Prophylactic effect of methylene blue against neurotoxicity of sodium nitroprusside

目的：测定硝普钠（ＳＮＰ）及环鸟苷酸（ｃＧＭＰ）对培养的小脑神经原的细胞毒性和亚甲蓝（ＭＢ）对其小鼠毒性的预防作用．方法：用Ｄｅｓｉ法测定ＳＮＰ和ｃＧＭＰ的小鼠小脑神经细胞毒性．测定ｉｃｖＳＮＰ的小鼠惊厥发生率和２４ｈ死亡率及ＭＢ对其毒性的预防作用．结果：给予ＳＮＰ１ｍｍｏｌ·Ｌ－１１０ｍｉｎ细胞存活率由对照组９２％降至３５％．ｃＧＭＰ０１ｍｍｏｌ·Ｌ－１作用１ｈ，细胞存活率由９４％降至４０％．ＳＮＰ２０ｎｍｏｌｉｃｖ使１／１０小鼠在２４ｈ内死亡，３０ｎｍｏｌ使１１／１３小鼠死亡．ＭＢ１００ｎｍｏｌｉｃｖ可预防１１／１３的ＳＮＰ中毒（３０ｎｍｏｌ，ｉｃｖ）小鼠发生惊厥及死亡，可完全消除ＳＮＰ２０ｎｍｏｌ的中毒效应．结论：ＳＮＰ和ｃＧＭＰ对小鼠小脑神经细胞有细胞毒性．亚甲蓝明显对抗ｉｃｖＳＮＰ小鼠的惊厥和死亡     

Emulsification/internal gelation as a method for preparation of diclofenac sodium–sodium alginate microparticles

Emulsification/internal gelation has been suggested as an alternative to extrusion/external gelation in the encapsulation of several compounds including non-steroidal anti-inflammatory drugs such as diclofenac sodium. The objective of the present study was a trial to formulate diclofenac sodium as controlled release microparticles that might be administered once or twice daily. This could be achieved via emulsification/internal gelation technique applying Box-Behnken design to choose these formulae. Box-Behnken design determined fifteen formulae containing specified amounts of the independent variables, which included stirring speed in rpm (X1), drug:polymer ratio (X2) and the surfactant span 80% (X3). The dependent variables studied were cumulative percent release after two hours (Y1), four hours (Y2) and eight hours (Y3). The prepared microparticles were characterized for their production yield, sizes, shapes and morphology, entrapment efficiency and Diclofenac sodium in vitro release as well. The results showed that the production yield of the prepared diclofenac sodium microparticles was found to be between 79.55% and 97.41%. The formulated microparticles exhibited acceptable drug content values that lie in the range 66.20–96.36%. Also, the data obtained revealed that increasing the mixing speed (X1) generally resulted in decreased microparticle size. In addition, scanning electron microscope images of the microparticles illustrated that the formula contains lower span concentration (1%) in combination with lower stirring speed (200 rpm) which showed wrinkled, but smooth surfaces. However, by increasing surfactant concentration, microspheres’ surfaces become smoother and slightly porous. Kinetic treatment of the in vitro release from drug-loaded microparticles indicated that the zero order is the drug release mechanism for the most formulae.     

