急性脑梗死静脉溶栓前后美国国立卫生研究院卒中量表评分与收缩压变化值在颅内出血性转化中的预测价值

目的 探索缺血性卒中静脉溶栓病人,出现颅内出血转化的危险因素.方法 收集分析2018年1月1日至2019年11月30日在皖南医学院弋矶山医院接受静脉溶栓治疗的123例急性脑梗死临床资料.溶栓24 h后采用头颅CT检查.将病人分为出血转化组(n=25)和非出血转化组(n=98).对比两组年龄、性别、吸烟史、饮酒史、溶栓前后病人收缩压和舒张压变化,发病到病人接受静脉溶栓治疗的时间,溶栓前后美国国立卫生研究院卒中量表(NIHSS)评分变化等,明确脑梗死病人行溶栓治疗后出血转化的危险因素.结果 两组在性别、烟酒史、发病到接受溶栓治疗时间等基线数据上差异无统计学意义(P>0.05);出血转化组与非出血组在发病年龄[(71.64±10.56)岁比(63.85±12.42)岁]、溶栓前NIHSS评分[11(6,14.5)分比7(4,12)分]、溶栓后2 h NIHSS评分[11(3,14.5)分比5(2,9)分],出血转化组均大于非出血组(P<0.05).但是出血转化组溶栓前后NIHSS评分差值低于非出血组[0(0,2)分比1(0,4)分,P<0.001]、溶栓前收缩压出血转化组较高[(160.88±20.24)mmHg比(150.79±21)mmHg,P=0.033],出血转化组溶栓前后收缩压变化值大于非出血转化组[(34.88±22.51)mmHg比(24.58±16.56)mmHg,P=0.011].logistic逐步回归分析提示年龄较大、溶栓前后收缩压差值、溶栓前后NIHSS评分变化值是脑梗死病人溶栓治疗后出血转化的危险因素(P>0.05).溶栓前后收缩压变化值和NIHSS评分变化值均对病人愈后有显著影响(P>0.05).结论 静脉溶栓后NIHSS评分变化值小、溶栓后收缩压变化值大是出血转化的危险因素.尤其是高龄病人,应充分考虑到病人血压情况和神经功能缺损程度等变化因素,并采用合适的干预手段、积极预防出血转化的发生.     

脑梗死患者溶栓后出血转化的危险因素分析

目的:探讨脑梗死患者溶栓后出血转化的危险因素.方法:选取2018-04～2020-12在本院确诊的949例脑梗死进行溶栓治疗的患者.根据是否发生溶栓后出血转化将949例患者分为出血转化组22例,无出血转化组927例.记录两组脑梗死患者的基本资料和临床指标,进行单因素分析和logistic多因素回归性分析影响脑梗死患者溶栓后出血转化的危险因素.结果:梗死患者溶栓后出血转化组与无出血转化组患者在年龄、性别、体质量指数(BMI)、高脂血症、吸烟史及酗酒史方面的对比,差异无统计学意义(P＞0.05);出血转化组与无出血转化组患者在溶栓前收缩压(SBP)、溶栓前舒张压(DBP)、糖尿病、脑梗死量表评分(NIHSS)方面的对比,差异有统计学意义(P＜0.05);多因素Logistic回归性分析结果显示,患者的SBP(≥140mmHg)及NIHSS评分≥21分是导致脑梗死患者溶栓后出血转化的独立危险因素(P＜0.05).结论:脑梗死患者溶栓后出现出血转化与患者的血压及NIHSS评分相关.     

