氢氯噻嗪与吲哒帕胺对肝、肾、血管细胞色素P450羟化酶影响

目的观察利尿剂对自发性高血压大鼠(SHR)的降压作用及对花生四烯酸细胞色素P450代谢途径中羟化酶(CYP4A1)的调节作用.方法 18只成年雌性SHR随机分为3组对照组;氢氯噻嗪(HCTZ, 10 mg*kg-1*d-1) 治疗组;吲哒帕胺(IND, 0.625 mg*kg-1*d-1)治疗组. 治疗开始至结束时每周测血压一次.4周后处死动物,分别用RT-PCR、Western-Blot法检测血管、肝、肾组织中细胞色素P4504A1(CYP4A1)mRNA及蛋白质表达.结果治疗组动物收缩压均明显低于对照组,且吲哒帕胺(IND)组(由治疗前191.2±3.8降到172.8±5.1 mmHg)的降压效果较氢氯噻嗪(HCTZ))组(由治疗前188.5±4.0降到176.0±5.6 mmHg)更明显(P<0.05).氢氯噻嗪与吲哒帕胺均引起大鼠组织中 CYP4A1 mRNA及蛋白水平上调,并且氢氯噻嗪组上调更显著(P<0.05).结论吲哒帕胺与氢氯噻嗪在降低血压的同时均上调CYP4A1的表达.提示联合使用CYP4A1抑制剂可能会增强吲哒帕胺与氢氯噻嗪的降压效果.     

利尿剂对高血压大鼠细胞色素P450表氧化酶及血管紧张素Ⅱ1型受体基因表达的影响

目的　噻嗪类利尿剂是广泛使用的降血压药物 ,然而其降血压机理仍然不完全清楚。本研究观察了氢氯噻嗪和吲哒帕胺对自发性高血压大鼠 (SHR)细胞色素P4 5 0 (CYP)表氧化酶 2C11及血管紧张素Ⅱ 1型受体 (AT1)基因表达的影响 ,以探讨其降低血压的分子机制。方法　成年雄性SHR随机分为三组 ,分别每日经胃管给予氢氯噻嗪 (10mg/kg)、吲哒帕胺 (0 6 2 5mg/kg)和等量去离子水灌胃 ,并测量血压和 2 4h尿量。 4周后 ,检测主要脏器的CYP表氧化酶 2C11和AT1表达情况及形态学变化。结果　氢氯噻嗪和吲哒帕胺用药 1周后动物血压降低 ,4周时降压幅度达到非常显著水平 ,与对照组比较P <0 0 1。同时在mRNA和蛋白质水平上调肾脏、心脏和主动脉中CYP表氧化酶 2C11和下调AT1基因表达 ;胶原染色显示 ,两种药物均能显著减少心肌胶原沉积 ,减轻高血压所致的肾脏损害。结论　噻嗪类利尿剂氢氯噻嗪和吲哒帕胺可能通过上调CYP表氧化酶及下调AT1降低血压和保护器官。     

氢氯噻嗪与螺内酯、卡托普利联合治疗原发性高血压

目的评价小剂量氢氯噻嗪(HCTZ)与螺内酯、卡托普利联用的降压疗效和安全性。方法采用多中心、随机、双盲、平行对照试验,选择轻中度高血压患者829例,经2周安慰剂洗脱期、6周HCTZ导入期后随机进入HCTZ12.5mg q.d组HCTZ12·5mg与螺内酯20mg q.d组HCTZ12·5mg q.d与卡托普利25mg b.i.d组治疗,共12个月,随访1次/月。治疗前、治疗6周末和治疗12个月末分别进行血生化检查并评估降压疗效及安全性。结果①治疗6周末,3组的坐位收缩压及舒张压(以下血压值均指坐位血压值)较治疗前明显下降(P<0·01,P<0·01)。治疗12个月末3组的血压值仍明显下降。HCTZ组、螺内酯组和卡托普利组患者的收缩压下降值分别为(10·5±17·3),(13·3±15·8),(14·6±17·4)mmHg,卡托普利组下降幅度较HCTZ组明显(P=0·034)。②HCTZ组、螺内酯组和卡托普利组降压达标率分别为34·9%、44·3%和47·1%,HCTZ组达标率低于其他两组(44·3%vs34·9%P=0·038;47·1%vs34·9%P<0·001),螺内酯和卡托普利2组间无统计学差异。③3组间副反应发生率无统计学差异。结论小剂量HCTZ与螺内酯、卡托普利联用降压安全有效。     

