Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations.

Cancer Lett. 2019 02 01;442:262-270

Authors: Loh AHP, Stewart E, Bradley CL, Chen X, Daryani V, Stewart CF, Calabrese C, Funk A, Miller G, Karlstrom A, Krafcik F, Goshorn DR, Vogel P, Bahrami A, Shelat A, Dyer MA

Abstract
Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

PMID: 30395907 [PubMed - indexed for MEDLINE]

Prediction of novel inhibitors for Crotalus adamanteus l-amino acid oxidase by repurposing FDA-approved drugs: a virtual screening and molecular dynamics simulation investigation.

Drug Chem Toxicol. 2019 Oct 31;:1-10

Authors: Khedrinia M, Aryapour H, Mianabadi M

Abstract
One of the deadliest enzymes in the snake venom is l-amino acid oxidase (LAAO) which plays an important role in the pathophysiological effects during snake envenomation. Some effects of this enzyme on the human body are apoptosis, platelet aggregation, edema, hemorrhage, and cytotoxicity. Hence, inhibiting the enzyme activity to reduce its degradation effects is of great medical and pharmacological importance. On the other hand, drug repurposing is a process to find the new existing drug for a new medical indication. Since Crotalus adamanteus LAAO has no crystal structure in the protein data bank, first, its 3D structure was constructed by homology modeling using 1REO as the template and then modeled structure was evaluated by several algorithms. We screened the FDA-approved drugs by structure-based virtual screening, molecular dynamics (MD) simulation, and Molecular Mechanics Poisson Boltzmann Surface Area (MM/PBSA) to identify new inhibitors for the snake venom LAAO. Interestingly, docking results revealed that half of the hits belong to the propionic acid derivatives drugs. In addition, MD simulation was performed to assess the interaction profile of the docked protein-hits complexes. Meanwhile, Arg88, Gln112, Lys345, Trp356 form consistent hydrogen bond interactions with Dexketoprofen, Flurbiprofen, Ketoprofen, Morphine, and Citric acid during simulation. According to the results, each of the four compounds can be an appropriate inhibitor of LAAO and since our study was based on drug repurposing could be evaluated in phase II clinical trials.

PMID: 31668098 [PubMed - as supplied by publisher]

Learning condyle repositioning during orthognathic surgery with a surgical navigation system.

Int J Oral Maxillofac Surg. 2019 Jul;48(7):952-956

Authors: Lartizien R, Zaccaria I, Savoldelli C, Noyelles L, Chamorey E, Cracowski JL, Bettega G

Abstract
Condyle repositioning during bilateral sagittal splint osteotomy (BSSO) is a challenging step for the inexperienced surgeon. We aimed to demonstrate the benefit of navigation for learning the condyle repositioning. We treated 100 patients who underwent a BSSO. A trainee performed the condyle repositioning of one side in two phases. In the first one, the trainee positioned without watching the screen of the Orthopilot Navigation system (ONS). In the second one, the trainee could use the ONS to replace the condyle. Heuristic, anatomical and functional scores of each phase were recorded. Heuristic (17% vs. 75%; p<0.0001), anatomical (35% vs. 86%; p<0.0001) and functional (14% vs. 56%; p<0.0001) scores were significantly greater with the ONS. The ONS is a promising and original intraoperative learning tool for the repositioning of the condyle during BSSO.

PMID: 30755359 [PubMed - indexed for MEDLINE]

Influence of the anatomical form of the posterior maxilla on the reliability of superior maxillary repositioning by Le Fort I osteotomy.

Int J Oral Maxillofac Surg. 2019 May;48(5):612-619

Authors: Tomomatsu N, Kurohara K, Nakakuki K, Yoshitake H, Kanemaru T, Yamaguchi S, Yoda T

Abstract
Certain patients with facial deformities require superior repositioning of the maxilla via Le Fort I osteotomy; however, the magnitude of superior repositioning of the maxilla is often less than expected. In this study, the correlation between the accuracy of superior repositioning of the maxilla and the anatomical form of the maxillary posterior region was examined. Seventy-five patients who underwent Le Fort I osteotomy without forward movement of the maxilla but with superior repositioning of the maxilla were included in this study. The bone volume around the descending palatine artery (DPA), the angle of the junction between the pterygoid process and the tuberosity, and the distance between the upper second molar and the pterygoid process were measured via three-dimensional analysis. A significant negative correlation (r=-0.566) was found between the bone volume around the DPA and the ratio of repositioning (actual movement divided by expected movement). It is possible that the superior repositioning of the maxilla expected prior to surgery was not sufficiently attained because of the large volume of bone around the DPA. The results of this study show that in some patients, superior repositioning was not achieved at the expected level because of bone interference attributable to the anatomical form of the maxillary posterior region.

