Identification of Novel Analgesics Through a Drug Repurposing Strategy

References

• Ashburn TT , ThorKB . Drug repositioning: identifying and developing new uses for existing drugs . Nat. Rev. Drug Discov.3 ( 8 ), 673 – 683 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Morgan S , GrootendorstP , LexchinJ , CunninghamC , GreysonD . The cost of drug development: a systematic review . Health Policy100 ( 1 ), 4 – 17 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Scannell JW , BlanckleyA , BoldonH , WarringtonB . Diagnosing the decline in pharmaceutical R&D efficiency . Nat. Rev. Drug Discov.11 ( 3 ), 191 – 200 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Booth B , ZemmelR . Prospects for productivity . Nat. Rev. Drug Discov.3 ( 5 ), 451 – 456 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Dimasi JA , HansenRW , GrabowskiHG . The price of innovation: new estimates of drug development costs . J. Health Econ.22 ( 2 ), 151 – 185 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Kola I , LandisJ . Can the pharmaceutical industry reduce attrition rates?Nat. Rev. Drug Discov.3 ( 8 ), 711 – 715 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Chong CR , SullivanDJ . New uses for old drugs . Nature448 ( 7154 ), 645 – 646 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Graul AI , LuponeB , CrucesE , StringerM . 2012 in review – part I: the year’s new drugs & biologics . Drugs Today49 ( 1 ), 33 – 68 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Sharlow ER . Revisiting repurposing . Assay Drug Dev. Technol.14 ( 10 ), 354 – 356 ( 2016 ).
   Web of Science ®Google Scholar
• Hurle MR , YangL , XieQ , RajpalDK , SanseauP , AgarwalP . Computational drug repositioning: from data to therapeutics . Clin. Pharm. Ther.93 ( 4 ), 335 – 341 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Papapetropoulos A , SzaboC . Inventing new therapies without reinventing the wheel: the power of drug repurposing . Br. J. Pharmacol.175 ( 2 ), 165 – 167 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Novac N . Challenges and opportunities of drug repositioning . Trends Pharmacol. Sci.34 ( 5 ), 267 – 272 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Rocha FA , SilvaFSJr. , LeiteACet al. Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release . Br. J. Pharmacol.164 ( 2b ), 828 – 835 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Jain NK , PatilCS , SinghA , KulkarniSK . Sildenafil-induced peripheral analgesia and activation of the nitric oxide–cyclic GMP pathway . Brain Res.909 ( 1-2 ), 170 – 178 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Wang L , ChoppM , SzaladAet al. Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice . PLoS ONE10 ( 2 ), e0118134 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Padhy BM , GuptaYK . Drug repositioning: re-investigating existing drugs for new therapeutic indications . J. Postgrad. Med.57 ( 2 ), 153 – 160 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Suaudeau C , ChaitA , CimetiereC , DebeaurepaireR . Analgesic effects of antibiotics in rats . Pharmacol. Biochem. Behav.46 ( 2 ), 361 – 364 ( 1993 ).
   PubMed Web of Science ®Google Scholar
• Liebregts R , KopskyDJ , HesselinkJM . Topical amitriptyline in post-traumatic neuropathic pain . J. Pain Symptom Manage.41 ( 4 ), e6 – 7 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , HesselinkJM . High doses of topical amitriptyline in neuropathic pain: two cases and literature review . Pain Pract.12 ( 2 ), 148 – 153 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , HesselinkJMK . Neuropathic pain as a result of acromegaly, treated with topical baclofen cream . J. Pain Symptom Manage.46 ( 4 ), E4 – E5 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , HesselinkJMK , BhaskarA , HaritonG , RomanenkoV , CasaleR . Analgesic effects of topical ketamine . Minerva Anestesiologica81 ( 4 ), 440 – 449 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , HesselinkJMK . Phenytoin in topical formulations augments pain reduction of other topically applied analgesics in the treatment of trigeminal neuralgia . J. Clin. Anesth.38 , 154 – 155 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , HesselinkJMK . Topical phenytoin for the treatment of neuropathic pain . J. Pain Res.10 , 469 – 473 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Bastos LFS , CoelhoMM . Drug repositioning: playing dirty to kill pain . CNS Drugs28 ( 1 ), 45 – 61 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Sisignano M , ParnhamMJ , GeisslingerG . Drug repurposing for the development of novel analgesics . Trend. Pharmacol. Sci.37 ( 3 ), 172 – 183 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Yella JK , YaddanapudiS , WangY , JeggaAG . Changing trends in computational drug repositioning . Pharmaceuticals (Basel)11 ( 2 ), pii: E57 ( 2018 ).
