The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients.

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition.

The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy.

Regression of Multiple Intracranial Meningiomas With Cessation of Progesterone Agonist Therapy: A Case Report.

In this case report, we discuss a patient who experienced spontaneous regression of multiple intracranial meningiomas that were treated conservatively for 5 years after cessation of megestrol acetate, an exogenous progestin. In addition, we discuss the previous literature describing the relationship between exogenous progesterone medications and meningioma growth. This case, along with others reported, implies that cessation of progesterone therapy, when feasible, may alter the natural history of meningioma growth and thus impact treatment decisions.

Minimally Invasive Image-Guided Transgluteal Approach for Resection of a Sciatic Nerve Tumor: A Technical Note.

There are a variety of surgical approaches to lesions around the sciatic notch. Historically, peripheral nerve surgeons prefer an infragluteal approach involving a large incision with reflection of the gluteus maximus to better visualize the operative field. This approach was imperative when lesion localization was imprecise. Comparatively, orthopedic surgeons prefer a muscle-splitting, transgluteal approach to operate on the static structures of the posterior hip. The transgluteal approach is significantly less morbid, allowing for same-day discharge and less extensive rehab given preservation of the gluteal muscle. In this article we describe the use of dynamic ultrasound imaging to localize and aid in the resection of three unique tumors around the sciatic notch using a minimally invasive, tissue-sparing, transgluteal technique. We offer a comprehensive description of the benefits, anatomic considerations, and nuances of using a transgluteal approach for the resection of lesions at the sciatic notch.

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells.

We have used three established human glioblastoma (GBM) cell lines-U87MG, A172, and T98G-as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.

Changes in Subjective Motivation and Effort During Sleep Restriction Moderate Interindividual Differences in Attentional Performance in Healthy Young Men.

PURPOSE: The effects of sleep restriction on subjective alertness, motivation, and effort vary among individuals and may explain interindividual differences in attention during sleep restriction. We investigated whether individuals with a greater decrease in subjective alertness or motivation, or a greater increase in subjective effort (versus other participants), demonstrated poorer attention when sleep restricted. PARTICIPANTS AND METHODS: Fifteen healthy men (M±SD, 22.3±2.8 years) completed a study with three nights of 10-hour time in bed (baseline), five nights of 5-hour time in bed (sleep restriction), and two nights of 10-hour time in bed (recovery). Participants completed a 10-minute psychomotor vigilance task (PVT) of sustained attention and rated alertness, motivation, and effort every two hours during wake (range: 3-9 administrations on a given day). Analyses examined performance across the study (first two days excluded) moderated by per-participant change in subjective alertness, motivation, or effort from baseline to sleep restriction. For significant interactions, we investigated the effect of study day2 (day*day) on the outcome at low (mean-1 SD) and high (mean+1 SD) levels of the moderator (N = 15, all analyses). RESULTS: False starts increased across sleep restriction in participants who reported lower (mean-1 SD) but not preserved (mean+1 SD) motivation during sleep restriction. Lapses increased across sleep restriction regardless of change in subjective motivation, with a more pronounced increase in participants who reported lower versus preserved motivation. Lapses increased across sleep restriction in participants who reported higher (mean+1 SD) but not preserved (mean-1 SD) effort during sleep restriction. Change in subjective alertness did not moderate the effects of sleep restriction on attention. CONCLUSION: Vigilance declines during sleep restriction regardless of change in subjective alertness or motivation, but individuals with reduced motivation exhibit poorer inhibition. Individuals with preserved subjective alertness still perform poorly during sleep restriction, while those reporting additional effort demonstrate impaired vigilance.

Therapy for glioblastoma: is it working?

Glioblastoma (GBM) remains one of the most intransigent of cancers, with a median overall survival of only 15 months after diagnosis. Drug treatments have largely proven ineffective; it is thought that this is related to the heterogeneous nature and plasticity of GBM-initiating stem cell lineages. Although many combination drug therapies are being positioned to address tumour heterogeneity, the most promising therapeutic approaches for GBM to date appear to be those targeting GBM by vaccination or antibody- and cell-based immunotherapy. We review the most recent clinical trials for GBM and discuss the role of adaptive clinical trials in developing personalised treatment strategies to address intra- and inter-tumoral heterogeneity.

Drug discovery in the era of Facebook--new tools for scientific networking.

Social networking is beginning to make an impact on the drug discovery process. While bioinformatics and chemoinformatics underpin research at a scientific level, rapid communication between individual researchers across continents now allows the global exchange of ideas, tools and technologies. Networking at this level of speed and reach is quite a recent phenomenon. It facilitates the development of common interests, accelerates technology transfer and increases cooperative and competitive behaviour. In this review, we critically evaluate different web based networking approaches as effective resources for the drug discovery scientist. We also ask whether social networking sites will evolve into serious and credible resources for the drug discovery community.

Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.

Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( Ki = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC50 = 5.5 and 6.7 µM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.

Probes for chemical genomics by design.

Chemical genomics represents a convergence of biology and chemistry in the era of global approaches to target identification and intervention. The success of genomics has led to a bottleneck in target validation that could be overcome by using small diverse organic compounds to interfere with biological processes. Because of the limitations of existing compound collections, this diversity can only fully be exploited using in silico design techniques to guide the selection of molecules with optimal binding properties. Structure-based design is used to create structures de novo that can be synthesized for use as chemical probes and drug leads.