Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization

The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo. The 36 amino-alkyl-cyclohexanes tested displaced [3H]-(+)-MK-801 binding to rat cortical membranes with K(i)s between 1.5 and 143 microM. Current responses of cultured hippocampal neurones to NMDA were antagonized by the same compounds with a wide range of potencies (IC50s of 1.3-245 microM, at -70 mV) in a use- and strongly voltage-dependent manner (delta 0.55-0.87). The offset kinetics of NMDA receptor blockade was correlated with equilibrium affinity (Corr Coeff. 0.87 P < 0.0001). As an example, MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) had similar blocking kinetics to those previously reported for memantine (K(on) 10.67 +/- 0.09 x 10(4) M(-1) s(-1), K(off) 0.199 +/- 0.02 s(-1), K(d) = K(off)/K(on) = 1.87 microM c.f. IC50 of 1.29 microM). Most amino-alkyl-cyclohexanes were protective against glutamate toxicity in cultured cortical neurones (e.g. MRZ 2/579 IC50 2.16 +/- 0.03 microM). Potencies in the three in vitro assays showed a relatively strong cross correlation (all corr. coeffs. > 0.72, P < 0.0001). MRZ 2/579 was also effective in protecting hippocampal slices against 7 min. hypoxia/hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50 of 7.01 +/- 0.24 microM. MRZ 2/579 showed no selectivity between NMDA receptor subtypes expressed in Xenopus oocytes but was somewhat more potent than in patch clamp experiments-IC50s of 0.49 +/- 0.11, 0.56 +/- 0.01 microM, 0.42 +/- 0.04 and 0.49 +/- 0.06 microM on NR1a/2A /2B, /2C and 2/D, respectively. In contrast, memantine and amantadine were both 3-fold more potent at NR1a/2C and NR1a/2D than NR1a/2A receptors. All Merz amino-alkyl-cyclohexane derivatives inhibited MES-induced convulsions in mice with ED50s ranging from 3.6 to 130 mg/kg i.p. The in vivo and in vitro potencies correlated indicating similar access of most compounds to the CNS. MRZ 2/579 administered at 10 mg/kg resulted in peak plasma concentrations of 5.3 and 1.4 microM following i.v. and p.o. administration respectively, which then declined with a half life of around 170-210 min. Analysis of A.U.C. concentrations indicates a p.o./i.v. bioavailability ratio for MRZ 2/579 of 60%. MRZ 2/579 injected i.p. at a dose of 5 mg/kg resulted in peak brain extracellular fluid (ECF) concentrations of 0.78 microM (brain microdialysates). Of the compounds tested MRZ 2/579, 2/615, 2/632, 2/633, 2/639 and 2/640 had affinities, kinetics and voltage-dependency most similar to those of memantine and had good therapeutic indices against MES-induced convulsions. We predict that these amino-alkyl-cyclohexanes, which all had methyl substitutions at R1, R2, and R5, at least one methyl or ethyl at R3 or R4 and a charged amino-containing substitution at R6, could be useful therapeutics in a wide range of CNS disorders proposed to involve disturbances of glutamatergic transmission.     

Plasma dopa concentrations after different preparations of levodopa in normal subjects

1 The concurrent administration of levodopa with a decarboxylase inhibitor produced a plasma concentration/time curve comparable with 1/4 to 1/5 of the dose of levodopa given alone.

2 There was no evidence to suggest that the decarboxylase inhibitor slowed the rate of elimination of levodopa from plasma.

3 Metoclopramide (Maxolon) increased the rate of levodopa absorption. Higher plasma concentrations of levodopa during the first 2 h after dosing were followed by lower plasma concentrations during the third and fourth hours. The amount of levodopa absorbed after Larodopa as indicated by the AUC was not altered by adding metoclopramide.

4 None of the current preparations of levodopa produced sustained plasma concentrations.

5 In vitro testing confirmed that Brocadopa Temtabs tablets disintegrate and dissolve slowly. In vivo, Brocadopa Temtabs behaved as a slow release preparation but it did not produce sustained plasma concentrations of levodopa.