吲哒帕胺、双氢氯噻嗪对1级高血压临床疗效的对比研究

目的　评价吲哒帕胺、双氢氯噻嗪对高血压 1级疗效并且比较。方法　 6 9名高血压 1级患者 ,分别随机分成2组。 35名服吲哒帕胺 2 .5mg 1日 1次 ,34名服双氢氯噻嗪 2 5mg 1日 3次 ,疗程均为 8周。 结果　两组降压有效率相近 88.5 7%、85 .2 9% ,动态血压显示吲哒帕胺控制 2 4小时血压明显较双氢氯噻嗪为优 ,不良反应发生率吲哒帕胺组少。结论　吲哒帕胺是治疗高血压 1级安全有效的降压药物。     

吲哒帕胺对高血压患者肱动脉血流介导的舒张功能的影响

目的探讨吲哒帕胺对高血压患者降压疗效及对肱动脉血流介导的舒张功能(FMD)的影响.方法轻度高血压患者53例,随机分为两组,一组服吲哒帕胺(2.5 mg,q.d),另一组服氢氯噻嗪组(25 mg,q.d),观察治疗3个月前后血压及肱动脉FMD的变化.结果吲哒帕胺与氢氯噻嗪均能显著降低血压(P＜0.01).吲哒帕胺治疗后肱动脉内皮依赖性舒张功能(EDD)明显提高(6.1%±0.8%比7.8%±0.8%,P＜0.01);而氢氯噻嗪治疗前后患者肱动脉EDD无明显变化(P＞0.05).结论轻度高血压患者的血管EDD的损伤是可逆的,吲哒帕胺平稳降压,且可以明显改善损伤的血管EDD.     

吲哒帕胺、双氢氯噻嗪对1级高血压临床疗效的对比研究

目的评价吲哒帕胺、双氢氯噻嗪对高血压1级疗效并且比较.方法 69名高血压1级患者,分别随机分成2组.35名服吲哒帕胺2.5 mg 1日1次,34名服双氢氯噻嗪25 mg 1日3次,疗程均为8周.结果两组降压有效率相近88.57%、85.29%,动态血压显示吲哒帕胺控制24小时血压明显较双氢氯噻嗪为优,不良反应发生率吲哒帕胺组少.结论吲哒帕胺是治疗高血压1级安全有效的降压药物.     

吲哒帕胺对高血压患者肱动脉血流介导的舒张功能的影响

目的探讨吲哒帕胺对高血压患者降压疗效及对肱动脉血流介导的舒张功能(FMD)的影响。方法轻度高血压患者53例,随机分为两组,一组服吲哒帕胺(2.5mg,q.d),另一组服氢氯噻嗪组(25mg,q.d),观察治疗3个月前后血压及肱动脉FMD的变化。结果吲哒帕胺与氢氯噻嗪均能显著降低血压(P<0.01)。吲哒帕胺治疗后肱动脉内皮依赖性舒张功能(EDD)明显提高(6.1%±0.8%比7.8%±0.8%,P<0.01);而氢氯噻嗪治疗前后患者肱动脉EDD无明显变化(P>0.05)。结论轻度高血压患者的血管EDD的损伤是可逆的,吲哒帕胺平稳降压,且可以明显改善损伤的血管EDD。     

褪黑素对大鼠肝微粒体细胞色素P450酶亚型CYP2C9、CYP2D6、CYP3A4活性的影响

目的 观察褪黑素对大鼠肝微粒体内细胞色素P450 (CYP450) 酶亚型CYP2C9、CYP2D6、CYP3A4活性的影响.方法 以生理盐水为对照,大鼠灌胃0.54 mg·kg-1·d-1的褪黑素,连续7 d,然后测定其肝微体中CYP2C9、CYP2D6、CYP3A4活性.结果 与对照组比较,褪黑素组CYP2C9、CYP2D6、CYP3A4的活性无变化(P>0.05).结论 褪黑素对CYP450酶 CYP2C9、CYP2D6、CYP3A4活性无影响.     

