trends in exploration of therapeutic targets · s/nm made by total synthesis inspired by a natural...

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Methods

Nature-derived approved drugs were identified as follows: The set of approved drugs and

the year of approval were collected from the literatures (e.g. Quarterly and annual reports

of FDA drug approval reports in Nature Biotechnology and Nature Reviews Drug

Discovery, reference 18 and 19), FDA website, and Drugbank20 and the Therapeutic target

database21. For the 2008-2012 drugs, only new molecular entities were included. The

initial set of approved nature-derived drugs were from the two recent papers18,19, which

were evaluated against the approved drug set to confirm their approval status, then their

nature-derived status was evaluated via comprehensive literature search to confirm that

either their natural product leads have been reported or they have been explicitly

mentioned as nature-derived in the literature that report their discovery. For the approved

drugs not covered by the initial set of nature-derived drugs (e.g. FDA approved drugs in

2011-2012, some approved vaccines), we conducted literature search to determine whether

or not they are nature-derived and, for the nature-derived ones, to find their natural product

leads.

Literature search was conducted by searching the original publications and review articles

by using combinations of such keywords as “drug name and alternative names”,

“discovery”, “species”, “natural product” and “nature”. While possible, the original

articles describing the discovery and optimization of each drug and lead were selected.

Some of the searched literatures are provided in Supplementary Table S2. The species

origin of a lead was determined via additional literature search based on the explicit report

that the lead “originates from”, “derived from”, “isolated from”, or “comes from” a species

Nature Biotechnology: doi:10.1038/nbt.3034

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or species-group (e.g. genus or family). The corresponding species-families of the host

species of these drugs as well as all the known species-families in the nature are from the

NCBI taxonomy database22. The species families that are in preexisting drug-productive

families or drug-productive clusters were described in our recent publications19.

Reference:

18． Newman, D.J. & Cragg, G.M. J Nat Prod. 75, 311-35 (2012)

19． Zhu, F. et al. Proc Natl Acad Sci USA. 108, 12943-8 (2011)

20． Knox, C. et al. Nucleic Acids Res. 39(Database issue):D1035-41. (2011)

21． Zhu, F. et al. Nucleic Acids Res. 40(Database issue):D1128-36. (2012)

22． Federhen, S. Nucleic Acids Res. 40(Database issue): D136–43. (2012)


Drug Generic Name Drug Targeted DiseaseFDA Approval

Drug Type

Year of Approval

Aclidinium bromide Bronchospasms associated with COPD Y 2012

Apixaban Stroke and systemic embolism in patients with non-valvular atrial fibrillation Y 2012

Avanafil Erectile dysfunction Y 2012Axitinib Advanced renal cell carcinoma Y 2012Bedaquiline fumarate Pulmonary multidrug-resistant tuberculosis Y 2012

Bosutinib monohydrate Chronic, accelerated or blast phase Ph+ chronic myelogenous leukaemia Y 2012

Cabozantinib s-malate Progressive, metastatic medullary thyroid cancer Y 2012

Carfilzomib Multiple myeloma Y ND 2012Citric acid; Magnesium oxide; Sodium picosulfate Cleansing of the colon before colonoscopy Y 2012

Cobicistat; Elvitegravir; Emtricitabine; Tenofovir disoproxil fumarate HIV-1 infection Y 2012

Crofelemer HIV-associated diarrhoea Y N 2012Enzalutamide Metastatic castration-resistant prostate Y 2012

GlucarpidaseToxic plasma methotrexate concentrations in patients with delayed methotrexate Y B* 2012

Ingenol mebutate Actinic keratosis Y N 2012

Ivacaftor Cystic fibrosis in patients with the G551D mutation in the CFTR gene Y 2012

Linaclotide Irritable bowel syndrome with constipation; chronic idiopathic constipation Y B* 2012

Lomitapide mesylate Homozygous familial Y 2012Lorcaserin hydrochloride Obesity Y 2012Lucinactant Prevention of respiratory distress syndrome Y ND 2012Mirabegron Overactive bladder Y 2012Ocriplasmin Symptomatic vitreomacular adhesion Y B* 2012

Omacetaxine mepesuccinate Chronic or accelerated-phase chronic myeloid leukaemia Y N 2012

Pasireotide diaspartate Cushing's disease Y ND 2012Peginesatide acetate Anaemia due to chronic kidney disease Y NM 2012

Perampanel Partial-onset seizures in patients with epilepsy Y 2012

Pertuzumab HER2-positive metastatic breast cancer Y B* 2012

Drug types:

N Natural product;ND Derived from a natural product and is usually a semisynthetic modification;NM Natural product mimic;B Biologics of non-human sources including peptides, nucleic acids, proteins, and antibodies;B* Biologics of human sources including peptides, nucleic acids, proteins, and antibodies;S* Made by total synthesis based on the pharmacophore from a natural product; S/NM Made by total synthesis inspired by a natural product;S*/NM Made by total synthesis inspired by the pharmacophore from a natural product;

Included here are drugs approved by FDA (new molecular entities only) and by other regulatory agencies in Europe and Japan etc

Supplementary Table S1 List of Approved Drugs Used in Our Analysis


Ponatinib hydrochloride Chronic, accelerated or blast-phase chronic myeloid leukaemia Y 2012

Raxibacumab Anthrax Y B* 2012Regorafenib Metastatic colorectal cancer Y 2012

TafluprostElevated intraocular pressure in patients with open-angle glaucoma or ocular Y ND 2012

Taliglucerase alfa Gaucher's disease Y B* 2012

Tbo-filgrastim Severe neutropaenia in patients with non-myeloid malignancies Y B* 2012

Teduglutide Short bowel syndrome Y B* 2012Teriflunomide Relapsing forms of multiple sclerosis Y 2012Tofacitinib citrate Severely active rheumatoid arthritis Y 2012

Vismodegib Metastatic or locally advanced basal cell carcinoma Y S* 2012

Ziv-aflibercept Metastatic colorectal cancer Y B* 2012Abiraterone Metastatic castration-resistant prostate Y ND 2011

Aflibercept Neovascular (wet) age-related macular degeneration Y B* 2011

Asparaginase erwinia chrysanthemi Acute lymphoblastic leukaemia Y B* 2011Azilsartan kamedoxomil Hypertension Y 2011Belatacept Organ rejection in kidney transplant Y B* 2011

Belimumab Active, autoantibody-positive, systemic lupus erythematosus Y B* 2011

Boceprevir HCV genotype 1 Y 2011

Brentuximab vedotin Hodgkin's lymphoma; systemic anaplastic large cell lymphoma Y 2011

Clobazam Seizures associated with Lennox–Gastaut syndrome Y 2011

Crizotinib ALK-positive advanced or metastatic Y 2011

Deferiprone Transfusional iron overload due to thalassaemia syndromes Y 2011

Ezogabine Partial-onset seizures Y 2011Fidaxomicin Clostridium difficile-associated diarrhoea Y N 2011Gabapentin enacarbil Moderate-to-severe restless legs syndrome Y 2011Icatibant Hereditary angioedema Y NM 2011Indacaterol maleate COPD Y 2011Ipilimumab Unresectable or metastatic melanoma Y B* 2011Linagliptin Type 2 diabetes Y ND 2011Rilpivirine HIV-1 infection Y NM 2011

Rivaroxaban Prophylaxis of deep vein thrombosis in hip and knee replacement surgery Y 2011

Roflumilast COPD exacerbations Y 2011Ruxolitinib phosphate Intermediate or high-risk myelofibrosis Y 2011Spinosad Head lice Y N 2011Telaprevir HCV genotype 1 Y NM 2011

Ticagrelor Thrombotic cardiovascular events in patients with acute coronary syndrome Y ND 2011

Vandetanib Unresectable or metastatic medullary thyroid cancer Y 2011

Vemurafenib BRAF-positive unresectable or metastatic melanoma Y 2011

Vilazodone hydrochloride Major depressive disorder Y 20113,4-diaminopyridine phosphate Lambert-Eaton Myasthenic Syndr ND 2010Alcaftadine Allergic conjunctivitis Y 2010Alpha1-proteinase inhibitor Emphysema Y B* 2010Bazedoxifene acetate Calcium metabolism 2010


Bilastine Antihistamine 2010Cabazitaxel; Xrp-6258 Prostate cancer Y ND 2010Carglumic acid Acute hyperammonaemia Y ND 2010

Ceftaroline fosamil Skin and skin-structure infections; community acquired pneumonia Y ND 2010

Collagenase clostridium histolyticum Dupuytren's contracture Y B 2010Corifollitropin alfa Infertility (female) B* 2010Dabigatran; Bibr 953 Stroke prevention in atrial fibrillation Y S*/NM 2010

Dalfampridine Improving walking in patients with multiple sclerosis Y ND 2010

Denosumab Postmenopausal osteoporosis? Y B* 2010Dienogest; Estradiol valerate Contraception Y 2010Diquafosol tetrasodium Dry eye syndrome 2010Eribulin; E7389; Nsc-707389; Eribulin mesylate Breast cancer Y ND 2010

Fingolimod; Fty720 Multiple sclerosis Y ND 2010Immune globulin subcutaneous, 20% liquid Primary immunodeficiencies Y B* 2010

Incobotulinumtoxina Cervical dystonia and blepharospasm Y B 2010Laninamivir octanoate Antiviral ND 2010Liraglutide Type 2 diabetes Y ND 2010Lurasidone hydrochloride Schizophrenia Y 2010Mifamurtide Anticancer ND 2010Miriplatin hydrate Anticancer 2010Pegloticase Gout Y B* 2010Peramivir Antiviral (H1N1] 2010

Polidocanol Uncomplicated spider veins and uncomplicated reticular veins Y 2010

Prucalopride Constipation 2010Tesamorelin HIV lipodystrophy Y B* 2010Tocilizumab Rheumatoid arthritis Y B* 2010Ulipristal Contraception Y ND 2010Velaglucerase alfa Gaucher's disease Y B* 2010Vernakalant hcl Atrial fibrillation 2010Vinflunine Anticancer ND 2010Zucapsacin Osteoarthritis ND 2010Abobotulinum-toxin a Cervical dystonia and glabellar lines Y B 2009Armodafinil Narcolepsy 2009Artemether; lumefantrine Malaria Y ND 2009Asenapine maleate Schizophrenia and bipolar disorder Y 2009Benzyl alcohol Head lice Y 2009Bepotastine besilate Allergic conjunctivitis Y 2009Besifloxacin hydrochloride Bacterial conjunctivitis Y 2009Canakinumab Cryopyrin-associated periodic syndromes Y B* 2009Catumaxomab Anticancer B 2009Chondrocelect Cartilage disorders B* 2009Coagulation factor ix Hemophilia B* 2009Dapoxetine hcl Premature ejaculation 2009Dexlansoprazole Antiulcer 2009Dronedarone hcl Atrial fibrillation and atrial flutter Y ND 2009Ecallantide Hereditary angioedema Y B 2009Eslicarbazepine acetate Antieplleptic 2009Everolimus; Rad-001; Sdz rad Renal cell carcinoma Y ND 2009Febuxostat Hyperuricaemia in patients with gout Y 2009


Golimumab Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis Y B* 2009

Igiv-hb Antiviral B* 2009Iloperidone Schizophrenia Y 2009Lasofoxifene tartrate Calcium metabolism 2009Milnacipran hydrochloride Fibromyalgia Y 2009Minodronate Calcium metabolism 2009Nalfurafine hcl Uremic pruritis ND 2009Niacin/laropiprant Hypocholesterolemic 2009Ofatumumab Chronic lymphocytic leukaemia Y B* 2009Pazopanib; Gw-786034 Renal cell carcinoma Y NM 2009Pitavastatin Hyperlipidaemia and mixed dyslipidaemia Y S*/NM 2009Pralatrexate Peripheral T cell lymphoma Y ND 2009

Prasugrel hydrochloride

Reduction of thrombotic cardiovascular events in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Y 2009

Romidepsin Cutaneous T cell lymphoma Y N 2009Saxagliptin hydrochloride Type 2 diabetes Y 2009Telavancin Complicated skin and skin structure Y ND 2009

Tolvaptan

Hypervolaemic and euvolaemic hyponatraemia, including patients with heart failure, cirrhosis and syndrome of inappropriate antidiuretic hormone

Y 2009

Uliprisnil acetate Contraception 2009Ustekinumab Moderate-to-severe plaque psoriasis Y B* 2009

VigabatrinInfantile spasms in children aged 1 month to 2 years and complex partial seizures in Y ND 2009

Alvimopan To accelerate gastrointestinal recovery following bowel resection surgery Y 2008

Artesunate; Amodiaquine; Asaq Antiparasitic ND 2008Bendamustine hydrochloride Chronic lymphocytic leukaemia Y 2008Biolimus a9 Restenosis ND 2008Blonanserin Antipsychotic 2008Ceftobiprole medocaril Antibacterial ND 2008Certolizumab pegol Crohn's disease Y B* 2008

Clevidipine Peri-operative hypertension when oral therapy is not feasible or not desirable Y 2008

Degarelix Advanced prostate cancer Y NM 2008Desvenlafaxine Major depressive disorder Y ND 2008Dienogest Endometriosis ND 2008

Difluprednate Inflammation and pain associated with ocular surgery Y ND 2008

Eltrombopag olamineThrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura

Y 2008

Etravirine HIV-1 Y 2008Fesoterodine fumarate Overactive bladder disorder Y 2008Fosaprepitant dimeglumine Antiemetic 2008Fospropofol disodium Monitored anaesthesia care sedation Y 2008Lacosamide Partial-onset seizures in epilepsy Y 2008Methylnaltrexone bromide Opioid-induced constipation Y ND 2008Oralair grasses Allergic rhinitis B 2008Pirfenidone Idiopathic pulmonary fibrosis 2008


PlerixaforAutologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma

Y 2008

Rh-thrombin Hemorrhage B* 2008Rh-thrombomodulin Anticoagulant B* 2008

RilonaceptCryopyrin-associated periodic syndromes including familial cold autoinflammatory syndrome and Muckle–Wells syndrome

Y B* 2008

RomiplostimThrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura

Y B* 2008

Rufinamide Seizures associated with Lennox–Gastaut syndrome Y 2008

Sf-1019 Diabetic neuropathies B 2008Silodosin Benign prostatic hyperplasia Y 2008Sitafloxacin hydrate Antifungal 2008Sugammadex sodium Antidote ND 2008Tapentadol hydrochloride Moderate to severe acute pain Y 2008Tetrabenazine Chorea associated with Huntington's Y 2008131i-chtnt Anticancer B* 2007Aliskiren hemifumarate Hypertension Y S*/NM 2007Ambrisentan Pulmonary arterial hypertension Y 2007Arformoterol tartrate COPD 2007Citrofen Antiarthritic N 2007Clevudine Antiviral (hepatitis B) 2007Colostrinin Dementia, Alzheimer's B 2007Curemisinin Antiallergic B 2007Doripenem; S-4661 Urinary tract infections Y ND 2007Eculizumab Paroxysmal nocturnal haemogobinuria Y B 2007Epoietin delta Hematopoiesis B* 2007Fluticasone furoate Antiallergic ND 2007Follitropin alfa/lutropin alfa Infertility (female) B* 2007Garenoxacin Antibacterial 2007Human immune globulin Idiopathic thrombocytopenia B* 2007Human thrombin Hemostasis B* 2007Hydroxyethyl starch Serious blood volume loss Y 2007Imidafenacin Overactive bladder 2007Ixabepilone; Bms-247550 Advanced or metastatic breast cancer Y ND 2007Lanreotide Acromegaly Y ND 2007Lapatinib; Lapatanib; Gw2016; Gsk572016 Advanced or metastatic breast cancer Y S/NM 2007

Lisdexamfetamine dimesylate ADHD Y ND 2007Maraviroc; Uk-427,857 CCR5-tropic HIV-1 Y S/NM 2007Methoxy polyethylene glycol-epoetin beta

Anaemia associated with chronic renal failure Y B* 2007

Nebivolol hydrochloride Hypertension Y 2007Nilotinib; Amn-107 Chronic myelogenous leukaemia Y ND 2007Raltegravir potassium HIV-1 Y 2007Retapamulin; Sb-275833 Impetigo Y ND 2007Revaprazan hydrochlorie Antiulcer 2007Rexin-g Anticancer B* 2007Rfsh/rhfsh Fertility inducer B* 2007Rh-erythropoietin-alfa Erythropoiesis B* 2007Rotigotine Early stage idiopathic Parkinson’s disease Y S/NM 2007Sapropterin dihydrochloride Hyperphenylalaninaemia Y ND 2007