   PubMedGoogle Scholar
• Burgess G , WilliamsD . The discovery and development of analgesics: new mechanisms, new modalities . J. Clin. Invest.120 ( 11 ), 3753 – 3759 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Woolf CJ . Overcoming obstacles to developing new analgesics . Nat. Med.16 ( 11 ), 1241 – 1247 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Woodcock J , WitterJ , DionneRA . Stimulating the development of mechanism-based, individualized pain therapies . Nat. Rev. Drug Discov.6 ( 9 ), 703 – 710 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Kroenke K , KrebsEE , BairMJ . Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews . General Hospital Psychiatry31 ( 3 ), 206 – 219 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Melnikova I . Pain market . Nat. Rev. Drug Discov.9 ( 8 ), 589 – 590 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Nightingale S . The neuropathic pain market . Nat. Rev. Drug Discov.11 ( 2 ), 101 – 102 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Williams PS , SewellRD , SmithHJ , GonzalezJP . Novel inhibitors of enkephalin-degrading enzymes. I: Inhibitors of enkephalinase by penicillins . J. Enzyme Inhib.3 ( 2 ), 91 – 101 ( 1989 ).
   PubMedGoogle Scholar
• Herman ZS , StachuraZ , LaskawiecG , KowalskiJ , ObuchowiczE . Antinociceptive effects of puromycin and bacitracin . Pol. J. Pharmacol. Pharm.37 ( 2 ), 133 – 140 ( 1985 ).
   PubMedGoogle Scholar
• Stepanovic-Petrovic RM , MicovAM , TomicMA , KovacevicJM , BoskovicBD . Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents . Anesthesiology120 ( 3 ), 737 – 750 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Rothstein JD , PatelS , ReganMRet al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression . Nature433 ( 7021 ), 73 – 77 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Gegelashvili G , BjerrumOJ . High-affinity glutamate transporters in chronic pain: an emerging therapeutic target . J. Neurochem.131 ( 6 ), 712 – 730 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Amin B , HajhashemiV , HosseinzadehH , AbnousK . Antinociceptive evaluation of ceftriaxone and minocycline alone and in combination in a neuropathic pain model in rat . Neuroscience224 , 15 – 25 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Macaluso A , BernabucciM , TrabuccoAet al. Analgesic effect of a single preoperative dose of the antibiotic ceftriaxone in humans . J. Pain14 ( 6 ), 604 – 612 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Bastos LF , De OliveiraAC , WatkinsLR , MoraesMF , CoelhoMM . Tetracyclines and pain . Naunyn Schmiedebergs Arch. Pharmacol.385 ( 3 ), 225 – 241 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Garrido-Mesa N , ZarzueloA , GalvezJ . Minocycline: far beyond an antibiotic . Br. J. Pharmacol.169 ( 2 ), 337 – 352 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Ji RR , XuZZ , GaoYJ . Emerging targets in neuroinflammation-driven chronic pain . Nat. Rev. Drug Discov.13 ( 7 ), 533 – 548 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Flatters SJ . The contribution of mitochondria to sensory processing and pain . Prog. Mol. Biol. Transl. Sci.131 , 119 – 146 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Bastos LF , AngustiA , VilacaMCet al. A novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice . Br. J. Pharmacol.155 ( 5 ), 714 – 721 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Wang X , GracePM , PhamMNet al. Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain . FASEB J.27 ( 7 ), 2713 – 2722 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Caruso I , MontroneF , FumagalliM , PatronoC , SantandreaS , GandiniMC . Rheumatoid knee synovitis successfully treated with intra-articular rifamycin SV . Ann. Rheum. Dis.41 ( 3 ), 232 – 236 ( 1982 ).
   PubMed Web of Science ®Google Scholar
• Fields HL , LevineJD . Pain–mechanics and management . West J. Med.141 ( 3 ), 347 – 357 ( 1984 ).
   PubMedGoogle Scholar
• Finnerup NB , AttalN , HaroutounianSet al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis . Lancet Neurol.14 ( 2 ), 162 – 173 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Finnerup NB , AttalN . Pharmacotherapy of neuropathic pain: time to rewrite the rulebook?Pain Manag.6 ( 1 ), 1 – 3 ( 2016 ).
   PubMedGoogle Scholar
• Moore RA , DerryS , AldingtonD , ColeP , WiffenPJ . Amitriptyline for fibromyalgia in adults . Cochrane Database Syst. Rev.7 , CD011824 ( 2015 ).
   PubMedGoogle Scholar
• Kautio AL , HaanpaaM , LeminenA , KalsoE , KautiainenH , SaartoT . Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms . Anticancer Res.29 ( 7 ), 2601 – 2606 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Smith EM , PangH , CirrincioneCet al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial . JAMA309 ( 13 ), 1359 – 1367 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Rouillon F , GorwoodP . The use of lithium to augment antidepressant medication . J. Clin. Psychiatry59 , 32 – 41 ( 1998 ).