不同血管紧张素转换酶、醛固酮合酶和α-内收蛋白基因多态性组合与氢氯噻嗪降压疗效的关系

目的研究原发性高血压(EH)患者血管紧张素转换酶(ACE)基因I/D、醛固酮合酶(CYP11B2)基因-344T/C和α-内收蛋白(α-adducin)基因G614T不同基因多态性组合与氢氯噻嗪(HCTZ)降压疗效的关系.方法829例EH患者同时服用HCTZ 12.5 mg,1次/d,共6周.资料完整的716例患者按ACE、CYP11B2及α-adducin不同基因多态性组合,比较不同基因多态性组合患者的降压疗效.结果27种不同多态性组合中,ACE-ID CYP-TT α-adducin-TG多态性组合在患者中分布频率最高(ACE-DD CYP-TC α-adducin-TT)基因多态性组合的患者收缩压下降值最大(17.7±30.5)mm Hg,显著高于其它基因多态性组合(P＜0.05);多元逐步回归分析提示:ACE基因DD型、α-adducin基因-TT型、ACE-DD十CYP11B2-TC α-adducin-TT基因多态性组合等是影响患者收缩压下降值的主要因素.结论不同ACE基因I/D、CYP11B2基因-344T/C、α-adducin基因G614T多态性组合患者对氢氯噻嗪的降压疗效存在差异;ACE-DD CYP11B2-TC α-adducin-TT基因多态性组合对HCTZ的降压疗效优于其他基因多态性组合的患者.     

氢氯噻嗪与螺内酯、卡托普利联合治疗原发性高血压

目的评价小剂量氢氯噻嗪(HCTZ)与螺内酯、卡托普利联用的降压疗效和安全性.方法采用多中心、随机、双盲、平行对照试验,选择轻中度高血压患者829例,经2周安慰剂洗脱期、6周HCTZ导入期后随机进入HCTZ 12.5 mg q.d组HCTZ 12.5 mg与螺内酯20 mg q.d组HCTZ 12.5 mg q.d与卡托普利25 mg b.i.d组治疗,共12个月,随访1次/月.治疗前、治疗6周末和治疗12个月末分别进行血生化检查并评估降压疗效及安全性.结果①治疗6周末,3组的坐位收缩压及舒张压(以下血压值均指坐位血压值)较治疗前明显下降(P＜0.01,P＜0.01).治疗12个月末3组的血压值仍明显下降.HCTZ组、螺内酯组和卡托普利组患者的收缩压下降值分别为(10.5±17.3),(13.3±15.8),(14.6±17.4)mmHg,卡托普利组下降幅度较HCTZ组明显(P=0.034).②HCTZ组、螺内酯组和卡托普利组降压达标率分别为34.9%、44.3%和47.1%,HCTZ组达标率低于其他两组(44.3%vs 34.9%P=0.038;47.1%vs34.9%P＜0.001),螺内酯和卡托普利2组间无统计学差异.③3组间副反应发生率无统计学差异.结论小剂量HCTZ与螺内酯、卡托普利联用降压安全有效.     

Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo

Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC50=2.24 nM, 95% CI=1.20-3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED90 of artesunate by approximately 15.6-fold in a pyronaridine-resistant P. berghei line and by approximately 200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.     

