Effect of pentoxifylline on endothelaemia and hypothalamic-pituitary-adrenocortical axis activation in female rats under stress exposure

Endothelial dysfunction may belong to negative consequences of stress exposure accompanied by activation of several stress systems including the hypothalamic-pituitary-adrenocortical (HPA) axis. The present experiments were aimed at testing the hypotheses that i) immobilization (IMO) stress results in sustained increase in endothelaemia for 24 h and that ii) pentoxifylline, a drug with endothelium protective properties, attenuates the rise in endothelaemia and HPA axis activation in female rats as shown previously in males. Circulating endothelial cells increased immediately after the IMO for 2 h, returned back to control levels at 12 h and increased again at 24 h. Stress-induced rise in adrenocorticotropic hormone (ACTH) and corticosterone levels was particularly high immediately after the IMO. Pretreatment with pentoxifylline (20 mg/kg subcutaneously for 7 days) attenuated the rise in endothelaemia and adrenal corticosterone measured at 24 h following IMO. Plasma levels of ACTH and proopiomelanocortin gene expression in the anterior pituitary were not affected by pentoxifylline treatment. The present results indicate that IMO stress in female rats induces a biphasic rise in endothelaemia early at the time of stress exposure and than 24 h thereafter. Based on these data and our previous study we can conclude that intensive stress has a negative influence on endothelial cells in both sexes and no gender differences seem to be present in the protective action of pentoxifylline.     

Protective effect of oxygen-derived free radical scavengers on the endothelium in vivo

The endothelo-protective activity of a series of low-molecular oxygen-derived free radical scavengers (OFRS) was tested in rats. A model of endothelaemia provoked by intravenous administration of hydrogen peroxide was used. With each OFRS the activity in the hydrogen peroxide model was compared with that in the less specific model using the provocation by citrate as a calcium chelating agent. Relatively unspecific but biologically important OFRS, ascorbic acid, tocopherol, troxerutin and glutathione were tested in the first phase of the study. A marked optimum of endothelo-protective activity was shown with all agents, the optimum against hydrogen peroxide having been observed at doses from 3 to 50 times lower than against citrate. Ascorbic acid, troxerutin and the combination of both were also tested in another model based on leg ischaemia produced by ligature of the common femoral artery. Without OFRS, a marked increase of endothelaemia was observed after 30-60 min ischaemia showing a second peak after the release of the ligature. This second peak was completely abolished by the preventive administration of OFRS in a dose which was also effective in the hydrogen peroxide model.     

Stress-induced rise in endothelaemia, von Willebrand factor and hypothalamic-pituitary-adrenocortical axis activation is reduced by pretreatment with pentoxifylline.

Stress is considered to be a risk factor of several diseases. The following hypotheses were tested: (1) single exposure to an intensive stressor is followed by endothelial stimulation and/or damage to endothelial cells, (2) potential stress-induced endothelial cell damage is reduced by repeated pretreatment with pentoxifylline and (3) pentoxifylline treatment modifies neuroendocrine activation during stress reflected by changes in hypothalamic-pituitary-adrenocortical (HPA) axis function. Rats were treated with saline or pentoxifylline (20 mg/kg, s.c.) once daily for 7 days and then exposed to single immobilization stress for 20 or 120 min. In saline pretreated rats, stress exposure was followed by a rise in endothelaemia, von Willebrand factor concentrations, adrenocorticotropic hormone (ACTH) and corticosterone release, as well as by enhanced gene expression of hypothalamic corticotropin releasing factor (CRH). Stress-induced changes were reduced by pretreatment with pentoxifylline. Significant inhibition was observed in endothelaemia, plasma ACTH and corticosterone concentration in the adrenals. Thus, signs of endothelial injury as well as stress-induced hormone levels were reduced by pretreatment with pentoxifylline, although there is no evidence for a causal relationship. This protective action of pentoxifylline might be of benefit in the prevention and therapy of some stress-related disorders.     

某三级甲等医院营养类药物使用情况调查

目的:通过对某三级甲等医院2012年全年处方进行分析,调查营养类药物使用情况。方法:通过回顾性方法、Microsoft Excel 2007、SPSS 16.0对数据进行分析。结果:肠内营养乳剂(TP)使用量最大;葡萄糖注射液(20 ml)使用量排名第一;脑外科应用营养类药物比较多;肠外营养类药物的发放量大于肠内营养类药物,差异具有统计学意义(P0.05);营养类药物应用年龄区间大,男女比例约为1:1。结论:本研究调查此三级甲等医院营养类药物的使用情况,为医生、患者和医院管理者在选择营养类药物提供了参考,为我国基本药物目录修改提供了依据。     

Reasons for failure of antihypertensive treatment.

