基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

Psilocybin-assisted psychotherapy for treatment-resistant depression: Which psychotherapy?

This perspective paper explores the choice of psychotherapy for psilocybin-assisted psychotherapy for treatment-resistant depression. There is evidence to support the use of some psychotherapies in treating ‘treatment-resistant’ depression, and emerging evidence for the efficacy of psilocybin. The next step which is the focus of this paper is to identify psychotherapies that are both effective and congruent with the psilocybin experience. The evidence for the efficacy of the psychotherapies is drawn from a Cochrane review and the analysis of their congruence with the psilocybin experience is drawn from a qualitative meta-synthesis of the experience of psilocybin. The paper will examine whether three one-to-one psychotherapies identified as effective in the treatment of treatment-resistant depression are compatible with the psilocybin experience. Each psychotherapy will be examined in relation to its congruence with the qualitative evidence that suggests the choice of psychotherapy needs to give priority to the subjective experience, facilitate emotional processing, support connectedness with others, acceptance of the self as emotional and support change based on the person's insights into their relationships with others and the world in which they live. We conclude that interpersonal psychotherapy and intensive short-term dynamic psychotherapy align with that experience, although others are currently being trialled.     

All who vomit are not bulimic

The case is made, supported by a clinical vignette, that psychogenic vomiting stands distinct from either anorexia or bulimia nervosa. It is best understood in terms of the symbolic communication model of hysterical conversion disorder. However, patients with psychogenic vomiting represents a heterogeneous population. The case report is followed by discussion of a number of issues that make clear the relationship of psychogenic vomiting to other eating disorders or to vomiting of organic origin.     

山奈酚通过抑制NLRP3炎症小体介导的脂肪组织炎症改善db/db小鼠胰岛素抵抗发生

目的：探讨山奈酚能否通过调控肥胖小鼠脂肪组织炎症改善胰岛素抵抗发生并研究作用机制。方法：db/m小鼠作为对照组,db/db雄性小鼠随机分为模型组、二甲双胍组(0.15 g·kg^-1·d^-1)和山奈酚组(50 mg·kg^-1·d^-1)。连续灌胃给药6周,每周记录小鼠体重,6周后进行葡萄糖耐量试验、胰岛素耐量试验、皮下和附睾白色脂肪组织质量测定;HE染色观察脂肪组织形态学变化,免疫组化法观察巨噬细胞向脂肪组织的浸润程度及巨噬细胞标志物F4/80的表达,实时荧光定量PCR检测TNF-α和IL-18以及Arg-1和IL-10的mRNA表达,蛋白质免疫印迹试验检测NLRP3、pro-caspase1、cle-caspase1和IL-1β表达。结果：与模型组相比,山奈酚能够显著抑制db/db小鼠脂肪质量增加,抑制脂肪细胞肥大。山奈酚组小鼠脂肪组织巨噬细胞浸润减少,TNF-α和IL-18 mRNA表达减少,Arg-1和IL-10 mRNA表达增加;山奈酚治疗能够抑制小鼠附睾脂肪组织NLRP3、caspase1以及...     

The natural history of disordered eating behavior and attitudes in adult women

This paper reports a survey of natural history of eating behavior and attitudes to weight and shape in British women attending a family planning clinic. Sixty-two women completed a battery of standardized tests, followed by a second questionnaire 18 months later. This rescreening represents the first report of an adult sample not self-defined as ill. The Eating Attitudes Test (EAT)-26 total score showed stability over time (r =.68) but a/so showed a nonsignificant increase in the number of “cases.” The self-reported weight and desired weight increased slightly but statistically over the whole sample in the follow-up period. Analysis of group variances showed evidence of a heterogeneity of variance which was more marked than evidence of group mean effects between responders and nonresponders. The self-reported heights were stable but self-report of historical weight limits showed impossible inconsistencies such that any data related to these must be interpreted with caution. We recommend that future follow-up studies report analysis of loss to follow-up both by group means and variances, that inconsistent responses be counted and explored, and that both group mean changes over time and correlations be reported since they convey different information.     

A comparative study of menarchal age and weight of bulimic patients and their sisters

Sixty-six consecutive bulimia nervosa patients and their sisters were compared for menar-chal age and weight. Bulimic women were significantly heavier, but not younger, at puberty then their sisters being brought up in the same home environment. The belief that the bulimics were relatively overweight at menarche was held not only by the future patients but also by their sisters and mothers. At the very least the data represent a common family myth prior to the development of the illness. Interviews suggested that the issue of shape and weight became mutually overvalued and led to the initial aberrant eating behavior. Heavier menarchal weight appears to be one of the factors which prime a susceptible girl to future bulimia.     

Skeletal maturation,growth, and hormonal and nutritional status in anorexia nervosa: An initial report

Bone growth is abnormal in anorexia nervosa, possibly connected with the immature hormonal status associated with low body weight. Measuring the serum levels of the bone isoenzyme of alkaline phosphatase is used as a sensitive indicator of renewed bone growth in a group of refceding anorectics. Initial results show a marked and maintained increase in levels of the enzyme, possibly due to a rise in body weight above a postulated critical level associated with hormonal changes.     

Infrequent delivery of a long-acting PTH-Fc fusion protein has potent anabolic effects on cortical and cancellous bone.

Skeletal anabolism with PTH is achieved through daily injections that result in brief exposure to the peptide. We hypothesized that similar anabolic effects could be achieved with less frequent but more sustained exposures to PTH. A PTH-Fc fusion protein with a longer half-life than PTH(1-34) increased cortical and cancellous BMD and bone strength with once- or twice-weekly injections. INTRODUCTION: The anabolic effects of PTH are currently achieved with, and thought to require, daily injections that result in brief exposure to the peptide. We hypothesized that less frequent but more sustained exposures to PTH could also be anabolic for bone, provided that serum levels of PTH were not constant. MATERIALS AND METHODS: PTH(1-34) was fused to the Fc fragment of human IgG1 to increase the half-life of PTH. Skeletal anabolism was examined in mice and rats treated once or twice per week with this PTH-Fc fusion protein. RESULTS: PTH-Fc and PTH(1-34) had similar effects on PTH/PTHrP receptor activation, internalization, and signaling in vitro. However, PTH-Fc had a 33-fold longer mean residence time in the circulation of rats compared with that of PTH(1-34). Subcutaneous injection of PTH-Fc once or twice per week resulted in significant increases in bone volume, density, and strength in osteopenic ovariectomized mice and rats. These anabolic effects occurred in association with hypercalcemia and were significantly greater than those achievable with high concentrations of daily PTH(1-34). PTH-Fc also significantly improved cortical bone volume and density under conditions where daily PTH(1-34) did not. Antiresorptive co-therapy with estrogen further enhanced the ability of PTH-Fc to increase bone mass and strength in ovariectomized rats. CONCLUSIONS: These results challenge the notion that brief daily exposure to PTH is essential for its anabolic effects on cortical and cancellous bone. PTH-derived molecules with a sustained circulating half-life may represent a powerful and previously undefined anabolic regimen for cortical and cancellous bone.