虫草素联合阿霉素干预乳腺癌细胞增殖及转移作用

研究了虫草素联合阿霉素在体外抑制三阴性乳腺癌MDA-MB-231细胞增殖及转移作用,评估了联合用药的作用效应,为虫草素在临床应用上增强抗乳腺癌作用提供了科学数据。研究结果表明,联合用药比单独用药作用效果更明显,根据Chou-Talalay法显示出在80μmol/L虫草素联合1μmol/L阿霉素的条件下,联合用药协同作用最优,CI值为0.665,细胞抑制率达到60.31%±1.06%;与对照组相比,平板克隆形成实验证明联合用药显著抑制细胞增殖,克隆形成率仅为7.03%±1.19%;显微观察细胞形态变化表明联合用药明显影响细胞生长;Hochest 33258染色、DNA Ladder发现联合用药对细胞凋亡诱导作用更显著,细胞凋亡率可达78.52%±11.18%;细胞划痕愈合实验检测联合用药显著抑制细胞迁移,细胞迁移率仅为18.82%±2.43%。本研究确证虫草素可协助阿霉素治疗乳腺癌的增敏作用。     

The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta‐analysis of direct comparisons

Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: −0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant.     

Relationships between the amount of saliva and medications in elderly individuals

Gerodontology 2010; doi: 10.1111/j.1741‐2358.2009.00358.x
Relationships between the amount of saliva and medications in elderly individuals Objective: To investigate medications that are related to volume of saliva in the elderly. Background data: In the elderly, many cases of mouth dryness may represent side effects of medication. Materials and methods: The volume of unstimulated saliva was measured for 30 s (cotton roll test), and with stimulation for 3 min (gum test) in 368 subjects 79–80 years old (177 men, 191 women). Medications were investigated using subject’s medication notebooks. Results: Mean volumes of unstimulated and stimulated saliva were 0.14 ± 0.13 and 4.30 ± 2.54 ml respectively. Significant differences were seen between gender and mean volume of saliva. The volume of unstimulated saliva was 0.16 ± 0.15 ml for men and 0.11 ± 0.10 ml for women. The volume of stimulated saliva was 4.99 ± 2.67 ml for men and 3.67 ± 2.25 ml for women. The percentage of subjects taking medication was 64.7% (238/368). Mean number of medications was 2.08 ± 2.26, with no significant difference with gender (2.01 ± 2.37 for men, 2.16 ± 2.16 for women). In a stepwise multiple regression analysis with volume of saliva as the objective variable and number of drugs by category as explanatory variables, significant explanatory variables in addition to gender and number of medications were blood‐coagulating agents, Ca antagonists and peptic ulcer drugs for volume of unstimulated saliva, and diabetes medications and peptic ulcer drugs for volume of stimulated saliva. Conclusion: These findings suggest that differences exist between gender in volume of saliva for elderly individuals, and that the volume of saliva is affected by the number and type of medications.     

金丝桃属植物化学成分研究进展

到目前为止,已从金丝桃属植物中分离得到300多种化合物,主要特征化学成分为萘骈二蒽酮、间苯三酚、酮和黄酮等类型化合物;也含有香豆素、苯丙素、萜类和挥发油等其它类型的化学成分。本文按照化合物结构类型进行了归纳,综述了该类植物的化学成分研究进展,同时简述了这些成分的相关药理作用。     

The Effect of Animal-Assisted Therapy on Pain Medication Use After Joint Replacement

Animal-assisted therapy (AAT) has been used in a variety of healthcare settings and studies to evaluate the potential patient benefits are warranted. This retrospective study measured the impact of AAT on the use of oral pain medications by adults after total joint replacement surgery. One group of patients received care in a hospital with an AAT program and the comparison group was in a hospital without an AAT program. Adult patient cohorts were matched on: age, gender, ethnicity, length of stay, and Diagnosis Related Group code for type of total joint replacement. Pain medication doses, converted into morphine equivalent daily doses (MEDD), were compared. Pain medication use was significantly less in the AAT group: 15.32 mg vs. 21.16 (t₍₁₁₉₎ = 2.72, p = 0.007). The effectiveness of AAT in decreasing the need for pain medication and its effect on patient well-being in the post-operative period and in other settings deserves further study.     

High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy

Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine—a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications.     