Parameters of anorectal and colonic motility in health and in severe constipation

Anorectal function and colonic transit was assessed in 17 severely constipated patients and 15 age-matched controls. The constipated patients were divided into those who had immobile perineum (perineal descent 1.0 cm during attempted defecation) and those who had a normal descent (>1.0 cm) of the perineum. When constipation was accompanied by an immobile perineum, patients had impaired balloon expulsion, impaired and delayed artificial stool expulsion, decreased straightening of the anorectal angle, decreased descent of the pelvic floor with defecation, and prolonged rectosigmoid colon transit compared with the patients with constipation who had a mobile perineum and with normal controls. The mobile-perineum group differed from controls only in colon transit times, having prolonged total colon transit. Anal sphincter resting pressures, immediate artificial stool expulsion, resting anorectal angles, and electromyography of the external anal sphincter and puborectalis did not differentiate the constipated patients from the controls. We concluded that descent of the perineum of <1 cm was associated with impaired expulsion, an adynamic anorectal angle, and slowed distal colon transit. This simple sign of pelvic floor function distinguished constipated patients with disordered expulsion from constipated patients with normal pelvic floor function. These patients may respond poorly to surgery and conventional management and would therefore be candidates instead for pelvic floor retraining. Accurate characterization and appreciation of pelvic floor dysfunction in patients with severe chronic constipation may improve the selection for and results of surgical and nonsurgical intervention.Supported in part by Research Grants DK37990, RR585, and DK34988 from the National Institutes of Health and by the Mayo Foundation, Rochester, Minnesota.     

Effects of dietary phytoestrogens in vivo and in vitro in rainbow trout and Siberian sturgeon: interests and limits of the in vitro studies of interspecies differences

A study of the effects of dietary genistein on trout and sturgeon in vivo showed that sturgeon was sensitive to 20 ppm of genistein, whereas trout was not. To analyze the origin of this interspecies difference in sensitivity, a cell culture technique was developed with hepatocytes from sturgeon and compared to results obtained with hepatocytes from trout in the same system. The hepatocyte culture proved to be useful as bioassay for estrogenicity. Vitellogenin (VTG), assayed by a specific enzyme-linked immunosorbent assay, was used as a biomarker of the estrogenic activity. 17 beta-Estradiol, its glucuronide and sulfate derivatives, and estradiol analogues (ethynylestradiol and diethylstilbestrol) were tested. Nonestrogenic compounds such as androgens, progesterone, and cortisol were tested as negative controls. VTG production was monitored at doses ranging from 1 nM to 10 microM estradiol. Phytoestrogens, from the isoflavone family, were tested individually at increasing doses exhibiting dose response curves for concentrations from 500 nM to 10 microM. With tamoxifen, an antagonist of estrogen receptors, the estrogenic effect was partially reduced. The effect was the same with ICI182,780 in sturgeon, whereas the effect was the opposite in trout. The estrogenic potency of the isoflavones ranged differently between the two species in the following order: biochanin A < daidzein = formononetin < genistein < equol in trout and biochanin A < genistein < daidzein < formononetin < equol in sturgeon. Further, in sturgeon, formononetin was the most potent phytoestrogen in vitro, whereas its activity was weakest in vivo. These data suggest that one must reconsider the relevance of heterologous estrogenic tests and of homologous in vitro tests for estrogenic potency of chemicals.     

The role of alcohol and drugs in homicides in England and Wales

BACKGROUND: The annual number of homicide convictions in England and Wales is increasing. Previous studies have highlighted the aetiological role of alcohol and drugs in homicide. AIMS: To examine rates of alcohol and drug misuse and dependence in people convicted of homicide; the role of alcohol and drugs in the offence; the social and clinical characteristics of alcohol- and drug-related homicides; and the social and clinical characteristics of patients with dual diagnosis who commit homicide. METHODS: A national clinical survey based on a 3-year (1996-9) consecutive sample of people convicted of homicide in England and Wales. Information on rates of alcohol and drug misuse/dependence, the role of alcohol and drugs in the offence and social and clinical characteristics of perpetrators were collected from psychiatric reports prepared for the court in homicide convictions. Detailed clinical information was gathered from questionnaires completed by mental health teams for those in contact with mental health services. RESULTS: Of the 1594 homicide perpetrators, more than one-third (42%) occurred in people with a history of alcohol misuse or dependence and 40% in people with a history of drug misuse or dependence. Alcohol or drug misuse played a contributory role in two-fifths of homicides. Alcohol played a major role in 52 (6%) and a minor role in 364 (39%) homicides. Drugs played a major role in six (1%) and a minor role in 138 (14%) homicides. Forty-two homicides (17%) were committed by patients with severe mental illness and substance misuse. Alcohol- and drug-related homicides were generally associated with male perpetrators who had a history of violence, personality disorders, mental health service contact and with stranger victims. CONCLUSIONS: Substance misuse contributes to the majority of homicides in England and Wales. A public health approach to homicide would highlight alcohol and drugs before severe mental illness.     

