Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood–brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.     

Disease control in asthmatic children seen in private practice in Switzerland

ABSTRACT

Background: Asthma is the most common chronic childhood disease in Switzerland with a prevalence of 10%. Asthma has a high economic burden accounting for high medical costs. Assessment of disease control is likely to be of help in the implementation of strategies to improve asthma. Therefore, we aimed to evaluate asthma control and therapy regimens among children in private practice.

Methods: We assessed asthma control as well as therapy regimens in 575 asthmatic children in an experience programme in Switzerland by using an abbreviated questionnaire based on the asthma control questionnaire and the child health questionnaire on Visit 1 and Visit 2.

Results: Good asthma control at Visit 1 was only present in 25.7% of asthmatic children. Occasional asthma symptoms, limitation of physical activity, nocturnal awakening and anxiety of the parent was present in 80.5%, 41.2%, 46.8% and 57% of the children, respectively. After adjustment of therapy regimens at Visit 1, mainly by adding a leukotriene receptor antagonist, asthma control was reported to be much better in 53.4% of the children at Visit 2.

Conclusions: As asthma control is inadequately achieved within a major portion of asthmatic children, it is imperative to find measures to improve asthma control and hence, to reduce the burden of disease.     

Enteroviral meningitis in children in Turkey

In the indexed medical literature, there have been a very limited number of studies to investigate the epidemiologic and clinical features of enteroviral meningitis in Turkey. The aim of the present retrospective study is to update the actual situation to recognize the spectrum and magnitude of this important clinical entity. Between June 1999 and December 2004, 612 cases of aseptic meningitis were followed up at our hospital. Enteroviral meningitis was defined by isolation of enteroviruses from cerebrospinal fluid (CSF) and/or stool samples. Mumps virus was detected in 310 cases (50.7%) and enteroviruses were the etiologic agents in 104 (17%) of the patients with aseptic meningitis. Most of the enteroviral meningitis cases (36 cases, 34.6%) were diagnosed in August and 70 (67.3%) of them were male. The mean age was 5.6 ± 3.4 years. The most common initial symptoms were fever (81.7%), vomiting (77.9%) and headache (57.7%). In the physical examination, 46.2% of the cases had neck stiffness and 38.5% had pharyngitis. Echovirus 30 was the most frequently (38 cases, 36.5%) isolated enterovirus with peaks in 1999, 2002 and 2004. The other frequently isolated enteroviruses were Coxsackie virus type B (17 cases, 16.3%), echovirus 6 (11 cases, 10.6%), echovirus 11 (6 cases, 5.8%), and echovirus 13 (4 cases, 3.8 %). Mean hospitalization time was 6.2 ± 2.4 days. All patients recovered without any sequelae. Enteroviruses have an important role in childhood aseptic meningitis cases in Turkey too, and the predominant serotypes vary according to years.     

Genotoxic effects of chlorophenoxy herbicide diclofop-methyl in mice in vivo and in human lymphocytes in vitro

Diclofop-methyl (DM) is a chlorophenoxy derivative used in large quantities for the control of annual grasses in grain and vegetable crops. In this study, the genotoxic effects of DM were investigated by measuring chromosomal aberrations (CAs) in mouse bone-marrow cells and CA and the comet assay in human peripheral lymphocytes. Mice were treated with 15.63, 31.25, 62.5, and 125?mg/kg body weight of DM intraperitoneally for 24 hours, and 15.63-, 31.25-, 62.5-, 125-, and 250-µg/mL concentrations were applied to human lymphocytes for both 24 and 48 hours. In in vivo treatments, DM significantly, but not dose dependently, increased the total chromosome aberrations, compared to both negative and solvent controls. Cell proliferation was significantly, but not dose dependently, affected by all doses. In in vitro treatments, DM (except 15.63 µg/mL) significantly and dose dependently increased the frequency of chromosome aberrations. Also, 250 µg/mL of 48-hour treatment was found to be toxic. Cell proliferation was significantly and dose dependently affected by DM applications, when compared to negative control. In in vitro treatments, DM significantly decreased the mitotic index only at the highest concentration for 24 hours, and 62.5- and 125-µg/mL concentrations for 48 hours. In the comet assay, a significant and dose-dependent increase in comet-tail intensity was observed at 62.5-, 125-, and 250-µg/mL concentrations. The mean comet-tail length was significantly increased in all concentrations. Our results demonstrate that DM is genotoxic in mammalian cells in vivo and in vitro.     

