Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.     

金属离子及氨基糖对大鼠肾脏N－乙酰氨基葡萄糖转移酶Ⅲ活性测定的影响

采用反相ＨＰＬＣ荧光测定法对大鼠肾脏Ｎ－乙酰氨基葡萄糖转移酶（ＧｎＴ）Ⅲ活性测定时二价金属离子及氨基糖的影响进行了研究。结果表明：ＧｎＴⅢ必须有二价金属离子激活，最佳激活离子为Ｍｎ￣（２＋）离子，其次为Ｍｇ￣（２＋）离子；二协金属离子对ＧｎＴⅢ的激活作用依次为Ｍｎ￣（２＋）＞Ｍｇ（２＋）＞Ｃｏ（２＋）＞Ｃａ￣（２＋）＞Ｎｉ￣（２＋）＞Ｂａ￣（２＋）＞Ｚｎ￣（２＋）。四种氨基糖（Ｎ－乙酰氨基葡萄糖ＧｌｃＮＡｃ，Ｎ－乙酰氨基半轧糖ＧａＩＮＡｃ，氨基葡萄糖ＧｌｃＮ，氨基半乳糖ＧａｌＮ），除ＧｌｃＮ使ＧｎＴ活性增加外，其余三种对ＧｎＴⅢ均有不同程度的抑制作用。     

猪卵透明带单克隆抗体的研制

用热溶猪卵透明带抗原免疫BALB/C 小鼠,取其脾细胞和SP2/O 细胞融合产生的杂交瘤。用间接免疫荧光和ELISA 方法筛选,经四次克隆化后,获得三株分泌猪卵透明带单克隆抗体杂交瘤细胞株(LPD_8,LPC_4,LPD_2)。通过间接免疫荧光试验,其中二株单克隆抗体(LPD_8,LPC_4)与人卵透明带有交叉反应。但它们在猪与人卵透明带上呈现的荧光部位有明显的不同,LPD_8位于整个透明带上,而LPC_4只见于透明带外层。LPD_2荧光位于透明带内层且与人卵无交叉反应。我们认为这种差别是由于抗原决定簇的不同所致。     

Posttraumatic skeletal muscle proteolysis: The role of the hormonal environment

To investigate the role of hormones as mediators of net skeletal muscle proteolysis following injury, healthy normal male volunteers received a continuous 76-hour infusion of the 3 stress hormones: hydrocortisone, glucagon, and epinephrine. As a control, each subject received a saline infusion during another 4-day period. Ten paired studies were conducted. Diets were constant and matched on both occasions. Triple hormone infusion achieved hormone concentrations similar to those seen following mild-moderate injury. After 72 hours of infusion, skeletal muscle intracellular glutamine concentrations were lower in the hormone studies than in the control group (N=4). Free amino acid concentrations in arterial whole blood and forearm amino acid efflux were little affected by hormonal infusion. Thus, alteration of the hormonal environment by the triple hormone infusion was not a sufficient stimulus to induce all of the changes in skeletal muscle proteolysis observed in critical illness. Since studies utilizing neurohormonal blockade have shown diminished net muscle proteolysis, the stress hormones appear to be necessary but not sufficient for the protein catabolic response to injury.

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Resumen Con el propósito de investigar el papel de las hormonas como agentes mediadores de la proteolisis muscular neta que se presenta en el trauma y en otros estados críticos, se administró una infusión de las 3 hormonas del estrés, hidrocortisona, glucagón, y epinefrina, a voluntarios sanos por períodos continuos de 76 horas. Como control, cada individuo recibió una infusión de solución salina durante otro período de 4 días. Se condujeron 10 estudios apareados, con dietas constantes y similares en ambas ocasiones. La infusión triple de hormonas produjo concentraciones sanguíneas hormonales similares a las observadas en pacientes con trauma leve-moderado. A las 72 horas de la infusión las concentraciones intracelulares de glutamina en el mÚsculo esquelético aparecieron menores que en los estudios de control (N=4). Las concentraciones de aminoácidos libres en la sangre arterial y el flujo de salida de aminoácidos en el antebrazo resultaron mínimamente afectados por la infusión hormonal. Por lo tanto, la alteración del medio hormonal producida por infusión triple de hormonas no representa un estímulo suficiente para inducir la totalidad de las alteraciones en la proteolisis del mÚsculo esquelético que se observa en la enfermedad crítica. Puesto que los estudios con bloqueo neurohumoral han demostrado una disminución en la proteolisis muscular neta, las hormonas del estrés parecen ser necesarias, pero no suficientes de por sí, para la respuesta catabólica a la injuria biológica.

