Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration.

Pharmaceutics. 2018 Nov 17;10(4):

Authors: Murashov MD, Diaz-Espinosa J, LaLone V, Tan JWY, Laza R, Wang X, Stringer KA, Rosania GR

Abstract
Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy.

PMID: 30453628 [PubMed]

Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening.

J Enzyme Inhib Med Chem. 2019 Dec;34(1):171-178

Authors: Sarwono AEY, Mitsuhashi S, Kabir MHB, Shigetomi K, Okada T, Ohsaka F, Otsuguro S, Maenaka K, Igarashi M, Kato K, Ubukata M

Abstract
Inosine 5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with kon values of 0.7 × 104 to 9.3 × 104 M-1·s-1. Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors.

PMID: 30451014 [PubMed - in process]

Efficacy of sertraline against Trypanosoma cruzi: an in vitro and in silico study.

J Venom Anim Toxins Incl Trop Dis. 2018;24:30

Authors: Ferreira DD, Mesquita JT, da Costa Silva TA, Romanelli MM, da Gama Jaen Batista D, da Silva CF, da Gama ANS, Neves BJ, Melo-Filho CC, Correia Soeiro MN, Andrade CH, Tempone AG

Abstract
Background: Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease.
Methods: In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches.
Results: Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 μM, and activity against bloodstream trypomastigotes, with IC50 of 14 μM. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline.
Conclusions: The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds.

PMID: 30450114 [PubMed]

Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells.

Cancer Med. 2018 Nov 18;:

Authors: Kakuguchi W, Nomura T, Kitamura T, Otsuguro S, Matsushita K, Sakaitani M, Maenaka K, Tei K

Abstract
AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin-related genes, and growth factors. HuR binds and stabilizes ARE-mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR-targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration-dependent manner were selected by DSF. Of them, suramin, an anti-trypanosomal drug, binds to HuR, exhibiting fast-on and fast-off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.

PMID: 30449075 [PubMed - as supplied by publisher]

Critical period plasticity-related transcriptional aberrations in schizophrenia and bipolar disorder.

Schizophr Res. 2018 Nov 12;:

Authors: Smith MR, Readhead B, Dudley JT, Morishita H

Abstract
Childhood critical periods of experience-dependent plasticity are essential for the development of environmentally appropriate behavior and cognition. Disruption of critical periods can alter development of normal function and confer risk for neurodevelopmental disorders. While genes and their expression relevant to neurodevelopment are associated with schizophrenia, the molecular relationship between schizophrenia and critical periods has not been assessed systematically. Here, we apply a transcriptome-based bioinformatics approach to assess whether genes associated with the human critical period for visual cortex plasticity, a well-studied model of cortical critical periods, are aberrantly expressed in schizophrenia and bipolar disorder. Across two dozen datasets encompassing 522 cases and 374 controls, we find that the majority show aberrations in expression of genes associated with the critical period. We observed both hyper- and hypo-critical period plasticity phenotypes at the transcriptome level, which partially mapped to drug candidates that reverse the disorder signatures in silico. Our findings indicate plasticity aberrations in schizophrenia and their treatment may need to be considered in the context of subpopulations with elevated and others reduced plasticity. Future work should leverage ongoing consortia RNA-sequencing efforts to tease out the sources of plasticity-related transcriptional aberrations seen in schizophrenia, including true biological heterogeneity, interaction between normal development/aging and the disorder, and medication history. Our study also urges innovation towards direct assessment of visual cortex plasticity in humans with schizophrenia to precisely deconstruct the role of plasticity in this disorder.

PMID: 30442475 [PubMed - as supplied by publisher]

Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update.

Expert Opin Investig Drugs. 2018 Nov 15;:

Authors: Han Y, Mesplède T

Abstract
INTRODUCTION: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent. Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing twenty potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development. Expert opinion: So far, twenty compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long non-coding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents.

PMID: 30430882 [PubMed - as supplied by publisher]

Entry Into New Therapeutic Areas: The Effect of Alliance on Clinical Trials.