Sphingosomal topotecan; Inx-0076 Oncological disease ND 2007Stiripentol Antiepileptic 2007Temsirolimus; Cci-779 Advanced renal cell carcinoma Y ND 2007Trabectedin; Ecteinascidin; Ecteinascidin-743; Et-743 Oncological disease N 2007

Vildagliptin Antidiabetic 2007Xp-828l Antipsoriatic B 2007Alglucosidase alfa Pompe's disease Y B* 2006Anecortave acetate Macular degeneration ND 2006Anidulafungin; Ver-002; V-echinocandin; Ly-303366 Oesophageal candidiasis Y ND 2006

Antithrombin alfa Anticoagulant B* 2006Avobenzone, ecamsule and

Prevention of sunburn Y 2006

Biskalcitrate potassium, metronidazole and tetracycline hydrochloride Gastric and duodenal ulcers Y 2006

Ciclesonide Allergic rhinitis Y ND 2006Darunavir; Tmc114 HIV Y S*/NM 2006Dasatinib Chronic myeloid leukaemia Y S/NM 2006Decitabine Myelodysplastic syndrome Y S* 2006Idursulfase Hunter syndrome (mucopolysaccharidosis Y B* 2006Lubiprostone Constipation Y ND 2006Mozavaptan Diuretic 2006Nimotuzumab Anticancer B 2006Nix-0699 Anti sickle cell anemia N 2006Paliperidone Schizophrenia Y 2006

Panitumumab EGFR-expressing metastatic colorectal carcinoma Y B* 2006

Polyphenon e External genital and perianal warts Y N 2006Posaconazole Aspergillus and Candida infections Y 2006

Ranibizumab Neovascular (wet) age-related macular degeneration Y B 2006

Ranolazine Chronic angina Y 2006Rasagiline mesylate Parkinson’s disease Y 2006Rh-alphaglucosidase Pompe's disease B* 2006Rhpth Osteoporosis B* 2006Rimonabant Antiobesity 2006Sitagliptin phosphate Type 2 diabetes Y 2006Sitaxsentan sodium Pulmonary arterial hypertensio 2006Suberoylanilide hydroxamic acid Cutaneous T-cell lymphoma Y ND 2006

Sunitinib malate; Su11248 Imatinib-resistant gastrointestinal stromal tumour and advanced renal cell carcinoma Y S/NM 2006

Telbivudine Chronic hepatitis B Y 2006Varenicline tartrate Smoking cessation Y 2006Abatacept Rheumatoid arthritis Y B* 2005

Ach-02 Immunological, inflammatory and related disease - Analgesic N 2005

Conivaptan hydrochloride Euvolemic hyponatremia in hospitalized patients Y 2005

Conjugated estrogens b Hormone replacement therapy ND 2005

Deferasirox Chronic iron overload due to blood transfusions Y 2005

Eberconazole Antifungal 2005Entecavir Chronic hepatitis B virus infection Y S* 2005Exenatide; Exenatide-4; Extenatide Type 2 diabetes Y ND 2005Fumagillin; Sr-90144 Antiparasitic N 2005Galsulfase Mucopolysaccharidosis VI Y B* 2005


Hyaluronidase Aids in absorption and dispersion of injected drugs Y 2005

hyaluronidase human Subcutaneous urography for improving resorption of radiopaque agents Y B* 2005

Insulin determir Type 1 and 2 diabetes Y B* 2005Insulin-detemir Diabetes mellitus B* 2005Ivabrandin hydrochloride Antianginal 2005L-alanyl-l-glutamine Mucositis ND 2005

Lenalidomide

Transfusion-dependent anaemia due to myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities

Y 2005

Luliconazole Antifungal 2005Lumiracoxib Osteoarthritis 2005Mecasermin Growth failure in children Y B* 2005

Mecasermin rinfabate Growth failure in children with severe primary IGF-1 deficiency Y B* 2005

Micafungin sodium; Fk463 Candida infections in patients undergoing haematopoietic stem cell transplantation Y ND 2005

Nelarabine T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma Y S* 2005

Nepafenac Pain and inflammation associated with cataract surgery Y 2005

Oral insulin Antidiabetic B* 2005Orthokine Antiarthritic B* 2005Paclitaxel-albumin; Abi-007; Paclitaxel nanoparticles Oncological disease N 2005

Pralmorelin Treatment of GH deficiency ND 2005Pramlintide acetate Type 1 and 2 diabetes Y 2005Ramelteon Insomnia Y 2005Sorafenib Advanced renal cell carcinoma Y S/NM 2005Tamibarotene Anticancer 2005Tetracaine Spinal anesthesia 2005Thc-cbd; Dronabinol; Cannabidiol; Gw-1000-02 Neurological disease N 2005

Tigecycline; Gar-936Complicated skin and skin structure infections and complicated intra-abdominal Y ND 2005

Tipranavir HIV-1 Y S*/NM 2005Triproamylin acetate Antidiabetic ND 2005Udenafil Male sexual dysfunction 2005Acamprosate calcium Alcohol dependence Y S* 2004Apomorphine hydrochloride Parkinson’s disease Y N 2004Azacytidine Myelodysplastic syndrome Y S* 2004Belotecan hydrochloride; Camptobell; Cdk-602 Oncological disease ND 2004

Bevacizumab Colorectal cancer Y B 2004Cetuximab Colorectal cancer Y B* 2004

Cinacalcet hydrochloride Secondary hyper-parathyroidism; hypercalcaemia Y 2004

Clofarabine Paediatric leukaemia Y S* 2004Darifenacin hydrobromide Overactive bladder Y 2004Duloxetine hydrochloride Diabetic peripheral neuropathy Y 2004Erlotinib hydrochloride Non-small-cell lung cancer Y S/NM 2004Estradiol; Levonorgestrel Hormone replacement therapy ND 2004Eszopiclone Insomnia Y 2004Glutamine Short bowel syndrome Y 2004


H-101 Anticancer B 2004Hexyl aminolevulinate Anticancer ND 2004Iloprost Pulmonary arterial hypertension Y ND 2004Indisetron hydrochloride Antiemetic 2004Insulin glulisine Diabetes Y B* 2004

Lanthanum carbonate Hyperphosphataemia in end-stage renal failure Y 2004

Mitiglinide calcium hydrate Antidiabetic 2004Natalizumab Multiple sclerosis Y B 2004Omega-3-acid ethyl esters Hypertriglyceridaemia Y 2004Omega-conotoxin mviia; Snx-iii; Snx-111; C1002; Ziconotide Severe chronic pain Y N 2004

Palifermin Mucositis Y B* 2004Pegaptanib sodium Neovascular age-related macular Y 2004Pemetrexed disodium Malignant pleural mesothelioma Y NM 2004Pentetate zinc trisodium Internal radioactive contamination Y 2004

Pregabalin Diabetic peripheral neuropathy and post-herpetic neuralgia pain Y ND 2004

Rifaximin Travellers’ diarrhoea Y ND 2004Solifenacin succinate Overactive bladder Y 2004Strontium ranelate Osteoporosis 2004Talaporfin sodium Anticancer ND 2004Telithromycin Respiratory infections Y ND 2004Tinidazole Giardiasis, amoebiasis and trichomoniasis Y 2004Tiotropium bromide Chronic obstructive pulmonary disease Y S*/NM 2004Trospium chloride Overactive bladder Y 2004Trypan blue Cataract surgery Y 2004Vapreotide acetate Anticancer ND 2004Von willebrand factor Hemostatic B* 2004Ximelagatran DVT; anticoagulant S/NM 2004Abarelix Advanced prostate cancer Y S*/NM 2003Agalsidase beta Fabry disease Y B* 2003Alefacept Psoriasis Y B* 2003Alfuzosin hydrochloride Benign prostate hyperplasia Y 2003Aprepitant Chemotherapy-induced nausea Y 2003Atazanavir; Bms-232632 HIV Y S*/NM 2003Azelnipidine Antihypertensive 2003Bortezomib; Ps-341; Ldp-341; Mln- Multiple myeloma Y S/NM 2003Carbenoxolone; Cbx; Glycyrrhetinic acid hydrogen sucinate

Immunological, inflammatory and related disease ND 2003

Co-artemether; Artemether-lumofantrine; Artemether-lumefantrine Antiparasitic ND 2003

Daptomycin; A21978c Antibacterial Y N 2003Desirudin Deep vein thrombosis B 2003Drospirenone; Estradiol Hormone replacement therapy ND 2003Efalizumab Psoriasis Y B 2003Emtricitabine HIV Y S* 2003Enfuvirtide; T-20 HIV Y ND 2003Epinastine hydrochloride Hay fever Y 2003Epipodophyllotoxin Oncological disease ND 2003Estradiol; Nomegestrol acetate Hormone replacement therapy ND 2003Ferric hexacyanoferrate(ii) Radioactive contamination Y 2003Fosamprenavir Antiviral S*/NM 2003Fosfluconazole Antifungal 2003Gefitinib Non-small-cell lung cancer Y S/NM 2003


Gemifloxacin mesylate Antibacterial Y 2003Hemoglobin glutamer Anemia B* 2003Ibandronate sodium Osteoporosis Y 2003Isoprenaline Cardiovascular disease ND 2003Iv human immunoglobulin Immunomodulator B* 2003Laronidase MPS-I Y B* 2003Levodopa/carbidopa/entacapone Parkinson’s disease Y 2003Memantine hydrochloride Alzheimer’s disease Y 2003Miglustat; N-butyl-1- Gaucher’s disease Y ND 2003Mycophenolate sodium; Mycophenolic acid

Immunological, inflammatory and related disease N 2003

Omalizumab Asthma Y B 2003Palonosetron hydrochloride Chemotherapy-induced nausea Y 2003Pegvisomant Acromegaly Y B* 2003Pulmonary insulin Antidiabetic B* 2003Rec-antihemophilic factor Haemophilia A Y B* 2003Rosiglitazone/metformin Type 2 diabetes Y 2003Rosuvastatin calcium Hypercholesterolaemia Y S*/NM 2003Sertaconazole nitrate Tinea pedis Y 2003Tadalafil Erectile dysfunction Y S*/NM 2003Tositumomab Non-Hodgkins lymphoma Y B* 2003Vardenafil Erectile dysfunction Y S*/NM 2003Acetyldigitoxin Cardiovascular disease ND 2002

Adalimumab Moderately to severely active rheumatoid arthritis Y B* 2002

Adefovir dipivoxil Chronic hepatitis B Y S* 2002Amrubicin hydrochloride; Sm-5887 Oncological disease ND 2002Aripiprazole Schizophrenia Y 2002Artesunate; As Antiparasitic ND 2002Atomoxetine hydrochloride Attention-deficit hyperactivity disorder Y 2002Balafloxacin Antibacterial 2002Biapenem Antibacterial ND 2002Dexmethylphenidate ADHD 2002Dibotermin alfa Tibia fractures in humans adjunct Y B* 2002Eletriptan hydrobromide Migraine Y 2002Eplerenone Hypertension Y ND 2002Escitalopram Antidepressant 2002Etoricoxib Antiarthritic 2002Ezetimibe High cholesterol Y 2002

Fulvestrant; Ici-182, 780 Hormone-receptor-positive metastatic breast cancer Y ND 2002

IbritumomabRelapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin’s Y B* 2002

Icodextrin Colloid osmotic agent Y 2002Immunoglobulin intravenous Antiviral B* 2002Landiolol Antiarrhythmic 2002Morphine sulfate Neurological disease N 2002Neridronic acid Calcium metabolism 2002

Nitazoxanide Paediatric diarrhoea caused by Cryptosporidium spp. and Giardia spp. Y 2002

Nitisinone; Ntbc Hereditary tyrosinaemia type 1 Y ND 2002Olmesartan medoxil Hypertension Y S/NM 2002

Oxaliplatin Colorectal cancer (in combination with 5-fluorouracil and leucovorin) Y 2002

Parecoxib sodium Analgesic 2002


Pazufloxacin Antibacterial 2002

Pegfilgastrim Neutropaenia in patients treated with cytotoxic chemotherapy Y B* 2002

Peginterferon alfa-2a Chronic hepatitis C infection in adults Y B* 2002Prulifloxacin Antibacterial 2002

RasburicaseManagement of plasma uric acid levels in paediatric patients with leukaemia, lymphoma and solid tumour malignancies

Y B* 2002

Restasis Keratoconjunctivitis sicca (chronic dry eye disease) Y N 2002

Rh-bmp-2/acs Bone disorders B* 2002Sivelestat sodium hydrate Respiratory distress syndrome 2002Sodium oxybate Narcolepsy with episodes of cataplexy Y ND 2002Tegaserod maleate Irritable bowel syndrome Y S*/NM 2002Temoporfin Anticancer S/NM 2002Teriparatide Osteporosis Y ND 2002Timodepressin Antipsoriatic 2002Treprostinil sodium Pulmonary arterial hypertension Y ND 2002

VoriconazoleInvasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp.

Y 2002

Acemannan Vulnerary B 2001Activated protein c concn DVT; anticoagulant B* 2001Agalsidase alfa Fabry disease B* 2001Alemtuzumab Anticancer Y B 2001Almotriptan malate Heavy migraine headache Y 2001Anakinra Antiarthritic Y B* 2001Bimatoprost Antiglaucoma Y ND 2001Bosentan Pulmonary arterial hypertension Y 2001Caspofungin acetate Antifungal Y ND 2001Cefditoren pivoxil Antibacterial Y ND 2001Choriogonadotropin alfa Hormone B* 2001Crotalidae fab Rattlesnake antivenom B 2001Darbepoietin alfa Erythropoiesis Y B* 2001Desloratadine Allergies Y 2001Drospirenone Contraception Y ND 2001Drotrecogin alfa Severe sepsis with multiple organ failure Y B* 2001Dutaseride BPH ND 2001Dutasteride Benign prostatic hyperplasia Y 2001Edarvarone Neuroprotective 2001Ertapenem sodium Moderate to severe bacterial infection Y ND 2001Etonogestrel; Ethinylestradiol Contraception Y ND 2001Falecalcitrol Sec. hyperthryoidism ND 2001Fondaparinux sodium DVT; anticoagulant Y ND 2001Formoterol fumarate Bronchodilator Y 2001Frovatriptan succinate Antimigraine Y 2001Fudosteine Expectorant ND 2001Galantamine hydrobromide; Galanthamine Neurological disease Y N 2001

Gusperimus trihydrochloride; 15-deoxyspergualin

Immunological, inflammatory and related disease ND 2001

Imatinib mesylate; Cgp5714b; Glivec; Sti571 Anticancer Y ND 2001

Levocetirizine Antihistamine 2001Levothyroxine Hypothyroidism 2001


Lutropin alfa Hormone B* 2001Methacycline; Metacycline; Methacyclin Antibacterial ND 2001

methyl aminolevulinate Actinic keratoses ND 2001Minocycline hydrochloride; Antibacterial ND 2001Nah2po4/na2hpo4 Bowel evacuant 2001Nesiritide Congestive heart failure Y ND 2001Norelgestromin; Ethinylestradiol Contraception Y ND 2001Op-1 Bone morphogenesis B* 2001Peginterferon alfa-2b Antiviral Y B* 2001Perspirone hydrochloride Antipsychotic 2001Pimecrolimus; Sdz-asm-981; Ascomycin

Immunological, inflammatory and related disease Y ND 2001

Rupatadine fumarate Antihistamine 2001Tenofovir disoproxil fumarate Antiviral Y S* 2001Travoprost Antiglaucoma Y ND 2001Ultracet Pain 2001Valdecoxib Osteoarthritis or rheumatoid arthritis Y 2001Valganciclovir Antiviral S* 2001Ziprasidone hydrochloride Atypical antipsychotic Y 2001Zoledronic acid Anticancer Y 2001Alosetron hydrochloride Irritable bowel syndrome Y 2000Argatroban Antithrombotic Y S*/NM 2000Arsenic trioxide Anticancer Y 2000Arteether; Beta arteether Antiparasitic ND 2000Articaine/Epinephrine Local anesthetic Y 2000Atosiban Premature birth ND 2000Balsalazide disodium Ulcerative colitis Y 2000Betotastine besilate Antiallergic 2000Bivalirudin; Bivalrudin Cardiovascular and metabolic disease Y ND 2000Botulinum toxin type b Blepharospasm and strabismus Y B 2000Bulaquine; Chloroquine Antiparasitic S* 2000Calcium polycarbophil Irritable bowel syndrome 2000Cetrorelix Fertility enhancer Y ND 2000Cevimeline hydrochloride Antixerostomia Y 2000Cholecalciferol Vitamin D deficiency 2000Colesevelam hydrochloride Hypolipidemic Y 2000Digoxin fab Digoxin toxicity B 2000Docosanol Antiviral agent Y ND 2000Dosmalfate Gastroprotectant ND 2000Egualen sodium Antiulcer ND 2000Framycetin Antibacterial ND 2000Gemtuzumab ozogamicin Oncological disease Y ND 2000Hirulog Anticoagulation ND 2000Insulin aspart Antidiabetic Y B* 2000Insulin glargine Antidiabetic Y B* 2000Lafutidine Antiulcer 2000Levobupivacaine Anesthetic 2000Levosimendan MI, acute 2000Linezolid Antibacterial Y 2000Liranaftate Antifungal 2000Lopinavir; Abt-378 Antiviral Y S*/NM 2000Maxacalcitol Calcium metabolism ND 2000Medroxyprogesterone; Estradiol Contraception ND 2000


