钙离子对4-氨基吡啶诱发肥大细胞释放组胺作用的影响

4-Aminopyridine(4-AP) has been shown to induce histamine release fromisolated peritoneal mast cells(PMC)in mice and rats. In the presence of extracellular calcium atnormal level(0.9 mmol·L^-1)histamine release induced by 4-AP(13. 6 mmol·L^-1) from mice PMCwas 33.0%±4.6%,while at low calcium concentration (0.5 mmol·L^-1) and in calcium-freemedium this parameter decreased to 25.5%±4.2%and 16.3%±3.7%respectively.Histaminerelease in response to 4-AP(10 mmol·L^-1)from rat PMC was 39.1%±6.7%(0.9 mmol·L^-1calcium),while at low calcium concentration(0. 5 mmol·L^-1) and in calcium-free medium thisparameter decreased to 29.3%±4.7%and 20.2%±2.9% respectively. Results of statisticalanalysis indicate that 4-AP induced histamine release is related to Ca²⁺ concentration. When rat PMCwere preincubated in calcium-free medium with EDTA 0.1 mmol·L^-1 for 180 min　4-AP inducedhistamine release was 13.8%±1.6%.This shows that 4-AP also elicited mobilization of endogenous calcium stores in mast cells.The mechanism of 4-AP　induced histamine release was discussed.     

4-氨基-2-氯吡啶的合成

4-氨基-2-氯吡啶(1)是医药及农药中间体[1～3],主要有以下3条合成路线:(1)2-氯-4-乙酰基吡啶与盐酸羟胺反应生成相应的肟,经Beckmann重排得到的2-氯-4-乙酰胺基吡啶再经水解制得,总收率77.8%[4,5].(2)2-氯-4-氨甲酰基吡啶在PhI(OAc)2作用下进行Hofmann重排制得,总收率85.4%[6].     

HPLC-DAD法测定2-氨基吡啶原料药中有关物质

目的 建立高效液相色谱法(HPLC)-二极管阵列检测器(DAD)法测定2-氨基吡啶原料药中的有关物质。方法使用Waters XBridge C₁₈色谱柱(250 mm×4.6 mm,5μm),流动相为10 mmol/L磷酸氢二钾(磷酸调pH值至7.5)–甲醇,梯度洗脱;检测波长为225 nm(2,4-二氨基吡啶、2,6-二氨基吡啶)、260 nm(4-氨基吡啶);体积流量1.0 mL/min;柱温为35℃;进样量：10μL。结果 4-氨基吡啶、2,4-二氨基吡啶、2,6-二氨基吡啶在0.01～2.00、0.01～2.00、0.06～2.00μg/mL线性关系良好。4-氨基吡啶、2,4-二氨基吡啶、2,6-二氨基吡啶的平均回收率分别为99.6%、97.5%、102.7%,RSD值分别为4.6%、2.6%、3.5%。结论 建立的方法操作简便、准确、灵敏度高、专属性强,可用于2-氨基吡啶原料药的质量控制。     

4-氨基吡啶对豚鼠心室肌钙和钠电流的影响

目的研究4-氨基吡啶(4-AP)对心肌细胞L型钙通道和钠通道的影响。方法用全细胞膜片钳技术考察4-AP对豚鼠心室肌细胞L型钙电流和钠电流的作用。结果4-AP0.1,0.5,1.0mmol·L^-1浓度依赖性地抑制L型钙电流(I_Ca,L)和钠电流(I_Na),抑制率分别为(11.6±1.7)%,(37.5±8.3)%和(54.5±6.9)%以及(22.1±14.3)%,(39.4±8.8)%和(62.3±6.8)%。0.5mmol·L^-14-AP使I_Ca,L和I_NaI-V曲线均上移。结论4-AP可浓度依赖性地阻滞豚鼠心室肌细胞L型钙通道和钠通道。     

4-甲基-3-硝基吡啶的合成

以2—氨基—4—甲基吡啶为原料，通过硝化、重氮化羟基置换、氯化及脱氯等4步反应制得标题物，总收率60％。     

4-氨基吡啶对牛磺酸调节突触体氨基酸释放的影响

AIM　To elucidate the mechanism of taurine-regulated amino acid release from synaptosomes. METHODS　Endogenous aspartate, glutamate and GABA release from cortical synaptosomes were measured by high performance liquid chromatography using stepwise elution system, Glutamate release was monitored by continuous fluorometry. RESULTS　4-Aminopyridine (3.0×10^-2 mol*L^-1) counteracted the taurine-induced inhibition of glutamate overflow (P<0.05), while aspartate and GABA release was not affected. Nimodipine (10^-5 mol*L^-1) combined with 4-aminopyridine was shown to decrease glutamate release (P<0.05). CONCLUSION　Taurine may regulate glutamate release through presynaptic L-type calcium channel and aslo act on Asp-and GABA-nereve terminal to regulate Asp and GABA release in rat cortex.     