One hundred patients whose hypertension was originally well controlled were carefully screened when a routine clinic visit showed that their blood pressure was above 170/100 mm Hg. Simple misconceptions accounted for 75 failures: 38 did not know they had to continue their drugs, 14 thought they should not take antihypertensive drugs if they had not had a meal, 13 did not know which drugs controlled their blood pressure, and 10 believed it was better not to take their drugs on clinic days. Eleven patients were using racemic alpha-methyldopa, which was ineffective; 11 others said they could not afford the drugs; only three intentionally stopped their drugs because of unpleasant side effects. Patients need to be thoroughly informed about their treatment and the number of drugs kept to a minimum.     

Dopaminergic and serotonergic drug use: a nationwide register-based study of over 1,300,000 older people

Objective

To investigate the use of dopaminergic and serotonergic drugs in elderly people.

Methods

We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1 347 564; 81% of the total population aged ≥65 years in Sweden). Main outcome measures were dopaminergic (enhancing and/or lowering) and serotonergic (enhancing and/or lowering) drugs and combinations of these.

Results

Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern.

Conclusion

Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.     

Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage.

The intake of anti-inflammatory drugs by 268 patients with colonic or small bowel perforation or haemorrhage was compared with that by a group of patients, matched for age and sex, with uncomplicated lower bowel disease. Patients with perforation or haemorrhage were more than twice as likely to be takers of anti-inflammatory drugs, but no association was detected with the intake of other types of drugs, particularly cardiovascular drugs. The association between complicated lower bowel disease and intake of anti-inflammatory drugs may be causal.     

Sensitivity to antibiotics and antibacterial preparations of conditionally pathogenic bacteria isolated from patients with gastrointestinal tract dysfunctions]

Sensitivity of 690 cultures of the conditionally pathogenic microbes of Enterobacteriaceae and Pseudomonadaceae to 17 drugs was studied with the agar diffusion method. It was found that 98.6 per cent of the cultures had multiple resistance to 2--10 drugs. Most of the cultures were resistant to erythromycin, carbenicillin and ampicillin. Different species of the conditionally pathogenic microorganisms were resistant to different numbers of the drugs. Thus, Ps. aeruginosa cultures were resistant to 6--10 drugs, the cultures of Citrobacter were resistant to 3--8 drugs and the cultures of Kl. pneumonia were resistant to 2--5 drugs. Levomycetin, tetracycline, streptomycin and biseptol proved to be the most active antibacterial drugs.     

Risk of agranulocytosis and aplastic anaemia in relation to use of antithyroid drugs. International Agranulocytosis and Aplastic Anaemia Study.

The relation of the use of antithyroid drugs to the risk of developing agranulocytosis and aplastic anaemia was evaluated in a population based case-control study with patients from Israel and seven regions in Europe. Data were obtained from cases and hospital controls by interview. Use of antithyroid drugs in the week before the onset of illness was compared in 262 patients with agranulocytosis and 1771 controls. Forty five patients (17%) and five controls (0.3%) had used antithyroid drugs. The relative risk was estimated to be 102 (95% confidence interval 38 to 275) taking into account confounding by other factors, including the use of other drugs. The excess risk for use of antithyroid drugs in any one week was estimated to be 6.3 cases of agranulocytosis per million users. Use of antithyroid drugs in a five month period ending one month before admission to hospital was compared in 135 patients with aplastic anaemia and 2145 controls. Four patients (3%) and five controls (0.2%) had taken drugs; the estimate of relative risk was 9.2 (95% confidence interval 1.8 to 47) after control for confounding. The estimate of excess risk of agranulocytosis with the use of antithyroid drugs was lower than found previously. Although the excess risk for aplastic anaemia was not calculated, these data suggest that it is very low.     