Optimized therapeutic scheme and individualized dosage of sodium 

目的：探讨丙戊酸钠联合氯硝西泮治疗对双相障碍I型躁狂发作患者的疗效和安全性。方法：共入组60例患者,随机分入丙戊酸钠联合氯硝西泮治疗组与丙戊酸钠联合氟哌啶醇对照组进行治疗,丙戊酸钠实施个体化药物剂量调整方案。于基线时、治疗第1,2,3,4,6,8,10,12,16周末,分别采用临床总体印象疾病总体严重度量表-双相障碍版（CGI-BP）、Young躁狂评定量表（YMRS）、简明精神病量表（BPRS）、汉密尔顿抑郁评定量表 (HAMD-21)、功能总体评定量表评定（GAS）评定疗效和测定丙戊酸钠血浓度。在基线状态、治疗第4,8,12,16周时,进行血生化、血常规、尿常规、ECG检查以及药物治疗副反应量表(TESS)评定,以评价安全性。结果:① 2组自治疗1周末CGI-BP（5.0±0.4,4.6±0.6）和YMRS（26.7±3.7,26.0±3.8）得分均较治疗前（5.3±0.5,5.2±0.4;30.4±1.5,29.7±1.4）有明显下降,差异有显著性（P<0.05）,自治疗第4周起,社会功能也较基线时有显著改善,而两组之间在上述指标方面的差异均无显著性（P>0.05）。治疗16周末,试验组和对照组的缓解率分别为93.3%和90%。② 对照组（63%）出现不良反应的总发生率高于试验组（40%）。③ 丙戊酸钠的有效治疗血浓度范围为76~124 μg&#8226;mL-1,有效维持血浓度范围为67~87 μg&#8226;mL-1。结论：丙戊酸钠联合氯硝西泮治疗双相I型障碍的疗效同丙戊酸钠联合氟哌啶醇相当,且转相率低,不良反应更少,安全性更高。     

Effect of phenytoin sodium on macrophages in rat wounds

本实验旨在研究苯妥英钠（ＰＳ）对伤口巨噬细胞（Ｍ）的影响．从置入大鼠背部伤口的聚乙烯醇海绵中收集巨噬细胞，分别测定其吞噬功能，肿瘤坏死因子α（ＴＮＦα）和白介素１（ＩＬ－１）的释放以及对成纤维细胞增殖调节作用，通过牵拉伤口组织致其断裂时溢出的水的重量而测定伤口牵张强度．结果表明，伤口Ｍ的功能在伤后ｄ５达到高峰，ＰＳ１，１０，５０ｇ·Ｌ－１浓度依赖性地增加伤后ｄ５的伤口Ｍ的数量，吞噬功能，ＴＮＦα和ＩＬ－１的释放，增强Ｍ对成纤维细胞增殖的刺激作用，增强伤口牵张强度．结果说明ＰＳ加速伤口愈合，与其增强Ｍ的功能有关．     

Inhibitory effects of vinpocetine on sodium current in rat cardiomyocytes

目的：研究长春西汀对心肌细胞钠电流的作用．方法：用全细胞膜片箝技术记录大鼠心肌细胞钠电流．结果：长春西汀可逆性抑制心肌细胞钠电流的作用为剂量依赖性和电压依赖性，但未发现频率或使用依赖性．长春西汀１０－８０μｍｏｌ·Ｌ－１，对钠电流的抑制作用为１３％±２％至７５％±６％．半数抑制浓度ＩＣ５０值（９５％可信限）为３６４（２８１－４７１）μｍｏｌ·Ｌ－１．在膜电位以１０ｍＶ的间隔从－９０ｍＶ阶梯状去极化至＋４０ｍＶ时，抑制作用呈逐渐增加的趋势，约在０ｍＶ左右达到最大抑制．长春西汀对钠通道的稳态激活和失活过程的影响，可使钠窗电流（缓慢失活的钠电流）减少．结论：长春西汀抑制大鼠心肌细胞的钠电流     

Skeletal effects of constant and terminated use of sodium risedronate in ovariectomized rats

目的：探讨利塞膦酸钠（Ｒｉｓ）使用和撤药对去卵巢大鼠骨骼的影响．方法：Ｒｉｓ５μｇ·ｋｇ－１，皮下注射一周两次．胫骨上段不脱钙骨制片测量．结果：（１）去卵巢喂水组胫骨骨小梁面积三组都减少，出现骨吸收大于骨形成的骨高转化率．（２）Ｒｉｓ治疗（Ｒｉｓｏｎ）的去卵巢组与（１）比，６０，８１和１５０天，骨小梁的面积分别增加（２１７％，１０８％和１０１％），并降低骨高转化率至对照组．与６０，８１天组比，１５０天组不能维持较高的骨量．（３）用Ｒｉｓ６０天，撤药观察，２１天时与（Ｒｉｓｏｎ）组无差异，９０天时骨小梁面积增高（＋２６％），并超过年龄对照组（＋２７％）．结论：Ｒｉｓ使用／撤药的方案对去卵巢大鼠有预防骨质疏松的作用．     