Meloxicam Antiarthritic Y 2000Mifepristone Abortifacient Y ND 2000Nateglinide Antidiabetic Y S* 2000Oxcarbazepine Anticonvulsant Y 2000Pamiteplase Antithrombotic B* 2000Pantoprazole sodium Antiulcer Y 2000Polytetrafluoroethylene Skin exposure paste Y 2000Proguanil Malaria 2000Ramatroban Antiallergic 2000Rivastigmine tartrate AntiAlzheimer Y 2000Taltirelin CNS Stimulant ND 2000Tenecteplase Antithrombotic Y B* 2000

Tinzaparin sodium Deep vein thrombosis and pulmonary embolism Y 2000

Trimegestone Hormone replacement therapy ND 2000Triptorelin pamoate Hormone-responsive cancers Y 2000Unoprostone isopropyl Antiglaucoma Y ND 2000Verteporfin Photosensitizer Y S* 2000Zofenapril calcium Antihypertensive 2000Zonisamide Antiepileptic Y 2000Alitretinoin Anticancer Y ND 1999Aminolevulinic acid hci Actinic keratoses Y N 1999Amprenavir Antiviral Y S*/NM 1999Arglabin Oncological disease N 1999Bexarotene Anticancer Y 1999Cilostazol Antithrombotic Y 1999Colestimide Hypolipidemic 1999Colforsin daropate hci Cardiovascular and metabolic disease ND 1999Conjugated estrogens a Hormone replacement therapy ND 1999Dalfopristin; Quinupristin Antibacterial Y ND 1999Denileukin diftitox Anticancer Y B* 1999Dermatan sulfate DVT; anticoagulant B* 1999Dexmedetomidine hydrochloride Sedative Y 1999Dofetilide Antiarrhythmic Y 1999Doxercalciferol Calcium metabolism Y ND 1999Entacapone AntiParkinsonian Y 1999Epirubicin hci Oncological disease Y ND 1999Exemestane Anticancer Y ND 1999Ganirelix acetate Ovulationi Y ND 1999Gatilfloxacin Antibacterial Y 1999Heptaplatin /sk-2053r Anticancer 1999Human neutral insulin Antidiabetic B* 1999Interferon gamma-1b Immunostimulant Y B* 1999

Ketotifen fumarate Allergic conjunctivitis,or the itchy red eyes caused by allergies Y 1999

Kinetin Skin photodamage S* 1999

Levalbuterol hci Immunological, inflammatory and related disease - Inflammatory disease S*/NM 1999

Levetiracetam Antiepileptic Y 1999Lomerizine hcl Antimigraine 1999Melevodopa; Chf-1301; L-dopa-methyester Neurological disease - AntiParkinsonian ND 1999

Mequinol 2%/Tretinoin 0.01% Melasma Y 1999Mobenakin Anticancer B* 1999


Moroctocog alfa Hemophilia B* 1999Moxifloxacin hydrochloride Antibacterial Y 1999Naftopidil Dysuria 1999Nifekalant hcl Antiarrhythmic 1999Nitric oxide Pulmonary hypertension Y 1999Orlistat; Tetrahydrolipstatin Cardiovascular and metabolic disease Y ND 1999Oseltamivir phosphate Influenza Y NM 1999Pemirolast potassium Antiasthmatic Y 1999Pioglitazone hydrochloride Antidiabetic Y 1999Poractant alfa Pulmonary surfactant Y N 1999Protein c concentrate Purpura fulminans B* 1999Rabeprazole sodium Antiulcer Y 1999Rapacuronium bromide Muscle relaxant Y ND 1999Rofecoxib Antiarthritic Y 1999Rosiglitazone maleate Antidiabetic Y 1999

Sirolimus; Rapamycin Immunological, inflammatory and related disease Y N 1999

Sodium ferric gluconate complexIron deficiency anemia, hemodialysis, erythropoietin therapy, and/or patients who have chronic kidney disease

Y 1999

Tasonermin Anticancer B* 1999Temozolomide Anticancer Y 1999Zaleplon Hypnotic Y 1999Zanamivir Antiviral Y NM 1999Abacavir sulfate Antiviral agent Y S* 1998Amtolmetin guacil Antiinflammatory 1998Basiliximab Immunosuppressant Y B* 1998Bemiparin sodium DVT; anticoagulant ND 1998Brinzolamide Agent for glaucoma Y 1998Calfactant RDS Y B 1998Candesartan cilexetil Antihypertensive agent Y S/NM 1998Capecitabine Antineoplastic agent Y S* 1998Cefoselis Antibacterial ND 1998Celecoxib Antiarthritic agent Y 1998Citalopram hydrobromide Antidepressant Y 1998Dihydroartemisinin Antiparasitic ND 1998Efavirenz Antiviral agent Y 1998Eptifibatide Agent for acute coronary syndrome Y S*/NM 1998Etanercept Antiarthritic agent Y B* 1998Fentanyl Anesthetic 1998Follitropin beta Hormone B* 1998Fomivirsen sodium Antiviral agent Y S*/NM 1998Infliximab Agent for Crohn's disease Y B* 1998Leflunomide Antiarthritic agent Y 1998Lepirudin Anticoagulant Y ND 1998Levonorgestrel; Ethinyl estradiol Contraception ND 1998Lobaplatin Anticancer 1998Loteprednol etabonate Agent for ocular inflammatory conditions Y ND 1998Mizolastine Antihistamine 1998Modafinil Agent for narcolepsy Y 1998Montelukast sodium Antiasthmatic agent Y 1998Monteplase Antithrombotic B* 1998Mosapride citrate Gastroprokinetic 1998Naratriptan hydrochloride Agent for migraine Y 1998


Palivizumab Antiviral Y B 1998Paricalcitol Agent for secondary hyperparathyroidism Y ND 1998Porcine neutral insulin Antidiabetic B 1998Rifapentine Antitubercular agent Y ND 1998Risedronate sodium Agent for Paget's disease of bone Y 1998Rizatriptan benzoate Agent for migraine Maxalt-MLT Y S*/NM 1998Sacrosidase Enzyme replacement therapy Y 1998Sevalamer hydrochloride Agent for hyperphosphatemia Y 1998Sildenafil citrate Agent for erectile dysfunction Y S*/NM 1998Telmisartan Antihypertensive agent Y S/NM 1998Thalidomide Immunomodulatory agent Y 1998Thyrotropin alfa Thyroid cancer Y B* 1998Tirofiban hcl Agent for acute coronary syndrome Y S/NM 1998Tolcapone Antiparkinson agent Y 1998Tolterodine tartrate Agent for overactive bladder Y 1998Trastuzumab Antineoplastic agent Y B 1998Valrubicin Antineoplastic agent Y ND 1998Alatrofloxacin mesylate Antibiotic Y 1997Anagrelide hydrochloride Hematological Y 1997Arbutamine Coronary artery disease Y 1997Becaplermin Agent for diabetic foot ulcers Y B* 1997Bromfenac sodium Antiinflammatory 1997Budipine AntiParkinsonian 1997Cefcapene pivoxil Antibacterial ND 1997Cefdinir Antibacterial agent Y ND 1997Cerivastatin Antihyperlipidemic agent Y 1997Clopidogrel bisulfate Antiplatelet agent Y 1997Daclizumab Immunosuppressant Y B 1997Delavirdine mesylate Antiviral Y 1997Dexfenfluramine Antiobesity 1997Dolasetron mesylate Antiemetic Y 1997Ebrotidine Antiulcer 1997Emedastine difumarate Antihistamine Y 1997

Ephedrine Immunological, inflammatory and related disease N 1997

Eprosartan Antihypertensive Y S/NM 1997Faropenem sodium; Fropenam Antibacterial ND 1997Fenoldopam mesylate Antihypertensive agent Y 1997Flurithromycin ethylsuccinate Antibacterial ND 1997Fomepizole Antidote Y 1997Grepafloxacin Antibacterial Y 1997Hesperetin Cardiovascular disease N 1997Imiquimod Antiviral Y 1997Incadronic acid Calcium metabolism 1997Insulin aspart; Ia protamine Antidiabetic B* 1997Interferon alfacon-1 Antiviral Y B* 1997Irbesartan Antihypertensive Y S/NM 1997Lercanidipine Antihypertensive 1997Letrozole Anticancer Y 1997Lornoxicam Antiinflammatory 1997Mibefradil hydrochloride Antihypertensive 1997Neflinavir mesylate; Nelfinavir Antiviral Y S*/NM 1997Oprelvekin Thrombocytopenia Y B* 1997Pivagabine Antidepressant 1997


Pramipexole dihydrochloride AntiParkinsonian Y 1997Quetiapine fumarate Neuroleptic Y 1997Raloxifene hydrochloride Agent to prevent osteoporosis Y 1997Reboxetine Antidepressant 1997Repaglinide Antidiabetic agent Y 1997Rituximab Anticancer Y B* 1997Ropinirole hcl AntiParkinsonian Y S*/NM 1997Samarium sm-153 lexidronam pentasodium Reduces pain caused by bone cancer Y 1997

Sibutramine Antiobesity agent Y 1997

Streptokinase Myocardial infarction and pulmonary embolism Y B 1997

Talc Sclerosing agent Y 1997

Tamsulosin hydrochloride Difficult urination, benign prostatic hyperplasia Y 1997

Tazarotene Antipsoriatic Y 1997Tiagabine hydrochloride Antiepileptic Y 1997Tiludronate disodium Calcium metabolism Y 1997Toremifene citrate Anticancer Y 1997Triclosan Bacterial infections 1997Troglitazone Antidiabetic Y 1997Trovafloxacin mesylate Antibacterial agent Y 1997Zolmitriptan Agent for migraine Y 1997Adapalene Acne vulgaris Y 1996Albendazole Antiparasitic Y 1996Alteplase Antithrombotic Y B* 1996Amlexanox Antiasthmatic Y 1996Amodiaquine; Sq Antiparasitic ND 1996Arandipine Antihypertensive 1996Atorvastatin calcium; Atorvastin Cardiovascular disease Y S*/NM 1996Azelastine hydrochloride Anti-histamines Y 1996Bentoquatam Bulk laxative, dermatologic formulas Y 1996Betain anhydrous Homocystinuria Y N 1996Brimonidine Antiglaucoma Y 1996Butenafine hydrochloride Antifungal Y 1996Cabergoline Antihyperprolactinemia Y ND 1996Camptothecin; Irinotecan Oncological disease Y ND 1996Cefepime Antibacterial Y ND 1996Certoparin sodium DVT; anticoagulant ND 1996Cidofovir Antiviral Y S* 1996Danaparoid sodium DVT; anticoagulant Y ND 1996Dexketoprofen trometamol Antiinflammatory 1996Digitoxin Cardiovascular disease N 1996Docetaxel Oncological disease Y ND 1996Donepezil hydrochloride AntiAlzheimer Y 1996Etoposide phosphate Oncological disease ND 1996Factor viia Hemophilia B* 1996Fexofenadine Antiallergic Y 1996Fosfomycin tromethamine Urinary tract infections Y N 1996Fosphenytoin sodium Antiepileptic Y 1996Gemcitabine hcl Anticancer Y S* 1996Glatiramer acetate Multiple sclerosis Y S* 1996Glycopin Immunostimulant 1996Ibandronic acid Calcium metabolism 1996


Indinavir sulfate; Idv Antiviral Y S*/NM 1996Insulin lispro Antidiabetic Y B* 1996Interferon beta-1a Relapsing forms of multiple sclerosis Y B* 1996Interferon gamma-n1 Antifungal B* 1996Irinotecan hydrochloride; Cpt-11 Oncological disease Y ND 1996Ivermectin Antiparasitic Y N 1996Latanoprost Antiglaucoma Y ND 1996Loprinone hcl Cardiotonic 1996Meropenem Antibacterial Y ND 1996Midodrine Symptomatic orthostatic hypotension Y 1996Miglitol Cardiovascular and metabolic disease Y ND 1996Mirtazapine Antidepressant Y 1996Nateplase Antithrombotic B* 1996Nevirapine Antiviral Y 1996Nilutamide Anticancer Y 1996Olanzapine Neuroleptic Y 1996Olopatadine hydrochloride Antiallergic Y 1996Oxycodone hcl Neurological disease ND 1996Penciclovir Antiviral Y S* 1996Pentosan polysulfate sodium Interstitial cystitis Y 1996Prezatide copper acetate Vulnerary N 1996Raltitrexed Cancers ND 1996Ramosetron Antiemetic S*/NM 1996Remifentanil hydrochloride Analgesic Y 1996Resp syncytial virus ig Antiviral B 1996Reteplase Antithrombotic Y B* 1996Ritonavir Antiviral Y S*/NM 1996Ropivacaine hydrochloride Anesthetic Y 1996Sertindole Neuroleptic S*/NM 1996Sodium phenylbutyrate Urea cycle disorders Y 1996Sparfloxacin Antibacterial Y 1996Sulfacetamide Bacterial infections 1996Talipexole AntiParkinsonian 1996Tandospirone Anxiolytic S/NM 1996Thymalfasin Hepatitis B* 1996Tizanidine hydrochloride Muscle relaxant Y 1996Topiramate Antiepileptic Y 1996Topotecan hcl Oncological disease Y ND 1996Trandolapril Cardiovascular disease Y S*/NM 1996Urea c-13 Helicobacter pylori infection Y 1996Valsartan Antihypertensive Y S/NM 1996Zafirlukast Antiasthmatic Y 1996Zileuton Antiasthmatic Y 1996Zinc hyaluronate Vulnerary ND 1996Zotarolimus; Abt-578 Oncological disease ND 1996Acarbose Cardiovascular and metabolic disease Y N 1995Alendronate sodium Calcium metabolism Y ND 1995Amifostine Cytoprotective Y 1995Anastrozole Anticancer Y 1995Azelaic acid Antiacne Y 1995Bicalutamide Anticancer Y 1995Carperitide Congestive heart failure N 1995Carvedilol Antihypertensive Y 1995Cefozopran hcl Antibacterial ND 1995


Ceftibuten Antibacterial Y ND 1995Cetirizine hydrochloride Antihistamine Y 1995Cinildipine Antihypertensive 1995Cisatracurium besilate Muscle relaxant S* 1995Defeiprone Chelator 1995Dexrazoxane hydrochloride Cardioprotective agent Y 1995Dirithromycin Antibacterial Y ND 1995Epoprostenol sodium Platelet aggreg. inhib. Y ND 1995Erdosteine Expectorant 1995Estrogens; Medroxyproesterone Hormone replacement therapy ND 1995Fadrozole hcl Anticancer 1995Fasudil hcl Neuroprotective 1995Flutrimazole Antifungal 1995Follitropin alfa Hormone B* 1995Glimepiride Antidiabetic Y 1995Ibutilide fumarate Antiarrhythmic Y 1995Itopride hcl Gastroprokinetic 1995Lamivudine Antiviral Y S* 1995Lansoprazole Antiulcer Y 1995Losartan potassium Antihypertensive Y S/NM 1995Mab17-1a Adjuvant/colorectal cancer B 1995Metformin hydrochloride Antidiabetic drug Y 1995Moexipril hci Cardiovascular disease Y S*/NM 1995

Mycophenolate mofetil Immunological, inflammatory and related disease Y ND 1995

Nalmefene hci Neurological disease Y ND 1995Nedaplatin Anticancer 1995Nisoldipine Antihypertensive Y 1995Porfimer sodium Anticancer Y 1995Pranlukast Antiasthmatic 1995Ranitidine bismuth citrate Antiulcer 1995Riluzole Neuroprotective Y 1995Saquinavir mesylate Antiviral Y S*/NM 1995Seratrodast Antiasthmatic 1995Sevoflurane Anesthetic Y 1995Suplast tosylate Antiallergic 1995Tirilazad mesylate Subarachnoid hemorrhage ND 1995Tramadol hydrochloride Moderate to moderately severe pain Y N 1995Valaciclovir hcl Antiviral S* 1995Actarit Antirheumatic 1994Ampiroxicam Antiinflammatory 1994Angiotensin ii Anticancer N 1994Asparaginase Oncological disease Y N 1994Betamethasone butyrate propion Antiinflammatory ND 1994Broxaterol Antiasthmatic 1994Budesonide Antiasthmatic Y ND 1994