抗疟药的研究——Ⅲ.2-(取代苯乙烯基)-4-氨基吡啶类的合成

本文报道2-(取代苯乙烯基)-4-(4′-二乙氨基-1′-甲基丁基氨基)-吡啶类的合成。动物筛选的初步结果表明:口服给药6.25mg/kg,化合物Ⅲ₂、Ⅲ₄和Ⅲ₇能完全抑制感染伯氏鼠疟原虫氯喹敏感株(Plalmodium berghei)小白鼠的原虫血症;皮下给药1.8mg/kg,化合物Ⅲ,即能达到完全抑制。     

抗疟药的研究——Ⅲ.2-(取代苯乙烯基)-4-氨基吡啶类的合成

本文报道2-(取代苯乙烯基)-4-(4′-二乙氨基-1′-甲基丁基氨基)-吡啶类的合成。动物筛选的初步结果表明:口服给药6.25mg/kg,化合物Ⅲ_2、Ⅲ_4和Ⅲ_7能完全抑制感染伯氏鼠疟原虫氯喹敏感株(Plalmodium berghei)小白鼠的原虫血症;皮下给药1.8mg/kg,化合物Ⅲ,即能达到完全抑制。     

钾通道开放剂拮抗4-氨基吡啶诱发大鼠肥大细胞释放组胺

4-氨基吡啶(4-AP)能诱发大鼠腹腔肥大细胞(PMC)释放组胺,且呈浓度依赖关系。钾通道开放剂二氮嗪(Dia),米诺地尔(Min)及钙拮抗剂硝苯啶(Nif)均能明显抑制4-AP诱发大鼠PMC释放组胺。实验结果提示,大鼠肥大细胞膜上可能存在钾通道,4-AP可能通过阻滞钾通道,使钙通道开放,Ca²⁺内流增加而促进组胺释放,钾通道开放剂可能是一类新的组胺释放拮抗剂。     

脑室内注射4-氨基吡啶诱发家兔惊厥

家兔icv 4-氨基吡啶(4-AP)8μg能诱发反复发作的惊厥,ECoG呈现高幅棘波。抗癫痫药苯妥英钠、苯巴比妥钠、安定均能有效控制4-AP诱发的惊厥,使ECoG棘波消失。丙戊酸钠也有一定效果。东莨菪碱、氟哌啶醇与酚妥拉明均能拮抗4-AP引起的惊厥。结果提示,4-AP诱发的惊厥可能与它促进中枢ACh;DA及NE等递质的释放有关。家兔icv 4-AP诱发的惊厥与常用的癫痫模型比较,有一定优点,可作为筛选抗癫痫药的动物模型之一。     

Higher susceptibility of taurine-deficient rats to seizures induced by 4-aminopyridine

The susceptibility of rats made deficient of taurine by treatment with guanidinoethane sulfonate (GES), to seizures induced by 4-aminopyridine was examined. Guanidinoethane sulfonate, at a concentration of 1% was administered to pregnant rats, in the drinking water 2–3 days prior to delivery and the treatment was continued during nursing. Pups were weaned to the same treatment until 6 weeks of age. This treatment decreased levels of taurine in the cerebral cortex by 70%. 4-Aminopyridine was injected intraperitoneally at doses ranging from 4–7 mg/kg. Taurine-deficient rats showed a greater susceptibility to seizures, as demonstrated by a lowered latency for clonic seizures, an increased incidence of tonic seizures and a higher postseizure mortality. These results suggest an involvement of endogenous taurine in nervous excitability.     