   PubMed Web of Science ®Google Scholar
• Mo M , ErdelyiI , Szigeti-BuckK , BenbowJH , EhrlichBE . Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment . FASEB J.26 ( 11 ), 4696 – 4709 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Pertovaara A . Noradrenergic pain modulation . Prog. Neurobiol.80 ( 2 ), 53 – 83 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Obata H . Analgesic mechanisms of antidepressants for neuropathic pain . Int. J. Mol. Sci.18 ( 11 ), ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Gebhardt S , Heinzel-GutenbrunnerM , KonigU . Pain relief in depressive disorders: a meta-analysis of the effects of antidepressants . J. Clin. Psychopharmacol.36 ( 6 ), 658 – 668 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Challapalli V , Tremont-LukatsIW , McnicolED , LauJ , CarrDB . Systemic administration of local anesthetic agents to relieve neuropathic pain . Cochrane Database Syst. Rev.4 , CD003345 ( 2005 ).
   Google Scholar
• Tremont-Lukats IW , ChallapalliV , McnicolED , LauJ , CarrDB . Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis . Anesth. Analg.101 ( 6 ), 1738 – 1749 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Derry S , WiffenPJ , MooreRA , QuinlanJ . Topical lidocaine for neuropathic pain in adults . Cochrane Database Syst. Rev.7 , CD010958 ( 2014 ).
   Google Scholar
• Wallace M , KudrowD , McelveenWet al. Clinical trial results: a randomized, double-blind, placebo controlled, trial of three-day bupivacaine transdermal patch (ELADUR) in patients with post-herpetic neuralgia . Am. Pain Soc.9 ( 4 ), 44 ( 2008 ).
   Google Scholar
• Chong C , SchugSA , Page-SharpM , JenkinsB , IlettKF . Development of a sublingual/oral formulation of ketamine for use in neuropathic pain preliminary findings from a three-way randomized, crossover study . Clin. Drug Invest.29 ( 5 ), 317 – 324 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Alviar MJM , HaleT , DungcaM . Pharmacologic interventions for treating phantom limb pain . Cochrane Database Syst. Rev.12 , CD006380 ( 2011 ).
   PubMedGoogle Scholar
• Chaparro LE , SmithSA , MooreRA , WiffenPJ , GilronI . Pharmacotherapy for the prevention of chronic pain after surgery in adults . Cochrane Database Syst. Rev.7 , CD008307 ( 2013 ).
   Google Scholar
• Dahmani S , MicheletD , AbbackPSet al. Ketamine for perioperative pain management in children: a meta-analysis of published studies . Pediatric Anesthesia21 ( 6 ), 636 – 652 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Zhou HY , ChenSR , PanHL . Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain . Expert Rev. Clin. Pharmacol.4 ( 3 ), 379 – 388 ( 2011 ).
   PubMedGoogle Scholar
• Shrestha R , PantS , ShresthaA , BatajooKH , ThapaR , VaidyaS . Intranasal ketamine for the treatment of patients with acute pain in the emergency department . World J. Emerg. Med.7 ( 1 ), 19 – 24 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Carr DB , GoudasLC , DenmanWTet al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study . Pain108 ( 1-2 ), 17 – 27 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Inzucchi SE , BergenstalRM , BuseJBet al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) . Diabetes Care35 ( 6 ), 1364 – 1379 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Mao-Ying QL , KavelaarsA , KrukowskiKet al. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model . PLoS ONE9 ( 6 ), e100701 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Zhou G , MyersR , LiYet al. Role of AMP-activated protein kinase in mechanism of metformin action . J. Clin. Invest108 ( 8 ), 1167 – 1174 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Melemedjian OK , AsieduMN , TilluDVet al. Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain . Molecular Pain7 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Byrne F , CheethamS , VickersS , ChapmanV . Characterisation of pain responses in the high fat diet/streptozotocin model of diabetes and the analgesic effects of antidiabetic treatments . J. Diabetes Res.2015 , 752481 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Oliveira ACP , BertolloCM , RochaLTS , NascimentoEB , CostaKA , CoelhoMM . Antinociceptive and antiedematogenic activities of fenofibrate, an agonist of PPAR alpha, and pioglitazone, an agonist of PPAR gamma . Eur. J. Pharmacol.561 ( 1-3 ), 194 – 201 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Churi SB , Abdel-AleemOS , TumberKK , Scuderi-PorterH , TaylorBK . Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor-gamma to rapidly inhibit neuropathic pain in rats . J. Pain9 ( 7 ), 639 – 649 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Jia HB , ZhuSH , JiQet al. Repeated administration of pioglitazone attenuates development of hyperalgesia in a rat model of neuropathic pain . Exp. Clin. Psychopharmacol.18 ( 4 ), 359 – 365 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Takahashi Y , Hasegawa-MoriyamaM , SakuraiT , InadaE . The macrophage-mediated effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuate tactile allodynia in the early phase of neuropathic pain development . Anesth. Analg.113 ( 2 ), 398 – 404 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Tsujie M , NakamoriS , OkamiJet al. Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferatoractivated receptor gamma/retinoid X receptor alpha pathway . Exp. Cell Res.289 ( 1 ), 143 – 151 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Choucair-Jaafar N , YalcinI , RodeauJL , WaltispergerE , Freund-MercierMJ , BarrotM . Beta2-adrenoceptor agonists alleviate neuropathic allodynia in mice after chronic treatment . Br. J. Pharmacol.158 ( 7 ), 1683 – 1694 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Yalcin I , TessierLH , Petit-DemouliereNet al. Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain . Exp. Neurol.221 ( 1 ), 115 – 121 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Hama AT , BroadheadA , LorrainDS , SagenJ . The antinociceptive effect of the asthma drug ibudilast in rat models of peripheral and central neuropathic pain . J. Neurotrauma29 ( 3 ), 600 – 610 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Fujita M , TamanoR , YonedaSet al. Ibudilast produces anti-allodynic effects at the persistent phase of peripheral or central neuropathic pain in rats: Different inhibitory mechanism on spinal microglia from minocycline and propentofylline . Eur. J. Pharmacol.833 , 263 – 274 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Rolan P , HutchinsonMR , JohnsonKW . Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease . Exp. Opin. Pharmacother.10 ( 17 ), 2897 – 2904 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Kwok YH , SwiftJE , GazeraniP , RolanP . A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine . J. Pain Res.9 , 899 – 907 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Vicuna L , StrochlicDE , LatremoliereAet al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase . Nat. Med.21 ( 5 ), 518 – 523 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Waszkielewicz AM , GuniaA , SloczynskaK , MaronaH . Evaluation of anticonvulsants for possible use in neuropathic pain . Curr. Med. Chem.18 ( 28 ), 4344 – 4358 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Fornasari D . Pharmacotherapy for neuropathic pain: a review . Pain Ther.6 , S25 – S33 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Jensen TS . Anticonvulsants in neuropathic pain: rationale and clinical evidence . Eur. J. Pain6 , 61 – 68 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Kopsky DJ , Keppel HesselinkJM . A new combination cream for the treatment of severe neuropathic pain . J. Pain Symptom Manage.39 ( 2 ), e9 – e10 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Watkins LR , HutchinsonMR , RiceKC , MaierSF . The “Toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia . Trend. Pharmacol. Sci.30 ( 11 ), 581 – 591 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Hutchinson MR , ZhangYN , BrownKet al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4) . Eur. J. Neurosci.28 ( 1 ), 20 – 29 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Hutchinson MR , NorthcuttAL , HiranitaTet al. Opioid activation of toll-like receptor 4 contributes to drug reinforcement . J. Neurosci.32 ( 33 ), 11187 – 11200 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Lewis SS , LoramLC , HutchinsonMRet al. (+)-Naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats . J. Pain13 ( 5 ), 498 – 506 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Younger J , MackeyS . Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study . Pain Med.10 ( 4 ), 663 – 672 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Shin EJ , NahSY , ChaeJSet al. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats . Neurochem. Int.50 ( 6 ), 791 – 799 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Shin EJ , NahSY , KimWKet al. The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan . Br. J. Pharmacol.144 ( 7 ), 908 – 918 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Olney N , RosenH . AVP-923, a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect and neuropathic pain . IDrugs13 ( 4 ), 254 – 265 ( 2010 ).
   PubMedGoogle Scholar
• Gambito ED , Gonzalez-SuarezCB , OquinenaTI , AgbayaniRB . Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis . Arch. Phys. Med. Rehabil.91 ( 8 ), 1291 – 1305 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Mccleane G . The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized, double blind, placebo controlled study . Eur. J. Pain4 ( 4 ), 355 – 360 ( 2000 ).
   PubMed Web of Science ®Google Scholar
• Walsh KE , BermanJR , BermanLA , VierreggerK . Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study . J. Gend. Specif. Med.5 ( 4 ), 21 – 27 ( 2002 ).
   PubMedGoogle Scholar
• Fletcher S , WrightM , WilkinsonA , FarrM , SellarsL . Locally applied transdermal nitrate patches for the treatment of ischaemic rest pain . Int J. Clin. Pract.51 ( 5 ), 324 – 325 ( 1997 ).