Ther Innov Regul Sci. 2018 Nov 14;:2168479018811829

Authors: Okada K, Sengoku S

Abstract
BACKGROUND:: Entry into a new therapeutic area, that is, one in which a pharmaceutical firm lacks experience, is a considerable challenge for firms that need to overcome scientific and technological barriers. To address this issue, the present study aims to explore the potentiality of alliances in an empirical manner.
METHODS:: From the clinical trials sponsored by 20 major pharmaceutical firms during 2008-2016 listed at ClinicalTrials.gov (n = 14,941 clinical trials), cases of entering a new therapeutic area for a pharmaceutical firm were extracted (n = 73), followed by statistical analyses to evaluate the effect of alliances in this regard.
RESULTS:: We found that the average number of participating organizations in the cases of entering a new therapeutic area was significantly larger than that in the cases of entering an area in which firms had experience ( P < .01), suggesting that alliance has a positive effect on new therapeutic entry for these pharmaceutical firms. Second, we found that the cases of partnering with nonindustrial or nongovernmental organizations (ie, universities, research institutes, hospitals, funding agencies, and others; n = 32 of the 73) were significantly associated with these new entry trials (adjusted odds ratio = 1.1, P < .05). Furthermore, we identified that 10 of the 32 clinical trials were associated with rare diseases, which is an overrepresentation compared to the occurrence in the universe (1015 of the 14,941; P < 10-5).
CONCLUSIONS:: These findings strongly suggest the importance of alliances with diversified partners in new therapeutic entry and also provide a basis for further detailed investigation of key success factors for pharmaceutical firms.

PMID: 30428715 [PubMed - as supplied by publisher]

Azithromycin and Roxithromycin define a new family of "senolytic" drugs that target senescent human fibroblasts.

Aging (Albany NY). 2018 Nov 14;:

Authors: Ozsvari B, Nuttall JR, Sotgia F, Lisanti MP

Abstract
Here, we employed a "senolytic" assay system as a screening tool, with the goal of identifying and repurposing FDA-approved antibiotics, for the targeting of the senescent cell population. Briefly, we used two established human fibroblast cell lines (MRC-5 and/or BJ) as model systems to induce senescence, via chronic treatment with a DNA-damaging agent, namely BrdU (at a concentration of 100 μM for 8 days). Cell viability was then monitored by using the SRB assay, to measure protein content. As a consequence of this streamlined screening strategy, we identified Azithromycin and Roxithromycin as two novel clinically-approved senolytic drugs. However, Erythromycin - the very closely-related parent compound - did not show any senolytic activity, highlighting the dramatic specificity of these interactions. Interestingly, we also show that Azithromycin treatment of human fibroblasts was indeed sufficient to strongly induce both aerobic glycolysis and autophagy. However, the effects of Azithromycin on mitochondrial oxygen consumption rates (OCR) were bi-phasic, showing inhibitory activity at 50 μM and stimulatory activity at 100 μM. These autophagic/metabolic changes induced by Azithromycin could mechanistically explain its senolytic activity. We also independently validated our findings using the xCELLigence real-time assay system, which measures electrical impedance. Using this approach, we see that Azithromycin preferentially targets senescent cells, removing approximately 97% of them with great efficiency. This represents a near 25-fold reduction in senescent cells. Finally, we also discuss our current results in the context of previous clinical findings that specifically document the anti-inflammatory activity of Azithromycin in patients with cystic fibrosis - a genetic lung disorder that results in protein mis-folding mutations that cause protein aggregation.

PMID: 30428454 [PubMed - as supplied by publisher]

Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3.

J Cell Mol Med. 2018 Nov 13;:

Authors: Jang WJ, Jung SK, Vo TTL, Jeong CH

Abstract
The concept of drug repositioning has recently received considerable attention in the field of oncology. In the present study, we propose that paroxetine can be used as a potent anticancer drug. Paroxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been widely prescribed for the treatment of depression and anxiety disorders. Recently, SSRIs have been reported to have anticancer activity in various types of cancer cells; however, the underlying mechanisms of their action are not yet known. In this study, we investigated the potential anticancer effect of paroxetine in human colorectal cancer cells, HCT116 and HT-29. Treatment with paroxetine reduced cell viability, which was associated with marked increase in apoptosis, in both the cell lines. Also, paroxetine effectively inhibited colony formation and 3D spheroid formation. We speculated that the mode of action of paroxetine might be through the inhibition of two major receptor tyrosine kinases - MET and ERBB3 - leading to the suppression of AKT, ERK and p38 activation and induction of JNK and caspase-3 pathways. Moreover, in vivo experiments revealed that treatment of athymic nude mice bearing HT-29 cells with paroxetine remarkably suppressed tumour growth. In conclusion, paroxetine is a potential therapeutic option for patients with colorectal cancer.

PMID: 30421568 [PubMed - as supplied by publisher]

Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach?

Eur J Cancer Prev. 2018 Nov 08;:

Authors: Kobayashi Y, Banno K, Kunitomi H, Nagai S, Takahashi T, Anko M, Iijima M, Takeda T, Matoba Y, Nakamura K, Tsuji K, Tominaga E, Aoki D

Abstract
Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.

PMID: 30418231 [PubMed - as supplied by publisher]

Supramolecular nanofibers self-assembled from cationic small molecules derived from repurposed poly(ethylene teraphthalate) for antibiotic delivery.