镇痛药Tifurac sodium

合成 2,3-二氢苯并呋喃(Ⅰ)与乙酰氯和三氯化铝在二氯甲烷中酰化生成5-乙酰基-2,3-二氢苯并呋喃(Ⅱ);(Ⅱ)与硫、1,4-吗啉(Ⅲ)、对甲苯磺酸高温下反应生成2-(2,3-二氢苯并呋喃-5)硫代乙酰吗啉(Ⅳ);Ⅳ与硫酸在醋酸水溶液中回流水解成2-(2,3     

Protection of sivelestat sodium in ischemia reperfusion brain injury in rats

Objective： To explore the protective effect and its mechanism of sivelestat sodium （SS） on cerebral ischemia reperfusion in rats. Methods： The neurons of neonate rat were cultured in vitro. The protective effects of sivelestat sodium on ischemic injury were observed by treating cells in glucose - free and oxygen -free medium. Neuron survival was measured by MTT reduction assay and the release of LDH; neutrophile elastase contents were determined by ELISA assay; intracellular calcium levers were measured by fluo -3 and confocal laser microscopy; malondialdehyde （MDA） contents, superoxide dismutase （SOD） activity and glutamic acid contents in neuron were measured by colorimetric method. The expression of Bcl - 2 and Bax in rat neurons were detected by immunohistochemistry ; the mrna sequences of Bcl - 2 and Bax were detected by RT - PCR; the expression of Bcl - 2, Bax and p - p38 MAPK proteins in rat neurons was detectd by Western blotting. Results： Sivelestat sodium protected the integrity and survival of cells and reduced LDH leakage, MDA contents, ncutrophile elastase contents, glutamic acid contents; increased SOD contents; decreased the mrna expression of bax and increased the mrna expression of Bcl - 2 ; decreased the protein expression of p - p38MAPK . The ratio of Bcl - 2/Bax in hippocampus neurons of models was lower than that of Sivelestat sodium groups. Conclusions： SS may play neuroprotectvie role by increasing neuron survival, reducing oxygen free radicals, calcium release, glutamate release and the expressions of bax and p -p38MAPK, and down - regulating the expressions of bcl -2.     

Protective effects of ditiocarb sodium against anoxic damage of primary cortical neurons in culture

取体外原代培养１４ｄ左右的大鼠皮层神经元，换上无血清除氧培养基并置通９５％Ｎ２＋５％ＣＯ２的缺氧罐中造成神经元缺氧．以研究缺氧对皮层神经元的损伤及二硫卡钠（ＤＴＣ）的保护作用．用存活神经元数目及神经元线粒体活性来评价神经元活力．乳酸脱氢酶（ＬＤＨ）活性及脂质过氧化产物丙二醛（ＭＤＡ）含量分别用紫外分光光度法和硫代巴比酸法测定，作为评价损伤的指标．原代培养皮层神经元分别缺氧４，５和６ｈ后，活细胞数显著减少，线粒体活性明显降低；ＬＤＨ释放及ＭＤＡ产生显著增加；而缺氧２ｈ后，仅活细胞数无明显变化．超氧阴离子清除剂超氧化物歧化酶（ＳＯＤ）可逆转上述变化，抑制缺氧对神经元的损伤，表明培养神经元缺氧损伤可能与自由基产生有关．类似ＳＯＤ作用，ＤＴＣ可显著对抗缺氧对神经元的损伤，剂量依赖地抑制缺氧引起的ＬＤＨ释放和ＭＤＡ形成的增加．结果表明：ＤＴＣ对神经元缺氧损伤具保护作用，其作用可能与清除自由基有关．     

