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11.
Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) – positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies. 相似文献
12.
Birgit T Priest Kenneth M Blumenthal Jaime J Smith Vivien A Warren McHardy M Smith 《Toxicon》2007,49(2):194-201
The tarantula venom peptides ProTx-I and ProTx-II inhibit voltage-gated sodium channels by shifting their voltage dependence of activation to a more positive potential, thus acting by a mechanism similar to that of potassium channel gating modifiers such as hanatoxin and VSTX1. ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency and represent the first potent peptidyl inhibitors of TTX-resistant sodium channels. Like gating modifiers of potassium channels, ProTx-I and ProTx-II conform to the inhibitory cystine knot motif, and ProTx-II was demonstrated to bind to sodium channels in the closed state. Both toxins have been synthesized chemically, and ProTx-II, produced by recombinant means, has been used to map the interaction surface of the peptide with the Nav1.5 channel. In comparison, beta-scorpion toxins activate sodium channels by shifting the voltage dependence of activation to more negative potentials, and together these peptides represent valuable tools for exploring the gating mechanism of sodium channels. 相似文献
13.
14.
目的 :研究双氯芬酸在正常志愿者的血药浓度及体内的药代动力学 ,为临床用药提供依据。方法 :16名健康男性志愿者 ,单剂量口服双氯芬酸钠肠溶片 10 0 mg,在不同时间点取静脉血 ,血药浓度采用高效液相色谱法 (HPL C)测定。由血药浓度数据获得各自的主要药动力学参数。结果 :志愿者单次服用 10 0 mg双氯芬酸钠肠溶片后的药代动力学参数 AUC0→∞ 、AU C0→ 8、Cmax、Tmax分别为 (5 .98± 1.4 7) mg.h/ L、(6 .15± 1.5 2 ) mg.h/ L、(2 .96± 0 .84 ) m g.h/ L、(2 .2 5± 0 .32 ) h。结论 :双氯芬酸钠肠溶片在我国正常志愿者的药代动力学参数与国外的相似。 相似文献
15.
采用高效液相色谱法测定双氯芬酸钠滴眼液的含量,方法简便,准确,能将药与杂质峰完全分离。应用化学动力学原理以恒温加试验预测双氯芬酸钠滴眼液稳定性及有效期,室温下有效期t^25℃0.9约为2.57年,与留样观察结果相符。 相似文献
16.
R. Lemmens-Gruber H. Marei P. Heistracher 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(2):230-238
GE 68 ((Rac.)-1-[3-(Phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol hydrochloride) is structurally related to propafenone,
and exerts negative inotropic and negative chronotropic effects similar to the parent drug, but lacks any β-adrenoceptor blocking
activity contrary to propafenone. Thus, the electrophysiological effects of GE 68 were studied in papillary muscles, left
atria, Purkinje fibres, sinoatrial nodes and ventricular myocytes of the guinea-pig heart with the intracellular microelectrode
technique and the patch-clamp technique in the cell-attached mode.
The decrease of the maximum upstroke velocity (V˙max) by GE 68 (1 to 10 μM) was use- and frequency-dependent. V˙max recovered from the use-dependent block with a time constant of 4.1 ± 0.6 s. In papillary muscles and Purkinje fibres action
potential duration was shortened, while it was prolonged in left atria and sinoatrial nodes. Half-maximal steady-state inactivation
of the sodium channels was shifted to more negative membrane potentials (control: –91.5 ± 0.8 mV, 10 μM GE 68: –97.9 ± 2.5 mV).
The peak of the current-voltage relationship and the reversal potential were not changed by GE 68. The amplitude of the unitary
current remained unaltered, while open state probability was decreased. The most striking effect of GE 68 was an increase
of the number of sweeps without single channel openings (1 μM: 2 fold, 10 μM: 6 fold). GE 68 also caused a decrease of the
mean open times, and an increase of the mean closed times in unmodified and pronase-modified sodium channels.
Besides the lack of β-adrenoceptor blocking activity, data present a faster recovery from the use-dependent block by GE 68
and a lower affinity to inactivated sodium channels compared to the reference drug propafenone, as well as differences in
the effect on single channel kinetics.
Received: 25 July 1996 / Accepted: 14 October 1996 相似文献
17.