Nanomedicine. 2018 01;14(1):165-172

Authors: Liu S, Fukushima K, Venkataraman S, Hedrick JL, Yang YY

Abstract
Low molecular weight cationic compounds were synthesized from re-purposed poly(ethylene teraphthalate) (PET) and used to self-assemble into high aspect ratio supramolecular nanofibers for encapsulation and delivery of anionic antibiotics. The antibiotic piperacillin/tazobactam (PT) was successfully loaded into the nanofibers through ionic interaction between anionic PT and the cationic nanofibers without loss of the nanofiber features. These PT-loaded nanofibers demonstrated high loading efficiency and sustained delivery for PT. The antimicrobial activity of PT-loaded nanofibers remained potent towards both Gram-positive and Gram-negative bacteria. Importantly, in a P. aeruginosa-infected mouse skin wound model, the treatment with the PT-loaded nanofibers was more effective than free PT for wound healing as evidenced by the significantly lower P. aeruginosa counts at the wound sites and histological analysis. This strategy can be applied to deliver a variety of anionic antibiotics for improved treatment efficacy of various infections.

PMID: 28974393 [PubMed - indexed for MEDLINE]

Antimicrobial and Antibiofilm Activity of Synergistic Combinations of a Commercially Available Small Compound Library With Colistin Against Pseudomonas aeruginosa.

Front Microbiol. 2018;9:2541

Authors: Torres NS, Montelongo-Jauregui D, Abercrombie JJ, Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK, Leung KP

Abstract
Biofilm-associated Pseudomonas aeruginosa infections remain a significant clinical challenge since the conventional antibiotic treatment or combination therapies are largely ineffective; and new approaches are needed. To circumvent the major challenges associated with discovery of new antimicrobials, we have screened a library of compounds that are commercially available and approved by the FDA (Prestwick Chemical Library) against P. aeruginosa for effective antimicrobial and anti-biofilm activity. A preliminary screen of the Prestwick Chemical Library alone did not yield any repositionable candidates, but in a screen of combinations with a fixed sub-inhibitory concentration of the antibiotic colistin we observed 10 drugs whose bacterial inhibiting activity was reproducibly enhanced, seven of which were enhanced by more than 50%. We performed checkerboard assays of these seven drugs in combination with colistin against planktonic cells, and analysis of their interactions over the complete combination matrix using the Zero Interaction Potency (ZIP) model revealed interactions that varied from highly synergistic to completely antagonistic. Of these, five combinations that showed synergism were down-selected and tested against preformed biofilms of P. aeruginosa. Two of the five combinations were active against preformed biofilms of both laboratory and clinical strain of P. aeruginosa, resulting in a 2-log reduction in culturable cells. In summary, we have identified synergistic combinations of five commercially available, FDA-approved drugs and colistin that show antimicrobial activity against planktonic P. aeruginosa (Clomiphene Citrate, Mitoxantrone Dihydrochloride, Methyl Benzethonium Chloride, Benzethonium Chloride, and Auranofin) as well as two combinations (Auranofin and Clomiphene Citrate) with colistin that show antibiofilm activity.

PMID: 30410476 [PubMed]

The Antiarrhythmic Drug, Dronedarone, Demonstrates Cytotoxic Effects in Breast Cancer Independent of Thyroid Hormone Receptor Alpha 1 (THRα1) Antagonism.

Sci Rep. 2018 Nov 08;8(1):16562

Authors: Elliott MJ, Jerzak KJ, Cockburn JG, Safikhani Z, Gwynne WD, Hassell JA, Bane A, Silvester J, Thu KL, Haibe-Kains B, Mak TW, Cescon DW

Abstract
Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone's cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone's anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.

PMID: 30410118 [PubMed - in process]

Developments in Blood-Brain Barrier Penetrance and Drug Repurposing for Improved Treatment of Glioblastoma.

Front Oncol. 2018;8:462

Authors: Harder BG, Blomquist MR, Wang J, Kim AJ, Woodworth GF, Winkles JA, Loftus JC, Tran NL

Abstract
Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies.

PMID: 30406029 [PubMed]

Repurposing of approved cardiovascular drugs against ischemic cerebrovascular disease by disease-disease associated network-assisted prediction.

Chem Pharm Bull (Tokyo). 2018 Nov 08;:

Authors: Zhao QQ, Li X, Luo LP, Qian Y, Liu YL, Wu HT

Abstract
Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only FDA-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease-disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.

PMID: 30404981 [PubMed - as supplied by publisher]

Impact of Precision Medicine on Drug Repositioning and Pricing: A Too Small to Thrive Crisis.

J Pers Med. 2018 Nov 05;8(4):

Authors: Tiriveedhi V

Abstract
The pricing of targeted medicines continues to be a major area of contention in healthcare economics. This issue is further complicated by redefining the role of molecular testing in precision medicine. Currently, whilst pricing of clinical laboratory diagnostics is cost-based, drug pricing is value-based. The pricing for molecular testing is under pressure to change the traditional business model, for it has a critical subsidiary role in determining the final value of targeted medicines. The market size for drugs is reduced by molecular testing when patients with the same disease are stratified based on their genetics, it is critical to determine the value of this new enhanced drug specificity to realize its full pricing potential. However, these value-based pricing strategies require a careful understanding of changing market conditions, especially, in the context of stratified patient segments made possible by precision medicine. In this article, we discuss the various factors impacting pricing decisions, and consider evolving economic trends in precision medicine.

