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91.
92.
Daniel Bertrand Sonia Bertrand Estelle Neveu Prabhavathi Fernandes 《Antimicrobial agents and chemotherapy》2010,54(12):5399-5402
Adverse effects have limited the clinical use of telithromycin. Preferential inhibition of the nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (α3β2 and NMJ), the ciliary ganglion of the eye (α3β4 and α7), and the vagus nerve innervating the liver (α7) could account for the exacerbation of myasthenia gravis, the visual disturbance, and the liver failure seen with telithromycin use. The studies presented here enable the prediction of expected side effects of macrolides in development, such as solithromycin (CEM-101).Although macrolides have been known to adversely affect liver function, the greater frequency and severity of liver damage by telithromycin than by other macrolides resulted in the withdrawal of its approval for use in simple infections such as sinusitis and bronchitis (9), although it remains licensed for serious and otherwise intractable pneumococcal pneumonia. Exploration and future development of new macrolides and ketolides require addressing the mechanisms underlying the telithromycin effects (5). Side effects on muscle function and vision led us to explore the possible interaction of telithromycin at nicotinic acetylcholine receptors (nAChRs) and to compare the effects caused by older, safer macrolides such as azithromycin and clarithromycin. In addition, we analyzed the uniqueness of telithromycin effects by investigating a novel ketolide, solithromycin (CEM-101). Although both telithromycin and solithromycin are ketolides, solithromycin does not share the pyridine-imidazole group of the telithromycin side chain (Fig. (Fig.11).Open in a separate windowFIG. 1.Chemical structures of the macrolides tested at the human nAChRs. The pyridine moiety of telithromycin has been highlighted for clarity.Compounds containing pyridine moieties are known to interact with nAChRs, and therefore, we focused on this aspect of the molecule structure. At first, we examined the neuromuscular junction receptors (NMJ). Synaptic transmission at the neuromuscular junction is mediated by acetylcholine (ACh) released from the motoneuron, causing activation of nAChRs expressed on muscle cells (1). nAChRs belong to the superfamily of ligand-gated channels and result from the assembly of five subunits around an axis of pseudosymmetry. Seventeen genes encoding nAChR subunits in humans, allowing the formation of a vast repertoire of receptor subtypes displaying distinct physiological and pharmacological properties, have been identified (2).All experiments were carried out with human nAChRs expressed in Xenopus laevis oocytes by cDNA. Oocytes were prepared, injected with cDNA encoding the nAChR subunits, and recorded using standard procedures (3). Currents evoked by ACh were recorded using a two-electrode voltage clamp, and cells were maintained at −80 mV with a GeneClamp axon instrument. Drugs were applied by immersion of the oocytes into the desired compound using an x-y-z-axis table controlled by Matlab software (MathWorks, Inc.).Sustained exposure of nAChRs to a fixed concentration of telithromycin, such as that encountered under therapeutic conditions (4, 8), caused a progressive inhibition of the ACh-evoked currents. The degree of inhibition varied with the function of the receptor subtype. Typical results obtained with an oocyte expressing the adult form of the human NMJ composed of the α1, β1, δ, and ɛ subunits are shown in Fig. Fig.2A.2A. These data illustrate that exposure to 2 μM telithromycin caused a progressive decline of the amplitude of the ACh-evoked current and confirm previously published data (6). Partial recovery of the ACh response was observed upon removal of telithromycin. Such partial recovery is frequently observed with open channel blockers. Reduction of the current amplitude was accompanied by a significant modification of the response time course as illustrated in Fig. Fig.2B,2B, which is also indicative of an open channel blocker effect. Average levels of inhibition of the ACh-evoked currents measured in several cells are represented in the histogram in Fig. Fig.2C.2C. These data illustrate that exposure to 2 μM telithromycin caused a profound inhibition of the ACh-evoked current (P < 0.005).Open in a separate windowFIG. 2.Telithromycin inhibits the muscular nAChRs. (A) Experimental protocol used to assess effects of telithromycin. Currents evoked by ACh (at 10 μM for 10 s) were measured at regular intervals (2 min). Following a stabilization period, cells were exposed to a sustained concentration of telithromycin (2 μM) as indicated by the bar. The response of the cells to the same ACh test pulse was determined over 20 min. Recovery from telithromycin effects was then assessed over 10 min. (B) Effects of telithromycin on the time course of the ACh-evoked current. A typical response recorded as a control is shown in gray, and the response of the same cell after a 20-min exposure to 2 μM telithromycin is indicated in black. (C) Histogram of the peak currents measured in a series of cells (n = 3). Currents were normalized to unity versus the average responses obtained for controls using the experimental protocol depicted in panel A. Bars indicate the standard errors of means (SEM).When tested against the ganglionic (α3β4), the brain high-affinity (α4β2), and the homomeric α7 receptors (Fig. (Fig.33 and Table Table1),1), exposure to 2 μM telithromycin