Trends in COPD mortality and hospitalizations in countries and regions of Asia-Pacific

Background and objective: The growing burden of COPD in the Asia‐Pacific region supports the need for more intensive research and analysis of the epidemiology of COPD to raise awareness of the disease and its causes, to ensure the development of effective national health policies and to facilitate equitable deployment of finite health‐care resources in the prevention and management of COPD. This study estimated and compared COPD mortality and hospital morbidity rates and trends in these rates over time across countries and regions of Asia‐Pacific. Methods: Data consistent with standard definitions of COPD (ICD‐9/ICD‐10) for the period 1991–2004 were obtained from national health statistics agencies. For countries/regions with complete national mortality and hospitalization data (Australia, Pacific Canada (British Columbia, Hong Kong, South Korea and Taiwan), annual age‐standardized mortality and hospitalization rates were calculated for men and women aged ≥ 40 years. Negative binomial regression modelling was used to estimate rate ratios for country/region, gender and age differences and general trends over time. Results: Mortality rates per 10 000 population ranged 6.4–9.2 in men, 2.1–3.5 in women and 3.7–5.3 overall in 2003. Corresponding ranges for morbidity were 32.6–334.7, 21.2–129 and 28.1–207.3 per 10 000. Trend analysis of data since 1997 produced annual percentage changes in mortality versus hospitalization of ?4.4% versus ?0.7% in Australia, ?3.6% versus 7.5% in Pacific Canada (British Columbia), ?7.15% versus ?5.6% in Hong Kong and ?2.9% versus ?4.2% in Taiwan. Conclusions: In Asia‐Pacific, overall mortality and morbidity rates are high and trends in mortality and morbidity vary between countries/regions. Differences in rates and trends for men and women most likely reflect the different trends in historical and prevalent smoking profiles for COPD in the different countries and regions.     

Morbidity and maternal and infant outcomes of hypertensive disorder in pregnancy in China in 2018

Hypertensive disorder in pregnancy is a disease that occurs during pregnancy. We aimed to analyze the morbidity and maternal and infant outcomes with respect to the hypertensive disorder in pregnancy in China in 2018. Clinical data of 38 590 cases from 161 hospitals were retrospectively collected. The differences in morbidity and maternal and infant mortality among the major regions and provinces were compared. The overall national average morbidity was 4.74%, and the ratios of gestational hypertension, preeclampsia, eclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia were 29.17%, 55.02%, 0.66%, 6.53%, and 8.62%, respectively. The overall maternal mortality was 0.61/100 000, and the case fatality was 0.13%. Morbidity associated with hypertensive disorder in pregnancy was 7.74% in North China, 6.62% in Northwest China, 6.40% in Central China, 5.83% in Northeast China, 4.28% in East China, 3.85% in South China, and 2.88% in Southwest China. The morbidity in each province was 1.62‐11.28%. The overall perinatal mortality was 3.59% (81.09% for stillbirths; 18.91% for neonatal deaths). Perinatal mortality decreased with increasing gestational weeks from 24 to 37 + 6 weeks. Perinatal mortality for delivery at 32 weeks of gestation in all regions of the country was <10%. Morbidity varied across regions in China, with the lowest in Southwest and the highest in North China. The low maternal mortality is related to the large‐scale development of standardized maternal health care in China. For severe hypertensive disorder patients, gestation should be prolonged to 32 weeks as often as possible for better neonatal survival rates.     

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.