PMID: 30503635 [PubMed - indexed for MEDLINE]

[Dutch Medicines Act also applicable to repurposing].

Ned Tijdschr Geneeskd. 2018 04 30;162:

Authors: van Wijngaarden J

Abstract
In this issue of the Dutch Journal of Medicine (NTvG), Strous and Van den Brink argue that Article 68 of the Dutch Medicines Act should be applied to repurposed drugs in a more liberal manner. Medicines prescribed on-label have been authorised by the relevant regulatory authority and are therefore guaranteed to have been substantiated by the necessary evidence and assessed for a positive benefit-risk balance. Article 68 states that medicines may be prescribed off-label only if they are described in the relevant professional treatment standards or guidelines. The more liberal application of Article 68 would allow the prescription of drugs that have not been adequately assessed for evidence substantiating their efficacy and safety in the field for which they are being prescribed. This is unwarranted, for repurposed drugs and for any other drug.

PMID: 30020570 [PubMed - indexed for MEDLINE]

Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy.

JCI Insight. 2018 06 07;3(11):

Authors: Jiang X, Lu W, Shen X, Wang Q, Lv J, Liu M, Cheng F, Zhao Z, Pang X

Abstract
Lung cancer patients treated with tyrosine kinase inhibitors (TKIs) often develop resistance. More effective and safe therapeutic agents are urgently needed to overcome TKI resistance. Here, we propose a medical genetics-based approach to identify indications for over 1,000 US Food and Drug Administration-approved (FDA-approved) drugs with high accuracy. We identified a potentially novel indication for an approved antidepressant drug, sertraline, for the treatment of non-small cell lung cancer (NSCLC). We found that sertraline inhibits the viability of NSCLC cells and shows a synergy with erlotinib. Specifically, the cotreatment of sertraline and erlotinib effectively promotes autophagic flux in cells, as indicated by LC3-II accumulation and autolysosome formation. Mechanistic studies further reveal that dual treatment of sertraline and erlotinib reciprocally regulates the AMPK/mTOR pathway in NSCLC cells. The blockade of AMPK activation decreases the anticancer efficacy of either sertraline alone or the combination. Efficacy of this combination regimen is decreased by pharmacological inhibition of autophagy or genetic knockdown of ATG5 or Beclin 1. Importantly, our results suggest that sertraline and erlotinib combination suppress tumor growth and prolong mouse survival in an orthotopic NSCLC mouse model (P = 0.0005). In summary, our medical genetics-based approach facilitates discovery of new anticancer indications for FDA-approved drugs for the treatment of NSCLC.

PMID: 29875309 [PubMed - indexed for MEDLINE]

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Loss-of-function mutations in human RGS2 differentially regulate pharmacological reactivity of resistance vasculature.

Mol Pharmacol. 2019 Oct 23;:

Authors: Phan HTN, Jackson WF, Shaw V, Watts SW, Neubig RR

Abstract
Regulator of G protein signaling 2 (RGS2) plays a role in reducing vascular contraction and promoting relaxation due to its GTPase accelerating protein activity toward Gαq. Previously, we identified 4 human loss-of-function (LOF) mutations in RGS2 (Q2L, D40Y, R44H and R188H). This study aimed to investigate whether those RGS2 LOF mutations disrupt the ability of RGS2 to regulate vascular reactivity. Isolated mesenteric arteries (MAs) from RGS2-/- mice showed an elevated contractile response to 5 nM angiotensin II and a loss of acetylcholine (ACh)-mediated vasoconstriction. Reintroduction of a wild-type RGS2-GFP plasmid into RGS2-/- MAs suppressed the vasoconstrictor response to angiotensin II. RGS2 LOF mutants failed to suppress the angiotensin II constriction response compared to RGS2 WT. In contrast, ACh-mediated vasoconstriction was restored by expression of RGS2 WT, D40Y and R44H but not by RGS2 Q2L or R188H. Phosphorylation of RGS2 D40Y and R44H by protein kinase G (PKG) may explain their maintained function to support relaxation in MAs. This is supported by phosphomimetic mutants and suppression of vasorelaxation mediated by RGS2 D40Y by a PKG inhibitor. These results demonstrate that RGS2 attenuates vasoconstriction in MAs and that RGS2 LOF mutations cannot carry out this effect. Among them, the Q2L and R188H mutants supported less relaxation to acetylcholine while relaxation mediated by the D40Y and R44H mutant proteins was equal to that with WT protein. Phosphorylation of RGS2 by PKG appears to contribute to this vasorelaxation. These results provide insights for precision medicine targeting the rare individuals carrying these RGS2 mutations. SIGNIFICANCE STATEMENT: The Regulator of G protein Signaling protein 2 (RGS2) has been implicated in control of blood pressure; rare mutations in the RGS2 gene have been identified in large scale human gene sequencing studies. Four human mutations in RGS2 that cause loss-of-function (LOF) in cell-based assays were examined in isolated mouse arteries for effects on both vasoconstriction and vasodilation. All mutants showed the expected LOF effects in suppressing vasoconstriction. Surprisingly, the D40Y and R44H mutant RGS2 showed normal control of vasodilation. We propose that this is due to rescue of the mislocalization phenotype of these two mutants by NO-mediated/PKG-dependent phosphorylation. These mechanisms may guide drug discovery or drug repurposing effort for hypertension by enhancing RGS2 function.

PMID: 31645376 [PubMed - as supplied by publisher]

Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.

Sci Rep. 2018 08 20;8(1):12471

Authors: Baig MS, Roy A, Saqib U, Rajpoot S, Srivastava M, Naim A, Liu D, Saluja R, Faisal SM, Pan Q, Turkowski K, Darwhekar GN, Savai R

Abstract
Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.

PMID: 30127400 [PubMed - indexed for MEDLINE]

Accurate Drug Repositioning through Non-tissue-Specific Core Signatures from Cancer Transcriptomes.

Cell Rep. 2019 Oct 22;29(4):1055

Authors: Xu C, Ai D, Shi D, Suo S, Chen X, Yan Y, Cao Y, Zhang R, Sun N, Chen W, McDermott J, Zhang S, Zeng Y, Han JJ

PMID: 31644902 [PubMed - in process]

Impact of tricyclic antidepressants, selective serotonin reuptake inhibitors, and other antidepressants on overall survival of patients with advanced lung cancer from 2004 to 2014: University of Cincinnati experience.

J Int Med Res. 2019 Oct 23;:300060519862469

Authors: Abdel Karim NF, Hassan R, Siddiqi NI, Eldessouki I, Gaber O, Rahouma M, Kamel M, Yellu M, Gulati S, Xie C, Magdy M, Pruemer J

PMID: 31640444 [PubMed - as supplied by publisher]

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

Sci Rep. 2018 10 08;8(1):14969

Authors: Han HW, Hahn S, Jeong HY, Jee JH, Nam MO, Kim HK, Lee DH, Lee SY, Choi DK, Yu JH, Min SH, Yoo J

Abstract
Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and innate immune cells were collected from the Gene Expression Omnibus (GEO) data repository and used for candidate drug selection based on the LINCS L1000 perturbation dataset. The anti-inflammatory effects of the selected candidate drugs were analyzed using activated macrophage cell lines. CGP-60474, an inhibitor of cyclin-dependent kinase, was the most potent drug. It alleviated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in activated macrophages by downregulating the NF-κB activity, and it reduced the mortality rate in LPS induced endotoxemia mice. This study shows that CGP-60474 could be a potential therapeutic candidate to attenuate the endotoxemic process. Additionally, the virtual screening strategy using the LINCS L1000 perturbation dataset could be a cost and time effective tool in the early stages of drug development.

PMID: 30297806 [PubMed - indexed for MEDLINE]

Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases.