急性缺血性脑卒中溶栓后出血性转化与灌注CT微血管通透性的相关性

目的探讨急性缺血性脑卒中病人溶栓后出血性转化发生情况及其与灌注 CT微血管通透性的相关性。方法选取 2014年 1月至 2016年 12月在石家庄市第三医院诊断为急性缺血性脑卒中病人 82例作为研究对象,采用回顾性分析法分析所有病人的临床资料,按照资料中治疗后是否发生出血性转化分为未出血组 43例和出血组 39例。所有病人均行头颅 CT检查,分析两组病人病侧灌注 CT的主要参数,绘制受试者工作特征曲线(ROC)对灌注 CT微血管通透性在急性缺血性脑卒中病人溶栓后出血性转化中的预测价值进行分析。结果 ①82例急性缺血性脑卒,中病人溶栓后 39例病人发生出血性转化,发生率为 47.56%;②两组病人年龄、美国国立卫生研究院卒中量表(NIHSS)评分及大面积脑梗死比例比较差异有统计学意义(P＜0.05); ③出血组病人表面通透性(PS)(15.31±1.45)mL·min-1·(100 g)-1明显高于未出血组病人(10.14±3.61)mL·min-1·(100 g)-1,且出血组病人脑血容量(CBV)和脑血流量(CBF)较未出血者明显较低,比较差异有统计学意义(P＜0.05); ④根据 ROC曲线结果显示, PS在 ROC曲线下的面积＞ 0.9,诊断界值为 5.86 mL·min-1·(100 g)-1对急性缺血性脑卒中病人溶栓后出血性转化的预测价值灵敏度为 94.72%,特异度为 88.11%;⑤非条件因素 logistic回归模型显示,年,龄较大、 NIHSS评分过高以及出现大面积梗死是导致急性缺血性脑卒中病人溶栓后出血性转化的独立危险因素(P＜0.05)。结论灌注 CT微血管通透性在急性缺血性脑卒中病人溶栓后出血性转化中的预测价值良好,当 PS值大于 5.86 mL·min-1·(100 g)-1时急性缺血性脑卒中病人溶栓后发生出血性转化的风险提高,能为临床静脉溶栓提供重要的参考依据。     

97例急性脑梗死患者阿替普酶静脉溶栓的疗效及出血性转化影响因素分析

目的:分析阿替普酶静脉溶栓治疗急性脑梗死患者的临床疗效和溶栓后发生出血性转化的相关因素.方法:190例急性脑梗死患者根据治疗方法的不同分为静脉溶栓组(n=97)和常规治疗组(n=93),比较治疗前和治疗后24 h、7 d NIHSS评分.静脉溶栓组患者根据有无出血分为出血性转化亚组(n=33)和无出血性转化亚组(n=64),比较年龄、性别、溶栓前血压、NHISS评分、血糖、溶栓时间、合并高血压、糖尿病、既往卒中病史、房颤病史等方面的差异.结果:治疗后24 h、7 d静脉溶栓组NHISS评分明显低于低于常规治疗组(P<0.05).多因素logistic回归分析结果显示,溶栓前血糖、溶栓前NHISS评分、既往房颤病史是阿替普酶静脉溶栓后发生出血性转化的独立影响因素.结论:阿替普酶静脉溶栓治疗发病6 h内急性脑梗死疗效优于常规治疗.溶栓前血糖较高、NIHSS评分较高、既往房颤病史的急性脑梗死患者应用阿替普酶静脉溶栓治疗后出血性转化发生率较高.     

大动脉粥样硬化型脑梗死中性粒细胞与淋巴细胞比值对静脉溶栓后出血转化的预测价值及神经功能预后的影响

目的 检测大动脉粥样硬化型脑梗死外周血中性粒细胞与淋巴细胞比值(NLR)对静脉溶栓后出血转化(HT)的预测价值及对神经功能预后的影响。方法 选取2013年6月至2021年6月在新乡医学院第三附属医院接受静脉溶栓治疗的大动脉粥样硬化型脑梗死病人147例，根据静脉溶栓后是否发生HT，将病人分为non-HT组(n=105)和HT组(n=42)。比较两组病人的一般临床资料，logistic多因素回归分析影响HT发生的危险因素，受试者工作曲线(ROC)评估NLR、收缩压、心房颤动和脑梗死体积≥10 cm3单独及联合预测HT发生的临床价值。根据NLR预测HT发生的临界值将病人分为NLR高水平组和NLR低水平组，比较两组病人出院后90 d神经功能预后不良率。结果 HT组病人年龄、收缩压、中性粒细胞(0.8±0.2)×10⁹/L、NLR7.4±0.3、谷草转氨酶(AST)(29.4±6.3)U/L和美国国立卫生研究院卒中量表(NIHSS)评分(6.2±1.7)分高于non-HT组(0.6±0.4)×10⁹/L、2.1±0.3、(21.6±5.4)U/L和(2...     