Cysteamine bitartrateEscape the metabolic defect in cystinosis and cystinuria, also used for treatment of radiation sickness

Y ND 1994

Dalteparin sodium DVT; anticoagulant Y ND 1994Dexibuprofen Antiinflammatory 1994Docarpamine Cardiotonic ND 1994Dorzolamide hydrochloride Antiglaucoma Y 1994Efonidipine hydrochloride Antihypertensive 1994


Famciclovir Antiviral Y S* 1994Fluvoxamine maleate Antidepressant Y 1994Imiglucerase Gaucher's disease Y B* 1994Lamotrigine Anticonvulsant Y 1994Lanoconazole Antifungal 1994Mofezolac Antiinflammatory 1994Nartograstim Hematopoiesis B* 1994Nazasetron hydrochloride Antiemetic 1994Nefazodone hydrochloride Antidepressant Y 1994Panipenem; Betamipron Antibacterial ND 1994Pegaspargase Anticancer Y B 1994Pimobendan Vasodilator 1994Pirmenol hydrochloride Antiarrhythmic 1994Polaprezinc Antiulcer ND 1994Porcine lung surfactant RDS B 1994Propagermanium Antiviral 1994Quinagolide hydrochloride Antihyperprolactinemia NM 1994Rimexolone Inflammatory disease Y ND 1994Rocuronium bromide Muscle relaxant Y ND 1994

Salmeterol Immunological, inflammatory and related disease - Inflammatory disease Y ND 1994

Salmeterol xinafoate Immunological, inflammatory and related disease - Inflammatory disease Y S*/NM 1994

Sobuzoxane Anticancer 1994Somatomedin-1 Hormone B* 1994Somatotropin Hormone B* 1994Spirapril hci Cardiovascular disease Y S*/NM 1994Stavudine Antiviral Y S* 1994

Tacrolimus; Fk-506; Fujimycin Immunological, inflammatory and related disease Y N 1994

Temocapril hydrochloride Cardiovascular disease S*/NM 1994Vinorelbine; Vrlb; Navelvine Oncological disease Y ND 1994Voglibose; Ao-128 Cardiovascular and metabolic disease N 1994Zinostatin stimalamer Oncological disease ND 1994Abciximab Antithrombotic Y B* 1993Acetorphan Antidiarrheal 1993Aniracetam Cognition enhancer 1993Aprotinin Ischemia Y B 1993Brodimoprin Antibacterial 1993Calcipotriene Psoriasis Y ND 1993Cinolazepam Hypnotic 1993Cisapride monohydrate Gastroprokinetic agent Y 1993Cladribine Anticancer Y ND 1993

Dimyristoylphosphatidylcholine/Perflexane

Patients with suboptimal echocardio-grams to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border

Y 1993

Dornase alfa Cyctic fibrosis Y B* 1993Ecabet sodium Antiulcer ND 1993Enoxaparin DVT; anticoagulant Y ND 1993Felbamate Antiepileptic Y 1993Fenofibrate Antihyperlipidemic agent Y 1993Fluvastatin sodium Cardiovascular disease Y S*/NM 1993Formestane Anticancer ND 1993Gabapentin Antiepileptic Y S* 1993


Granisetron hydrochloride Antiemetic Y 1993Imidapril hci Cardiovascular disease S*/NM 1993Interferon beta-1b Multiple sclerosis Y B* 1993Levocabastine hydrochloride Antihistamine Y 1993Levofloxacin Antibacterial 1993Levomethadyl acetate Opiate dependence Y 1993

Lodoxamide tromethamine In vivo Type I immediate hypersensitivity reaction Y 1993

Loratadine Antihistamine Y 1993Miltefosine Anticancer ND 1993Nadifloxacin Antibacterial 1993Neltenexine Cystic fibrosis 1993Neticonazole hci Antifungal 1993Parnaparin sodium DVT; anticoagulant ND 1993Perindopril Cardiovascular disease Y S*/NM 1993Pidotimod Immunostimulant 1993Pramiracetam h2so4 Cognition enhancer 1993Reviparin sodium Anticoagulant ND 1993Rimantadine hydrochloride Antiviral drug Y 1993Risperidone Neuroleptic Y 1993Sarpogrelate hci Platelet aggreg. inhib. 1993Sorivudine Antiviral S* 1993Strontium chloride sr-89 Bone tumors Y 1993Tacalcitol Antipsoriatic ND 1993Tacrine hci AntiAlzheimer Y 1993

Torsemide Edema associated with congestive heart failure, hypertension Y 1993

Trimetrexate glucuronate PCP/Toxoplasmosis Y ND 1993Venlafaxine Antidepressant Y 1993Zaltoprofen Antiinflammatory 1993Aceclofenac Antiinflammatory 1992Aldesleukin Anticancer Y B* 1992Amlodipine besylate Antihypertensive Y 1992

Andrographolide Antibacterial - Chemotherapy: Bacillary dysentery N 1992

Atovaquone Antiparasitic Y S* 1992Barnidipine hydrochloride Antihypertensive 1992Beraprost sodium Platelet aggreg. inhib. ND 1992Bisoprolol fumarate Antihypertensive Y 1992Butibufen Antiinflammatory 1992Cefetamet pivoxil hcl Antibacterial ND 1992Cefpirome sulfate Antibacterial ND 1992Cefpodoxime proxetil Antibacterial Y ND 1992Celmoleukin Anticancer B* 1992Deprodone propionate Antiinflammatory 1992Desflurane Anesthetic Y 1992Duteplase Antithrombotic B* 1992Epalrestat Antidiabetic 1992Finasteride 5 alpha-reductase inhibitor Y ND 1992Fleroxacin Antibacterial 1992Flosequinan Cardiotonic 1992Ha-1a Antisepsis B* 1992Halofantrine Antimalarial agent Y 1992Hu neutral insulin Antidiabetic B* 1992


Interferon gamma-1a Anticancer B* 1992Itraconazole Antifungal Y 1992Lofexidine Opiate detoxification 1992Lomefloxacin Antibacterial Y 1992Masoprocol Oncological disease Y N 1992Mivacurium chloride Muscle relaxant Y S* 1992Molgramostim Hematopoiesis B* 1992Muromonab-cd3 Immunosuppressant Y B* 1992Nedocromil sodium Antiallergic Y ND 1992Oxaprozin Antiinflammatory Y 1992Paclitaxel Oncological disease Y N 1992Paroxetine hydrochloride Antidepressant drug Y 1992Propiverine hydrochloride Urinary incontinence 1992Pro-urokinase Antithrombotic B* 1992Rifabutin; Rfb Antibacterial Y ND 1992Rufloxacin hydrochloride Antibacterial 1992Sotalol hydrochloride Ventricular tachycardias, atrial fibrillation Y 1992Sumatriptan succinate Antimigraine Y S*/NM 1992Tazobactam sodium Antibacterial ND 1992Teceleukin Anticancer B* 1992Telmesteine Mucolytic 1992Teniposide; Vm-26 Oncological disease Y ND 1992Terbinafine hydrochloride Antifungal Y 1992Tilisolol hydrochloride Antihypertensive 1992Tropisetron Antiemetic 1992Zalcitabine; Ddc; Ddcyd; Dideoxycytidine Antiviral Y S* 1992

Zolpidem tartrate Insomnia, Brain disorders Y 1992Alglucerase Enzyme Y B* 1991Alpidem Anxiolytic 1991Amorolfine hydrochloride Antifungal 1991Arteflene; Ro 42-1611 Antiparasitic ND 1991Azithromycin Antibacterial Y ND 1991Benazepril hydrochloride Cardiovascular disease Y S*/NM 1991Benidipine hydrochloride Antihypertensive 1991Beractant Neonatal respiratory distress syndrome Y ND 1991Calcipotriol Antipsoriatic ND 1991Cefotiam hexetil hydrochloride Antibacterial ND 1991Cefprozil; Cefproxil Antibacterial Y ND 1991Centchroman Contraception 1991Clarithromycin Antibacterial Y ND 1991Cloricromen Antithrombotic 1991Clospipramine hydrochloride Neuroleptic 1991Dezocine Analgesic 1991Didanosine; 2',3'-dideoxyinosine; Ddi Antiviral Y S* 1991Doxacurium chloride Muscle relaxant Y S* 1991Enoxacin Antibacterial Y 1991Etodolac Antiinflammatory Y 1991Felodipine Antihypertensive Y 1991Filgrastim Immunostimulant Y B* 1991Fludarabine phosphate Anticancer Y S* 1991Flumazenil Benzodiazepine antagonist Y 1991Foscarnet sodium Antiviral Y 1991Fosinopril sodium Cardiovascular disease Y S*/NM 1991


Gallium nitrate Calcium metabolism 1991

Histrelin

For the treatment of central precocious puberty, also be used to treat endometriosis, polycystic ovarian disease, uterine leiomyomas, severe premenstrual syndrome and acute intermittent porphyria

Y ND 1991

Isosorbide 5-mononitrate Antianginal Y 1991Lacidipine Antihypertensive 1991Lenogastrim Hematopoiesis B* 1991Loracarbef Antibacterial Y ND 1991Mirimostim Hematopoiesis B* 1991Moxonidine Antihypertensive 1991Nabumetone Antiinflammatory Y ND 1991Nemonapride Neuroleptic 1991Onabotulinumtoxina Various cosmetic and medical procedures Y B 1991Ondansetron hydrochloride Antiemetic Y 1991Oxacillin sodium Antibacterial ND 1991Pamidronate disodium Osteoporosis Y 1991Pentostatin; Deoxycoformycin Oncological disease Y N 1991Pilsicainide hydrochloride Antiarrhythmic 1991Pravastatin Cardiovascular disease Y N 1991Quinapril Cardiovascular disease Y S*/NM 1991Ramipril Cardiovascular disease Y S*/NM 1991Ritodrine Premature labour 1991Romurtide Immunostimulant 1991Sargramostim Immunostimulant Y B* 1991Sertraline hydrochloride Antidepressant Y 1991Silteplase Antithrombotic B* 1991Simvastatin; Simvastin Cardiovascular disease Y N 1991Succimer Chelator Y 1991Temafloxacin hydrochloride Antibacterial 1991Ticlopidine Stroke Y 1991Altretamine Antineoplastic agent Y 1990Aminoprofen Antiinflammatory 1990Antazoline phosphate Ocular allergies 1990Arbekacin Antibacterial ND 1990Bambuterol Bronchodilator 1990Bepridil hydrochloride Angina Y 1990Bisantrene hydrochloride Anticancer 1990Botulinum toxin type a Strabismus B 1990Capsaicin; Algrx 4975 Neurological disease N 1990Cefodizime sodium Antibacterial ND 1990Cilazapril Cardiovascular disease S*/NM 1990Cinitapride Gastroprokinetic 1990Colfoscerid palmitate Respiratory distress syndrome 1990Dapiprazole hydrochloride Reverse mydriasis after eye examination Y 1990Doxazosin mesylate Antihypertensive Y 1990Droxicam Antiinflammatory 1990Ebastine Antihistamine 1990Eflornithine hcl Antiparasitic Y ND 1990Erythropoietin beta Erythropoiesis B* 1990Estazolam Insomnia Y 1990Ethyl icosapentate Antithrombotic ND 1990Factor ix Hemophilia B* 1990


Fluconazole Antifungal Y 1990Fluticasone propionate Inflammatory disease Y ND 1990Halobetasol propionate Antiinflammatory Y ND 1990Idarubicin hydrochloride Oncological disease Y ND 1990Isradipine Antihypertensive Y 1990Levamisole Colon Cancer Y 1990Manidipine hydrochloride Antihypertensive 1990Moclobemide Antidepressant 1990Moricizine hydrochloride Antiarrhythmic Y 1990Nafarelin acetate Precocious puberty and endometriosis Y ND 1990Ofloxacin Antibacterial Y 1990Olsalazine sodium Antiinflammatory Y 1990Pegademase bovine Immunostimulant Y B 1990Pipecuronium Spasms, Pain Y 1990Pumactant Respiratory distress syndrome ND 1990Rebamipide Antiulcer 1990Remoxipride hydrochloride Antipsychotic S*/NM 1990Sermorelin acetate Growth hormone deficiency Y ND 1990Setraline hydrochloride Antidepressant 1990Tazanolast Antiallergic 1990Tiracizine hydrochloride Antiarrhythmic 1990Tisokinase Antithrombotic B* 1990Tosufloxacin Antibacterial 1990Tropesin Antiinflammatory 1990Vesnarinone Cardiotonic 1990Acitretin Antipsoriatic ND 1989Adenosine Antiarrhythmic Y N 1989

Carboplatin Chemotherapy drug used against some forms of cancer Y 1989

Cefixime Antibacterial Y ND 1989Cefmetazole sodium Antibacterial Y ND 1989Cefpiramide sodium Antibacterial Y ND 1989Citalopram Antidepressant 1989Clomipramine hydrochloride Tricyclic antidepressant (TCA) Y 1989Clozapine Atypical antipsychotic Y 1989Delapril Cardiovascular disease S*/NM 1989Deslorelin Oncological disease ND 1989Dilevalol Antihypertensive 1989Dopexamine Cardiotonic S*/NM 1989Droxidopa AntiParkinsonian S*/NM 1989

Epoetin alfaAnemia resulting from chronic kidney disease and myelodysplasia, from the treatment of cancer

Y B* 1989

Fepradiinol Antiinflammatory 1989Flutamide Oncological disease Y ND 1989Fotemustine Anticancer 1989Ganciclovir Antiviral Y S* 1989Goserelin Oncological disease Y ND 1989Human factor viii Hemophilia B* 1989Ibudilast Antiasthmatic 1989Indecainide Antiarrhythmic 1989Interferon alfa-n3 Antiviral Y B* 1989Interferon gamma Inflammatory disease B* 1989Interleukin-2 Anticancer B* 1989


Ipriflavone Calcium metabolism ND 1989Irsogladine Antiulcer 1989Ketorolac Pain Y 1989Ketorolac tromethamine Analgesic Y 1989Lmw heparin Anticoagulant ND 1989Mefloquine hci Antiparasitic Y ND 1989Metipranolol hydrochloride Glaucoma Y 1989Nilvadipine Antihypertensive 1989

Omeprazole

Dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), laryngopharyngeal reflux (LPR) and Zollinger–Ellison syndrome

Y 1989

Propafenone hydrochloride Anti-arrhythmic Y 1989Propofol Anesthetic Y 1989Recdna somatotropin Hormone B* 1989Rilmazafone Hypnotic 1989Rv-11 Antibacterial N 1989Selegiline hcl AntiParkinsonian Y 1989Setiptiline Antidepressant 1989Solamargine Oncological disease N 1989Tolrestat Antidiabetic 1989Acrivastine Antihistamine 1988Alacepril Cardiovascular disease S*/NM 1988Alpha-1 antitrypsin Antiemphysemic B* 1988Alpiropride Antimigraine 1988Amosulalol Antihypertensive 1988Cadralazine Antihypertensive 1988Carteolol hydrochloride Glaucoma Y 1988Carumonam Antibacterial ND 1988Choline alfoscerate Nootropic ND 1988Cicletanine Antihypertensive 1988Clobenoside Vasoprotective 1988Denopamine Cardiotonic S*/NM 1988Diclofenac Rheumatoid arthritis Y 1988Enoximone Cardiotonic 1988Epervudine Antiviral S* 1988Erythromycin acistrate; Cas 96128-89- Antibacterial ND 1988Erythropoietin alfa Erythropoiesis B* 1988Ethanolamine oleate Sclerosant Y S* 1988Exifone Nootropic 1988Flomoxef sodium Antibacterial ND 1988Flutropium bromide Antitussive ND 1988Fosfomycin trometamol Antibacterial N 1988Gamolenic acid Antiallergic N 1988Guaimesal Expectorant 1988Halopredone acetate Antiarthritic ND 1988Hydrocortisone aceponate Antiinflammatory ND 1988Ifosfamide; Mesna || ifosfamide Cancer Y 1988Indeloxazine hci Nootropic 1988Isepamicin Antibacterial ND 1988Josamycin Antibacterial N 1988Levodropropizine Antitussive 1988Limaprost Antithrombotic ND 1988Mesna Adjuvant in cancer chemotherapy Y 1988