A gene-specific cerebral types 1, 2, and 3 RyR protein knockdown induces an antidepressant-like effect in mice

Elevation of baseline intracellular calcium levels was observed in platelets or lymphoblasts of patients with bipolar affective disorders suggesting an altered intracellular Ca(2+) homeostasis in the pathophysiology of mood disorders. The role of supraspinal endoplasmic ryanodine receptors (RyRs), which allow mobilization of intracellular Ca(2+) stores, in the modulation of depressive states was, then, investigated. Ryanodine and FK506 reduced the immobility time in the mouse forced swimming test showing an antidepressant-like profile comparable with that produced by amitriptyline and clomipramine. We generated types 1, 2, and 3 RyR knockdown mice by using selective antisense oligonucleotides (aODN) to investigate the role of each RyR isoform. A gene-specific cerebral RyR protein level reduction in knockdown animals was demonstrated by immunoblotting, immunoprecipitation, and immunohistochemical experiments. Repeated intracerebroventricular administration of aODNs complementary to the sequence of the types 1, 2, or 3 RyR produced an antidepressant-like response in the forced swimming test. The aODN-induced reduction of immobility time was temporary and reversible and did not impair motor coordination, spontaneous mobility, and exploratory activity. These findings identify cerebral RyRs as critical targets underlying depressive states and should facilitate the comprehension of the pathophysiology of mood disorders and help developing of new therapeutical strategies.     

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial

Background: Medication adherence is critical for success of clinical trials.

Objective: To assess oral riboflavin is an adherence marker.

Methods: Riboflavin was incorporated into active treatment and placebo pills for a clinical trial lasting for 2 years.

Results: The accuracy (area under the receiver operating curve) of urinary riboflavin was 0.91 as a binary classifier of adherence, and was similar or better than for two active study ingredients daidzein (0.92) and genistein (0.87) (all p?<?0.0001). Decreased adherence over time was similar in the two study groups.

Conclusion: Riboflavin is an accurate and useful biomarker for study pill ingestion.     

Antidepressant-like deliverables from the sea: evidence on the efficacy of three different brown seaweeds via involvement of monoaminergic system

Brown seaweeds exhibit several health benefits in treating and managing wide array of ailments. In this study, the antidepressant-like effect of methaolic extracts from Sargassum swartzii (SS), Stoechospermum marginatum (SM), and Nizamuddinia zanardinii (NZ) was examined in forced swimming test (FST), in rats. Oral administration of SS, SM, and NZ extract (30–60 mg/kg) exhibited antidepressant-like activity in FST by reducing immobility time as compared to control group, without inducing significant change in ambulatory behavior in open field test. In order to evaluate the involvement of monoaminergic system, rats were pretreated with the inhibitor of brain serotonin stores p-chlorophenylalanin (PCPA), dopamine (SCH23390 and sulpiride), and adrenoceptor (prazosin and propranolol) antagonists. Rats receiving treatment for 28 days were decapitated and brains were analyzed for monoamine levels. It may be concluded that the extracts of SS, SM, and NZ produces antidepressant-like activity via modulation of brain monoaminergic system in a rat model.     

Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta‐analysis

It is common experience for practising psychiatrists that individuals with schizophrenia vary markedly in their symptomatic response to antipsychotic medication. What is not clear, however, is whether this variation reflects variability of medication‐specific effects (also called “treatment effect heterogeneity”), as opposed to variability of non‐specific effects such as natural symptom fluctuation or placebo response. Previous meta‐analyses found no evidence of treatment effect heterogeneity, suggesting that a “one size fits all” approach may be appropriate and that efforts at developing personalized treatment strategies for schizophrenia are unlikely to succeed. Recent advances indicate, however, that earlier approaches may have been unable to accurately quantify treatment effect heterogeneity due to their neglect of a key parameter: the correlation between placebo response and medication‐specific effects. In the present paper, we address this shortcoming by using individual patient data and study‐level data to estimate that correlation and quantitatively characterize antipsychotic treatment effect heterogeneity in schizophrenia. Individual patient data (on 384 individuals who were administered antipsychotic treatment and 88 who received placebo) were obtained from the Yale University Open Data Access (YODA) database. Study‐level data were obtained from a meta‐analysis of 66 clinical trials including 17,202 patients. Both individual patient and study‐level analyses yielded a negative correlation between placebo response and treatment effect for the total score on the Positive and Negative Syndrome Scale (PANSS) (ρ=–0.32, p=0.002 and ρ=–0.39, p<0.001, respectively). Using the most conservative of these estimates, a meta‐analysis of treatment effect heterogeneity provided evidence of a marked variability in antipsychotic‐specific effects between individuals with schizophrenia, with the top quartile of patients experiencing beneficial treatment effects of 17.7 points or more on the PANSS total score, while the bottom quartile presented a detrimental effect of treatment relative to placebo. This evidence of clinically meaningful treatment effect heterogeneity suggests that efforts to personalize antipsychotic treatment of schizophrenia have potential for success.