Drug self-assembly: A phenomenon at the nanometer scale with major impact in the structure–biological properties relationship and the treatment of disease

Under water-rich conditions, small amphiphilic and hydrophobic drug molecules self-assemble into supramolecular nanostructures. Thus, substantial modifications in their interaction with cellular structures and the ability to reach intracellular targets could happen. Additionally, drug aggregates could be more toxic than the non-aggregated counterparts, or vice versa. Moreover, since self-aggregation reduces the number of effective “monomeric” molecules that interact with the target, the drug potency could be underestimated. In other cases, the activity could be ascribed to the non-aggregated molecule while it stems from its aggregates. Thus, drug self-assembly could mislead from drug throughput screening assays to advanced preclinical and clinical trials. Finally, aggregates could serve as crystallization nuclei. The impact that this phenomenon has on the biological performance of active compounds, the inconsistent and often controversial nature of the published data and the need for recommendations/guidelines as preamble of more harmonized research protocols to characterize drug self-aggregation were main motivations for this review. First, the key molecular and environmental parameters governing drug self-aggregation, the main drug families for which this phenomenon and the methods used for its characterization are described. Then, promising nanotechnology platforms investigated to prevent/control it towards a more efficient drug development process are briefly discussed.     

How does cognitive therapy prevent relapse in residual depression? Evidence from a controlled trial.

This study examined the cognitive mediation of relapse prevention by cognitive therapy (CT) in a trial of 158 patients with residual depression. Scores based on agreement with item content of 5 questionnaires of depression-related cognition provided no evidence for cognitive mediation. A measure of the form of response to those questionnaires, the number of times patients used extreme response categories ("totally agree" and "totally disagree"), showed significant and substantial prediction of relapse, differential response to CT, and conformity to mediational criteria. CT reduced relapse through reductions in absolutist, dichotomous thinking style. CT may prevent relapse by training patients to change the way that they process depression-related material rather than by changing belief in depressive thought content. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrochemical properties of self-assembled monolayer based on mono-(6-deoxy-6-mercapto)-β-cyclodextrin toward controlled molecular recognition

The present work describes the construction of nanoporous assemblies based on single self-assembled monolayer (SAM) of mono-(6-deoxy-6-mercapto)-β-cyclodextrin (βCDSH) and two-component monolayers of βCDSH and 11-mercaptoundecanoic acid. An investigation of its supramolecular properties toward the tricyclic antidepressants drugs chlorprothixene and imipramine is also presented. The adsorption process was investigated by using surface plasmon resonance and the selectivity of the SAM was verified by using electroactive species permeable and not permeable into the cyclodextrin SAM, such as ferrocenemonocarboxylic acid, hexacyanoferrate, methylene blue and hexamineruthenium (II). The redox probe was chosen based on its capability to permeate the grafted cyclodextrin molecules and its electrochemical characteristics. It was applied to imipramine and chlorprothixene competitive assay by the mono-(6-deoxy-6-mercapto)-β-cyclodextrin self-assembled cavity. Finally, the pK_a of the surface and its effects on thee host-guest interaction properties were also investigated.     

全二维气相色谱/飞行时间质谱对饱和烃分析的图谱识别及特征

采用全二维气相色谱/飞行时间质谱分析方法对典型石油样品中饱和烃组分进行了定性分析,依据极性大小和环数多少的分布特征,解析了点阵图谱中的烷烃、单环烷烃、双环烷烃、单金刚烷和双金刚烷系列、三环萜烷类、甾烷类和藿烷类等生物标志化合物的识别;讨论了典型生物标记化合物单金刚烷、三环萜烷和藿烷类的全二维点阵谱图特征;检测到过去GC/MS分析中常被忽视的C₃₁~C₃₅三环萜烷,为石油地质实验和研究提供了参考依据。全二维气相色谱/飞行时间质谱相比于GC/MS灵敏度更高、峰容量更大,适合复杂混合物体系的分析,对石油样品的分析有很好的应用前景。     

Prediction of Long-Term Treatment Response to Selective Serotonin Reuptake Inhibitors (SSRIs) Using Scalp and Source Loudness Dependence of Auditory Evoked Potentials (LDAEP) Analysis in Patients with Major Depressive Disorder

Background: Animal and clinical studies have demonstrated that the loudness dependence of auditory evoked potentials (LDAEP) is inversely related to central serotonergic activity, with a high LDAEP reflecting weak serotonergic neurotransmission and vice versa, though the findings in humans have been less consistent. In addition, a high pretreatment LDAEP appears to predict a favorable response to antidepressant treatments that augment the actions of serotonin. The aim of this study was to test whether the baseline LDAEP is correlated with response to long-term maintenance treatment in patients with major depressive disorder (MDD). Methods: Scalp N1, P2 and N1/P2 LDAEP and standardized low resolution brain electromagnetic tomography-localized N1, P2, and N1/P2 LDAEP were evaluated in 41 MDD patients before and after they received antidepressant treatment (escitalopram (n = 32, 10.0 ± 4.0 mg/day), sertraline (n = 7, 78.6 ± 26.7 mg/day), and paroxetine controlled-release formulation (n = 2, 18.8 ± 8.8 mg/day)) for more than 12 weeks. A treatment response was defined as a reduction in the Beck Depression Inventory (BDI) score of >50% between baseline and follow-up. Results: The responders had higher baseline scalp P2 and N1/P2 LDAEP than nonresponders (p = 0.017; p = 0.036). In addition, changes in total BDI score between baseline and follow-up were larger in subjects with a high baseline N1/P2 LDAEP than those with a low baseline N1/P2 LDAEP (p = 0.009). There were significantly more responders in the high-LDAEP group than in the low-LDAEP group (p = 0.041). Conclusions: The findings of this study reveal that a high baseline LDAEP is associated with a clinical response to long-term antidepressant treatment.     

Molecular Consequences of Depression Treatment: A Potential In Vitro Mechanism for Antidepressants-Induced Reprotoxic Side Effects

The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants’ and neuroleptic drugs’ toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.     

海安凹陷TX8井二叠系油源研究

海安凹陷TX8井上二叠统龙潭组(P2l)碳质泥岩的有机质丰度最高,距油气显示段最近,但生物标志化合物对比研究结果表明,TX8井二叠系中的油气与龙潭组泥岩具有更好的亲缘关系,甾烷特征分析认为二叠系中的油气有可能有三叠系青龙组(T1q)的贡献。二叠系油砂饱和烃色谱特征不仅表明二叠系成藏后有过油气破坏过程,而且可以二叠系烃源岩有晚期生烃及再次充注过程,是二叠系烃源岩有效性的直接证据,这对下扬子区海相中、古生界的油气勘探具有重要意义。     

Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of acute and chronic antidepressant treatments.

Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy

Natural products and their derivatives represent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds (BA-TPQ, TBA-TPQ, and TCBA-TPQ) has been accomplished and the mechanisms of action (MOA) and structure-activity relationships (SAR) have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids (unrelated to inhibition of Topoisomerase II) warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of in vitro and in vivo anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

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