基质金属蛋白酶9水平在脑梗死出血转化中的临床意义

目的 探讨血浆基质金属蛋白酶9(MMP-9)水平在急性脑梗死出血转化中的临床意义.方法 157例发病24 h内急性脑梗死患者,根据是否存在出血转化分为脑梗死组(梗死组,135例)和脑梗死出血转化组(转化组,22例);于起病24 h急诊行血浆MMP-9水平测定,并分析其与脑梗死出血转化、梗死体积大小和病情严重程度的相关性.结果 转化组血浆MMP-9水平高于梗死组(P＜0.01);梗死体积大者血浆MMP-9水平也明显高于中、小梗死者(P＜0.01);NIH卒中量表(NIHSS)评分≥7分者血浆MMP-9的含量亦明显上调(P＜0.01).结论 血浆MMP-9水平与脑梗死出血转化的发生及梗死体积大小、病情严重程度相关.脑梗死早期检测血浆MMP-9可作为临床预测脑梗死出血转化的参考指标.     

急性脑梗死阿替普酶溶栓后早期神经功能恶化预测模型的构建与验证

目的探讨阿替普酶治疗急性脑梗死病人出现早期神经功能恶化(END)的危险因素,构建联合预测因子并验证预测效能。方法回顾性分析2017年1月至2020年5月淮南市第一人民医院208例经阿替普酶溶栓治疗急性脑梗死病人的临床资料(建模组),根据治疗后72 h内是否发生END分为恶化组54例和未恶化组154例。根据建模组危险因素的回归系数构建联合预测因子,计算截断点,并应用于2020年6月至2020年8月50例病人验证预测效能(验证组)。结果恶化组中入院美国国立卫生研究院卒中量表(NIHSS)>7分的比例明显高于未恶化组(79.6%比46.8%,P<0.05),治疗后24 h内END发生率最高(17.3%)。单因素分析病人的血糖、收缩压、体质量指数(BMI)、白细胞计数、脂蛋白(a)、肌酐水平、责任大血管闭塞占比、入院NIHSS评分、TOAST分型等指标与END发生有相关性(P<0.05);多因素分析发现高血糖、高BMI、高白细胞计数、高脂蛋白(a)、高肌酐、责任大血管闭塞、入院时NIHSS评分高是发生END的独立危险因素;根据回归系数构建联合预测因子L=1×血糖+0.327×BMI +0.742×白细胞计数+0.026×脂蛋白(a)+0.143×肌酐?2.104×责任大血管闭塞+0.225×入院时NIHSS评分,截断点为38.984 6。把联合预测因子应用于50例验证组病人,预测正确率为78.0%,敏感性75.0%,特异性81.6%,AUC=0.921。结论入院NIHSS评分越高溶栓后发生END的风险越大,且24 h以内是高发期。联合预测因子对阿替普酶溶栓治疗急性脑梗死病人发生END有较好的预测效能,可为临床提供可靠的帮助。     

急性脑梗死患者溶栓后合并出血相关因素分析

目的:分析急性脑梗死患者溶栓后出血性转化(HT)的相关危险因素。方法:给予75例急性脑梗死患者尿激酶(UK)静脉溶栓治疗,观察溶栓后HT发生情况,将患者分为HT组和对照组(未发生HT),收集患者一般资料、尿激酶(UK)剂量、是否合并感染等,比较两组NIHSS评分与血小板计数(PLT)、凝血酶原时间(PT)、纤维蛋白原(FIB)、国际标准化比值(INR)、甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)等指标水平。结果:溶栓后HT发生率为20.00%,即HT组15例,对照组60例。HT组发病至溶栓间隔时间、糖尿病病史患者占比、合并高血脂症和心房纤颤患者占比、溶栓前TC和LDL-C水平、NIHSS评分、溶栓后舒张压均显著高于对照组(P<0.05)。Logistic多因素回归分析NIHSS评分、溶栓后舒张压、合并心房纤颤、糖尿病病史、合并高血脂症及溶栓前TC和LDL-C水平均为溶栓后HT的危险因素。结论:NIHSS评分高、发病至溶栓间隔时间较长、溶栓后舒张压升高、合并心房纤颤、糖尿病病史、合并高血脂症均是急性脑梗死患者溶栓后HT发生的危险因素,临床可参考上述危险因素对HT进行早期识别及给予防治措施。     