Midecamycin Antibiotic N 1988Misoprostol Antiulcer Y ND 1988Naftifine hydrochloride Antifungal Y 1988Nicardipine hydrochloride High blood pressure and angina Y 1988Nimodipine Vasodilator; cerebral Y 1988Nipradilol Antihypertensive 1988Nizatidine Antiulcer Y 1988Nizofenone fumarate Nootropic 1988Octreotide Antisecretory Y ND 1988Oxiconazole nitrate Antifungal Y 1988Ozagrel sodium Antithrombotic 1988Pergolide mesylate AntiParkinsonian Y ND 1988Pirarubicin Oncological disease ND 1988Piroxicam cinnamate Antiinflammatory 1988Propentofylline propionate Vasodilator; cerebral ND 1988Rilmenidine Antihypertensive 1988Secalciferol Calcium metabolism ND 1988Taurolidine Antibacterial 1988Teicoplanin Antibacterial N 1988Tiamenidine hcl Antihypertensive 1988Tibolone Anabolic metabolism ND 1988Tinazoline Nasal decongestant 1988Tiopronin Urolithiasis Y ND 1988Xamoterol fumarate Cardiotonic 1988Zinc acexamate Antiulcer 1988Amsacrine Anticancer 1987Anabasine hcl Anti-smoking 1987Anistreolase; Anistreplase Antithrombotic B* 1987Apraclonidine hydrochloride Sympathomimetic Y 1987Artemether Antiparasitic ND 1987Artemisinin; Qinghaosu Antiparasitic N 1987Aspoxicillin Antibacterial ND 1987Benexate hci Antiulcer 1987Bevantolol hcl Antihypertensive 1987Bifemelane hci Nootropic 1987Bucillamine Immunomodulator N 1987Carprofen Antiarthritic Y 1987Cefmenoxime hydrochloride Antibiotic Y ND 1987Cefminox sodium Antibacterial ND 1987Cefpimizole Antibacterial ND 1987Cefteram pivoxil Antibacterial ND 1987Cefuzonam sodium Antibacterial ND 1987Ciprofloxacin hydrochloride Fluoroquinolone antibiotic Y 1987Disodium pamidronate Calcium metabolism 1987Doxifluridine Anticancer S* 1987Enalaprilat Cardiovascular disease S*/NM 1987Encainide hcl Antiarrhythmic 1987Epidermal growth factor Vulnerary B* 1987Eptazocine hbr Analgesic S* 1987Factor viii Hemophilia B* 1987Fenticonazole nitrate Antifungal 1987Flunoxaprofen Antiinflammatory 1987Fluoxetine hydrochloride Antidepressant Y 1987Ganglioside gm1 Antithrombotic N 1987


Gestodene; Ethinylestradiol Contraception ND 1987Guglipid Lipoprotein disorders N 1987Hidrosmin Cardiovascular disease ND 1987Hyaluronate sodium Joint lubricant B* 1987Ibuprofen guaiacol ester Antiinflammatory 1987Interferon alfa Antiviral B* 1987Lenampicillin hci Antibacterial ND 1987Levosulpiride Antipsychotic 1987Lisinopril Cardiovascular disease Y S*/NM 1987Lonidamine Anticancer 1987Lovastatin; Mevinolin Cardiovascular disease Y N 1987Mesalamine Antiinflammatory Y 1987Metaclazepam Anxiolytic 1987Metergolin Antihyperprolactinemia ND 1987Micinicate Cardiovascular disease 1987Midoriamin Antiulcer 1987Milrinone Cardiotonic Y 1987Mitoxantrone hci Oncological disease Y S* 1987Mometasone furoate Antiinflammatory Y ND 1987Mupirocin Antibacterial Y N 1987Ornoprostil Antiulcer ND 1987Oxiracetam Nootropic 1987Penbutolol sulfate Hypertension Y 1987Picotamide Antithrombotic 1987Pinacidil Antihypertensive 1987Plaunotol Antiulcer N 1987Ranimustine Anticancer 1987Repirinast Antiallergic 1987Rifamixin Antibacterial ND 1987Roxithromycin Antibacterial ND 1987Setastine hci Antihistamine 1987Spizofurone Antiulcer 1987Sultamicillin tosilate Antibacterial ND 1987Surfactant ta Respiratory distress syndrome B 1987Tenoxicam Antiinflammatory 1987Terazosin hydrochloride Antihypertensive Y 1987Terconazole Antifungal Y 1987Tertatolol hcl Antihypertensive 1987

Ubenimex Immunological, inflammatory and related disease - Immunostimulant N 1987

Ursodiol Metabolic byproducts of intestinal bacteria Y N 1987Zidovudine; Zdv; Azt; Azidothymidine; 3'-azido-3'- Antiviral Y S* 1987

Zuclopenthixol acetate Antipsychotic 1987Adrafinil Psychostimulant 1986Alfentanil hydrochloride Opioid analgesic drug Y 1986Amfenac sodium Antiinflammatory 1986Amisulpride Antipsychotic 1986Arotinolol hci Antihypertensive 1986Azosemide Diuretic 1986Aztreonam Antibacterial Y N 1986Beclobrate Hypolipidemic 1986Binifibrate Hypolipidemic 1986Brovincamine fumarate Vasodilator, cerebral ND 1986


Buspirone hydrochloride Generalized anxiety disorder Y 1986Butoconazole Antifungal 1986Cloconazole hci Antifungal 1986Clodronate disodium Calcium metabolism 1986Clofazimine Leprosy Y 1986Defibrotide Antithrombotic B 1986Deflazacort Antiinflammatory ND 1986Esmolol hydrochloride Antiarrhythmic Y 1986Etretinate Severe psoriasis Y 1986Famotidine Antiulcer Y 1986Felbinac Antiinflammatory 1986Flurbiprofen sodium Antiinflammatory Y 1986Flutoprazepam Anxiolytic 1986Gestrinone Antiprogestogenic ND 1986Gonadoreline-6-d-trp acetate Oncological disease ND 1986Guanfacine hydrochloride Sympatholytic Y 1986Idebenone Nootropic ND 1986Interferon alfa2a Anticancer Y B* 1986Interferon alfa-2b Antiviral Y B* 1986Interferon alfa-n1 Antiviral B* 1986Ipratropium; Ipratropium bromide Anticholinergic Y ND 1986Ketoprofen Rheumatoid arthritis and pain Y 1986Lentinan Oncological disease N 1986Levacecarnine hci Nootropic ND 1986Lobenzarit sodium Antiinflammatory 1986Loxoprofen sodium Antiinflammatory 1986Mabuteroi hcl Bronchodilator 1986Medifoxamine fumarate Antidepressant 1986Nafamostat mesylate Pancreatitis 1986Nomegestrol acetate Progestogen ND 1986Norfloxacin Antibacterial Y 1986Norgestimate Progestogen ND 1986Oxymetazoline Nasal congestion 1986Permethrin Infection with Sarcoptes scabiei Y 1986Piproxen Antiinflammatory 1986Prednicarbate Inflammatory disease ND 1986Propacetamol hcl Analgesic 1986Rokitamycin Antibacterial ND 1986Ronifibrate Hypolipidemic 1986Roxatidine acetate hci Antiulcer 1986

Schizophyllan Immunological, inflammatory and related disease - Immunostimulant N 1986

Soluble insulin Antidiabetic B* 1986Sulbactam sodium Beta-lactamase inhibitor ND 1986

Tranexamic acidTreat or prevent excessive blood loss during surgery and in various other medical conditions

Y ND 1986

Triptorelin Oncological disease ND 1986Troxipide Antiulcer 1986Zopiclone Hypnotic 1986Acipimox Hypolipidemic 1985Amiodarone hydrochloride Antiarrhythmic agent Y ND 1985Astromycin sulfate Antibacterial N 1985Auranofin Antiarthritic Y 1985


Beta-acetyldigoxin Cardiovascular disease ND 1985Betaxolol hci Cardiovascular disease Y S*/NM 1985Bopindolol Antihypertensive 1985Bunazosin hcl Antihypertensive 1985Bupropion hydrochloride Antidepressant Y 1985Camostat mesylate Anticancer 1985Cefbuperazone sodium Antibacterial ND 1985Cefotetan Antibacterial Y ND 1985Ceftazidime pentahydrate Antibacterial Y ND 1985Cibenzoline succinate Antiarrhythmic 1985Cimetropium bromide Antispasmodic ND 1985Ciprofibrate Hypolipidemic 1985

Clobetasol propionate Various skin disorders including eczema and psoriasis Y 1985

Diacerein Antirheumatic 1985Doxefaxepam Hypnotic 1985Doxofylline Bronchodilator ND 1985Elcatonin Calcium metabolism ND 1985Enalapril maleate Cardiovascular disease Y S*/NM 1985Enprostil Antiulcer ND 1985Flecainide acetate Antiarrhythmic Y 1985Flupirtine maleate Analgesic 1985Haem arginate Porphyria ND 1985Human insulin zinc suspension Antidiabetic B* 1985Imipenem Antibacterial ND 1985Imipenem; Cilastatin Antibacterial ND 1985Interferon beta Antiviral B* 1985Ketanserin Antihypertensive 1985Leuprolide acetate Oncological disease Y ND 1985Levobunolol hydrochloride Antiglaucoma Y 1985Levocarnitine Nutritional supplement Y ND 1985Malotilate Hepatoprotectant 1985Mexiletine Ventricular arrhythmias Y 1985Midazolam maleate Sedative Y 1985Miokamycin; Miocamycin; Mom Antibacterial N 1985

Monoctanoin Dissolve gallstones that are caused by cholesterol Y 1985

Nabilone Neurological disease Y ND 1985Nadroparin calcium Anticoagulant ND 1985Nimesulide Antiinflammatory 1985Nitrendipine Antihypertensive 1985Pefloxacin mesylate Antibacterial 1985Podophyllotoxin; Podofilox Antiviral N 1985Porcine isophane insulin Antidiabetic B 1985Progabide Anticonvulsant S* 1985Quazepam Hypnotic Y 1985Ribavirin Antiviral Y ND 1985Rosaprostol Antiulcer ND 1985Ru-41740 Immunomodulator B 1985Salmon calcitonin Osteoporosis B 1985Sodium bicarbonate; Tartaric acid Metabolic acidosis Y 1985Somatrem Hormone Y B* 1985Sulconazole nitrate Antifungal Y 1985Sulglycotide Antiulcer B 1985


Thc; Dronabinol; Delta9-tetrahydrocannabinol Neurological disease Y N 1985

Thymopentin Immunomodulator ND 1985Trientine hydrochloride Wilson's disease Y 1985Trimazosin hcl Antihypertensive 1985Ulinastatin Pancreatic disorders B* 1985Acebutolol hydrochloride Hypertension, Arrhythmias Y 1984Admantanium bromide Antiseptic 1984Almagate Antiulcer 1984Amoxicillin; Clavulanic acid Antibacterial ND 1984Amrinone Cardiotonic Y 1984Anti-thymocyte globulin Immunosuppressant B* 1984

Bitolterol mesylate Used for the relief of bronchospasm in conditions such as asthma and COPD Y 1984

Bucladesine sodium Cardiotonic S*/NM 1984Buserelin acetate Oncological disease ND 1984Butoctamide Hypnotic 1984Cefonicid sodium; Cefonicide; Antibacterial ND 1984Ceforanide Antibacterial Y ND 1984Ceftriaxone sodium Antibacterial Y ND 1984Detomidine hcl Sedative 1984Divistyramine Hypocholesterolemic 1984Emorfazone Analgesic 1984Etizolam Anxiolytic 1984Flutazolam Anxiolytic 1984Fosfosal Analgesic S* 1984Glibenclamide Diabetes mellitus Y 1984Glipizide Anti-diabetic drug Y 1984Hydromorphone Pain 1984Ibopamine hci Cardiotonic ND 1984Indobufen Antithrombotic 1984Isofezolac Antiinflammatory 1984Labetalol Hypertension Y 1984Lidamidine hcl Antiperistaltic 1984Melinamide Hypocholesterolemic ND 1984Mepixanox Analeptic 1984Metapramine Antidepressant 1984Mexazolam Anxiolytic 1984

Mizoribine Immunological, inflammatory and related disease N 1984

Nafcillin Antibacterial ND 1984Naltrexone Alcohol dependence Y 1984Naltrexone hci Neurological disease Y ND 1984Nicorandil Vasodilator; coronary ND 1984Nicotine Insecticide Y N 1984Papaverine Neurological disease N 1984Pentamidine isethionate Antimicrobial Y 1984

PentoxifyllineIntermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia

Y ND 1984

Piketoprofen Antiinflammatory 1984Pimaprofen Antiinflammatory 1984Pimozide Antipsychotic Y 1984Quinfamide Antiparasitic 1984Sofalcone Antiulcer ND 1984


Sufentanil citrateIn operating suites and critical care where pain relief is required for a short period of Y 1984

Temocillin disodium Antibacterial ND 1984Teprenone Antiulcer ND 1984Timiperone Neuroleptic 1984Tiquizium bromide Antispasmodic 1984Tocainide hcl Antiarrhythmic Y 1984Toloxatone Antidepressant 1984Vecuronium bromide Muscle relaxant Y ND 1984(+)-catechin Haemostatic N 1983Acetohydroxamic acid Hypoammonuric Y 1983Afloqualone Muscle relaxant 1983Alminoprofen Analgesic 1983Amineptine Antidepressant 1983Antithrombin iii Anticoagulant B* 1983Astemizole Antihistamine 1983Atracurium General anesthesia Y 1983Befunolol hci Antiglaucoma S* 1983Bifonazole Hypnotic 1983Brotizolam Hypnotic 1983Budralazine Antihypertensive 1983Bumetanide Edema associated with congestive heart Y 1983Butyl flufenamate Antiinflammatory 1983Cadexomer iodine Vulnerary 1983Ceftizoxime sodium Antibacterial Y ND 1983Cefuroxime axetil Antibacterial Y ND 1983Celiprolol hcl Antihypertensive S* 1983Chenodiol Anticholelithogenic Y N 1983Ciclosporin; Cyclosporine; Cyclosporin; Ciclosporin a;

Immunological, inflammatory and related disease Y N 1983

Elliptinium acetate Oncological disease ND 1983Enocitabine Anticancer S* 1983Eperisone hci Muscle relaxant 1983Fenbuprol Choleretic 1983Gallopamii hcl Antianginal 1983Gemeprost Abortifacient ND 1983Halometasone Inflammatory disease ND 1983Hydrocortisone butyrate Inflammatory disease ND 1983Indalpine Antidepressant 1983Indapamide Hypertension Y 1983Isoxicam Antiinflammatory 1983Linsidomine Antianginal 1983Loprazolam mesylate Hypnotic 1983Meglutol Hypolipidemic 1983Meptazinol hcl Analgesic 1983Muzolimine Diuretic 1983Nefopam hcl Analgesic 1983Netilmicin sulfate Antibacterial Y ND 1983Nitrefazole Alcohol deterrent 1983Oxitropium bromide Bronchodilator ND 1983Pirbuterol Bronchodilator 1983Promegestone Progestogen ND 1983

Ranitidine hydrochloride Peptic ulcer disease (PUD) and gastroesophageal reflux disease Y 1983


Suprofen Analgesic 1983Tianeptine sodium Antidepressant 1983Tioconazole Antifungal Y 1983Tiropramide Antispasmodic 1983Toposar; Vp-16 Oncological disease Y ND 1983Triprolidine Hay fever 1983 Aciclovir Antiviral Y S* 1982Alclometasone dipropionate Inflammatory disease Y ND 1982Apalcillin sodium Antibacterial ND 1982Biphasic porcine insulin Antidiabetic B 1982Cefoperazone sodium Antibacterial Y ND 1982Chloramphenicol Antibacterial N 1982Chymopapain Herniated lower lumbar discs in the spine Y B 1982Ciclopirox Antifungal Y 1982Cromoglicate Allergic rhinitis 1982Dextromethorphan; Dxm; Dm Neurological disease - Antitussive ND 1982Diflunisal Pain Y 1982

Diltiazem hydrochloride Hypertension, angina pectoris, and some types of arrhythmia Y 1982