PMID: 30400625 [PubMed]

Repurposing of commercially available anti-coccidials identifies diclazuril and decoquinate as potential therapeutic candidates against Besnoitia besnoiti infection.

Vet Parasitol. 2018 Sep 15;261:77-85

Authors: Jiménez-Meléndez A, Rico-San Román L, Hemphill A, Balmer V, Ortega-Mora LM, Álvarez-García G

Abstract
Repurposing of currently marketed compounds with proven efficacy against apicomplexan parasites was used as an approach to define novel candidate therapeutics for bovine besnoitiosis. Besnoitia besnoiti tachyzoites grown in MARC-145 cells were exposed to different concentrations of toltrazuril, diclazuril, imidocarb, decoquinate, sulfadiazine and trimethoprim alone or in combination with sulfadiazine. Drugs were added either just prior to infection of MARC-145 cells (0 h post infection, hpi) or at 6 hpi. A primary evaluation of drug effects was done by direct immunofluorescence staining and counting. Potential effects on the host cells were assessed using a XTT kit for cell proliferation. Compounds displaying promising efficacy were selected for IC50 and IC99 determination by qPCR. In addition, the impact of drugs on the tachyzoite ultrastructure was assessed by TEM and long-term treatment assays were performed. Cytotoxicity assays confirmed that none of the compounds affected the host cells. Decoquinate and diclazuril displayed invasion inhibition rates of 90 and 83% at 0 h pi and 73 and 72% at 6 h pi, respectively. The remaining drugs showed lower efficacy and were not further studied. Decoquinate and diclazuril exhibited IC99 values of 100 nM and 29.9 μM, respectively. TEM showed that decoquinate primarily affected the parasite mitochondrium, whilst diclazuril interfered in cytokinesis of daughter zoites. The present study demonstrates the efficacy of diclazuril and decoquinate against B. besnoiti in vitro and further assessments of safety and efficacy of both drugs should be performed in the target species.

PMID: 30253854 [PubMed - indexed for MEDLINE]

A Network-Based Cancer Drug Discovery: From Integrated Multi-Omics Approaches to Precision Medicine.

Curr Pharm Des. 2018 Nov 05;:

Authors: Turanli B, Karagoz K, Gulfidan G, Sinha R, Mardinoglu A, Arga KY

Abstract
A complex framework of interacting partners including genetic, proteomic, and metabolic networks that cooperate to mediate specific functional phenotypes drives human biological processes. Recent technological and analytical advances in "omic" sciences allow the identification and elucidation of reprogramming biological functions in response to perturbations in cells and tissues. To understand such a complex system, biological networks are generated to reduce the complexity into relatively simple models, and the integration of these molecular networks from different perspectives is implemented for a holistic interpretation of the entire system. Ultimately, network-based methods will effectively facilitate the development and improvement of precision medicine by directing therapies based on the underlying biology of a given patient's disease. The goal of precision medicine is to identify novel therapeutic strategies that can be optimized for each disease type or each patient based on the underlying genetic, environmental, and lifestyle factors. Pharmaco-omics analyses based on an integration of pharmacology and various "omics" data types can be employed to develop effective treatment strategies using particular drugs and doses that are tailored to each individual. In the current review, we first present the core elements of network-based systems biology in the context of pharmaco-omics followed by integration of multi-omics data using various biological networks. Next, we provide an opening into precise medicine and drug targeting based on network approaches. Lastly, we review the current significant efforts as well as the accomplishments and limitations in precise drug targeting with the utility of network-based guided drug discovery methods for effective treatment of breast cancer.

PMID: 30398107 [PubMed - as supplied by publisher]

New tricks for an old dog: a repurposing approach of apomorphine.

Eur J Pharmacol. 2018 Nov 02;:

Authors: Auffret M, Drapier S, Vérin M

Abstract
Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant(-like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way.

PMID: 30395851 [PubMed - as supplied by publisher]

An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva.

Stem Cell Reports. 2018 Oct 24;:

Authors: Hino K, Zhao C, Horigome K, Nishio M, Okanishi Y, Nagata S, Komura S, Yamada Y, Toguchida J, Ohta A, Ikeya M

Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), a type I receptor for bone morphogenetic proteins. Despite numerous studies, no drugs have been approved for FOP. Here, we developed a high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 by utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice, including FOP-ACVR1 transgenic mice and HO model mice utilizing FOP-iPSCs. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling.

PMID: 30392977 [PubMed - as supplied by publisher]