazolam anesthesia have been reported. We hypothesized that remimazolam would have weaker hemodynamic effects than would propofol. To test this, we simultaneously evaluated the hemodynamics using the estimated continuous cardiac output (esCCO) system and heart rate variability (HRV) during anesthesia induction. METHODS: This was a single-center, observational, retrospective study of patients undergoing dental surgery under general anesthesia between 2020 and 2022. Seventy patients were divided into two groups: remimazolam (R group; n=34) and propofol (P group; n=36). The information obtained from the anesthesia records, patient information, esCCO system parameters, and HRV were integrated and analyzed. The percentages of various parameters were set to 100% for the pre-induction phase as the baseline. RESULTS: The %MAP (noninvasive mean arterial blood pressure) decreased over a narrower range in the R compared to the P group (-17.8% (-26.3%, -11.9%) vs. -22.6% (-32.9%, -17.0%); P=0.039). The %HR (heart rate) increased significantly in the R group and decreased in the P group (+10.7% (+6.5%, +18.6%) vs. -6.5% (-14.5%, +8.4%); P<0.01). The %SVesCCO (stroke volume calculated using the esCCO system) decreased significantly in both groups, but the R group showed a smaller difference compared to the P group (- 5.1% (-7.7%, -2.1%) vs. -10.0% (-13.8%, -5.6%); P<0.01). The rates of change in %LF nu (normalized unit of low frequency) and %HF nu (normalized unit of high frequency) were lower for the R than for the P group, although the difference was not significant (+6.8% (-14.5%, 32.4%) vs. +9.2% (-7.2%, +59.7%), P=0.30; +7.9% (-51.0%, +66.9%) vs. +22.8% (-26.1%, +61.6%), P=0.57). CONCLUSION: Remimazolam demonstrated a lower MAP reduction rate than propofol. A compensatory increase in HR occurred with a decrease in stroke volume. However, the HR increase was not attributable to the autonomic nervous system.
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Human interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that plays a critical role in the regulation of the immune response and the development of various inflammatory diseases. In this publication, we disclose our efforts toward the discovery of IL-1ß binders that interfere with IL-1ß signaling. To this end, several technologies were used in parallel, including fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening. The utilization of distinct technologies resulted in the identification of new chemical entities exploiting three different sites on IL-1ß, all of them also inhibiting the interaction with the IL-1R1 receptor. Moreover, we identified lysine 103 of IL-1ß as a target residue suitable for the development of covalent, low-molecular-weight IL-1ß antagonists.
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Interleucina-1beta , Humanos , Descubrimiento de Drogas , Interleucina-1beta/metabolismo , Ligandos , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , ADN/química , Biblioteca de GenesRESUMEN
Human interleukin-1ß (hIL-1ß) is a pro-inflammatory cytokine involved in many diseases. While hIL-1ß directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1ß-directed therapies. Here we describe the discovery of a low-molecular weight hIL-1ß antagonist that blocks the interaction with the IL-1R1 receptor. Starting from a low affinity fragment-based screening hit 1, structure-based optimization resulted in a compound (S)-2 that binds and antagonizes hIL-1ß with single-digit micromolar activity in biophysical, biochemical, and cellular assays. X-ray analysis reveals an allosteric mode of action that involves a hitherto unknown binding site in hIL-1ß encompassing two loops involved in hIL-1R1/hIL-1ß interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1ß function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of hIL-1ß directed therapeutics.
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Citocinas , Delgadez , Humanos , Interleucina-1beta , Peso Molecular , Sitios de Unión , BiofisicaRESUMEN
A small percentage of cases of dermatomyositis are positive for anti-mitochondrial antibodies (AMA), a known marker for primary biliary cirrhosis. AMA-positive myositis is a rare disease that has been reported to be accompanied by myocarditis, resulting in low left ventricular function, supraventricular arrhythmias, and abnormalities of the conduction system. We present a case of AMA-positive myocarditis resulting in sinus arrest during general anesthesia. A 66-year-old female with AMA-positive myocarditis underwent artificial femoral head replacement for osteonecrosis of the femoral head under general anesthesia. During general anesthesia, a nine-second sinus arrest occurred without any inducement. The sinus arrest was thought to be influenced by not only over-suppression caused by severe supraventricular tachycardia derived from sick sinus syndrome but sympathetic depression caused by general anesthesia. Because of the potential for life-threatening cardiovascular events during anesthesia in patients with AMA-positive myositis, it was considered essential to provide adequate preoperative management and intraoperative monitoring during anesthesia for patients with this disease. Herein, we report our case with a literature review.