我院2004年门急诊处方及抗菌药物合理应用分析

目的了解我院抗菌药物使用状况,为临床合理用药提供参考依据。方法随机抽取2004年门急诊处方样本2444份,依据统计学方法归纳制表并进行综合分析。结果2004年门急诊每张处方药品数平均为3.24种;注射给药处方数占西药总处方数的33.43%,高于北京三甲医院水平(约10%);抗菌药物使用率为43.54%,高于上海、武汉等城市水平(约35%);一线抗菌药物使用率为70.56%,二线抗菌药物使用率为29.37%,抗菌药物分级使用状况总体符合规定;抗菌药物联合用药比率为26.22%,单一用药比率达73.78%,属基本合理范围。结论我院抗菌药用药以一线抗菌药物为主,合理用药是主流,但也存在一定问题,宜制定相应措施,提高用药合理性和安全性。     

2010调脂治疗领域进展

2010年在调脂治疗领域针对他汀治疗心血管病的防治又进行了许多探索。本文通过综述他汀类药物的国际大规模临床试验结果,重新评价了他汀类药物在冠心病一级预防和冠心病二级预防中的地位,阐明了强化他汀治疗的意义;对他汀的心肾保护作用和安全性新证据进行了说明。     

Errors in time in pharmacokinetic studies

Pharmacokinetic models with errors in the time variable were developed and explored by simulation in NONMEM. The precision of estimated parameters decreased with increasing error magnitude. The usual asymptotic standard error estimates were biased low by 10-50% Accuracy and precision were not greatly diminished by ignoring errors in time when fitting models.     

Pradigastat disposition in humans: in vivo and in vitro investigations

1.?Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients.

2.?Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans.

3.?In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma.

4.?In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed.

5.?Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.     

Changes in immunoreactive somatostatin in brain following lidocaine-induced kindling in rat

The kindling phenomenon has become a useful model for studying epileptogenesis. The present authors have previously reported increased levels of immunoreactive somatostatin (IR-SRIF) in various regions of the brain of electrically-amygdaloid kindled (EAK) rats. In this study, an examination was made of immunoreactive somatostatin in pharmacologically-kindled (PK) rats. Sixteen male Sprague-Dawley rats were injected intraperitoneally (i.p.) with a subthreshold dose of lidocaine (60 mg/kg), once daily. Once the kindling phenomenon was established, kindled rats (7), non-kindled rats (9) and controls (6) were sacrificed by microwave irradiation. Another group of 5 rats was injected with a single suprathreshold dose of lidocaine (110 mg/kg) and killed 10 min after the resultant seizure. Various brain areas were removed and assayed for immunoreactive somatostatin in kindled rats. Immunoreactive somatostatin was significantly greater than in controls in the amygdala (56%; P less than 0.02), entorhinal + piriform cortex (50%; P less than 0.05) and hypothalamus (29%; P less than 0.02). In non-kindled rats, immunoreactive somatostatin increased only in the amygdala (58%; P less than 0.02). No difference was found in the immunoreactive somatostatin content of rats injected with an suprathreshold dose of lidocaine compared to controls. The alteration of immunoreactive somatostatin, in both lidocaine-kindled and electrically-amygdaloid kindled rats suggests a possible role of this neuropeptide in kindling.     

纳米材料在止血方面的研究进展

纳米材料因其独特的微观结构优势,已被广泛应用于材料制备、微电子与计算机技术、医学与健康、环境与能源等领域.与传统止血材料相比,纳米材料在一定程度上能提高传统止血药物的生物利用度和稳定性,增强药物的缓控与靶向释放,为现代化新型止血材料的发展奠定了良好的基础.对脂质体、纳米粒、自组装纳米肽、纳米纤维等多种纳米止血材料的前沿...     

Calcium transport in rat small intestine in vitro and in vivo

Summary Intestinal calcium (Ca) transport was studied in the rat jejunum by the in vitro perfusion technique of Fisher and Parsons and in the tied loop in vivo. Mucosal uptake and absorption of Ca was examined under the following conditions: rising intraluminal Ca-concentrations (0.5–128 meq/l); inhibition of energy dependent metabolism (2,4-dinitrophenol, N₂, low temperature); net water flow, out of or into the intestinal lumen; addition of strontium (Sr); pretreatment with low Ca-diet and with 6-methyl-prednisolone.The concentration-dependent Ca absorption curve rose steeply at low Ca-concentrations but changed to a slowly rising straight line above 16 meq/l Ca⁺⁺. In contrast, Ca uptake into the intestinal wall was directly related to Ca concentration, was linear from the beginning and paralleled the straight part of the absorption curve.Ca absorption was decreased by inhibition of energy dependent metabolism, addition of Sr and pretreatment with prednisolone. Pretreatment with low Ca diet increased Ca absorption and direction of net water flow (solvent drag) had no effect on it.Mucosal uptake of Ca was similar to Ca absorption except that metabolic inhibition increased Ca uptake but decreased Ca absorption.These results are compatible with the concept of a passive mucosal uptake and of an active absorption of Ca at low intraluminal Ca concentrations with additional passive component at high Ca concentrations.Supported by the Deutsche Forschungsgemeinschaft.     

药物非临床毒代动力学研究进展

药物非临床毒代动力学是药代动力学在全身暴露评价中的延伸,或为非临床毒性研究的一部分,或为某一专设支持性研究,可为药物临床试验或应用提供安全性依据。目前毒代动力学已由最初的解释毒性试验结果逐渐扩展至毒性机制研究,成为在药物非临床和临床研究间的桥梁,同时其研究范围也扩展至药物代谢产物等的安全性评价中。本文就毒代动力学的实施、复合因素以及国内外研究进展进行综述,并展望其发展新方向。