Econazole Fungal infections Y 1982Ethyl loflazepate Anxiolytic 1982Etomidate Anaesthetic agent Y 1982Extract of serenoa repens Benign prostatic hypertrophy N 1982Flumecinol Hepatoprotectant 1982Gonadorelin Hypothalamic hypogonadism Y 1982Guanabenz High blood pressure Y 1982Guanadrel sulfate Antihypertensive Y 1982Insulin recombinant human Diabetes Y B* 1982Isophane insulin Antidiabetic B* 1982Isotretinoin; Isotrentoin Antiacne Y N 1982Lisuride maleate Antihyperprolactinemia ND 1982Malathion Pediculosis Y 1982Methypranolol Antiglaucoma 1982Micronomicin sulfate Antibacterial N 1982Moxalactam disodium; Latamoxef Antibacterial ND 1982Phenmetrazine Obesity 1982Pindolol Hypertension and angina Y 1982Piroxicam Anti-inflammatory Y 1982Pirprofen Antimigraine 1982Pranoprofen Antiinflammatory 1982Praziquantel Anthelmintic Y 1982Sodium cellulose po4 Hypocalciuric Y ND 1982Streptozocin; Streptozotocin; Stz Oncological disease Y N 1982Talniflumate Cystic fibrosis 1982Tranilast Antiasthmatic 1982Triazolam Severe insomnia Y 1982Urofollitrophin Infertility; female B* 1982Zotepine Antipsychotic 1982Aclarubicin Oncological disease N 1981

AlbuterolRelief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease

Y 1981

Alizapride Antiemetic 1981Alprazolam Anxiolytic Y 1981


Alprostadil Erectile dysfunction Y N 1981Amezinium methylsulfate Antihypotensive 1981Amikacin Antibacterial ND 1981Amiloride hydrochloride Potassium-sparing diuretic Y 1981Atenolol Cardiovascular disease Y ND 1981Azurene Antipsychotic 1981Buprenorphine Neurological disease Y ND 1981Captopril; Sq14225; Capropril Cardiovascular disease Y ND 1981Carmofur Anticancer S* 1981Cefotaxime sodium Antibacterial Y ND 1981Cefotiam hcl Antibacterial ND 1981Ceftiofur Antibacterial ND 1981Clinofibrate Lipoprotein disorders 1981Cloranolol hcl Antihypertensive 1981Desogestrel; Ethinylestradiol Contraception ND 1981Estramustine Antineoplastic Y ND 1981Flunisolide Allergic rhinitis Y 1981Gemfibrozil Antiathersclerotic Y 1981Halazepam Anxiolytic Y 1981Indoramin hcl Antihypertensive S* 1981Inosine pranobex Antiviral S* 1981Isosulfan blue Delineation of lymphatic vessels Y 1981Ketoconazole Antifungal Y 1981Lonazolac calcium Antiinflammatory 1981Magnesium sulfate Acute pain 1981Mepindolol sulfate Antihypertensive 1981Mezlocillin Antibacterial Y ND 1981Morantel tartrate Mature gastrointestinal nematode infections 1981Morniflumate Antiarthritic 1981

NifedipineAntianginal (especially in Prinzmetal's angina) and antihypertensive, pulmonary hypertension

Y 1981

Nifurzide Antidiarrheal 1981Nitroglycerin Angina pectoris 1981Oxatomide Antiallergic 1981Oxtriphylline Cough 1981Paromomycin sulfate Antibacterial N 1981Penbutanol sulfate Antihypertensive 1981Peplomycin Oncological disease N 1981Piperacillin; Tazobactam Antibacterial Y ND 1981Piretanide Diuretic 1981

Salbutamol; Albuterol Immunological, inflammatory and related disease - Inflammatory disease ND 1981

Sodium bicarbonate Metabolic acidosis 1981Sucralfate Duodenal ulcers Y 1981Sulfadoxine Malaria 1981Sulphadoxine Malaria 1981Sulprostone Abortifacient ND 1981Temazepam Insomnia Y 1981Trazodone Depression Y 1981Trifusal Antithrombotic 1981Tulobuterol hcl Bronchodilator 1981Urapidil Antihypertensive 1981Verapamil Hypertension and angina Y 1981


Alpha-acetyldigoxin Cardiovascular disease ND 1980Aminoglutethimide Anticancer Y 1980Amoxapine Depression Y 1980Bacampicillin Antibacterial Y ND 1980Calcidiol Vitamin D deficiency 1980Cefsulodin Antibiotic ND 1980Cinoxacin Urinary tract infections Y 1980Dipivefrin Open-angle glaucoma 1980Huperzine; Huperzine a Neurological disease N 1980Maprotiline Depression Y 1980

Meclofenamate sodium Joint, muscular pain, arthritis and dysmenorrhea Y 1980

Meclofenamic acid Joint and muscular pain 1980Oxamniquine Schistosomiasis Y 1980Oxytocin Induced labour 1980Phenylbutazone Chronic pain 1980Sanguinarine Dental plaque inhibitor N 1980Santonin Anthelmintic - Ascaricide N 1980Silymarin Antihepatotoxic N 1980Stevioside Sweetener N 1980Terbutyline Antihypertensive ND 1980Theobromine Vasodilator, Diuretic N 1980Trifluridine Anti-herpesvirus antiviral drug Y 1980Trimethoprim Urinary tract infections 1980Vasicine; Peganine Oxytocic N 1980Xanthotoxin; Ammoidin; 8-methoxypsoralen Leukoderma, Vitiligo N 1980

Yohimbine Aphrodisiac N 1980

AmcinonideItching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact

Y 1979

Carboprost tromethamine Postpartum hemorrhage caused by uterine atony not controlled by other methods Y 1979

Cefaclor; Cefachlor; Cefaclorum Antibacterial Y ND 1979Cyclacillin Antibiotic Y ND 1979Dapsone Pneumocystis carinii pneumonia 1979Daunorubicin; Daunomycin; Rubomycin c Oncological disease Y N 1979

Estrone Menopausal and postmenopausal disorders 1979Gentamicin Antibacterial N 1979Isoetharine Asthma 1979Isoflurane Anesthesia Y 1979Metoclopramide hydrochloride Antiemetic and gastroprokinetic agent Y 1979Metyrosine Antihypertensive Y 1979Minoxidil Hypertension Y 1979

Nadolol Hypertension and for the long-term treatment of angina pectoris Y 1979

Nalbuphine Neurological disease Y ND 1979Procaine Anesthetic 1979

Scopolamine Immunological, inflammatory and related disease - Sedative N 1979

Trimipramine maleate Antidepressant, anxiolytic, antipsychotic, sedative, and analgesic effects Y 1979

Vindesine; Vds Oncological disease ND 1979

(+-)-tetrahydropalmatine; Rotundine Immunological, inflammatory and related disease - Analgesic; Sedative; Tranquillizer N 1978


Adoniside Cardiovascular disease N 1978

Aescin Immunological, inflammatory and related disease - Inflammatory disease N 1978

Agrimophol Anthelmintic - Chemotherapy N 1978Ajmalicine Circulatory disorders N 1978Allantoin Vulnerary N 1978Allyl isothiocyanate Rubefacient N 1978Anisodamine Anticholinergic N 1978Anisodine Anticholinergic N 1978Arecoline Anthelmintic - Chemotherapy N 1978Asiaticoside Vulnerary N 1978

Berberine Antibacterial - Chemotherapy: Bacillary dysentery N 1978

Bromocriptine mesylatePituitary tumors, Parkinson's disease (PD), hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes

Y ND 1978

Butabarbital Insomnia 1978Butorphanol tartrate Opioid analgesic Y 1978

CalcitriolIncreasing the uptake of calcium from the gut into the blood, and (2) possibly increasing the release of calcium into the

Y N 1978

Camphor Rubefacient N 1978Cefadroxil; Cefadroxil hemihydrate Antibacterial Y ND 1978Cefamandole nafate; Cephamandole Antibacterial Y ND 1978Cefoxitin sodium Antibacterial Y ND 1978Cisplatin Cancers Y 1978Cissampeline Skeletal muscle relaxant N 1978

Colchiceine amide Oncological disease - Chemotherapy: Antitumor agent N 1978

Convallatoxin Cardiovascular disease N 1978Cynarin Choleretic N 1978Danthron; 1,8-dihydroxy- Laxative N 1978

Demecolcine Oncological disease - Chemotherapy: Antitumor agent N 1978

Deslanoside Cardiovascular disease N 1978Desmopressin acetate Diabetes insipidus, bedwetting, or nocturia Y B* 1978Digitalin Cardiovascular disease N 1978Dimethyl sulfoxide Cancer and other conditions Y 1978Divalproex sodium Antiepileptic Y 1978Dobutamine Heart failure and cardiogenic shock Y 1978Gitalin Cardiovascular disease N 1978Glaucine Antitussive N 1978Glaziovine; Glasiovine Antidepressant N 1978Glycyrrhizin; Glycyrrhetic acid Sweetener, Addison's disease N 1978

Hemsleyadin Antibacterial - Chemotherapy: Bacillary dysentery, Antipyretic N 1978

Hesperidin Capillary fragility N 1978Hexachlorophene Bacterial infections 1978Hydrastine Haemostatic, Astringent N 1978Hydroxocobalamin Vitamin B12 deficiency 1978Hyoscyamine Anticholinergic N 1978Kawain Cardiovascular disease N 1978Khellin Bronchodilator N 1978Lanatoside a Cardiovascular disease N 1978Lanatoside b Cardiovascular disease N 1978


Lanatoside c Cardiovascular disease N 1978Menthol Rubefacient N 1978Metoprolol tartrate Cardiovascular disease Y ND 1978Monocrotaline Oncological disease - Antitumor agent N 1978Natamycin; Pimaricin Antifungal N 1978

Neoandrographolide Antibacterial - Chemotherapy: Bacillary dysentery N 1978

Nordihydroguaiaretic acid Antioxidant N 1978Ouabain; G-strophanthin Cardiovascular disease N 1978Pachycarpine; (+)-sparteine Oxytocic N 1978Palmatine; Filiraurine Antipyretic, Detoxicant N 1978Picrotoxin Analeptic N 1978Rescinnamine Cardiovascular disease N 1978Rorifone Antitussive N 1978Rotenone Piscicide N 1978Rutin Capillary fragility N 1978

Salicin Immunological, inflammatory and related disease - Analgesic N 1978

Sennoside a Cardiovascular disease N 1978Sennoside b Cardiovascular disease N 1978Seractide acetate CNS drugs Y 1978Strychnine Neurological disease N 1978Sulindac Acute or chronic inflammatory conditions Y 1978Thymol Antifungal - Chemotherapy: Antifungal N 1978Timolol maleate Glaucoma, heart attacks and hypertension Y 1978Vincamine Cerebral stimulant N 1978Azatadine maleate Antihistamine and anticholinergic Y 1977Azlocillin Antibacterial ND 1977Baclofen Multiple sclerosis Y 1977Carbidopa Parkinson's disease 1977Carmustine Alkylating agent Y 1977Cimetidine Heartburn and peptic ulcers Y 1977Clemastine Allergic rhinitis Y 1977Clocortolone pivalate Various skin disorders Y 1977

Colestipol hydrochloride Lower blood cholesterol, specifically low-density lipoprotein Y 1977

Cyclobenzaprine Depression Y 1977Desoximetasone Inflammatory diseases Y 1977Diflorasone diacetate Anti-inflammatory and anti-itching agent Y 1977Dinoprostone Vaginal suppository Y N 1977Disopyramide phosphate Antiarrhythmic Y 1977

Etidronate disodium Strengthen bone, treat osteoporosis, and treat Paget's disease of bone Y 1977

LorazepamAnxiolysis, anterograde amnesia, sedation/hypnosis, anticonvulsion, antiemesis and muscle relaxation

Y 1977

Probucol Coronary artery disease Y 1977Quinacrine Giardiasis and cutaneous leishmaniasis 1977Tamoxifen Breast cancer Y 1977Beclomethasone dipropionate Asthma, rhinitis, sinusitis, aphthous ulcers Y 1976Butalbital Headache 1976Candicidin Antifungal N 1976Cefalexin; Cephalexin Antibacterial ND 1976Chlorhexidine Bacterial infections 1976


Chlorotrianisene Treatment of menopause, deficiencies in ovary function, and prostate cancer 1976

Chloroxine Antibacterial Y 1976Danazol Menorrhagia Y 1976Dextroamphetamine sulfate ADHD; narcolepsy ND 1976

Epinephrine bitartrate Immunological, inflammatory and related disease - Inflammatory disease Y N 1976

Fenoprofen calcium Non-steroidal anti-inflammatory drug Y 1976

Fibrinogen Deep vein thrombosis or pulmonary embolism Y N 1976

Glutethimide Insomnia 1976Glycine Dietary shortage 1976

Lactulose Chronic constipation and hepatic encephalopathy Y 1976

Lomustine; Ccnu Brain tumors Y 1976

Loperamide hydrochlorideAgainst diarrhea resulting from gastroenteritis or inflammatory bowel Y 1976

Naproxen Anti-inflammatory Y 1976Neocarzinostatin Oncological disease N 1976

Pentetate calcium trisodium yb-169

Treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination

Y 1976

Phendimetrazine Obesity 1976Prazosin hydrochloride Sympatholytic Y 1976Progesterone Infertile in women 1976

Protirelin Spinocerebellar degeneration and disturbance of consciousness Y B* 1976

Somatropin Growth hormone deficiency Y B* 1976Theophylline Respiratory diseases N 1976Ticarcillin; Clavulanate Antibacterial Y ND 1976Tolmetin Rheumatoid arthritis and osteoarthritis Y 1976VIDARABINE Antiviral Y S* 1976Betamethasone dipropionate Anti-inflammatory N 1975

Clonazepam Anxiolytic, anticonvulsant, muscle relaxant, sedative, and hypnotic Y 1975

Clotrimazole Fungal infections Y 1975Dacarbazine Antineoplastic Y 1975Digoxin; Digitalis Cardiovascular disease N 1975

Eupatilin Immunological, inflammatory and related disease N 1975

Loxapine Psychotic disorders Y 1975Menotropins Growth hormone deficiency N 1975Oxybutynin Urinary and bladder difficulties Y 1975Pemoline Stimulant drug Y 1975Pentobarbital Insomnia 1975

Pseudoephedrine Immunological, inflammatory and related disease - Sympathomimetic N 1975

Sulfacytine Urinary tract infections Y 1975Tobramycin sulfate Antibacterial Y N 1975

Triptolide Immunological, inflammatory and related disease N 1975

Amoxicillin; Amoxycillin Antibacterial ND 1974Benzquinamide Antiemetic 1974

Benzylpenicilloyl polylysine As a skin test before the administration of penicillin Y 1974


Betamethasone sodium phosphate Anti-inflammatory N 1974Cefapirin; Cephapirin Antibacterial ND 1974Cefradine; Cephradine Antibacterial ND 1974Clonidine Hypertension 1974Cloxacillin; Cloxacillin sodium Antibacterial ND 1974Cyclopentolate Pediatric eye examinations 1974Dantrolene sodium Muscle relaxant Y 1974Dopamine hydrochloride Neurological disease Y N 1974Doxorubicin; Doxorubicin hydrochloride; Hydroxydaunorubicin Oncological disease Y N 1974

Halcinonide Certain skin conditions Y 1974Ibuprofen Pain Y 1974L-dopa Neurological disease - AntiParkinsonism N 1974Lindane Infestations of lice and scabies 1974Mebendazole Worm infestations Y 1974Methyltestosterone Oncological disease ND 1974Miconazole Fungal infections 1974Miconazole nitrate Antifungal Y 1974Molindone Schizophrenia Y 1974

Potassium perchlorate Pain, Lung Cancer - Non-small Cell, Nausea And Vomiting Y 1974

Terbutaline Asthma Y 1974Tolbutamide Diabetes mellitus 1974Acetylcholine chloride Neurological disease Y N 1973

Atropine

Anticholinergic - For the treatment of poisoning by susceptible organophosphorous nerve agents having cholinesterase activity as well as organophosphorous or carbamate

N 1973

Bleomycin; Bleomycin a2; Bleomycin b2) Oncological disease Y N 1973

Calusterone Oncological disease ND 1973Diazoxide Hypertension Y 1973Etidronic acid Paget's disease 1973Kanamycin Antibacterial N 1973Mazindol Obesity Y 1973Mepyramine maleate Allergies 1973Metolazone Diuretic Y 1973Orciprenaline Asthma Y 1973Silver sulfadiazine Bacterial infections 1973Sulfamethoxazole Bacterial infections 1973Bupivacaine Anesthetic Y 1972Carbachol Cholinomimetic Y 1972Carbenicillin Antibacterial ND 1972Carindacillin; Carbenicillin indanyl Antibacterial ND 1972

Clorazepate dipotassium Anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant Y 1972

Dapotum d Ascariasis and enterobiasis 1972

Desonide Atopic dermatitis (eczema), seborrheic dermatitis, contact dermatitis and psoriasis Y 1972

Dimenhydrinate Nausea and vomiting 1972Enflurane Anesthesia Y 1972Fluorometholone Inflammatory diseases 1972Fosfestrol Anticancer ND 1972Heparin sodium Anticoagulant N 1972