     

Association of aggressive behavior with altered serotonergic function in patients who are not suicidal

OBJECTIVE: The purpose of this study was to determine whether aggression and serotonergic dysfunction are related in the absence of a history of suicidal behavior. Although serotonergic dysfunction has been implicated in aggressive and impulsive behavior, most studies of such behavior have included individuals with a history of suicide attempts. Low concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) have been consistently associated with suicidal behavior, presenting a potential confound in the link between aggression and serotonergic dysfunction. METHOD: The authors examined the association between aggression and CSF 5-HIAA concentrations in a group of 64 patients who had different DSM-III-R axis I diagnoses and no past suicidal behavior. Aggressive (N=35) and nonaggressive (N=29) groups were defined by a median split on a six-item history of adulthood aggressive behavior. RESULTS: The aggressive group had significantly lower CSF 5-HIAA concentrations than the nonaggressive group. Aggressive individuals also scored significantly higher on self-report measures of hostility, impulsiveness, and sensation seeking. CSF 5-HIAA concentrations, however, did not correlate with self-reported hostility and impulsivity. CONCLUSIONS: There is an association between aggressive behavior and serotonergic dysfunction independent of suicidal behavior in patients with axis I disorders who exhibit relatively milder forms of aggressive behavior. Analogous to findings with suicidal behavior, a low concentration of CSF 5-HIAA is related to aggressive behavior but does not show the same relationship to the continuum of aggressive feelings and thoughts.     

脂蛋白脂肪酶基因突变的研究

目的：筛查国人脂蛋白脂肪酶(LPL)基因的突变，并探讨其与高甘油三酯血症的关系。方法：对高甘油三酯血症组(48例)和正常甘油三酯对照组(121例)的各扩增片段进行分析，电泳图谱异常者进行PCR产物测序。对于频率较高的多态性位点，引入限制性核酸内切酶位点利用PCR-RFLP进行鉴定。结果：在高甘油三酯血症人群中，检出2例内含子3受位剪接点上游6bp的C→T转换的突变杂合子，1例外显子5Pm^207→Leu突变杂合子，在全部样品中检出1例Ser^447→stop突变纯合子，50例Ser^447→stop杂合子。结论：天津地区人群中存在着LPL基因突变，除Ser^447→stop外，内含子3和外显子5的突变多与高甘油三酯血症相关，可能是高甘油三酯血症的遗传易感因子。     

氧化亚氮混合气体用于分娩镇痛135例临床研究

目的观察氧化亚氮混合气体在分娩过程中的作用,分析其分娩结局.方法选择临床自愿吸入氧化亚氮混合气体无痛分娩的第1胎头位的初产妇135例为观察组,随机抽取同期分娩的产妇190例为对照组,观察其分娩过程及结局.结果无痛分娩组产妇紧张、焦虑及疼痛程度较对照组明显降低,剖宫产率明显降低(P＜0.05),两组总产程、新生儿评分及产后出血量无统计学意义.结论氧化亚氮混合气体无痛分娩法方便、安全、有效,值得临床推广应用.     

海洋岩虫抗菌肽筛选及抗癌活性的初步研究

将岩虫匀浆液经反相浓缩、凝胶过滤和亲和柱层析获得活性组分，在体外用MTS／PMS(氮兰四唑盐／吩嗪硫酸甲酯)方法筛选抗菌肽，再分别用MTS／PMS方法和ELISA—AFP(甲胎蛋白)方法检测其对人肝癌细胞株HepG2增殖、AFP分泌及对正常大鼠成骨细胞株MC3T3-E1增殖的影响。结果表明，纯化的岩虫抗菌肽为组成型碱性蛋白(MW8．1kDa，pI8．6)，不同浓度抗菌肽对肝癌细胞增殖和AFP的分泌均有抑制作用，抑制作用大小与抗菌肽浓度呈正相关性；对正常成骨细胞未见明显的抑制和杀伤作用。     

河北省部分高校大学生结核菌素试验结果分析

目的了解结核菌在大学生群体中的感染状况及PPD试验过程中存在的问题,为采取相应的干预措施提供依据。方法随机抽取河北省8所高校,对其在2001~2004年新入学大学生的PPD试验记录及监测报表进行统计分析。结果河北省部分高校大学生接种人口数量明显增多;经χ2检验,2001~2004年PPD试验的阳性率、强阳性率差异有统计学意义(P<0.005),阳性率随时间呈明显下降趋势、强阳性率随时间呈缓慢上升趋势。结论高校应进一步加强PPD试验的监测力度,提高PPD的监测质量。