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81.
《Expert opinion on pharmacotherapy》2013,14(3):323-329
Introduction: Cystic fibrosis (CF) is an inherited rare disease characterised by recurrent pulmonary infection, pancreatic malabsorption and a number of other multisystem effects. In the past few years new drugs specifically designed to treat CF have entered the pipeline, and some are now used in clinical practice. Areas covered: Clinical trial results from CF trials reported or ongoing within the last 3 years are discussed. A literature and trials registry search of trials and meta-analyses involving patients with CF was conducted, from which the most exciting developments were selected. Expert opinion: Drugs to address the basic defect in CF have finally come to market, albeit for a limited number of patients with a specific genotype. Traditional areas of CF therapeutics continue to be developed, with modest success, including drugs to modulate the airway surface liquid, new pancreatic supplements, antibiotics and new treatments for endocrine complications of CF. 相似文献
82.
《European neuropsychopharmacology》2014,24(2):309-320
Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/kg, ip) with new derivatives of isothiourea (0.5–1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC50 values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance. 相似文献
83.
目的 探讨即时及长期持续气道正压通气(continuous positive airway pressure,CPAP)治疗对于阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)患者血管内皮功能及自主神经调制的影响.方法 共有23例呼吸暂停/低通气指数(apnea/hypopnea index,AHI)≥15次/h的OSAHS患者[AHI (58.8±28.4)次/h]纳入该研究.所有受试者均为男性,年龄为(43.2±10.7)岁,体质量指数为(33.7±8.3) kg/m2.该研究采用动脉增加指数(AAI)作为血管内皮功能的测量指标、心率变异(HRV)及血压变异(BPV)的各频谱成分作为自主神经调制的评价指标,对纳入研究的受试者接受整夜及长期(6个月)的CPAP治疗后其血管内皮功能及自主神经的变化进行评价.结果 整夜CPAP治疗时:睡眠前后AAI、HRV及BPV各成分均无显著改变;与无CPAP治疗时相比,睡眠后的HRVLF(60.8±10.4 vs 69.8±13.8,P<0.001)、HRV LF/HF(2.4±1.1vs 3.8±1.8,P<0.001)及BPV LF(66.5±11.6 vs 78.5±14.8,P<0.001)有显著降低,HRV HF(29.5±11.7 vs20.7±9.7,P<0.05)有显著升高,而AAI无显著变化.6个月CPAP治疗后:与治疗前相比,睡眠前的AAI(8.1±1.8 vs12.8±2.3,P<0.001)显著降低,HRV LF(58.3±9.7 vs 63.4±11.5,P<0.05)、HRV LF/HF(2.0±0.8 vs 2.5±1.2,P<0.05)及BPV LF(60.5±12.1vs67.7±13.2,P<0.05)显著降低,HRV HF(35.5±9.8 vs 28.8±10.1,P<0.05)显著升高;但若停止CPAP治疗1个晚上,则晨起血压升高、自主神经功能紊乱仍会发生,但与6个月前未CPAP治疗时相比均有所减缓.结论 整夜CPAP治疗除了可降低OSAHS患者的晨起血压升高,还可显著改善晨起自主神经紊乱,而长期有效CPAP治疗可显著改善基础内皮功能及自主神经调制,并可减缓OSAHS患者对阻塞性呼吸事件的心血管反应,因而可降低心血管疾病发生率、改善心血管预后. 相似文献
84.
Synaptic transmission has been shown to be modulated by purinergic receptors. In the cerebellum, spontaneous inhibitory input to Purkinje neurons is enhanced by ATP via P2 receptors, while evoked excitatory input via the granule cell parallel fibers is reduced by presynaptic P1 (A1) adenosine receptors. We have now studied the modulation of the complex GABAergic input to granule cells by the purinergic receptor agonists ATP and adenosine in acute rat cerebellar tissue slices using the whole-cell patch-clamp technique. Our experiments indicate that ATP and adenosine substantially reduce the bicuculline- and gabazine-sensitive GABAergic input to granule cells. Both phasic and tonic inhibitory components were reduced leading to an increased excitability of granule cells. The effect of ATP and adenosine could be blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not by other P1 and P2 receptor antagonists, indicating that it was mediated by activation of A1 adenosine receptors. Our results suggest that, in the cerebellar network, A1 receptor activation, known to decrease the excitatory output of granule cells, also increases their excitability by reducing their complex GABAergic input. These findings extend our knowledge on purinergic receptors, mediating multiple modulations at both inhibitory and excitatory input and output sites in the cerebellar network. 相似文献
85.
Bär H Wende P Watson L Denger S van Eys G Kreuzer J Jahn L 《Basic research in cardiology》2002,97(1):9-16
Restenosis is the major obstacle interfering with a successful long-term outcome of balloon angioplasty. Neointima formation
following endothelial injury is the result of phenotype modulation and proliferation of smooth muscle cells (SMC). To characterize
these time-dependent changes, a rat balloon injury model of carotid artery restenosis was assessed. We applied monoclonal
antibodies recognizing desmin, sm-α-actin and smoothelin, a novel marker specific for the differentiated phenotype of SMC.
Neointima formation could be seen from day 7 after injury onwards. During early phases, the number of smoothelin-positive
cells in the media was decreased compared with uninjured controls. Smoothelin staining was absent in the neointima during
formation. Increased levels of smoothelin in both media and neointima were observed at days 28 and 56, correlating with a
decrease in proliferation as assessed by Ki-67 antigen staining. No such changes were observed for desmin and sm-α-actin.