   PubMed Web of Science ®Google Scholar
• Datta S , WaghrayT , TorresM , GlusmanS . Amiodarone decreases heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain . Anesth. Analg.98 ( 1 ), 178 – 184 ; table of contents ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Akada Y , OgawaS , AmanoKet al. Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats . Eur. J. Pharmacol.536 ( 3 ), 248 – 255 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Mcgowan E , HoytSB , LiXH , LyonsKA , AbbadieC . A peripherally acting Na(v)1.7 sodium channel blocker reverses hyperalgesia and allodynia on rat models of inflammatory and neuropathic pain . Anesth. Analg.109 ( 3 ), 951 – 958 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Carroll IR , KaplanKM , MackeySC . Mexiletine therapy for chronic pain: survival analysis identifies factors predicting clinical success . J. Pain Symptom Manage.35 ( 3 ), 321 – 326 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Giovannoni MP , GhelardiniC , VergelliC , Dal PiazV . Alpha2-agonists as analgesic agents . Med. Res. Rev.29 ( 2 ), 339 – 368 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Blaudszun G , LysakowskiC , EliaN , TramerMR . Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials . Anesthesiology116 ( 6 ), 1312 – 1322 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Engelman E , MarsalaC . Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis . Br. J. Anaesth.110 ( 1 ), 21 – 27 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Schnabel A , ReichlSU , PoeppingDM , KrankeP , Pogatzki-ZahnEM , ZahnPK . Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials . Paediatr. Anaesth.23 ( 2 ), 170 – 179 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Linde K , RossnagelK . Propranolol for migraine prophylaxis . Cochrane Database Syst Rev.2 , CD003225 ( 2004 ).
   Google Scholar
• Davidson EM , DoursoutMF , SzmukP , ChellyJE . Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats . Can. J. Anaesth.48 ( 1 ), 59 – 64 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Favaro-Moreira NC , ParadaCA , TambeliCH . Blockade of beta(1)-, beta(2)- and beta(3)-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats . Eur. J. Pain16 ( 9 ), 1302 – 1310 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Vale ML , BenevidesVM , SachsDet al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain . Br. J. Pharm.143 ( 7 ), 833 – 844 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Liu J , FengXM , YuMet al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain . Neurosci. Lett.412 ( 3 ), 268 – 272 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Mika J . Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness . Pharmacol. Rep.60 ( 3 ), 297 – 307 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Izadpanah F , MojtahedzadehM , AghamirSMK , AtharikiaD , DashtiS , AbbasiA . Effect of intravenous pentoxifylline in inflammatory response in patients undergoing nephrolithotomy . J. Endourol.23 ( 2 ), 323 – 328 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Groeneweg G , HuygenFJPM , NiehofSPet al. Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: a randomized controlled trial . BMC Musculoskeletal. Disord.9 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Grace PM , RolanPE , HutchinsonMR . Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain . Brain Behav. Immun.25 ( 7 ), 1322 – 1332 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Geranton SM , Jimenez-DiazL , TorsneyCet al. A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states . J. Neurosci.29 ( 47 ), 15017 – 15027 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Price TJ , RashidMH , MillecampsM , SanojaR , EntrenaJM , CerveroF . Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR . J. Neurosci.27 ( 51 ), 13958 – 13967 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Orhan CE , OnalA , UlkerS . Antihyperalgesic and antiallodynic effect of sirolimus in neuropathic pain and the role of cytokines in this effect . Neurosci. Lett.481 ( 1 ), 17 – 20 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• George A , MarziniakM , SchafersM , ToykaKV , SommerC . Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin . Pain88 ( 3 ), 267 – 275 ( 2000 ).
   PubMed Web of Science ®Google Scholar
• Barsante MM , RoffeE , YokoroCMet al. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis . Eur. J. Pharmacol.516 ( 3 ), 282 – 289 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Wahane VD , KumarVL . Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis . Pharmacol. Res.61 ( 4 ), 329 – 333 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Garcia GG , MirandaHF , NoriegaVet al. Antinociception induced by atorvastatin in different pain models . Pharmacol. Biochem. Behav.100 ( 1 ), 125 – 129 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Miranda HF , NoriegaV , OlavarriaL , ZepedaRJ , SierraltaF , PrietoJC . Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice . Basic Clin. Pharmacol. Toxicol.109 ( 6 ), 438 – 442 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Shi XQ , LimTKY , LeeS , ZhaoYQ , ZhangJ . Statins alleviate experimental nerve injury-induced neuropathic pain . Pain152 ( 5 ), 1033 – 1043 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Edmonds SE , WinyardPG , GuoRet al. Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial . Ann. Rheum. Dis.56 ( 11 ), 649 – 655 ( 1997 ).