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Résumé Pour étudier le rôle des hormones dans la protéolyse posttraumatique de muscle squelettique, des volontaires de sexe mâle en bonne santé ont été perfusés pendant 76 heures avec les 3 hormones de stress: hydrocortisone, glucagon, et adrénaline. En contrôle, chaque patient a reÇu une perfusion de sérum physiologique pendant quatre jours. Dix études appariées ont été faites. Pendant les deux études, l'alimentation était la mÊme et constante. La perfusion des 3 hormones a provoqué une concentration semblable à celle qu'on observe après un traumatisme moyen. Après 72 heures, le taux de glutamine dans les muscles squelettiques était plus bas dans l'étude hormonale que dans l'étude contrôle (N=4). La concentration en acides aminés libres dans le sang artériel et notamment l'arrivée de sang dans l'avant-bras n'étaient que peu influencées par la perfusion hormonale. Ainsi, la perfusion avec augmentation de la concentration des 3 hormones de stress ne suffisait pas pour provoquer la protéolyse musculaire squelettique que l'on observe lors des maladies graves. Puisque d'autres études ont montré que le blocage neurohormonal diminue nettement la protéolyse musculaire, les hormones de stress semblent donc nécessaires mais non suffisantes dans la réponse catabolique protéinique au traumatisme.

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Supported by the National Institutes of Health Trauma Center Grant P50-GM 29327-03 and Clinical Research Center Grant no. 290-9299.     

二氧化硅活化巨噬细胞中早期生长反应因子-1及其信号转导通路的研究

目的 探讨早期生长反应因子(Egr-1)及其信号转导在矽肺发生发展中的作用。方法用细胞免疫荧光、原位杂交方法检测二氧化硅(SiO2)刺激后Egr-1的表达定位,用报道质粒及EMSA检测其活性改变;用激酶活性分析法检测si0：刺激巨噬细胞后ERK1／2活性改变,进一步用激酶抑制剂初步探讨SiO2活化Egr-1的信号转导通路。结果SiO2刺激RAW264．7细胞短时间Egr-1核蛋白表达及转录因子明显增加;且在处理后30～60min,Egr-1核蛋白结合活性明显升高(为未处理组的20倍);在刺激后15min ERK1／2活性开始升高,30min达高峰(活性为对照组的29倍)而后渐降至基础水平;进一步用激酶阻断发现,Egr-1 mRNA及蛋白表达均减少。结论SiO2能激活巨噬细胞中Egr-1,且此过程可能由ERK1／2、p38介导,提示SiO2-ERK1／2、p38-Egr-1通路可能在矽肺发生发展过程中起重要作用。     

金针菇子实体多糖提取物对人肝癌SMMC—7721细胞的抑增殖作用

金针菇子实体经热水提取，乙醇沉淀，胰蛋白酶水解，Ｓｅｖａｇ法去除蛋白质，乙醇分级沉淀等处理得金针菇子实体多糖。研究了该多糖对人肝部ＳＭＭＣ－７７２１细胞生长曲线，有丝分裂指数及线粒体活性的影响。结果表明该多糖对体外培养的人肝癌ＳＭＭＣ－７７２１细胞具一定抑制作用。     

散发性急性戊型肝炎血清抗体动态变化和肝脏超微…

为探讨散发性戊型肝为血清抗体动态变化，应用酶联免疫法（ＥＩＡ）检测了７例急性戊型肝炎抗戊型肝炎病毒（ＨＥＶ）ＩｇＧ和ＩｇＭ抗体、并对１例２进行了肝超微结构病理检测，结果表明，发病１０天至４５天内抗ＨＥＶ－ＩｇＧ和ＩｇＭ滴度最高，发病第４０天仍有肝细胞肿胀，胞浆空化和线粒体固缩等病理变化。患者轿清抗－ＨＥＶＩｇＭ滴度在４５天后逐渐下降，２个月内全中消失，抗－ＨＥＶＩｇＭ滴度在４５天后逐渐下降，２个月     

Characterization of the UL4 gene product of herpes simplex virus type 2

Summary.  We have identified the herpes simplex virus type 2 (HSV-2) UL4 gene product using a rabbit polyclonal antiserum raised against a recombinant 6xHis-UL4 fusion protein expressed in Escherichia coli. The antiserum reacted specifically with a 27-kDa protein in HSV-2 186-infected cell lysates. The protein was not detectable in the presence of the viral DNA synthesis inhibitor, suggesting that the UL4 gene was expressed as a γ₂ gene. Indirect immunofluorescence studies localized the UL4 protein within the nucleus as discrete punctate forms at late times postinfection. However, when expressed in the absence of other viral proteins, the UL4 protein was limited to the cytoplasm, indicating that an interaction with one or more other virus-induced proteins was responsible for the nuclear localization during infection. Subnuclear fractionation studies showed that the protein was released from the nuclear structure of infected cells by high salt treatment. Moreover, the UL4 protein was detected in purified virions and light particles. Received December 24, 1997 Accepted February 4, 1998