抗过敏药Nedocromil sodium

经大量的药理和免疫学试验证明,在一系列吡喃喹啉类衍生物中,nedocromil sodium是值得在病理性炎症和变态反应方面进行临床评价的一个药物。合成4-(N-乙酰-N-乙胺基)-2-羟基苯乙酮(Ⅰ)与3-溴丙烯(Ⅱ)在DMF中通过K_2CO_3烷基化得到烯丙醚(Ⅲ),Ⅲ在二乙苯胺中回流得到其异构体4-(N-乙酰-N-乙胺基)-3-烯丙基-2-羟基苯乙酮(Ⅳ)。Ⅳ在乙醇中通H_2以Pa/C催化还原得到对应的丙基衍生物(Ⅴ),此产物加HBr在回流的醋酸水溶液中脱乙酰基得到4-乙胺基-3-丙基-2-羟基苯乙酮(Ⅵ)。在回流的乙醇中VI与乙炔二羧二甲酯(Ⅶ)发生加成反应得到氨基马来酸盐(Ⅷ),用多磷酸在     

Co-expression of NaVβ subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins

Background and Purpose

Voltage-gated sodium channels (VGSCs) are assembled from two classes of subunits, a pore-bearing α-subunit (Na_V1) and one or two accessory β-subunits (Na_Vβs). Neurons in mammals can express one or more of seven isoforms of Na_V1 and one or more of four isoforms of Na_Vβ. The peptide μ-conotoxins, like the guanidinium alkaloids tetrodotoxin (TTX) and saxitoxin (STX), inhibit VGSCs by blocking the pore in Na_V1. Hitherto, the effects of Na_Vβ-subunit co-expression on the activity of these toxins have not been comprehensively assessed.

Experimental Approach

Four μ-conotoxins (μ-TIIIA, μ-PIIIA, μ-SmIIIA and μ-KIIIA), TTX and STX were tested against Na_V1.1, 1.2, 1.6 or 1.7, each co-expressed in Xenopus laevis oocytes with one of Na_Vβ1, β2, β3 or β4 and, for Na_V1.7, binary combinations of thereof.

Key Results

Co-expression of Na_Vβ-subunits modifies the block by μ-conotoxins: in general, Na_Vβ1 or β3 co-expression tended to increase k_on (in the most extreme instance by ninefold), whereas Na_Vβ2 or β4 co-expression decreased k_on (in the most extreme instance by 240-fold). In contrast, the block by TTX and STX was only minimally, if at all, affected by Na_Vβ-subunit co-expression. Tests of Na_Vβ1 : β2 chimeras co-expressed with Na_V1.7 suggest that the extracellular portion of the Na_Vβ subunit is largely responsible for altering μ-conotoxin kinetics.

Conclusions and Implications

These results are the first indication that Na_Vβ subunit co-expression can markedly influence μ-conotoxin binding and, by extension, the outer vestibule of the pore of VGSCs. μ-Conotoxins could, in principle, be used to pharmacologically probe the Na_Vβ subunit composition of endogenously expressed VGSCs.     

Blockade of paeoniflorin on sodium current in mouse hippocampal CA_1 neurons

AIM: To study the blockade of paeoniflorin (Pae) on I_(Na) in the acutely isolated hippocampus neurons of mice. METHODS: The whole-cell patch clamp technique was used. RESULTS: Pae inhibited I_(Na) in frequency-dependent and concentration-dependent manners, with an IC_(50) of 271μmol/L. Pae 0.3 mmol/L shifted the activation potential of the maximal I_(Na) from -40 mV to -30 mV, shifted the steady-state activation and inactivation curves toward more positive and negative potentials by 10.8 mV, and 18.2 mV, respectively, and postponed the recovery of I_(Na) inactivation state from (4.2±0.7) ms to (9.8±1.2) ms. CONCLUSION: Pae inhibited I_(Na) in mouse hippocampus neurons.     

Modulation of gap junctions by nitric oxide contributes to the anti-arrhythmic effect of sodium nitroprusside?

Background and purpose:

Nitric oxide (NO) donors provide a preconditioning-like anti-arrhythmic protection in the anaesthetized dog. As NO may modulate gap junction (GJ) function, the present study investigated whether this anti-arrhythmic effect is due to a modification of GJs by NO, derived from the NO donor sodium nitroprusside (SNP).