二巯基丙磺酸钠对苯硫丹和多噻烷急性中毒小鼠的保护作用 总被引:1,自引:0,他引:1
用二巯基丙磺酸钠对苯硫丹、多噻烷急性染毒小鼠进行保护解救。结果表明:二巯基丙磺酸钠对该两农药急性染毒小鼠具有显著的保护作用(P<0.05)。本实验填补了以二巯基丙磺酸钠作为首选药物治疗沙蚕毒系现有全部品种急性中毒解毒谱的空白。 相似文献
18.
Although non-steroidal anti-inflammatory drug-induced colopathy is well described, colonic perforations complicating non-steroidal anti-inflammatory drug intake are rare. We report a patient with rheumatoid arthritis who was on long-term diclofenac and presented with early colonic stricture formation and a caecal perforation, which to the best of our knowledge, has only been reported once before. It is important to suspect this diagnosis in patients on non-steroidal anti-inflammatory drug therapy who present with an acute abdomen. 相似文献
19.
目的:观察高渗氯化钠高氧液对失血性休克家兔动脉血气和血乳酸值的影响,评价其对失血性休克的早期救治效果。方法:制备高渗氯化钠溶液(HS)、生理盐水高氧液(NSO)和高渗氯化钠高氧液(HSO)。30只雄性家兔制备失血性休克模型[于10min内使平均动脉压(MAP)降至40mmHg(1mmHg=0.133kPa),维持60min],随机分为NSO,HS,HSO组3个治疗组。分别按6mL/kg剂量5min内静脉输入NSO,HS和HSO。记录休克前后及给药后心率(HR)、呼吸(RR)、MAP及尿滴(UD),测定休克前、休克60min,给药后30,60,120min时血乳酸(BL)和动脉血气值。最后观察尸肺,测定肺系数。结果:HS和HSO组均显著地改善MAP,HR和UD,降低BL,改善代谢性酸中毒,肺系数明显低于NSO组。HSO与NSO及HS比较,能更显著地降低血BL,提高动脉血氧饱和度(SaO2)和动脉血氧分压(PaO2)。结论:HSO较HS和NSO能更显著地降低血BL,提高SaO2和PaO2,对失血性休克的早期救治具有较高的使用价值。 相似文献
20.
Prof. M. Martens M.D. 《Clinical rheumatology》1997,16(1):25-31
Summary The efficacy and safety of local action transcutaneous flurbiprofen 40 mg [flurbiprofen LAT] patches and diclofenac sodium tablets, 50 mg b.d., were compared in an open, multicentre, randomized, parallel-group study in patients with soft-tissue rheumatism. Patches were replaced at 12-hourly intervals. Clinical assessments were performed after 7 and 14 days of treatment. Fifty-six patients were treated with flurbiprofen LAT and 53 with diclofenac. Six withdrawals (three from each group) occurred during the treatment period.A statistically significant difference was observed in favour of flurbiprofen LAT for the principal measure, namely the investigator's opinion of overall change in clinical condition: 49/53 (92%) patients treated with flurbiprofen LAT had improved by day 14 compared with 36/49 (73%) patients receiving diclofenac sodium (p=0.03; eligible dataset). There were also statistically significant differences in favour of flurbiprofen LAT for the investigator's assessments of the overall severity of the clinical condition (p=0.03; eligible dataset), for the severity of pain at the region treated (p=0.04; intent-to-treat), and for the severity of tenderness (p<0.001; intent-to-treat). Supplementary analgesia (paracetamol) was required by two patients in the flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT in the average daily consumption of paracetamol was significant (p=0.04). The patients' assessment of severity of pain on movement also favoured flurbiprofen LAT (p =0.049; eligible dataset), but there were no statistically significant differences in day or night pain or quality of sleep. For the patients' opinion of treatment there was, however, a statistically significant difference in favour of flurbiprofen LAT (p=0.02). Of the patients receiving flurbiprofen LAT, 94% regarded it as a convenient form of treatment.With respect to tolerability 8/56 (14%) patients applying flurbiprofen patches reported a total of nine adverse effects (AEs) (mainly local, mild skin irritations), vs 9/52 (17%) patients receiving diclofenac, who reported 12 AEs. Most AEs in the enteric-coated diclofenac group were of a gastrointestinal nature (one of which was severe). In terms of the proportion of patients reporting AEs related to the digestive system, there was a statistically significant difference in favour of flurbiprofen LAT (p=0.011).In conclusion, local treatment of soft-tissue rheumatism with flurbiprofen LAT was demonstrably superior to benchmark oral therapy with diclofenac sodium over a 2-week period in terms of both efficacy and gastrointestinal tolerability. Flurbiprofen LAT provided both an effective and convenient form of topical SAID treatment. 相似文献