生物技术药物药代动力学研究的方法学和实验设计

生物技术药物由于自身具有的特点 ,使得其在体内的药代动力学机制比传统药物更为复杂。近年来 ,对于这类药物在体内的代谢机制的研究日趋增加 ,研究方法也日趋成熟。概述了生物技术药物的药代动力学研究方法以及实验设计的特点。     

On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production

To examine the influence on aromatase and sulfatase pathways in estrogen pool by drugs reported to cause gynecomastia as the side effect, 29 ethical drugs were incubated with human placental microsomes as an enzyme source. The percent inhibition of drugs on aromatase pathway was obtained by sum of the velocity constants of two products, estrone (E1) and estradiol (E2) from testosterone (T) as the substrate, and that on sulfatase pathway was obtained as the velocity constant of production of E1 from estrone sulfate (E1S). Although several drugs including ketoconazole showed a significant inhibition effect on aromatase pathway at their non-clinical over-dose concentration (100 microM), no influence on the inhibition was observed in any drugs at their approximately therapeutic concentration (1 microM). However, several drugs including spironolactone gave the product ratio (E2/E1) having higher value than that of the control, the result means spironolactone inhibits the conversion of E2 to E1. No inhibitory effect of the drugs tested on estrogen production from E1S (sulfatase pathway) was confirmed. The results suggest the possibility that the tested drugs known to cause gynecomastia have no inhibitory effect essentially on aromatase and sulfatase pathways.     

海洋微生物药物的开发和应用

概要介绍了海洋微生物药物的开发和应用现状,海洋微生物药物的研究开发技术和方法,并展望了海洋微生物药物及其资源的开发和应用前景。     

Co-treatment with the anti-malarial drugs mefloquine and primaquine highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition

The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells.     

Quality of cardiovascular drugs prescribing in Croatia 2003-2008

The aim of the study was to determine cardiovascular drugs utilization and quality of prescribing in Croatia from 2003 to 2008. Data on the outpatient utilization of cardiovascular drugs in Croatia were collected during 2003-2008. Data on the size and number of packages, were obtained from Croatian institute for Health Insurance (CIHI). Based on the data obtained, the numbers of DDD and DDD per 1000 inhabitants per day (DDD/1000/day) were calculated for all cardiovascular drugs. Quality of drugs prescribing was assessing using Drug Utilization 90% (DU90%) method. Renin-angiotensin system agents showed highest share in the utilization of group C drugs, followed by calcium channel blockers. These two groups of drugs accounted for half of the overall cardiovascular drug utilization. Greatest changes were observed in the groups of renin-angiotensin system agents and hypolipemics. The number of drugs within DU90% segment increased between 2003 and 2008. In the same period Cost/DDD decreased.     

Role of drugs in traffic accidents.

Serum samples from 201 drivers who presented at emergency departments within six hours after being injured in a road accident and 325 control drivers selected randomly at petrol stations were screened for drugs by combined thin-layer and gas chromatography. Blood alcohol concentrations were also measured, and a questionnaire on the subjects'' state of health and use of drugs administered. At interview 30 patients (15%) and 44 controls (13%) said that they had taken drugs in the previous 24 hours. Four patients (2%) and six controls (2%) said that they had taken psychotropic drugs, but serum analysis detected psychotropic drugs in 10 patients (5%) and eight controls (2.5%). Diazepam was found in 16 of the 18 subjects in whom psychotropic drugs were detected. Alcohol was detected in 30 patients (15%) and three controls (1%). Drug use appeared to be somewhat lower in Finland than in other Western countries, and illness to be a more important traffic hazard than drugs in general. Interview was not a reliable method of establishing whether drivers had taken psychotropic drugs. Taking diazepam may increase the risk of being involved in a traffic accident, but alcohol was the most powerful risk factor.     

Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle.

Sodium currents were studied under voltage clamp in the presence of neutral, amine, and quaternary local anesthetic compounds. Use-dependent block was observed as a cumulative depression of INa seen with repetitive depolarizing test pulses applied at frequencies of 2-10s-1. With quaternary QX-314, the time constant of use dependence was long, and with neutral benzocaine, very short. With lidocaine and procaine, increasing external pH (pHo) changed the time constant from long to short, but alterations of internal pH have no effect. Inactivation in Na channels was measured by the influence of prepulses on peak INa during test pulses. Single-stimulus inactivation curves were shifted more with lidocaine at high pHo than at low pHo, but inactivation curves measured during pulse trains with any of the drugs and at any pHo were strongly shifted. All measurements show that the drug-receptor reaction was slow for amine drugs at low pHo, as for quaternary drugs at any pHo, and fast for amine drugs at high pHo, as for neutral drugs at any pHo. The major effect of low pHo on amine drugs was to reduce the concentration of drugs in the fiber and to protonate drug molecules on the receptor, thus trapping them in the blocking position for a longer time. Direct effects of pH on the receptor seemed minimal.