Pancuronium Anesthetic Y 1972Pristinamycin; Pristinamycine Antibacterial N 1972Prolixin decanoate Chronic schizophrenics 1972Sodium fluoride f-18 Positron emission tomography Y 1972Amphetamine Attention-deficit disorder N 1971Capreomycin Antibacterial N 1971Cefazolin; Cefazoline; Cephazolin Antibacterial ND 1971Dicloxacillin; Dicoxacillin Antibacterial ND 1971Flucytosine Antimycotic drug Y 1971Fluocinonide Inflammatory diseases Y 1971Megesterol acetate Anticancer ND 1971Megestrol acetate Oncological disease Y ND 1971Naloxone; Naltrexate Neurological disease Y ND 1971Naphazoline Minor eye irritations 1971Pyrazinamide Tuberculosis 1971Rifampicin; Rifampin; Rifaldazine; R/amp; Rofact Antibacterial ND 1971

Rose bengal sodium i-131 Photoscanning the liver and testing liver function Y 1971

Sulfisoxazole Urinary tract infections 1971Tretinoin Antiulcer Y ND 1971Cefaloglycin; Cephaloglycin Antibacterial ND 1970Clindamycin Antibacterial ND 1970Colistimethate sodium Pulmonary infections ND 1970Droperidol Nausea and vomiting 1970Flavoxate Muscle Relaxant Y 1970Floxuridine Oncological disease Y S* 1970Floxuridine/5-fluorouracil Colorectal cancer Y 1970Flucloxacillin; Floxacillin Antibacterial ND 1970Flurazepam Insomnia Y 1970

Ketamine hydrochloride General anesthesia, intensive care, analgesia ,and bronchospasm Y 1970

Levodopa Dietary supplement Y N 1970Lithium carbonate Manic and bipolar disorder Y N 1970Mecillinam; Amdinocillin; Pivmecillinam; Amdinocillin pivoxil Antibacterial ND 1970

Mesoridazine Schizophrenia Y 1970Mitotane Antineoplastic Y 1970Norethindrone acetate Oncological disease ND 1970Penicillamine Antibiotic Y ND 1970Plicamycin Anticancer Y N 1970Cytarabine Cancers of white blood cells Y S* 1969Cytosine arabinoside; Ara-c Oncological disease S* 1969Doxepin Depression Y 1969Medrysone Eye inflammation Y 1969Piperacetazine Antipsychotic Y 1969Procarbazine hydrochloride Antineoplastic Y 1969Sutilains Ulcer Y B 1969Testolactone Oncological disease Y ND 1969Troleandomycin; Oleandocetine Antibacterial ND 1969Acetaminophen Pain 1968Amantadine Influenzavirus A infection 1968Azathioprine Immunosuppressive Y 1968Carbamazepine Anticonvulsant and mood-stabilizing Y 1968


Deferoxamine mesylate Acute iron poisoning Y N 1968Isosorbide dinitrate Angina pectoris and anal fissure 1968Physostigmine; Eserine Neurological disease N 1968Viomycin sulfate Antibacterial N 1968Chlorprothixene Psychotic disorders 1967Clofibrate Dysbetalipoproteinemia Y 1967Clomiphene citrate Hypothalamus Y 1967Diphenidol Nausea and vomiting Y 1967Doxycycline Antibacterial ND 1967Epicillin Antibacterial ND 1967Ethacrynic acid Loop diuretic Y 1967Ethambutol hydrochloride Bacteriostatic antimycobacterial drug Y 1967Haloperidol Schizophrenia Y 1967Hydroxyurea Antineoplastic drug Y 1967Mefenamic acid Non-steroidal anti-inflammatory drug Y 1967Pentazocine Neurological disease Y N 1967Propranolol Cardiovascular disease Y ND 1967Protriptyline Depression Y 1967Thiabendazole Dutch Elm disease Y 1967Thiothixene Psychoses like schizophrenia Y 1967Allopurinol Hyperuricemia and its complications Y 1966Amphotericin Antibacterial N 1966Ethynodiol diacetate Hormonal contraceptives 1966Furosemide Loop diuretic Y 1966Pipobroman Refractory chronic myeloid leukaemia Y 1966Sulfameter Urinary tract infections Y 1966Thioguanine Oncological disease Y S* 1966Tolazamide Diabetes mellitus Y 1966Clomocycline Antibacterial ND 1965Collagenase Enzyme Y B* 1965

Diethylstilbestrol

Gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement

1965

Doxapram hydrochloride Respiratory failure Y 1965Ethinyl estradiol Antineoplastic ND 1965Ethionamide Antibiotic Y 1965Flurandrenolide Anti-inflammatory Y 1965Hydroxyprogesterone Oncological disease ND 1965Indomethacin Patent ductus arteriosus Y 1965Oxazepam Anxiety disorder Y 1965Oxytetracycline Antibacterial N 1965Potassium chloride Hypokalemia 1965Prilocaine Anesthetic Y 1965Sulfanilamide Bacterial infections 1965Testosterone Anticancer N 1965Vinblastine; Vlb; Vinca leukoblastine sulfate; Vbl Oncological disease Y N 1965

Acetohexamide Diabetes mellitus Y 1964Aminocaproic acid Bleeding disorders Y ND 1964Cefacetrile; Cephacetrile Antibacterial ND 1964Cefalotin sodium; Cephalothin Antibacterial ND 1964Cefroxadine Antibacterial ND 1964Ceftezole; Ceftezol Antibacterial ND 1964


Cycloserine Antibacterial N 1964Dactinomycin; Actinomycin d Oncological disease Y N 1964Desipramine Depression 1964Dromostanolone Oncological disease ND 1964Erythromycin Antibacterial N 1964Ethylestrenol Testosterone deficiency in male patients Y 1964Lincomycin Antibacterial N 1964Mannitol Renal failure 1964

Melphalan Multiple myeloma and ovarian cancer, and occasionally malignant melanoma Y 1964

Nalidixic acid Bacterial infections Y 1964Neomycin Antibacterial N 1964Nortriptyline Depression Y 1964Nystatin Antifungal N 1964

Oxandrolone Androgenicity accompanied by moderate anabolic effect Y 1964

Polymyxin b sulfate Antibacterial N 1964

Pralidoxime chlorideCombat poisoning by organophosphates[1] or acetylcholinesterase inhibitors (nerve agents) in conjunction with atropine and

Y 1964

Triamterene Hypertension and edema Y 1964

Trioxsalen Phototherapy treatment of vitiligo and hand eczema Y N 1964

Acetylcysteine Mucolytic agent, Paracetamol (acetaminophen) overdose Y 1963

Dexbrompheniramine Hay fever 1963

DiazepamAnxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic

Y 1963

Fluocinolone acetonide Reduce skin inflammation and relieve Y ND 1963Fusafungine Antibiotic N 1963Idoxuridine Anti-herpesvirus antiviral drug Y ND 1963Lymecycline Antibacterial ND 1963Metronidazole Antibiotic Y 1963Quinethazone Hypertension Y 1963Tetracycline Antibacterial N 1963Vincristine; Vcr; Leurocristine Oncological disease Y N 1963Anisotropine methylbromide Peptic ulcer disease 1962Fluorouracil Oncological disease Y S* 1962Fusidic acid Antibacterial N 1962Griseofulvin; Grisovin Antifungal N 1962Metaxalone Muscle relaxant Y 1962Methyldopa Hypertension Y 1962Methysergide Migraine headaches Y 1962Stanozolol Anaemia and hereditary angioedema Y ND 1962Thioridazine Schizophrenia Y 1962Uracil mustard Lymphatic malignancies Y 1962Acetophenazine maleate Typical antipsychotic Y 1961Amitriptyline Depression and chronic pain Y 1961Ampicillin; Pivampicillin Antibacterial ND 1961Betamethasone Inflammatory diseases Y 1961Chromomycin a3 Oncological disease N 1961Colchicine Oncological disease N 1961Cyproheptadine Allergies Y 1961Dipyridamole Pulmonary hypertension Y 1961


Ethchlorvynol Insomnia 1961Glycopyrrolate Muscarinic anticholinergic Y 1961Mestranol First oral contraceptives 1961Metyrapone Adrenal insufficiency and Cushing's Y 1961Mithramycin Anticancer N 1961Phenelzine sulfate Antidepressant and anxiolytic Y 1961Polythiazide Hypertension Y 1961Spectinomycin Antibiotic N 1961Thiethylperazine Nausea and vomiting Y 1961

Tranylcypromine sulfate Major depressive episode without melancholia Y ND 1961

Benzphetamine hydrochloride Anorectic Y 1960Benzthiazide High blood pressure 1960Chlordiazepoxide Anxiety disorder Y 1960Chlormezanone Spasms, Pain Y 1960Chlorthalidone Hypertension Y 1960Demeclocycline Antibacterial N 1960Diphenoxylate Diarrhea 1960

Echothiophate iodide Glaucoma and, in some cases, accommodative esotropia Y 1960

Ergotamine Neurological disease N 1960Ethosuximide Anticonvulsant Y 1960Glucagon hydrochloride Pancreatic tumors Y B* 1960Guanethidine Hypertension Y 1960Mepivacaine Anesthetic 1960Methohexital sodium Anaesthetics Y 1960Methyclothiazide Hypertension Y 1960Meticillin; Methicillin Antibacterial ND 1960Oxyphenbutazone Non-steroidal anti-inflammatory drug Y 1960Propiomazine Insomnia Y 1960Reserpine; Trichlormethiazide; Trichlormethiazide Diuretic Y 1960

Spironolactone

Heart failure, ascites in patients with liver disease, low-renin hypertension, hypokalemia, secondary hyperaldosteronism , and Conn's syndrome

Y 1960

Trichlormethiazide Oedema and hypertension 1960Tropicamide Antimuscarinic Y 1960Bendroflumethiazide High blood pressure 1959

Biperiden hydrochloride An antiparkinsonian agent of the anticholinergic type Y 1959

Carisoprodol Muscle relaxant Y 1959Cyclophosphamide Cancers Y 1959Demecarium bromide Open-angle glaucoma Y 1959Diethylpropion hydrochloride Stimulant drug Y 1959Fluphenazine Psychotic disorders Y 1959Hydrochlorothiazide Luid retention Y 1959Hydroflumethiazide Diuretic Y 1959Imipramine Depression Y 1959Isocarboxazid Antidepressant and anxiolytic Y 1959Medroxyprogesterone acetate Oncological disease Y ND 1959Methazolamide Chronic and acute open-angle glaucoma 1959Nadrolone phenylpropionate Anticancer ND 1959Nandrolone phenpropionate Oncological disease Y ND 1959Oxymorphone Neurological disease ND 1959


Phentermine Obesity Y 1959Sulfinpyrazone Gout Y 1959Thiotepa Cancer Y 1959Trifluoperazine Schizophrenia Y 1959Virginiamycin Antibiotic ND 1959Benzonatate Oral cough suppressant, or antitussive Y 1958Chlorothiazide sodium || Diuretic Y 1958Chlorpropamide Type 2 diabetes mellitus Y 1958Chlorzoxazone Acute painful musculoskeletal conditions 1958Colistin Antibiotic N 1958Dexamethasone Oncological disease Y ND 1958Dichlorphenamide Chronic glaucoma Y 1958Furazolidone Diarrhea 1958Halothane Anesthetic Y 1958Phenylpropanolamine Obesity 1958Rifamycin b Antibacterial N 1958

Sodium polystyrene sulfonate Acute and chronic kidney disease for patients suffering from hyperkalaemia Y 1958

Trolamine polypeptide oleate condensate

For removal of impacted cerumen prior to ear examination, otologic therapy and/or audiometry

Y 1958

Vancomycin Antibacterial N 1958Anisindione Anticoagulant Y 1957Brompheniramine Allergic rhinitis 1957Chlorambucil Chronic lymphocytic leukemia Y 1957Chlorpromazine Schizophrenia Y 1957Deserpidine Cardiovascular disease Y N 1957Dextropropoxyphene Pain 1957Ethotoin Anticonvulsant Y 1957Iron dextran Iron deficiency 1957Isoflurophate Glaucoma 1957Meclizine Nausea and vomiting 1957Methocarbamol Central muscle relaxant Y 1957Methsuximide Anticonvulsant Y 1957Methylprednisolone Oncological disease Y ND 1957Orphenadrine Parkinson's disease Y 1957Perphenazine Schizophrenia and bipolar disorder Y 1957Phenprocoumon Thrombosis 1957Polyestradiol phosphate Prostate cancer Y 1957Propoxyphene hydrochloride Analgesic Y 1957Triamcinolone Oncological disease Y ND 1957Triflupromazine Psychoses Y 1957Ambenonium chloride Myasthenia gravis Y 1956Fluoxymesterone Oncological disease Y ND 1956Hydrocortamate Inflammatory diseases Y 1956Hydroxyzine Anxiety disorder Y 1956Liothyronine sodium Hypothyroidism and myxedema coma Y 1956Mecamylamine Hypertension Y 1956Mepenzolate bromide Antimuscarinic Y 1956Mitomycin c; Mitomycin Oncological disease N 1956Phenytoin Seizures 1956Prochlorperazine Nausea and vomiting Y 1956Promazine Psychomotor agitation Y 1956Chloroprocaine hydrochloride Local anesthetic Y 1955


Fludrocortisone Cerebral salt-wasting syndrome 1955Hydroxychloroquine sulfate Antimalarial Y 1955Meprobamate Anxiety disorder Y 1955Methylphenidate Traumatic brain injury 1955Novobiocin Antibacterial N 1955Phytonadione Vitamin K deficiency 1955Pinitol Expectorant N 1955Prednisolone Oncological disease Y ND 1955Prednisone Oncological disease Y ND 1955Procyclidine Parkinson's disease Y 1955Proquanil Malaria 1955

Pyridostigmine bromideTreat muscle weakness in people with myasthenia gravis and to combat the effects of curariform drug toxicity

Y 1955

Reserpine Cardiovascular disease N 1955Spiramycin Antibiotic N 1955Thiamphenicol Antibiotic ND 1955Benztropine Parkinson's disease Y 1954Bromodiphenhydramine Hay fever 1954

Busulfan Cell cycle non-specific alkylating antineoplastic agent Y 1954

Carzinophilin Oncological disease N 1954Metaraminol Hypotension 1954

Methoxsalen Psoriasis, eczema, vitiligo, and some cutaneous lymphomas Y N 1954

Methylmorphine Neurological disease N 1954Primidone Anticonvulsant Y 1954Sarkomycin Anticancer N 1954Tridihexethyl Acquired nystagmus Y 1954Warfarin Cardiovascular disease Y N 1954Acetazolamide Glaucoma Y 1953Edetate calcium disodium Chelation therapy Y 1953Ergoloid mesylate Alzheimer's Disease Y 1953Hydralazine Hypertension Y 1953Hydroxystilbamidine isethionate Blastomycosis 1953Levorphanol Pain 1953Mercaptopurine Oncological disease Y S* 1953Methotrexate sodium Antimetabolite, Antifolate Y S* 1953Methscopolamine bromide Peptic ulcers Y 1953Nitrofurantoin Urinary tract infection Y 1953Phenoxybenzamine hydrochloride Hypertension Y 1953Propantheline Excessive sweating Y 1953Proparacaine hydrochloride Anesthetic Y 1953Pyrimethamine Protozoal infections Y 1953Sulfamethizole Urinary tract infections Y 1953Thyrotropin Thyroid cancer Y B* 1953Vitamin a Night blindness N 1953Vitamin b1 Vitamin B1 Deficiency N 1953Vitamin b3 Lipid disorders, cardiovascular disease N 1953Vitamin b6 Vitamin B6 deficiency N 1953Vitamin c Vitamin C deficiency N 1953Hydrocortisone Inflammatory diseases 1952Isoniazid Tuberculosis 1952Leucovorin calcium Cancer chemotherapy Y N 1952


Monobenzone Vitiligo Y 1952

Phentolamine mesylate Control of hypertensive emergencies, most notably due to pheochromocytoma Y 1952

Phenylephrine Ophthalmic disorders 1952Primaquine Malaria 1952

Succinylcholine chloride Induce muscle relaxation and short-term paralysis Y 1952

Disulfiram Alcohol dependence Y 1951Dyphylline Acute bronchial asthma Y 1951Edrophonium chloride Myasthenia gravis Y 1951Mephentermine Hypotension 1951Methantheline bromide Antimuscarinic Y 1951Phenacemide Epilepsy Y 1951Probenecid Uricosuric Y 1951

Promethazine Allergic disorders, itching, nausea and vomiting 1951

Chlorpheniramine Allergic rhinitis and uriticaria 1950Chlortetracycline; Chlorotetracycline Antibacterial N 1950