   PubMed Web of Science ®Google Scholar
• Brand C , SnaddonJ , BaileyM , CicuttiniFM . Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study . Ann. Rheum. Dis.60 ( 10 ), 946 – 949 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Lu R , Kallenborn-GerhardtW , GeisslingerG , SchmidtkoA . Additive antinociceptive effects of a combination of vitamin C and vitamin E after peripheral nerve injury . Naunyn Schmiedebergs Arch. Pharmacol.385 , 54 – 55 ( 2012 ).
   Web of Science ®Google Scholar
• Lu RR , Kallenborn-GerhardtW , GeisslingerG , SchmidtkoA . Additive antinociceptive effects of a combination of vitamin C and vitamin E after peripheral nerve injury . PLoS ONE6 ( 12 ), ( 2011 ).
   Web of Science ®Google Scholar
• Stracke H , LindemannA , FederlinK . A Benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy . Exp. Clin. Endocrinol. Diabetes104 ( 4 ), 311 – 316 ( 1996 ).
   PubMed Web of Science ®Google Scholar
• Holland S , SilbersteinSD , FreitagF , DodickDW , ArgoffC , AshmanE . Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society . Neurology78 ( 17 ), 1346 – 1353 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Kragstrup TW . Vitamin D supplementation for patients with chronic pain . Scand. J. Primary Health Care29 ( 1 ), 4 – 5 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Helde-Frankling M , Bjorkhem-BergmanL . Vitamin D in pain management . Int. J. Mol. Sci.18 ( 10 ), ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Al-Nimer MS . Vitamin D: Is it a primary hormone targeting the migraine headache or just as adjunct therapy?Neurosciences22 ( 1 ), 69 – 69 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Gazerani P , FuglsangR , PedersenJGet al. A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D3 supplementation in adult patients with migraine . Curr. Med. Res. Opin.1 – 9 ( 2018 ).
   Google Scholar
• Perkins JR , LeesJ , Antunes-MartinsAet al. PainNetworks: a web-based resource for the visualisation of pain-related genes in the context of their network associations . Pain154 ( 12 ), ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Jin GX , WongSTC . Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines . Drug Discov. Today19 ( 5 ), 637 – 644 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Li J , ZhengS , ChenB , ButteAJ , SwamidassSJ , LuZ . A survey of current trends in computational drug repositioning . Brief Bioinform.17 ( 1 ), 2 – 12 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Li YY , JonesSJ . Drug repositioning for personalized medicine . Genome Med.4 ( 3 ), 27 ( 2012 ).
   PubMedGoogle Scholar
• Gills J , Lo PiccoloJ , TsurutaniJet al. Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo . Clin. Cancer Res.13 ( 17 ), 5183 – 5194 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Chow WA , JiangCL , GuanM . Anti-HIV drugs for cancer therapeutics: back to the future?Lancet Oncol.10 ( 1 ), 61 – 71 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Fabian MA , BiggsWH , TreiberDKet al. A small molecule–kinase interaction map for clinical kinase inhibitors . Nat. Biotechnol.23 ( 3 ), 329 – 336 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Karaman MW , HerrgardS , TreiberDKet al. A quantitative analysis of kinase inhibitor selectivity . Nat. Biotechnol.26 ( 1 ), 127 – 132 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Schuessler B . What do we know about duloxetine’s mode of action? Evidence from animals to humans . BJOG113 , 5 – 9 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Mease PJ . Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors . Am. J. Med.122 ( 12 Suppl. ), S44 – 55 ( 2009 ).
   PubMedGoogle Scholar
• Marcus DA . Duloxetine use in painful conditions . Exp. Opin. Pharmacother.12 ( 8 ), 1333 – 1340 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Bradley D . Why big pharma needs to learn the three ‘R’s . Nat. Rev. Drug Discov.4 ( 6 ), 446 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Emig D , IvlievA , PustovalovaOet al. Drug target prediction and repositioning using an integrated network-based approach . PLoS ONE8 ( 4 ), e60618 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Cheng FX , LiuC , JiangJet al. Prediction of drug-target interactions and drug repositioning via network-based inference . PLoS Computational Biol.8 ( 5 ), ( 2012 ).
   Web of Science ®Google Scholar
• Zhao SW , LiS . Network-Based relating pharmacological and genomic spaces for drug target identification . PLoS ONE5 ( 7 ), ( 2010 ).
   Web of Science ®Google Scholar
• Yang L , AgarwalP . Systematic drug repositioning based on clinical side-effects . PLoS ONE6 ( 12 ), ( 2011 ).