Following balloon injury, SMC in both the media and the neointima underwent an early, reversible dedifferentiation, followed
by proliferation. The novel SMC-specific marker protein smoothelin can be used to monitor this SMC (de)differentiation in
neointima and media. These findings support the pivotal role of SMC phenotype modulation in neointima formation and restenosis.
Received: 29 January 2001, Returned for revision: 20 February 2001, Revision received: 26 June 2001, Accepted: 2 July 2001 相似文献
86.
William Gibson Penny Moss Tak Ho Cheng Alexandre Garnier Anthony Wright Benedict M. Wand 《The journal of pain》2018,19(3):330-339
Many factors interact to influence threat perception and the subsequent experience of pain. This study investigated the effect of observing pain (extrinsic threat) and intrinsic threat of pain to oneself on pressure pain threshold (PPT). Forty socially connected pairs of healthy volunteers were threat-primed and randomly allocated to experimental or control roles. An experimental pain modulation paradigm was applied, with non-nociceptive threat cues used as conditioning stimuli. In substudy 1, the extrinsic threat to the experimental participant was observation of the control partner in pain. The control participant underwent hand immersion in noxious and non-noxious water baths in randomized order. Change in the observing participant's PPT from baseline to mid- and postimmersion was calculated. A significant interaction was found for PPT between conditions and test time (F2,78?=?24.9, P?<?.005). PPT increased by 23.6%?±?19.3% between baseline and during hand immersion (F1,39?=?43.7, P?<?.005). Substudy 2 investigated threat of imminent pain to self. After a 15-minute break, the experimental participant's PPT was retested (“baseline 2”). Threat was primed by suggestion of whole arm immersion in an icier, larger water bath. PPT was tested immediately before anticipated arm immersion, after which the experiment ended. A significant increase in PPT between “baseline 2” and “pre-immersion” was seen (t?=??7.6, P?=?.005), a pain modulatory effect of 25.8?±?20.7%. Extrinsic and intrinsic threat of pain, in the absence of any afferent input therefore influences pain modulation. This may need to be considered in studies that use noxious afferent input with populations who show dysfunctional pain modulation.
Perspective
The effect on endogenous analgesia of observing another's pain and of threat of pain to oneself was investigated. Extrinsic as well as intrinsic threat cues, in the absence of any afferent input, increased pain thresholds, suggesting that mere threat of pain may initiate analgesic effects in traditional noxious experimental paradigms. 相似文献87.
88.
目的 研究移植后供体心脏自主神经功能的恢复情况.方法 通过对216例心脏移植患者术后10年内24h动态心电图心率变异的随访分析,评价心脏移植术后供体心脏的自主神经功能变化.结果 移植心脏的心率变异功率频谱在术后第四年开始出现增长.亚组分析表明:35.2%的患者在术后数年内未出现明显心率变异功率谱的变化;约60%的患者在心脏移植术后第六年出现心率变异总功率谱的增加,低频功率谱增长,但高频功率谱未出现明确改变;7.4%患者心率变异功率谱在移植术后出现了明显的变化,低频和高频功率谱在术后第四年开始显著增长,超过其他患者.结论 只有为数不多的心脏移植患者在心脏移植术后逐渐出现功能性心脏自主神经功能恢复,而大多数供体心脏在术后的10年内仍保持着自主神经去神经化. 相似文献
89.
Antonella Rosa Mariella Nieddu Alessandra Piras Angela Atzeri Danilo Putzu Antonio Rescigno 《Nutrients》2015,7(2):849-864
The present study aimed to examine the potential anticancer properties of fixed oil obtained from Maltese mushroom (Cynomorium coccineum L.), an edible, non-photosynthetic plant, used in traditional medicine of Mediterranean countries to treat various ailments and as an emergency food during the famine. We investigated the effect of the oil, obtained from dried stems by supercritical fractioned extraction with CO2, on B16F10 melanoma and colon cancer Caco-2 cell viability and lipid profile. The oil, rich in essential fatty acids (18:3n-3 and 18:2n-6), showed a significant growth inhibitory effect on melanoma and colon cancer cells. The incubation (24 h) with non-toxic oil concentrations (25 and 50 μg/mL) induced in both cancer cell lines a significant accumulation of the fatty acids 18:3n-3 and 18:2n-6 and an increase of the cellular levels of eicosapentaenoic acid (20:5n-3) with anticancer activity. Moreover, the oil exhibited the ability to potentiate the growth inhibitory effect of the antitumor drug 5-fluorouracil in Caco-2 cells and to influence the melanin content in B16F10 cells. The results qualify C. coccineum as a resource of oil, with potential benefits in cancer prevention, for nutraceutical and pharmaceutical applications. 相似文献
90.
In the immune oncology era, the clinical efficacy of immune checkpoint inhibitors (ICIs) against most solid cancers is well known. In hepatocellular carcinoma, the recent success of combination therapy with targeting agents has accelerated the search for novel combination strategies. Radiotherapy (RT), an attractive modality, can be combined with ICIs, which act as strong modulators of the tumor immune microenvironment. Herein, we discuss immune modulation caused by radiation and the current trials of RT–ICI combination treatment as well as future perspectives. 相似文献