他汀给药时机对行rt-PA溶栓急性脑梗死患者神经功能损伤程度、实验室指标及并发症发生风险的影响

目的探讨他汀给药时机对行rt-PA急性脑梗死患者神经功能损伤程度、实验室指标及并发症发生风险的影响。方法选择行rt-PA急性脑梗死患者共130例,以随机数字表法分为A组(65例)和B组(65例);其中A组患者在rt-PA溶栓后给予他汀10 mg/d口服治疗,B组患者在rt-PA溶栓前给予他汀10 mg/d口服治疗;比较两组患者预后良好率、症状性颅内出血发生率,以及治疗前后NIHSS评分、Barthel指数评分、MMP-9、HMGB1、IL-17水平等。结果 B组患者预后良好率显著高于A组(P<0.05);B组患者治疗后NIHSS评分和Barthel指数评分均显著优于A组、治疗前(P<0.05);B组患者治疗后HMGB1、MMP-9及IL-17水平均显著低于A组及治疗前(P<0.05);两组患者症状性颅内出血发生率比较差异无统计学意义(P>0.05)。结论他汀溶栓前给药用于行rt-PA急性脑梗死患者,可有效降低患者神经功能损伤程度,提高其日常生活质量,下调HMGB1、MMP-9及IL-17水平,改善其临床预后,且未增加症状性颅内出血风险,优于溶栓后给药。     

外周血血小板/淋巴细胞比值、纤维蛋白原/白蛋白比值与缺血性卒中静脉溶栓后出血转化的相关性

目的 探讨缺血性卒中(AIS)病人静脉溶栓后外周血血小板/淋巴细胞比值(PLR)、纤维蛋白原/白蛋白比值(FAR)与出血转化(HT)的关系。方法 选取2019年3月至2020年5月在青岛大学附属医院接受静脉溶栓治疗的133例AIS病人作为研究组,根据AIS病人静脉溶栓后是否发生HT,分为HT组20例,非HT组113例;分析影响AIS病人静脉溶栓后HT发生的因素;检测并比较各组PLR、FAR大小;使用ROC曲线分析PLR、FAR对AIS病人静脉溶栓后HT发生的预测价值;采用多因素logistic回归分析AIS病人静脉溶栓后HT发生的危险因素。结果 HT组美国国立卫生研究院卒中量表(NIHSS)评分[(16.20±4.35)分比(10.09±3.15)分]、改良Rankin量表(mRS)评分[(4.55±0.89)分比(1.33±0.47)分]、空腹血糖(FPG)[(8.91±1.21)mmol/L比(7.43±1.10)mmol/L]、纤维蛋白原(FBI)[(3.56±0.14)g/L比(3.31±0.11)g/L]、中性粒细胞计数[(6.92±1.73)×10⁹/...     

Spectinomycin modification. III Chloro-deoxy analogs.

9-Epichloro-9-deoxy-4(R)-dihydrospectinomycin (3), 9-chloro-9-deoxy-4(R)-dihydrospectinomycin (7), 9-deoxy-8, 9-epimino-4(R)-dihydrospectinomycin (6), and 9-epichloro-9-deoxy-spectinomycin (10) have been prepared and their structures established by proton magnetic resonance. These analogs are devoid of antibiotic activity.     

Synthesis and antibacterial activities of C-21 functionalized derivatives of (9R)-9-amino-9-deoxoerythromycins A and B.

Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin.     

A hypomorphic allele of aryl hydrocarbon receptor-associated protein-9 produces a phenocopy of the AHR-null mouse

The aryl hydrocarbon receptor-associated protein-9 (ARA9) is a chaperone of the aryl hydrocarbon receptor (AHR). The AHR has been shown to play a late developmental role in the normal closure of a fetal hepatovascular shunt known as the ductus venosus (DV). Given that Ara9-null mice display early embryonic lethality, we generated a hypomorphic Ara9 allele (designated Ara9(fxneo)) that displays reduced ARA9 protein expression. In an effort to demonstrate the role of ARA9 protein in AHR-mediated DV closure, we used combinations of Ara9 wild-type [Ara9(+/+)], null [Ara9(-/-)], and hypomorphic [Ara9(fxneo/fxneo)] alleles to produce mice with a graded expression of the ARA9 protein. Liver perfusion studies demonstrated that although none of the Ara9(+/+) mice displayed a patent DV, the shunt was observed in 10% of the Ara9(+/fxneo) mice, 55% of the Ara9(+/-) mice, and 83% of the Ara9(fxneo/fxneo) mice. That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development.     