inhibited up to 90% of the α3β4 and α7 ACh-evoked currents whereas lesser inhibition was observed with clarithromycin and azithromycin. However, the comparable degrees of inhibition caused by the three macrolides at the neuromuscular junction suggest that the inhibition at these receptors alone cannot explain the previously reported risk of muscle failure in myasthenia patients receiving telithromycin (7). We therefore turned our attention to the structural differences among macrolides. A particularity of telithromycin is its pyridine-imidazole-containing moiety. In addition, a review of telithromycin metabolism revealed pyridine-imidazole and pyridine-imidazole-N-oxide (10). Pyridine-N-oxide was tested as a control. Pyridine-imidazole and pyridine-N-oxide-imidazole markedly inhibited the neuromuscular junction receptors (Fig. (Fig.44 and Table Table2).2). The greatest degree of inhibition was caused by pyridine-N-oxide-imidazole, which also inhibited the α7 nAChRs. Furthermore, this compound also inhibited α3β2 nAChRs, which are thought to be expressed on the presynaptic ending of the neuromuscular junction (10), by up to 25%. This finding suggests that telithromycin and its metabolites inhibit both the pre- and postsynaptic receptors and that the dual action of telithromycin and its metabolites may exacerbate myasthenia gravis symptoms. Concentration-inhibition curves for telithromycin, azithromycin, clarithromycin, and solithromycin were determined to further delineate the spectrum of activity at the nAChRs. Figure 5A to D show that α3β4 receptors are preferentially inhibited by telithromycin, with a 50% inhibitory concentration (IC50) of telithromycin of 0.1 μM. At the highest concentration (10 μM), telithromycin almost abolishes the ACh-evoked current at this receptor subtype. At least a 10-fold shift toward lower sensitivity was observed with azithromycin and clarithromycin. Solithromycin, which has a macrolide/ketolide core ring similar to that of telithromycin but not the pyridine moiety at its side chain, shows a clear difference in the inhibition profile. While marked inhibition was observed for solithromycin concentrations above 3 μM, the IC50 of solithromycin is more than 30-fold higher than that of telithromycin and at least 3-fold higher than that of azithromycin or clarithromycin. Results obtained for the α7 receptors (Fig. 5B and E) showed a similar trend, with telithromycin causing the greatest inhibition and having an IC50 of about 0.15 μM. This value is close to that observed for the α3β4 receptors and roughly 10-fold lower than that of azithromycin. Analysis of the IC50s alone may give a false impression of the blockade caused by macrolide exposure. For example, while the α7 receptors display rather high-level sensitivity to clarithromycin, the inhibition reaches a plateau at only 30% inhibition. Thus, even at the highest concentration of clarithromycin, about 60% of the ACh response remains, whereas only 10% or less of the response was observed with telithromycin. Comparison of telithromycin and solithromycin inhibition profiles further underlines the critical role of the pyridine moiety, emphasized by the difference in IC50s between these two ketolides. We also examined the concentration-inhibition curves for the four macrolides at the α4β2 nAChRs, which are the high-nicotine-affinity receptors in the central nervous system (CNS). Concentration-inhibition curves obtained for this receptor subtype are shown in Fig. 5C and F. Interestingly, while these receptors also displayed the greatest sensitivity to telithromycin, the IC50 was about 4 μM, which is significantly higher than that observed for α3β4 or α7 nAChRs. Moreover, azithromycin, clarithromycin, and solithromycin displayed even higher IC50s for α3β4 and α7 nAChRs.Open in a separate windowFIG. 3.Differential inhibition of nAChRs caused by three macrolides. Measurements were carried out using the protocol depicted in Fig. Fig.2A.2A. The bar graph represents a plot of the normalized ACh-evoked current measured after 20 min of incubation in the presence of the macrolide versus the control. Bars indicate the SEM obtained for at least 5 cells. These data illustrate the preferential inhibition caused by telithromycin at the α3β4 and α7 receptors.Open in a separate windowFIG. 4.Effects of three putative metabolites of telithromycin. The levels of inhibition caused by a 20-min exposure to the putative telithromycin metabolites at a 2 μM concentration were determined using the experimental protocol illustrated in Fig. Fig.2A.2A. The plot of the maximum inhibition observed for each of the metabolites for four nAChR subtypes clearly illustrates the differential effects observed at the receptors. Note that the greatest inhibition was observed at α7 with pyridine-N-oxide-imidazole.Open in a separate windowFIG. 5.Inhibition of ganglionic and central nAChRs by four macrolides. (A to C) Concentration-inhibition curves for α3β4, α7, and α4β2 with telithromycin (closed circles) and the novel ketolide CEM-101 (open circles). (D to F) Concentration-inhibition curves for α3β4, α7, and α4β2 with azithromycin (open triangles) and clarithromycin (open squares). Responses obtained from three to seven cells were normalized versus the ACh-evoked current measured as a control and plotted as a function of the logarithm of the macrolide concentration. Bars indicate the standard errors of means. Continuous curves through the data points are the best fits obtained with the empirical Hill equation.