   Web of Science ®Google Scholar
• Kinnings SL , LiuN , BuchmeierN , TongePJ , XieL , BournePE . Drug discovery using chemical systems biology: repositioning the safe medicine comtan to treat multi-drug and extensively drug resistant tuberculosis . PLoS Computational Biol.5 ( 7 ), ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Jadamba E , ShinM . A Systematic framework for drug repositioning from integrated omics and drug phenotype profiles using pathway-drug network . Biomed. Res. Int.2016 , 7147039 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Li J , LuZY . Pathway-based drug repositioning using causal inference . BMC Bioinformatics14 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kotelnikova E , YuryevA , MazoI , DaraseliaN . Computational approaches for drug repositioning and combination therapy design . J. Bioinform. Comput. Biol.8 ( 3 ), 593 – 606 ( 2010 ).
   PubMedGoogle Scholar
• Gaiteri C , DingY , FrenchB , TsengGC , SibilleE . Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders . Genes Brain. Behav.13 ( 1 ), 13 – 24 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Iorio F , RittmanT , GeH , MendenM , Saez-RodriguezJ . Transcriptional data: a new gateway to drug repositioning?Drug Discov. Today18 ( 7-8 ), 350 – 357 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Wang Y , YellaJ , ChenJ , MccormackFX , MadalaSK , JeggaAG . Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers . BMC Pulm. Med.17 ( 1 ), 133 ( 2017 ).
   PubMedGoogle Scholar
• Lamb J , CrawfordED , PeckDet al. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease . Science313 ( 5795 ), 1929 – 1935 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Musa A , GhoraieLS , ZhangSDet al. A review of connectivity map and computational approaches in pharmacogenomics (bbw112, 2017) . Brief. Bioinform.18 ( 5 ), 903 – 903 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Barrett T , SuzekTO , TroupDBet al. NCBI GEO: mining millions of expression profiles – database and tools . Nucleic Acids Res.33 ( Database issue ), D562 – 566 ( 2005 ).
   PubMedGoogle Scholar
• Barrett T , TroupDB , WilhiteSEet al. NCBI GEO: mining tens of millions of expression profiles – database and tools update . Nucleic Acids Res.35 ( Database issue ), D760 – 765 ( 2007 ).
   PubMedGoogle Scholar
• Subramanian A , NarayanR , CorselloSMet al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles . Cell171 ( 6 ), 1437 – 1452e1417 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Niculescu AB , Le-NiculescuH , LeveyDFet al. Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs . Mol. Psychiatry ( 2019 ).
   Web of Science ®Google Scholar
• Angermueller C , ParnamaaT , PartsL , StegleO . Deep learning for computational biology . Mol. Syst. Biol.12 ( 7 ), 878 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Luo H , WangJ , LiMet al. Drug repositioning based on comprehensive similarity measures and Bi-Random walk algorithm . Bioinformatics32 ( 17 ), 2664 – 2671 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Oh M , AhnJ , YoonY . A network-based classification model for deriving novel drug-disease associations and assessing their molecular actions . PLoS ONE9 ( 10 ), e111668 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Gottlieb A , SteinGY , RuppinE , SharanR . PREDICT: a method for inferring novel drug indications with application to personalized medicine . Mol. Syst. Biol.7 , 496 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Liu Z , GuoF , GuJet al. Similarity-based prediction for Anatomical Therapeutic Chemical classification of drugs by integrating multiple data sources . Bioinformatics31 ( 11 ), 1788 – 1795 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Schadt EE . Molecular networks as sensors and drivers of common human diseases . Nature461 ( 7261 ), 218 – 223 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Azuaje F . Drug interaction networks: an introduction to translational and clinical applications . Cardiovasc. Res.97 ( 4 ), 631 – 641 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Brown AS , PatelCJ . A review of validation strategies for computational drug repositioning . Brief. Bioinform.19 ( 1 ), 174 – 177 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Lee WH . Open access target validation is a more efficient way to accelerate drug discovery . PLoS Biol.13 ( 6 ), ( 2015 ).
   Web of Science ®Google Scholar
• Carter AJ , DonnerA , LeeWH , BountraC . Establishing a reliable framework for harnessing the creative power of the scientific crowd . PLoS Biol.15 ( 2 ), ( 2017 ).
   Web of Science ®Google Scholar
• Munos B . Can open-source drug R&D repower pharmaceutical innovation?Clin. Pharmacol. Ther.87 ( 5 ), 534 – 536 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Lakhani KR , BoudreauKJ , LohPRet al. Prize-based contests can provide solutions to computational biology problems . Nat. Biotechnol.31 ( 2 ), 108 – 111 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Arrowsmith J , MillerP . Trial watch: Phase II and Phase III attrition rates 2011-2012 . Nat. Rev. Drug Discov.12 ( 8 ), 569 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Gewandter JS , DworkinRH , TurkDCet al. Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations . Pain155 ( 9 ), 1683 – 1695 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Oprea TI , MestresJ . Drug repurposing: far beyond new targets for old drugs . AAPS J.14 ( 4 ), 759 – 763 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Sternitzke C . Drug repurposing and the prior art patents of competitors . Drug Discov. Today19 ( 12 ), 1841 – 1847 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Mucke HaM . Drug repositioning in the mirror of patenting: surveying and mining uncharted territory . Front. Pharmacol.8 , 927 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Nishimura Y , HaraH . Editorial: Drug repositioning: current advances and future perspectives . Front. Pharmacol.9 , 1068 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Nishimura Y , TagawaM , ItoH , TsurumaK , HaraH . Overcoming obstacles to drug repositioning in Japan . Front. Pharmacol.8 ( 2017 ).