Geroscience. 2019 Oct 21;:

Authors: Yang J, Peng S, Zhang B, Houten S, Schadt E, Zhu J, Suh Y, Tu Z

Abstract
A key goal of geroscience research is to identify effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by screening compounds in model organisms; whether they will be effective in humans is largely unknown. Here we present a new strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological interventions that may "reverse" the age-associated transcriptional changes occurred in these subnetworks. We applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project. For the top 31 identified compounds, 19 of them showed at least some evidence supporting their function in improving metabolic traits or lifespan, which include type 2 diabetes drugs such as pioglitazone. As the query aging genes were refined to the ones with more intimate links to diseases, ANDRU identified more meaningful drug hits than the general approach without considering the underlying network structures. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

PMID: 31637571 [PubMed - as supplied by publisher]

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG.

Dis Model Mech. 2019 Oct 21;:

Authors: Iyer S, Sam FS, DiPrimio N, Preston G, Verheijen J, Murthy K, Parton Z, Tsang H, Lao J, Morava E, Perlstein EO

Abstract
Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation affecting over 1,000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. In order to identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multi-species drug repurposing screen using a first-ever worm model of PMM2-CDG followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 are plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains range from 30% to 400% over baseline depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

PMID: 31636082 [PubMed - as supplied by publisher]

Drug Repurposing Approach for Developing Novel Therapy Against Mupirocin-Resistant Staphylococcus aureus.

Assay Drug Dev Technol. 2019 Oct;17(7):298-309

Authors: Mujwar S, Deshmukh R, Harwansh RK, Gupta JK, Gour A

Abstract
Multidrug resistance (MDR) is a major health issue for the treatment of infectious diseases throughout the world. Staphylococcus aureus (S. aureus) is a Gram-positive bacteria, responsible for various local and systemic infections in humans. The continuous and abrupt use of antibiotics against bacteria such as S. aureus results in the development of resistant strains. Presently, mupirocin (MUP) is the drug of choice against S. aureus and MDR (methicillin-resistant). However, S. aureus has acquired resistance against MUP as well due to isoleucyl-tRNA synthetase (IleS) mutation at sites 588 and 631. Thus, the aim of the present study was to discover novel bioactives against MUP-resistant S. aureus using in silico drug repurposing approaches. In silico drug repurposing techniques were used to obtain suitable bioactive lead molecules such as buclizine, tasosartan, emetine, medrysone, and so on. These lead molecules might be able to resolve this issue. These leads were obtained through molecular docking simulation based virtual screening, which could be promising for the treatment of MUP-resistant S. aureus. The findings of the present work need to be validated further through in vitro and in vivo studies for their clinical application.

PMID: 31634019 [PubMed - in process]

Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment.

Mol Psychiatry. 2019 Oct 18;:

Authors: Hegvik TA, Waløen K, Pandey SK, Faraone SV, Haavik J, Zayats T

Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

PMID: 31628418 [PubMed - as supplied by publisher]

Analysis of defective pathways and drug repositioning in Multiple Sclerosis via machine learning approaches.

Comput Biol Med. 2019 Oct 09;115:103492

Authors: deAndrés-Galiana EJ, Bea G, Fernández-Martínez JL, Saligan LN

Abstract
BACKGROUND: Although some studies show that there could be a genetic predisposition to develop Multiple Sclerosis (MS), attempts to find genetic signatures related to MS diagnosis and development are extremely rare.
METHOD: We carried out a retrospective analysis of two different microarray datasets, using machine learning techniques to understand the defective pathways involved in this disease. We have modeled two data sets that are publicly accessible. The first was used to establish the list of most discriminatory genes; whereas, the second one was utilized for validation purposes.
RESULTS: The analysis provided a list of high discriminatory genes with predictive cross-validation accuracy higher than 95%, both in learning and in blind validation. The results were confirmed via the holdout sampler. The most discriminatory genes were related to the production of Hemoglobin. The biological processes involved were related to T-cell Receptor Signaling and co-stimulation, Interferon-Gamma Signaling and Antigen Processing and Presentation. Drug repositioning via CMAP methodologies highlighted the importance of Trichostatin A and other HDAC inhibitors.
CONCLUSIONS: The defective pathways suggest viral or bacterial infections as plausible mechanisms involved in MS development. The pathway analysis also confirmed coincidences with Epstein-Barr virus, Influenza A, Toxoplasmosis, Tuberculosis and Staphylococcus Aureus infections. Th17 Cell differentiation, and CD28 co-stimulation seemed to be crucial in the development of this disease. Furthermore, the additional knowledge provided by this analysis helps to identify new therapeutic targets.