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Nanostructured LiMnO2 integrated with Li3PO4 was successfully synthesized by the mechanical milling route and examined as a new series of positive electrode materials for rechargeable lithium batteries. Although uniform mixing at the atomic scale between LiMnO2 and Li3PO4 was not anticipated because of the noncompatibility of crystal structures for both phases, our study reveals that phosphorus ions with excess lithium ions dissolve into nanosize crystalline LiMnO2 as first evidenced by elemental mapping using STEM-EELS combined with total X-ray scattering, solid-state NMR spectroscopy, and a theoretical ab initio study. The integrated phase features a low-crystallinity metastable phase with a unique nanostructure; the phosphorus ion located at the tetrahedral site shares faces with adjacent lithium ions at slightly distorted octahedral sites. This phase delivers a large reversible capacity of â¼320 mA h g-1 as a high-energy positive electrode material in Li cells. The large reversible capacity originated from the contribution from the anionic redox of oxygen coupled with the cationic redox of Mn ions, as evidenced by operando soft XAS spectroscopy, and the superior reversibility of the anionic redox and the suppression of oxygen loss were also found by online electrochemical mass spectroscopy. The improved reversibility of the anionic redox originates from the presence of phosphorus ions associated with the suppression of oxygen dimerization, as supported by a theoretical study. From these results, the mechanistic foundations of nanostructured high-capacity positive electrode materials were established, and further chemical and physical optimization may lead to the development of next-generation electrochemical devices.
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Ab initio molecular dynamics (AIMD) simulations were carried out for ππ*-excited 1,1'-dimethylstilbene (dmSB) at the spin-flip time-dependent density functional theory (SF-TDDFT) level with the TSF-index technique, to get insights into the substitution effects on the photoisomerization dynamics of stilbene (SB). It is found that the reaction path from the Franck-Condon structure of cis-dmSB is oriented toward the 4,4-dihydrophenanthrene (DHP) side from the beginning, which is in contrast to the case of SB where the pathway is oriented toward the twist side in the initial stage. The optimized geometries of minima and the minimum-energy conical intersection (MECI) suggested that molecules in the DHP region could easily decay to the ground state. On the other hand, S1/S0-MECI and S1-minimum in the twist region have a relatively different geometry from each other, which is consistent with the experimental observation of the long lifetime of the perpendicular structure. AIMD simulations showed that more trajectories enter the well of the DHP side than the well of the twist side and that all of the trajectories going to the DHP side reached the S1/S0-CI region within â¼0.2 ps on average, while very few trajectories reached S1/S0-CI even after 1 ps in the twist region. Decrease in the S1 population in the cis and twist regions qualitatively reproduced the temporal profiles of the transient absorption bands of dmSB observed in the visible and ultraviolet regions, respectively.
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Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTPgammaS binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those of L-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of L-glutamate. AMN082 (< or = 10 microM) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders.
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Compuestos de Bencidrilo/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/fisiopatología , Regulación Alostérica , Sitio Alostérico/efectos de los fármacos , Animales , Células CHO , Cricetinae , Hormonas/metabolismo , Receptores de Glutamato Metabotrópico/químicaRESUMEN
In patients who had undergone the first surgery for cleft lip and in whom the volume of tissue was smaller for the upper lip than for the lower lip, transfer of tissue from the lower lip using a full-length mucous flap allowed the tissue volume of the upper lip to be increased and external appearance of the lips to be improved. The subjects of this study were 6 patients who underwent this surgery between February and September 2001 and were followed for up to 3 years postoperatively. This surgery can be performed under topical anesthesia, without necessitating restriction on mouth opening and oral ingestion. Furthermore, it allows easy adjustment of the tissue volume in both upper and lower lips. This operative procedure is recommended for cases of cleft lip where surgical treatment has been performed before and the tissue volume is smaller in the upper prolabium than in the vermilion.