   Web of Science ®Google Scholar
• Nugent T , PlachourasV , LeidnerJL . Computational drug repositioning based on side-effects mined from social media . PeerJ4 , e3154 ( 2016 ).
   Google Scholar
• Nagaraj AB , WangQQ , JosephPet al. Using a novel computational drug-repositioning approach (DrugPredict) to rapidly identify potent drug candidates for cancer treatment . Oncogene37 ( 3 ), 403 – 414 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Xu X , HuangM , ZouX . Docking-based inverse virtual screening: methods, applications, and challenges . Biophys. Rep.4 ( 1 ), 1 – 16 ( 2018 ).
   PubMedGoogle Scholar
• Kim S , ThiessenPA , BoltonEEet al. PubChem Substance and Compound databases . Nucleic Acids Res.44 ( D1 ), D1202 – 1213 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Gaulton A , HerseyA , NowotkaMet al. The ChEMBL database in 2017 . Nucleic Acids Res.45 ( D1 ), D945 – D954 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Wishart DS , FeunangYD , GuoACet al. DrugBank 5.0: a major update to the DrugBank database for 2018 . Nucleic Acids Res.46 ( D1 ), D1074 – D1082 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Ursu O , HolmesJ , KnockelJet al. DrugCentral: online drug compendium . Nucleic Acids Res.45 ( D1 ), D932 – D939 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Keenan AB , JenkinsSL , JagodnikKMet al. The library of integrated network-based cellular signatures NIH program: system-level cataloging of human cells response to perturbations . Cell Syst.6 ( 1 ), 13 – 24 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Koleti A , TerrynR , StathiasVet al. Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: integrated access to diverse large-scale cellular perturbation response data . Nucleic Acids Res.46 ( D1 ), D558 – D566 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Rose PW , PrlicA , AltunkayaAet al. The RCSB protein data bank: integrative view of protein, gene and 3D structural information . Nucleic Acids Res.45 ( D1 ), D271 – D281 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Janezic D , KoncJ . ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites . Nucleic Acids Res.42 ( Web Server issue ), W215 – W220 ( 2015 ).
   Google Scholar
• Konc J , JanezicD . ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites . Nucleic Acids Res.42 ( W1 ), W215 – W220 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Salentin S , SchreiberS , HauptVJ , AdasmeMF , SchroederM . PLIP: fully automated protein-ligand interaction profiler . Nucleic Acids Res.43 ( W1 ), W443 – W447 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Corsello SM , BittkerJA , LiuZHet al. The drug repurposing hub: a next-generation drug library and information resource . Nat. Med.23 ( 4 ), 405 – 408 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Tang J , TanoliZUR , RavikumarBet al. Drug target commons: a community effort to build a consensus knowledge base for drug-target interactions . Cell Chem. Biol.25 ( 2 ), 224 – 229 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Koscielny G , AnP , Carvalho-SilvaDet al. Open targets: a platform for therapeutic target identification and validation . Nucleic Acids Res.45 ( D1 ), D985 – D994 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Brown AS , PatelCJ . A standard database for drug repositioning . Sci. Data4 , 170029 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Shameer K , GlicksbergBS , HodosRet al. Systematic analyses of drugs and disease indications in RepurposeDB reveal pharmacological, biological and epidemiological factors influencing drug repositioning . Brief. Bioinform.19 ( 4 ), 656 – 678 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Fang J , GaoL , MaHet al. Quantitative and Systems Pharmacology 3. Network-based identification of new targets for natural products enables potential uses in aging-associated disorders . Front. Pharmacol.8 , 747 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Wang X , LiuC , WangJ , FanY , WangZ , WangY . Proton pump inhibitors increase the chemosensitivity of patients with advanced colorectal cancer . Oncotarget8 ( 35 ), 58801 – 58808 ( 2017 ).
   PubMedGoogle Scholar
• Ikemura K , HiramatsuS , OkudaM . Drug repositioning of proton pump inhibitors for enhanced efficacy and safety of cancer chemotherapy . Front. Pharmacol.8 , 911 ( 2017 ).
   PubMed Web of Science ®Google Scholar