Effects of long-term 4-aminopyridine therapy on glucose tolerance and glucokinetics in patients with spinal cord injury

STUDY OBJECTIVE: To assess the effects of the potassium channel blocker, 4-aminopyridine, on glucose tolerance and glucokinetics in patients with spinal cord injury. DESIGN: Prospective, dose level-blinded study. SETTING: University-affiliated, tertiary-level care, Veterans Affairs medical center, and a university-affiliated research center. PATIENTS: Thirty-one patients with spinal cord injury of more than 1 year's duration. INTERVENTION: In a fasting state, patients ingested 75 g of glucose and completed a 5-hour oral glucose tolerance test before and after 6 months of treatment with an oral, immediate-release formulation of 4-aminopyridine. MEASUREMENTS AND MAIN RESULTS: The time course of glucose plasma concentrations during the oral glucose tolerance tests was profiled for each patient, and glucokinetic parameters were estimated. Results were compared at baseline and after 6 months of treatment with 4-aminopyridine. Of the 31 patients, 29 (94%) had impaired glucose tolerance at baseline. After 6 months of treatment with 4-aminopyridine, 12 (41%) of the 29 patients had a 2-hour postprandial glucose level that no longer supported a diagnosis of impaired glucose tolerance. No significant changes or clinically important trends were seen in fasting blood glucose concentrations or in other glucokinetic parameters in these patients. CONCLUSIONS: The long-term administration of an oral, immediate-release formulation of 4-aminopyridine to patients with longstanding spinal cord injury was associated with readily discernible, potentially clinically significant improvements in glucose tolerance. Because impaired glucose tolerance is a common finding in patients with spinal cord injury, more research, including randomized controlled trials with large study populations, is warranted on this potential treatment.     

气滞胃痛颗粒促进胃肠运动和镇痛作用研究

目的：观察气滞胃痛颗粒对小鼠胃肠动力的影响和镇痛作用,为气滞胃痛颗粒的临床合理应用提供理论依据。方法：以胃肠内标记物葡聚糖蓝-2000在小鼠胃内色素残留及小肠内推进比为指标,观察气滞胃痛颗粒对小鼠胃排空及肠推进的影响;以醋酸所致小鼠扭体反应为疼痛指标,观察气滞胃病颗粒的镇痛作用。结果：气滞胃痛颗粒低、中、高剂量组（1．25g／kg、2．50g／kg、5．00g/kg）可以改善阿托品和多巴胺引起的小鼠胃排空障碍、以及小肠推进抑制作用;对吗啡引起的小鼠胃排空障碍和小肠推进抑制作用无显著影响;中、高剂量组可以促进正常小鼠胃排空,高剂量促进小肠推进。低、中、高剂量组可以显著减少醋酸引起的小鼠扭体次数。结论：气滞胃痛颗粒具有促进小鼠胃肠动力和镇痛作用。     

4-aminopyridine derivatives: A family of novel modulators of voltage-dependent sodium channels

The interactions of a family of aminopyridine derivatives with Site II of the voltage-dependent sodium channel were examined by measuring the ability of these compounds to inhibit [³H]batrachotoxin binding and veratridine-induced increases in [Ca²⁺]_i. Aminopyridines substituted with indole, carbazole, and pyrrole rings were evaluated. All compounds that had an aromatic ring linked to the amine group of 4-aminopyridine showed positive results in both assays. For example, the most potent compound, besipirdine (N-(n-propyl)-N-(4-pyridinyl)-1H-indol-1-amine), had IC₅₀ values of 5 μM and 23.8 μM in the two assays, respectively. Small substitutions on either the aromatic ring or on 4-aminopyridine did not substantially change their potencies. Indoles linked to the amino group of 2- and 3-aminopyridine also showed positive results. These results indicate that aminopyridine derivatives substituted with an aromatic ring on the amino nitrogen are inhibitors of voltage-dependent sodium channels. Drug Dev. Res. 44:8–13, 1998. © 1998 Wiley-Liss, Inc.     

In Vitro electrophysiological activity of nerispirdine, a novel 4-aminopyridine derivative

• 1 The non‐selective K⁺ channel blocker 4‐aminopyridine (4‐AP) has shown clinical efficacy in the treatment of neurological disorders such as multiple sclerosis. The clinical usefulness of 4‐AP is hampered by its ability to produce seizures. Nerispirdine, an analogue of 4‐AP, is currently under clinical investigation for the treatment of multiple sclerosis. In contrast with 4‐AP, nerispirdine is not proconvulsant, suggesting mechanistic differences between the two drugs.
• 2 Using whole‐cell patch‐clamp electrophysiology, we compared the effects of 4‐AP and nerispirdine on the cloned human K⁺ channels K_v1.1 and K_v1.2, expressed in Chinese hamster ovary cells, and on voltage‐dependent Na⁺ channels recorded from human SH‐SY5Y cells.
• 3 Nerispirdine inhibited K_v1.1 and K_v1.2 with IC₅₀ values of 3.6 and 3.7 μmol/L, respectively. 4‐Aminopyridine was approximately 50‐fold less potent at blocking these channels. Nerispirdine also inhibited voltage‐dependent Na⁺ channel currents recorded from human SH‐SY5Y cells with an IC₅₀ of 11.9 μmol/L when measured from a –70 mV holding potential. In contrast, 4‐AP had no effect on Na⁺ channel currents.
• 4 The results demonstrate that nerispirdine, like 4‐AP, can inhibit axonal K⁺ channels and that this mechanism may underlie the ability of the drug to enhance neuronal conduction. Unlike 4‐AP, nerispirdine can also inhibit neuronal Na⁺ channels, a mechanism that may explain why nerispirdine lacks proconvulsant activity.

