The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

Antimalarial Properties of Imipramine and Amitriptyline12

Dietary riboflavin deficiency is known to diminish malarial parasitemia. In this study, we determined whether imipramine and amitriptyline, drugs which inhibit riboflavin metabolism, have antimalarial efficacy. In addition, we evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of Plasmodium falciparum (FCR3) in the absence and presence of these drugs (10 to 75 μM) was measured by determining (³H)hypoxanthine uptake by intraerythrocytic parasites for 48 h in RPMI 1640 medium. The uptake of (³H)hypoxanthine was significantly reduced in a dose-dependent manner by both imipramine and amitriptyline. The IC₅₀ values of imipramine and amitriptyline at 48 h were 56 and 45 μM, respectively. Both drugs enhanced hemolysis induced by FP (10 or 20 μM). No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, imipramine and amitriptyline, possess substantial antimalarial properties.     

抗炎性细胞因子与抑郁症

细胞因子假说是关于抑郁症发病机理的重要假说,为探讨抑郁症的发病机理和临床治疗方法提供了新方向.细胞因子分为前炎性细胞因子和抗炎性细胞因子.前炎性细胞因子与抑郁症的发病密切相关,而抗炎性细胞因子可能具有抗抑郁的作用.本文着重综述抗炎性细胞因子与抑郁症的关系.抗炎性细胞因子如白介素10、白介素1受体拮抗剂、白介素4、白介素13、转化生长因子β和脂联素等,在抑郁症中表达下降;补充外源抗炎性细胞因子则具有一定的抗抑郁作用.抗炎性细胞因子可通过拮抗前炎性细胞因子的作用,并与MAPK信号通路、神经递质和糖皮质激素相互作用而参与到抑郁症中.抗抑郁药能使抗炎性细胞因子的表达上升,这可能是药物起效的机制之一.抗炎策略在抑郁症的治疗中有重要应用前景.     

Morningness–eveningness and treatment response in major depressive disorder

In a large, prospective, 8-week open study of 721 outpatients receiving agomelatine treatment for a current major depressive episode (MDE), morningness–eveningness (Composite Scale of Morningness) was assessed before and after treatment to investigate possible changes in morningness–eveningness after treatment and evaluate whether morningness–eveningness at baseline predicted treatment response. A change towards morningness was observed after treatment. This change was greater in responders than non-responders. Moreover, being a morning type at baseline was an independent predictor of response to treatment. Once thought to be a trait variable, morningness–eveningness is a potential treatment target that should be systematically assessed in MDE patients.     

(−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

The interaction of (−)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (−)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca²⁺ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC₅₀ = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the [³H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [³H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6′ and 13′ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9′ is the minimum structural component for (−)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the α1/ε transmembrane interface from the adult muscle AChR. In conclusion, (−)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.     

Oxygenation Reactions of Various Tricyclic Fused Aromatic Compounds Using Escherichia coli and Streptomyces lividans Transformants Carrying Several Arene Dioxygenase Genes

Bioconversion (biotransformation) experiments on arenes (aromatic compounds), including various tricyclic fused aromatic compounds such as fluorene, dibenzofuran, dibenzothiophene, carbazole, acridene, and phenanthridine, were done using the cells of Escherichia coli transformants expressing several arene dioxygenase genes. E. coli carrying the phenanthrene dioxygenase (phdABCD) genes derived from the marine bacterium Nocardioides sp. strain KP7 converted all of these tricyclic aromatic compounds, while E. coli carrying the Pseudomonas putida F1 toluene dioxygenase (todC1C2BA) genes or the P. pseudoalcaligenes KF707 biphenyl dioxygenase (bphA1A2A3A4) genes was not able to convert these substrates. Surprisingly, E. coli carrying hybrid dioxygenase (todC1::bphA2A3A4) genes with a subunit substitution between the toluene and biphenyl dioxygenases was able to convert fluorene, dibenzofuran, and dibenzothiophene. The cells of a Streptomyces lividans transformant carrying the phenanthrene dioxygenase genes were also evaluated for bioconversion of various tricyclic fused aromatic compounds. The ability of this actinomycete in their conversion was similar to that of E. coli carrying the corresponding genes. Products converted from the aromatic compounds with these recombinant bacterial cells were purified by column chromatography on silica gel, and identified by their MS and ¹H and ¹³C NMR analyses. Several products, e.g., 4-hydroxyfluorene converted from fluorene, and cis-1,2-dihydroxy-1,2-dihydrophenanthridine, cis-9,10-dihydroxy-9,10-di-hydrophenanthridine, and 10-hydroxyphenanthridine, which were converted from phenanthridine, were novel compounds.     

Pyrazolo[1,5-a]quinazoline scaffold as 5-deaza analogue of pyrazolo[5,1-c][1,2,4]benzotriazine system: synthesis of new derivatives,biological activity on GABAA receptor subtype and molecular dynamic study

To investigate the binding affinity of GABA_A receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (K_i?=?834.7?nM).     

抗抑郁新药的研究与开发

随着社会经济高速发展,人们面临的社会竞争和心理压力加大,导致抑郁症逐渐成为现代社会的常见及高发疾病,所以临床上对 抗抑郁新药的需求日益增长。概述近年来欧美上市的抗抑郁新药和目前临床III期在研的部分抗抑郁小分子药物的合成工艺及临床研究进 展。     

Evolution of the prevalence and incidence of consumption of antidepressants in a Spanish region (2002-2007)

Background The treatment of depressive disorders involves the administration of drugs of proven efficacy at the correct doses and for specific periods of time, in conjunction with psychotherapeutic support.Aim To assess the evolution of the consumption of antidepressants in the Health Region of Lleida (Spain).Method A retrospective cohort study of the antidepressant medication prescribed via the Spanish National Health System in the Health Region of Lleida between 2002 and 2007. The variables recorded in the study were age, sex, number of patients in antidepressant treatment in the Health Region of Lleida, length of treatment and type of drug. The prevalence of the population of the health region who were receiving antidepressant drugs and the incidence for each particular year was calculated.Results The mean prevalence of patients in treatment with antidepressant drugs was 8.5% (5% in men and 12.1% in women). The highest prevalence was observed in the higher age groups. By therapeutic groups, selective serotonin reuptake inhibitors (SSRIs) were the most frequently prescribed, five times more than the next group, tricyclics/heterocyclics. The follow-up assessment of the medication prescribed showed that one out of every four patients did not continue treatment after the first month, and 38.4% did not continue after three months. Very few were treated for more than six months.Conclusion This study stresses the high rate of antidepressant treatment in the older women's group. One of every four treatments initiated did not last more than one month. Over the six-year period, 16 506 patients dropped out of treatment.