Experimental approach:

In chloralose-urethane-anaesthetized, open-chest dogs, either saline (controls; n= 11) or SNP (0.2 µg·kg⁻¹·min⁻¹; n= 10) was infused at a rate of 0.5 mL·min⁻¹ by the intracoronary route. The infusions were started 20 min prior to and maintained throughout the entire 60 min occlusion period of the left anterior descending coronary artery. The severity of ischaemia and of arrhythmias, tissue electrical impedance and permeability, as well as the phosphorylation of connexin43, were assessed.

Key results:

Compared with the controls, SNP infusion markedly suppressed the total number of ventricular premature beats (666 ± 202 vs. 49 ± 18; P < 0.05), and the number of ventricular tachycardiac episodes (8.1 ± 2.3 vs. 0.2 ± 0.1; P < 0.05) without significantly modifying the incidence of ventricular tachycardia or ventricular fibrillation. The severity of ischaemia (epicardial ST-segment changes, inhomogeneity of electrical activation) and tissue electrical impedance changes were significantly less in the SNP-treated dogs. SNP improved GJ permeability and preserved the phosphorylated form of connexin43.

Conclusion and implications:

The anti-arrhythmic protection resulting from SNP infusion in the anaesthethized dog may, in part, be associated with the modulation of gap junctional function by NO.     

Enhancement of blood-brain barrier permeability to sodium fluorescein by stimulation of µ opioid receptors in mice

Summary The effects of opioids on the permeability of the blood-brain barrier (BBB) were examined in mice with sodium fluorescein as an indicator of the permeability. The brain was perfused with saline 30 min after injection of sodium fluorescein (40 mg/kg, i. v.) and examined by fluorometry. Morphine hydrochloride (0.3–10 mg/kg, s. c.) markedly increased the brain level of sodium fluorescein dose-dependently without influencing the plasma level, when administered 20 min before sodium fluorescein injection. Intracerebroventricularly (i. c. v.) injected morphine hydrochloride (0.5 and 1.0 Erg) increased the brain sodium fluorescein level. Buprenorphine (0.1 and 0.5 mg/kg, s. c.) was also effective. However, pentazocine, ethylketazocine, U-50488H and SKF-10047 had no significant influence. The i.c.v. administration of [D-Ala², McPhe⁴, Gly(ol)⁵]enkephalin (0.1 g) and [D-Ala², D-Leu⁵]enkephalin (0.5 g) but not of [D-Thr², Leu⁵]enkephalin-Thr increased the brain level of sodium fluorescein significantly. A small dose of naloxone (i. p.) significantly inhibited the effects of morphine, buprenorphine, [D-Ala², McPhe⁴, Gly(ol)⁵]enkephalin and [D-Ala³, D-Leu⁵]enkephalin. ICI-174864 co-administered i. c. v. with [D-Ala², D-Leu⁵]enkephalin was ineffective in antagonizing the effect of the latter. These findings suggest that the stimulation of µ opioid receptors results in an increase in BBB permeability to sodium fluorescein. Send offprint requests to K. Saeki     

Pharmacokinetics of omeprazole in rats with dextran sulfate sodium–induced ulcerative colitis

Omeprazole is a commonly used drug in patients with ulcerative colitis (UC). This study investigated the pharmacokinetics of omeprazole in rats with UC induced by dextran sulfate sodium (DSS). The pharmacokinetics of intravenously administered omeprazole (20 mg/kg) was investigated in normal and UC rats using LC-MS/MS. The formation of 5-OH omeprazole, a main metabolite of omeprazole, in rat liver microsomes (RLMs) from normal and UC rats was compared. The protein levels of CYP1A2, CYP2D1, and CYP3A1 in the liver were measured by Western blot. Compared with normal rats, UC rats had increased plasma concentrations of omeprazole, resulting in an increased AUC_0–240 min and decreased CL. DSS treatment decreased the formation rate of 5-OH omeprazole in RLMs but did not change the affinity of the enzymes. The V_max and CL_int of RLMs from UC rats were 62% and 48% those of RLMs from normal rats, respectively. The hepatic CYP1A2 and CYP3A1 protein levels in UC rats were 42.6 and 45.2% lower than those in normal rats, respectively; however, the protein levels of CYP2D1 in the two groups were similar. The activity and expression of some hepatic CYP450 isoforms were decreased by UC, leading to changes in the pharmacokinetics of omeprazole.     