PMID: 31627017 [PubMed - as supplied by publisher]

Identification of chlorprothixene as a potential drug that induces apoptosis and autophagic cell death in acute myeloid leukemia cells.

FEBS J. 2019 Oct 18;:

Authors: Du Y, Li K, Wang X, Aman KC, Junaid M, Wei D

Abstract
Although acute myeloid leukemia (AML) is a highly heterogeneous malignance, the common molecular mechanisms shared by different AML subtypes play critical roles in AML development. It is possible to identify new drugs that are effective for various AML subtypes based on the common molecular mechanisms. Therefore, we developed a hypothesis-driven bioinformatic drug screening framework by integrating multiple omics data. In this study, we identified that chlorprothixene，a dopamine receptor antagonist, could effectively inhibit growth of AML cells from different subtypes. RNA-seq analysis suggested that chlorprothixene perturbed a series of crucial biological processes such as cell cycle, apoptosis and autophagy in AML cells. Further investigations indicated that chlorprothixene could induce both apoptosis and autophagy in AML cells, and apoptosis and autophagy could act as partners to induce cell death cooperatively. Remarkably, chlorprothixene was found to inhibit tumor growth and induce in situ leukemic cell apoptosis in the murine xenograft model. Furthermore, chlorprothixene treatment could reduce the level of oncofusion proteins PML-RARα and AML1-ETO, thus elevate the expression of apoptosis-related genes and lead to AML cell death. Our results provided new insights for drug repositioning of AML therapy, and confirmed that chlorprothixene might be a potential candidate for treatment of different subtypes of AML by reducing expression of oncofusion proteins.

PMID: 31625692 [PubMed - as supplied by publisher]

Off-label uses of drugs for depression.

Eur J Pharmacol. 2019 Oct 14;:172732

Authors: Skånland SS, Cieslar-Pobuda A

Abstract
The prescription of drugs for depression is rising rapidly. One of the reasons for this trend is their many off-label uses. Up to one third of all prescriptions are for non-indicated use, which in addition to drug repurposing includes different dosing or duration than those recommended. In this review, we elaborate on what antidepressants can treat besides depression. The five classes of drugs for depression are introduced, and their mechanisms of action and serious side effects are described. The most common off-label uses of antidepressants are discussed, with a special focus on treating eating disorders, sleep problems, smoking cessation and managing chronic pain. Depression is often a comorbidity when antidepressants are chosen as therapy, but good therapeutic effects have been observed for other conditions also when depression is not involved. Finally, a new type of antidepressant developed from the hallucinogenic "party drug" ketamine is briefly introduced. This recent development suggest that antidepressants will keep playing a central role in medicine for years to come.

PMID: 31622593 [PubMed - as supplied by publisher]

Selective Estrogen Receptor Modulators (SERMs): Mechanistic Insights Against Microbial Infections.

Curr Mol Med. 2019 Oct 14;:

Authors: Garg A, Singh B, Sharma R, Singh A, Kumar A

Abstract
BACKGROUND: Infections are one of the leading causes of death worldwide and current available treatment remains unsatisfactory due to rise in the cases of antimicrobial resistance. Thus, there is a need for the development of new drugs with different mechanism of action. However, the development of new antimicrobials agents is a long and expensive process. Hence, most of the pharmaceutical companies are looking forward for repurposing already available drugs against microbial infections.
METHODOLOGY: The data related to SERMs and microbial infection has been extracted from Pub Med (from January 1997 to December 2018). A total of 101 studies have been published from 1997 -2018 regarding SERMs and microbial infections.
RESULTS: On the basis of inclusion and exclusion criteria, 25 studies have been included for the analysis of level of evidence regarding antimicrobial effects of SERMs. Emerging reports have indicated the antimicrobial property of selective estrogen receptor modulators (SERMs) against normal and resistant strains under in vitro and in vivo conditions against wide variety of microorganisms through different mechanism of action.
CONCLUSION: In conclusion, SERMs could be developed as a broad spectrum antimicrobial agent alone or in combination with existing antimicrobial agents.

PMID: 31622201 [PubMed - as supplied by publisher]