Open in a separate windowaCompounds were tested at 2 μM concentrations. Results are means ± SEM (n = 3 to 5).
Open in a separate windowaCompounds were tested at 2 μM concentrations. Results are means ± SEM (n = 3 to 5).Altogether, these data reveal an otherwise unexpected action of telithromycin at the nAChRs with a blockade of the ACh-evoked currents at clinically relevant concentrations. Both the sensitivity to telithromycin and the degree of blockage indicate that these mechanisms can readily account for the observed side effects. Effects at the ganglionic receptors α3β4 and α7 explain the blockade of the ciliary ganglion neurotransmission and the resulting vision blur. These data provide for the first time a predictor measure of the unwanted side effects of telithromycin. 相似文献
TABLE 1.
Macrolides inhibit nAChR responsesReceptor type | % Inhibition of ACh-evoked current by sustained (20-min) exposurea to: | ||
---|---|---|---|
Telithromycin | Azithromycin | Clarithromycin | |
αa7 | 88 ± 2 | 51 ± 12 | 49 ± 3 |
α3β4 | 90 ± 1 | 56 ± 7 | 38 ± 5 |
α4β2 | 24 ± 7 | 25 ± 13 | 0 |
NMJ | 45 ± 16 | 38 ± 10 | 47 ± 7 |
TABLE 2.
Putative metabolites of telithromycin inhibit nAChR responsesReceptor type | % Inhibition of ACh-evoked current by sustained (20-min) exposurea to: | ||
---|---|---|---|
Pyridine-N-oxide | Pyridine-imidazole | Pyridine-N-oxide-imidazole | |
α7 | 0 | 44 ± 11 | 72 ± 5 |
α3β2 | 5 ± 17 | 0 | 25 ± 4 |
α3β4 | 28 ± 11 | 53 ± 3 | 41 ± 23 |
α4β2 | 12 ± 24 | 42 ± 13 | 35 ± 7 |
NMJ | 21 ± 18 | 51 ± 5 | 56 ± 11 |
93.
细胞因子和凋亡相关基因在小鼠帕金森病模型中的表达 总被引:2,自引:0,他引:2
帕金森病是一种多发于老年的神经系统退行性疾病,它的发病机制有以下推测:氧化应激;神经营养因子的缺乏;内源性和外源性神经毒素。近年来研究表明,在人帕金森病病例及小鼠帕金森病模型中都观察到了黑质内神经元的凋亡,而且白细胞介素-1β(IL-1β)、IL-2、IL-4、IL-6、肿瘤坏死因子(TNF-α)等细胞因子的表达在人帕金森病脑和小鼠帕金森病模型脑中也有上调。本研究拟探讨凋亡基因B细胞淋巴瘤/白血病-2(Bcl-2)和B细胞淋巴瘤/白血病-2X相关蛋白(Bax)与炎症因子IL-1α和IL-10在帕金森病脑中的表达部位、表达时间以及凋亡基因与细胞因子之间的相互关系。 相似文献
94.
95.
F Tinturier A Tondriaux E Lobjoie A Khoury A Groshens C Galy P Neveu M Ossart 《Phlébologie》1989,42(1):59-68
The introduction of new anesthetic drugs and the option of administering anesthesia to outpatients for venous surgery of the lower limbs have modified the anesthesiologist's strategy. In addition, the final decision depends on the number of attending physicians (family doctor, phlebologist, surgeon, anesthesiologist, and of course, on the patient). The essential elements which determine the choice are: the methods preferred by the anesthesiologist, the patient's wishes, the duration, type and painful nature of the procedure. All types of anesthetic protocols may be employed. General anesthesia is often preferable because of its flexible administration and local anesthesia because it is simple to administer. Loco-regional anesthetics can be substituted for local types of anesthesia in bilateral surgical procedures but these are difficult to administer on an outpatient basis. Development of new drugs such as propofol is tending to give general anesthesia in outpatients an important role once again. 相似文献
96.
A retrospective study of 250 patients operated upon for infrarenal abdominal aorta aneurysm provided data for evaluation of the surgical risk as a function of three developmental situations: asymptomatic aneurysms, aneurysms evolving by subacute symptomatology and ruptured aneurysms. Mortality varied as a function of group, being 3% for the asymptomatic group, 21% for evolving aneurysms and 69% for ruptured aneurysms. Perioperative mortality was related to age and cardiovascular risk factors. Various clinical and pathologic aspects as well as means of follow up review are discussed, allowing definition of therapy as a function of previous clinical status and evolution of the aneurysm. 相似文献
97.