碳青霉烯类抗生素 ertapenem sodium

商品名:Invanz;开发与上市厂商:美国默克公司研制,2002年4月首次在美国上市,后相继在英国、爱尔兰、以色列和菲律宾上市。?A适应证：本品适用于治疗成人的多种细菌感染,包括腹内感染、皮肤和皮肤组织感染、尿路感染、妇产科感染及肺炎。     

OTC laxative use of sodium picosulfate â results of a pharmacy-based patient survey (cohort study)

OBJECTIVES: Constipation is one of the most frequent gastrointestinal symptoms. Traditionally, drug therapy for constipation is not prescribed and controlled by physicians. Instead, laxatives are sold by pharmacists as over-the-counter (OTC) medication. The aim of this study was to explore the safety and usage pattern of the OTC laxative sodium picosulfate use by collecting data from patients at their pharmacies. The study describes how self-treatment of constipation is practiced. In addition, the characteristics of patients buying the contact laxative, sodium picosulfate, for self-treatment of constipation were analyzed. METHODS: The survey was a pharmacy-based observational study (PHOBS) in community pharmacies in Germany. Participating pharmacists asked customers requesting a specific contact laxative to participate in the study. Customers gave verbal informed consent to study participation before receiving a structured questionnaire to be completed at home and then returned to the pharmacy. RESULTS: Data from 1,845 patients recruited by 243 pharmacies were collected. Compliance with the recommended dosage of 5 a 10 mg/day was 96%, compliance with the indication of constipation was 99%. More than 90% rated the efficacy as "very good" to "good". There was no weakening of the efficacy rating with increasing duration of use. 8% of patients reported mild-to-moderate adverse events. Nearly 60% of respondents reported to be satisfied with less than 1 bowel movement per day. Therefore, users appear to have a rational way of using OTC laxatives. CONCLUSIONS: Self-medication of constipation with sodium picosulfate is efficacious and considered to be safe.     

Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA

Voltage-gated sodium channels are important in initiating and propagating nerve impulses in various tissues, including cardiac muscle, skeletal muscle, the brain, and the peripheral nerves. Hyperexcitability of these channels leads to such disorders as cardiac arrhythmias (Na(v)1.5), myotonias (Na(v)1.4), epilepsies (Na(v)1.2), and pain (Na(v)1.7). Thus, there is strong motivation to identify isoform-specific blockers and the molecular determinants underlying their selectivity among these channels. μ-Conotoxin KIIIA blocks rNa(v)1.2 (IC(50), 5 nM), rNa(v)1.4 (37 nM), and hNa(v)1.7 (97 nM), expressed in mammalian cells, with high affinity and a maximal block at saturating concentrations of 90 to 95%. Mutations of charged residues on both the toxin and channel modulate the maximal block and/or affinity of KIIIA. Two toxin substitutions, K7A and R10A, modulate the maximal block (52-70%). KIIIA-H12A and R14A were the only derivatives tested that altered Na(v) isoform specificity. KIIIA-R14A showed the highest affinity for Na(v)1.7, a channel involved in pain signaling. Wild-type KIIIA has a 2-fold higher affinity for Na(v)1.4 than for Na(v)1.7, which can be attributed to a missing outer vestibule charge in domain III of Na(v)1.7. Reciprocal mutations Na(v)1.4 D1241I and Na(v)1.7 I1410D remove the affinity differences between these two channels for wild-type KIIIA without affecting their affinities for KIIIA-R14A. KIIIA is the first μ-conotoxin to show enhanced activity as pH is lowered, apparently resulting from titration of the free N terminus. Removal of this free amino group reduced the pH sensitivity by 10-fold. Recognition of these molecular determinants of KIIIA block may facilitate further development of subtype-specific, sodium channel blockers to treat hyperexcitability disorders.