白藜芦醇对U937细胞基质金属蛋白酶-9转录的抑制作用

目的:观察白藜芦醇对佛波酯诱导的U937细胞中基质金属蛋白酶-9活性的影响,并从蛋白、mRNA及核转录因子激活蛋白-1(AP-1)水平对其影响进行分析。方法:酶谱法测定U937细胞培养上清中MMP-9的活性;Western blot法考察MMP-9蛋白的生成;RT-PCR法检测MMP-9 mRNA的表达;电泳迁移率变动分析法(EMSA)研究核转录因子SP-1的活性。结果:PMA 10nmol/L 可显著诱导无血清培养的U937细胞中MMP-9活性(P<0.01);白藜芦醇在1和10 μmol/L浓度下可抑制 PMA 10 nmol/L诱导的MMP-9活性(P<0.05 和P<0.01);PMA 10 nmol/L可显著诱导U937细胞中MMP-9蛋白生成(P<0.01)和MMP-9 mRNA的表达(P<0.01),白藜芦醇在1、10μmol/L浓度下可抑制PMA 10 nmol/L诱导的MMP-9蛋白生成和MMP-9 mRNA的表达(P<0.05);白藜芦醇在10、1和0.1μmol/L浓度下可抑制PMA诱导的U937细胞中AP-1的活化。结论:白藜芦醇可有效地抑制PMA诱导的U937细胞中MMP-9的活性,其作用可能是通过抑制PMA诱导的U937细胞核转录因子AP-1活化,进而降低MMP-9 mRNA表达,减少MMP-9蛋白生成而实现的。     

Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein, a major causal factor for atherosclerosis. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), a major component of marijuana, has suggested to suppress atherosclerosis. Although Δ(9)-THC seems to be attractive for the prevention of atherosclerosis, there is no information about whether or not 15-LOX isoform can be inhibited by Δ(9)-THC. In the present study, Δ(9)-THC was found to be a direct inhibitor for 15-LOX with an IC(50) (50% inhibition concentration) value of 2.42 μM. Furthermore, Δ(9)-THC-11-oic acid, a major and nonpsychoactive metabolite of Δ(9) -THC, but not another Δ(9)-THC metabolite 11-OH-Δ(9)-THC (psychoactive), was revealed to inhibit 15-LOX. Taken together, it is suggested that Δ(9) -THC can abrogate atherosclerosis via direct inhibition of 15-LOX, and that Δ(9)-THC-11-oic acid is shown to be an "active metabolite" of Δ(9) -THC in this case.     

磷酸氟达拉滨的有关物质研究

目的制备磷酸氟达拉滨的3个特定杂质,以加强磷酸氟达拉滨原料药和制剂产品的质量控制。方法首次以9-β-D-阿拉伯呋喃糖-2-氟腺嘌呤-5'-磷酸酯(磷酸氟达拉滨)为起始原料,分别合成9-β-D-阿拉伯呋喃糖-2-羟基腺嘌呤-5'-磷酸酯(杂质A)和9-β-D-阿拉伯呋喃糖-2-乙氧基腺嘌呤-5'-磷酸酯(杂质F);以9-β-D-阿拉伯呋喃糖-2-氟腺嘌呤(氟达拉滨)为起始原料,经磷酰化、水解反应合成9-β-D阿拉伯呋喃糖-2-氟腺嘌呤-3',5'-二磷酸酯(杂质C)。采用制备色谱对以上3个杂质进行纯化。结果制备了磷酸氟达拉滨3个特定杂质,并通过高分辨质谱、核磁共振等方法进行了结构鉴定。结论制备的化合物可作为磷酸氟达拉滨原料药和制剂产品质量控制的杂质对照品,可对特定杂质进行准确的定性定量控制。     

CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin

Delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent of marijuana, is subject to first pass hepatic metabolism primarily by hydroxylation to yield active and inactive oxygenated products. The primary metabolite is formed via oxidation of the allylic methyl group to yield 11-hydroxy-delta9-THC, which is oxidized further to 11-nor-9-carboxy-delta9-THC. The hydroxylation is thought to be mediated by CYP2C9. The present study was designed to address the kinetics and pharmacogenetics of CYP2C-mediated metabolism of (delta9)-THC by studying its metabolism in human liver microsomes and expressed enzymes. Expressed CYP2C9.1 exhibited high affinity for the hydroxylation of delta9-THC (apparent Km, 2 microM), similar to that observed in human liver microsomes (apparent Km 0.8 microM). In contrast, the calculated intrinsic clearance (apparent Vm/Km) for CYP2C9.2 and CYP2C9.3 was approximately 30% that of the wild type, CYP2C9.1. Given the high affinity of CYP2C9 for the hydroxylation of delta9-THC, we evaluated the potential for an interaction between delta9-THC, 11-hydroxy-delta9-THC, or 11-nor-9-carboxy-delta9-THC and the CYP2C9 substrate, phenytoin. Surprisingly, delta9-THC increased the rate of phenytoin hydroxylation in human liver microsomes and expressed CYP2C9 enzyme. Similar increases in rate were observed with co-incubation of 11-hydroxy-delta9-THC and 11-nor-9-carboxy-delta9-THC with phenytoin. These in vitro data suggest the potential for an interaction from the concomitant administration of delta9-THC and phenytoin that could result in decreased phenytoin concentrations in vivo.     

CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population

The genetically polymorphic cytochrome P450 2C9 (CYP2C9) metabolizes many important drugs. Among them, phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and p-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 h. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH [defined as urinary volumex(S)-p-HPPH urinary concentration] and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), both markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in the genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra test). Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, analysis of variance (ANOVA) and P<0.0001, Kruskal-Wallis test, respectively) and decreased in the order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8 and CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r=0.08, P=0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r=0.21, P=0.001 and r=0.25, P<0.001, respectively). Furthermore, significant relation was found between urinary excretion of (R)-p-HPPH and CYP2C9 genotype (P=0.035) and levels significantly increased in the genotype order: CYP2C9*1/*9, CYP2C9*1/*1, CYP2C9*9/*11, CYP2C9*1/*8 and CYP2C9*1/*5 (P<0.001, Jonckheere-Terpstra test). In summary, the present study demonstrates that, in a Black population, CYP2C9*5, *6, *8 and *11 variants, but not CYP2C9*9, are associated with a decreased phenytoin metabolism. The data also confirm the limited contribution of MDR1 gene to inter-individual phenytoin pharmacokinetic variation.     

A rational search for the separation of psychoactivity and analgesia in cannabinoids.

The compound 9-beta-hydroxy-hexahydrocannabinol [(-)-9 beta-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid (equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the alpha face). (-)-9 beta-OH-HHC was synthesized by the addition of methyl Grignard to 9-oxo-11-nor-HHC. Its alpha epimer was obtained by the regiospecific epoxide ring opening of 9 alpha, 10 alpha-epoxy-HHC acetate. (-)-9 beta-OH-HHC and (-)-9 alpha-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than (-)-trans-delta 9-tetrahydrocannabinol (delta 9-THC) in all tests including the tail flick test for antinociception (analgesia). Molecular mechanics calculations [MMP2(85)] revealed that, in the global minimum energy conformation of (-)-9 beta-OH-HHC, the axial methyl at C-9 protrudes into the alpha face of the molecule, while the axial hydroxyl at C-9 in (-)-9 alpha-OH-HHC protrudes into this same face. These calculations also identified a higher energy carbocyclic ring (twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the alpha face. The minimal activity of both compounds is attributed to these higher energy forms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis, characterization and in vitro antimicrobial activity of novel sulfonylureas of 15-membered azalides

Three series of the novel sulfonylurea derivatives of 15-membered azalides, i.e. 9a-N-[N'-(aryl)sulfonylcarbamoyl] (4a-4f, 5a-5f), 9a-N-{N'-[(aryl)sulfonylcarbamoyl-gamma-aminopropyl]} (10a-10f, 11a, 11c) and 9a-N-{N'-(beta-cyanoethyl)-N'-[(aryl)sulfonylcarabamoyl-gamma-aminopropyl]} (14a-14f, 15a, 15b, 15f) derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2) and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3) were prepared and their structures elucidated by NMR and IR spectroscopic methods and mass spectrometry. Minimal inhibitory concentration (MIC) of these compounds was determined on a panel of sensitive and resistant Gram-positive and Gram-negative bacterial strains. Several compounds of the series of 9a-N-[N'-(aryl)sulfonylcarbamoyl] derivatives that showed significant improvements in activity against inducible resistant Streptococcus pyogenes strain were suggested for further optimization.