Teegwendé V. Porgo Lynne Moore Coralie Assy Xavier Neveu Catherine Gonthier Simon Berthelot Belinda J. Gabbe Peter A. Cameron Francis Bernard Alexis F. Turgeon 《Value in health》2021,24(4):530-538
ObjectivesTo develop a hospital indicator of resource use for injury admissions.MethodsWe focused on resource use for acute injury care and therefore adopted a hospital perspective. We included patients ≥16 years old with an Injury Severity Score >9 admitted to any of the 57 trauma centers of an inclusive Canadian trauma system from 2014 to 2018. We extracted data from the trauma registry and hospital financial reports and estimated resource use with activity-based costing. We developed risk-adjustment models by trauma center designation level (I/II and III/IV) for the whole sample, traumatic brain injuries, thoraco-abdominal injuries, orthopedic injuries, and patients ≥65 years old. Candidate variables were selected using bootstrap resampling. We performed benchmarking by comparing the adjusted mean cost in each center, obtained using shrinkage estimates, to the provincial mean.ResultsWe included 38 713 patients. The models explained between 12% and 36% (optimism-corrected r2) of the variation in resource use. In the whole sample and in all subgroups, we identified centers with higher- or lower-than-expected resource use across level I/II and III/IV centers.ConclusionsWe propose an algorithm to produce the indicator using data routinely collected in trauma registries to prompt targeted exploration of potential areas for improvement in resource use for injury admissions. The r2 of our models suggest that between 64% and 88% of the variation in resource use for injury care is dictated by factors other than patient baseline risk. 相似文献
98.
Lack of social support is becoming increasingly important as a psychosocial risk factor in the study of coronary heart disease (CHD). There may also be an association between vital exhaustion and lack of social support. Because most research has focused on men, we decided to explore the associations between structural and functional social support and first myocardial infarction (MI) in women. Subjects were 79 women hospitalized with a First MI (mean age 59.3; SD = 9.3) and 90 women hospitalized with an acute surgical event (mean age 57.4: SD = 9 1). MI cases reported more vital exhaustion than did controls (p < ,040), and exhausted women reported less structural (p < .001) and functional support (p < .000). After controlling for age, hypertension, diabetes, menopausal status, smoking, nonanginal pain, and vital exhaustion, multiple logistic regression analysis showed that poor structural support was associated with an increased risk for MI. These results suggest that social support is associated with vital exhaustion, which is a well-known risk factor for CHD. Furthermore, it is suggested that women with only a few confidants are more at risk for MI even after adjustment for well-known risk factors for CHD. 相似文献
99.
Frédéric Doussau Jean-Luc Dupont Dorine Neel Aline Schneider Bernard Poulain Jean Louis Bossu 《Expert opinion on drug discovery》2017,12(10):1011-1022
Introduction: Demyelinating disorders, characterized by a chronic or episodic destruction of the myelin sheath, are a leading cause of neurological disability in young adults in western countries. Studying the complex mechanisms involved in axon myelination, demyelination and remyelination requires an experimental model preserving the neuronal networks and neuro-glial interactions. Organotypic cerebellar slice cultures appear to be the best alternative to in vivo experiments and the most commonly used model for investigating etiology or novel therapeutic strategies in multiple sclerosis.Areas covered: This review gives an overview of slice culture techniques and focuses on the use of organotypic cerebellar slice cultures on semi-permeable membranes for studying many aspects of axon myelination and cerebellar functions.Expert opinion: Cerebellar slice cultures are probably the easiest way to faithfully reproduce all stages of axon myelination/demyelination/remyelination in a three-dimensional neuronal network. However, in the cerebellum, neurological disability in multiple sclerosis also results from channelopathies which induce changes in Purkinje cell excitability. Cerebellar cultures offer easy access to electrophysiological approaches which are largely untapped and we believe that these cultures might be of great interest when studying changes in neuronal excitability, axonal conduction or synaptic properties that likely occur during multiple sclerosis. 相似文献
100.
Anne Maas MSc Heleen Maurice-Stam PhD Leontien C. M. Kremer MD PhD Alied van der Aa-van Delden MSc Eline van Dulmen-den Broeder PhD Wim J. E. Tissing MD PhD Jacqueline J. Loonen MD PhD Helena J. H. van der Pal MD PhD Andrica C. H. de Vries MD PhD Marry M. van den Heuvel-Eibrink MD PhD Cécile Ronckers PhD Sebastian Neggers MD PhD Dorine Bresters MD PhD Marloes Louwerens MD Margriet van der Heiden-van der Loo PhD Marloes van Gorp PhD Martha Grootenhuis PhD Dutch LATER study group 《Cancer》2023,129(16):2553-2567