     

胃癌根治术后不同胃肠减压方式对患者胃肠功能恢复的影响

目的观察不同胃肠减压方式对胃癌根治术后患者胃肠功能恢复的影响。方法将61例行胃癌根治术的患者随机分为无负压自然引流组（观察组,31例）和持续负压吸引组（对照组,30例）;观察比较两组患者术后胃液引流量、肛门首次排气时间、术后不适症状、胃管拔除时间及术后住院时间。结果观察组术后胃液引流量、不适症状和术后并发症差异无统计学意义（P〉0.05）。术后观察组患者的肛门首次排气时间、胃管拔出时间及出院时间分别为（2.75±1.03）、（3.02±0.71）、（14±5.62）d,均低于对照组的（3.89±1.01）、（4.45±0.65）、（18±5.45）d,差异均有统计学意义（P〈0.05）。结论无负压引流方式相较于持续负压引流方式,具有缩短患者胃管留置时间和住院时间等优势,有利于患者胃肠功能的恢复,值得临床推广。     

Contrasting effects of tetraethylammonium and 4-aminopyridine on the gastrointestinal function of mice

Many different K+ channels have been identified in the gastrointestinal tract, and the two classical K+ channel blockers, tetraethylammonium and 4-aminopyridine, show different sensitivity for these channels. The aim of the present study was to compare the effects of tetraethylammonium and 4-aminopyridine on the gastrointestinal function of mice. 4-Aminopyridine (5 mg/kg, p.o.) inhibited, but tetraethylammonium (40 mg/kg, p.o.) enhanced, the intestinal propulsion of a charcoal suspension in conscious mice. Studies in vitro showed that perfusion of 5 mM 4-aminopyridine increased the maximal contractile force and minimal relaxation force, and decreased the amplitude and frequency of the peristaltic contraction of the isolated duodenum. However, perfusion of 5 mM tetraethylammonium increased the maximal contractile force, the minimal relaxation force and the amplitude of the contraction. The effects of tetraethylammonium and 4-aminopyridine on the duodenal contraction could be abolished completely by application of 5 microM verapamil. Our results in vivo and in vitro showed that tetraethylammonium and 4-aminopyridine had contrasting effects on the gastrointestinal function of mice.     

“枳术丸”合剂对腹部术后胃肠功能的影响

目的：观察“枳术丸”合剂对促进腹部术后胃肠功能恢复的临床效果。方法：１４５例患者随机分为两组．对照组７０例患者术后给予电解质液、抗生素等静脉输液;治疗组７５例患者应用同样方法外,于术后第１天经口给予“枳术丸”合剂。结果：术后肠功能恢复时间治疗组（５０．３±５．６）ｈ与对照组（７９．８±８．９）ｈ比较有显著性差异（Ｐ＜０．０５）．粘连性肠梗阻术后随访 １年,再次粘连梗阻治疗组 １例,对照组 １４例,两组之间比较有显著性差异（Ｐ＜０．０１）。结论：“积术九”合剂可以促进肠蠕动,对腹部术后胃肠功能恢复有促进作用。     

早期肠内营养对肝胆外科手术后患者胃肠道功能影响观察

目的：探讨不同的肠内营养方式对肝胆患者外科手术术后胃肠功能恢复的影响。方法回顾性总结56例肝胆外科手术患者资料。结果观察组患者经早期肠内营养后,预后营养指数平均值为（48.1±3.2）分,明显高于对照组统计数据,P＜0.05,另外,观察组患者治疗后的总有效率为93.3%,明显高于对照组总有效率（80.8%）,P＜0.05。结论早期肠内营养方式对肝胆患者外科手术术后胃肠功能恢复具有积极的临床意义。