Corticotropin Addison's disease, Cushing's Disease, circadian rhythm Y B* 1950

Cortisone acetate

Adrenal insufficiency, allergic, inflammatory, and autoimmune disorders, asthma, acute transplant rejection and the graft-versus-host disease

Y N 1950

Dicyclomine hydrochloride Anticholinergic Y 1950Diethylcarbamazine Lymphatic filariasis 1950Methimazole Hyperthyroidism Y 1950

Norepinephrine bitartrate Attention-deficit/hyperactivity disorder, depression, and hypotension Y ND 1950

Procainamide Ventricular arrhythmias Y 1950Quinidine Antiarrhythmic N 1950

Sulfasalazine Rheumatoid arthritis, inflammatory bowel disease Y 1950

Mechlorethamine hydrochloride Anticancer Y 1949Paramethadione Paramethadione syndrome 1949Sulfamerazine Bacterial infections 1949Sulfamethazine Bacterial infections 1949Trihexyphenidyl Parkinson's disease 1949Bacitracin Antibacterial N 1948Bethanechol Urinary retention 1948Caffeine; Ergotamine tartrate Vascular headaches N 1948Doxylamine succinate Antihistamine Y 1948Lidocaine Anesthetic 1948Tolazoline Peripheral vasoconstriction 1948Tripelennamine Asthma Y 1948Dienestrol Atrophic vaginitis 1947Methadone Cough 1947Phenoxymethylpenicillin; Penicillin v Antibacterial ND 1947Propylthiouracil Hyperthyroidism 1947Dihydroergotamine Migraine headaches 1946Dihydroergotoxine Alzheimer's disease 1946Diphenhydramine Vertigo/Meniere's disease Y 1946Ethanol Intractable chronic pain 1946Folic acid Folate deficiency N 1946Mephenytoin Epilepsy 1946


Methylergonovine Excessive bleeding 1946Sodium tetradecyl sulfate Varicose and spider veins of the leg Y 1946Streptomycin sulfate Antibacterial N 1946Trimethadione Epileptic conditions 1946Dicumarol Bishydroxycoumarin 1944Hydrocodone Pain Y 1943

Methamphetamine Attention Deficit Disorder with Hyperactivity ND 1943

Benzylpenicillin; Penicillin g Antibacterial N 1942

Estrogens, conjugatedHot flashes, and burning, itching, and dryness of the vagina and surrounding Y N 1942

Gramicidin s Antibiotic ND 1942Meperidine hydrochloride Opioid analgesic drug Y 1942Ergocalciferol Hypoparathyroidism 1941Sulfadiazine Urinary tract infections 1941Chloroquine Antiparasitic ND 1940Inulin Measure kidney function B 1940Quinine Antiparasitic N 1940Sulfapyridine Dermatitis herpetiformis 1939

Pilocarpine Glaucoma. For the treatment of radiation-induced dry mouth N 1900

Aspirin; Acetylsalicylic acid; Asa Immunological, inflammatory and related disease - Inflammatory disease ND 1898

Heroin; Diacetylmorphine Neurological disease N 1898Noscapine (narcotine) Antitussive N 1895Cocaine; Benzoylmethyl ecgonine Neurological disease N 1884Cotinine Insecticide N 1560


Drug Generic Name Target

Year of

Approval

Drug

Type Lead

Drug Lead

Scaffold

Group

Drug Lead

SourceDrug development History (Ref in

Pubmed ID)

Lead Discov

ery Metho

d

Lead Discovery Time

Drug Developme

nt Approach

and Outcome

Drug Developme

nt Timeli

ne

Omacetaxine

mepesuccinate

Ribosome A site

2012 ND

Homoharringtonin

e

Cephalotaxine alkaloid

s

Cephalotaxus

harringtonia

Homoharringtonine (HHT) is a natural alkaloid that is obtained

from various Cephalotaxus species. In mid 1990s, HHT was studied as

salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon-alpha

therapy. However, the remarkable success of imatinib mesylate in the

treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable

semisynthetic form of HHT, and its activity in imatinib-resistant CML has established this agent for the

second time as a valuable option in the management of this disease

(19739234)

LTS of NPs

Late 1960s

Optimization of a novel and potent NP into a drug with

new mechanism against drug-

resistant cancer

Mid 1990s

to 2012

Crofelemer

Cystic fibrosis transmembrane conduct

ance regulato

r, calcium activate

d channel anoctam

in 1

2012 NProanthocyanid

ins

Croton lechleri

Crofelemer, a purified proanthocyanidin oligomer

extracted from the blood-red bark latex of the South American

medicinal plant Croton lechleri (dragon's blood). The sap of C. lechleri has been used in South

American countries like Ecuador and Peru for many years to treat

diarrheas, including dysentery and cholera, and various lung, stomach,

and other conditions. In early 1990s, Crofelemer was isolated from the plant latex used by the

indigenous people. In late 1990s, additional pharmacological studies

have shown that crofelemer reduced fluid secretion in cell culture and

mouse models (9886979, 19808995)

Focused

search of well-established

medicinal

plants

Early 1990s

Development of a

novel and effective NP into a first-

in-class drug with

novel mechanism

Late 1990s

to 2012

Supplementary Table S2 Detailed information of Nature-Derived Small Molecule Drugs Approved in 2008-2012


Carfilzomib

20S proteaso

me2012 ND Epoxo

micin

Epoxyketone

containing

oligopeptides

Actinomyces sp.

Epoxomicin was first discovered by Bristol-Myers Squibb (BMS,

Tokyo, Japan) from an unidentied

Actinomycetes strain, No. Q996-17, based on its in vivo antitumor activity against murine B16

melanoma tumors. Despite its promising antitumor activity,

epoxomicin did not draw much attention because of its poor drug-

like properties, namely the presence of a peptide backbone and the labile

epoxy ketone pharmacophore, epoxomicin possesses

unprecedented selectivity for proteasome, an effort to optimize

the compound via a classical medicinal chemistry approach led to YU-101, which showed more potent

nhibitory activity against the proteasome than both epoxomicin and bortezomib, a boronic acid-

based synthetic proteasome inhibitor previously known

proteasome inhibitors (1468981, 23575525)

LTS of NPs

Early 1990s

Optimization of a novel, selective but less potent NP into a

drug with a new target-

binding mechansim

for more sustained effect and

against drug-resistant cancer

Late 1990s

to 2012

Pasireotide diaspartate

Ostatin receptor

5 2012 ND Somat

ostatin

GPCR targetin

g peptide hormon

es & analogs (cyclohexapept

ides)

Homo sapiens

The unique pharmacological effects of the natural ligand SRIF-14 are

from its universal high-affinity binding to all somatostatin receptor subtypes sst1-sst5. However, SRIF-14 has a very short in vivo half-life

of less than 3 min, limiting its therapeutic utility, capitalizing on structure-activity relationships and

involving transposition of functional groups from SRIF into a reduced

size cyclohexapeptide template, has led to the discovery of SOM230, a

novel, stable cyclohexapeptide somatostatin mimic that exhibits unique high-affinity binding to human somatostatin receptors

(subtypes sst1-sst5) (18395969, 12773038)

Isolation of

hormones/fac

tors

Early 1970s

Optimization of a

natural ligand of broader target

coverage but shorter

half-life into a drug with improved efficacy & PK profile

Early 2000s

to 2012


Spinosad 2011 N

Spinosyn A,

Spinosyn D

Spinosyns

Saccharopolyspora spinosa

In 1990-1993, screening of fungal species identified the drug

(20150928)

Screening of non-

traditional

species of drug-produc

tive family

or order

Early 1990s

Development of a

novel and selective NP into a drug with novel mechanism against drug-

resistant pathogen

Early 1990s

to 2011

Fidaxomicin

RNA polymer

ase2011 N

Macrolides

(tiacumicins)

Actinomycete

Dactylosporangiu

m aurantiac

um subspeci

es hamdene

sis

Isolated in 1986, shown good activity in 1987, and good PK in

2004, remained unexplored until the late 90’s when Optimer

Pharmaceuticals began the commercial development

(23111588)

Screening of non-

traditional

species of drug-produc

tive family

or order

Mid 1980s

Development of a

novel and potent NP with good PK profile

into the 2nd drug for a disease in 30 years

Late 1990s

to 2011

Abiraterone

CYP17A1 2011 ND

Progesterone

s

Progestogens

Homo sapiens

In 1993-1994, abiraterone acetate (AA) was developed as a selective

and irreversible inhibitor of CYP17. Building on the efficacy of

ketoconazole while trying to address its limitations, AA was developed

by rational design based on a pregnenolone parent structure. Identification of key molecular

features provided for more potent inhibition of CYP17, clinical trial

started in 2003 (22130117, 22198164 )

Natural

substrate

analogs as

starting point

for deriving drug lead

against a new target

Mid 1990s

Optimization of a

natural substrate

analog of a new target into a more potent and

target-selective

drug

Mid 1990s

to 2011

Linagliptin

Dipeptidyl

peptidase 4

2011 ND Xanthine

Xanthine

analogs

Homo sapiens

Reported in 2002, HTS of 500K compounds identified a lead with NP scaffold, optimization leads to Highly Potent, Selective, Long-Acting, and Orally Bioavailable

DPP-4 Inhibitor, A unique characteristic of linagliptin that

differentiates it from other members of the class is its primarily nonrenal

route of excretion (18052023, 21603986)

HTS Early 2000s

Optimization of a novel and potent

NP derivative

into a potent drug

with improved PK over

alternatives

Early 2000s

to 2011


Ticagrelor

Adenosine

diphosphate

receptor P2Y12

2011 ND

Adenosine

triphosphate

Purine nucleos

ide analogs

Homo sapiens

Reported in 2000, using ATP, the natural antagonist (pIC50 = 3.5) of the P2Y12 receptor, as a chemical

starting point, Ticagrelor was discovered as a potent and selective P2Y12 receptor antagonist suitable

for intravenous use only (17827008)

Screening of focuse

d librarie

s structurally

similar to

natural substra

tes

Late 1990s

Optimization of a sub-potent NP

into the first reversible-

binding drug with improved potency,

selectivity and PK profile

Late 1990s

to 2011

Rilpivirine

HIV reverse

transcriptase

2011 NM

Diarylpyrimidines

(Pyrimidine)

Pyrimidine

nucleotides

Homo sapiens

Soon after the NNRTIs were being used in clinical settings, it became

apparent that this class of RT inhibitors is vulnerable to HIV’s

high mutation rate, Mutations in the NNRTI binding pocket render the

inhibitors inactive without affecting dversely the catalytic competency of

the RT enzyme, structural modification of loviride lead to

DATA, but it is ineffective against then newly emerged double mutants

of the HIV-1 virus. In 1998, replacement of key components by NP pyrimidine and further structual

modification of other structural components lead to an atractive

drug lead DAPY (R147681) with potent inhibition against double

mutations, further optimization in 1999 and 2001 lead to the discovery

of leetravirine and Rilpivirine respectively (15771411, 15771434)

Incorporation of NP structure into drug leads

ineffective

against drug-resista

nt pathog

ens

Late 1990s

Optimization of a novel NP mimetic

active against drug-

resistant pathogen

into a drug with

improved potency,

half-life and ADR profile

Early 2000s

to 2011


TelaprevirHCV

NS3/4A protease

2011 NM

NS5A-5B

substrate

decamer

peptide

HCV

Reported in 2000, Initial studies to make a peptidomimetic inhibitor

began with truncation of a decamer peptide inhibitor derived from the natural NS5A-5B substrate, based on the Examination of the crystal

structure that shows protease active site is extremely hydrophobic, flat and exposed to solvent, with few pockets to increase the affinity for an inhibitor to bind, parts of the

natural substrate that were critical for binding to the protease active

site were spread over a large surface area, consistent with the co-complex

crystal structure of the HCV protease domain with the decamer

peptide, To compensate and increase affinity, a reversible

covalent inhibitor tetraaldehyde peptide was developed and used as a starting point for deriving the drug

(22068541)syntheses to optimize compound

binding to the active site61

Natural

substrate

analogs as

starting point

for deriving non-peptide

drug lead

against a new target

Late 1990s

Optimization of a

natural substrate analog

against a new target into potent

and selective

non-peptide drug with improved treatment rate and duration

Late 1990s

to 2011

IcatibantBradykinin B2

receptor2011 NM Brady

kinin

GPCR targetin

g peptide homone

s

Homo sapiens

Reported in 1999, The Bradykinin B2 receptor antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-

Tic-Oic-Arg) was used as a template for the de novo design and synthesis

of a small number of non-peptide lead compounds based on the 1,4-benzodiazepin-2-one framework. Two of the compounds have been

found to exhibit moderate K(i) values of 8.9 and 9.2 microM at the

human Bradykinin B2 receptor, which in 2001 were subsequently

optimized into potent and selective drug (10091703, 11514020)

Natural

ligand analogs as a starting point

for deriving non-peptide

drug lead

Late 1950s

Optimization of a sub-

potent peptide into

potent selective

non-peptide drug that

can be easily

carried, stored and

self-administere

d

Late 1990s

to 2011

UlipristalProgeste

rone receptor

2010 ND Progesterone

Progestogens

Homo sapiens

In late 1970s, glucocorticoid receptor antagonist RU 38486 was

derived based on Progesterone scaffold, which also displayed marked antiprogestin activity, leading to the development of

mifepristone, then Ulipristal (CDB-2914) were subsequently developed

in the 2000s for improved target selectivity (i.e. good progesterone

antagonist and lower antiglucocorticoid activity)

(2343294, 8725382, 14667994)

Screening of focuse

d librarie

s structurally

similar to

natural ligands

Late 1970s

Optimization of a

potent but non-

selective NP derivative drug into a drug with improved

target selectivity

and efficacy

Early 2000s

to 2010


Liraglutide

Glucagon-like

peptide 1

receptor

2010 ND

Peptidomimetic of

GLP-1 peptid

e

GPCR targetin

g peptide hormon

es & analogs

Homo sapiens

Reported in 1987, GLP-1 was identified as an incretin hormone

and shown to be more effective than GIP in stimulating insulin release on a molar basis. In 1993, GLP-1 was found to have anti-diabetes effect,

but is degraded by DPP-4 leading to shortend half-life, since early 2000s

efforts have been directed at the development of non-peptide analogs with prolonged half-life (22555471,

10512614 )

Isolation of

hormones/fac

tors

Late 1980s

Optimization of a potent peptide

ligand with low-half-life into a non-

peptide drug with improved half-life

Early 2000s

to 2010

Dabigatran; BIBR

953

Thrombin 2010 S*/N

M

Thrombin-

interacting

part of fibrino

gen

Homo sapiens (156922

65)

Reported in 1979, peptides resembing thrombin natural

substrate sequence was found to inhibit thrombin, In early 1990s,

NAPAP was derived as peptidomimetic thrombin inhibitor, In 2002, on the basis of the X-ray

crystal structure of the peptide-like thrombin inhibitor NAPAP

complexed with bovine thrombin, non-peptide analog was developed

for improved PK (11960487, 23408233)

Natural

substrate

analogs as

starting point


Late 1970s

Structure-based

design to convert a potent but

less selective NP

mimetic with lower

half-life into the first oral

drug approved in

50 years with

improved efficacy,

stability and PK profiles

Early 2000s

to 2010

Eribulin; E7389; NSC-

707389; eribulin mesylate

Microtubule 2010 ND

Halichondrin

B

Macrolides

Halichondria

okadai (108432

09)

In mid 1980s, highly potent anticancer Halichondrin B was discovered from compounds

isolated from a marine species based on bioassays, In 2004, structurally

simplified analog of a resource-strained bioactive NP,

Halichondrin B, was derived and subsequently developed into a

potent drug (15482921, 21684798)

LTS of NPs

Mid 1980s

Structural simplificati

on of a resource-strained

potent NP into a drug with novel

target-binding mode

Early 2000s

to 2010


Fingolimod; FTY720

Serine palmitoyltransfe

rase inhibitor

2010 ND

Myriocin;

ISP-1; Thermozymocidin

Mmino fatty acids

Isaria (184978

96)

In early 1990, ISP-1 was identified as the source of immunosuppressant

activity from the culture broth of Isaria sinclairii and displayed a

nearly 10-fold increase in activity over cyclosporin A. Remarkably

ISP-1 achieves its biological ctivity in a much simpler structure than cyclosporin A. The amphiphilic

nature of ISP-1, imparts the compound with poor cellular

permeability and oral bioavailability; since 1995 the lead

optimization effort sought to improve these properties,

Simplification of the parent structure by removing functionality or chirality helped to identify the

minimum pharmacophore required for activity, many of the simplified

analogs continued to be more potent than cyclosporin A in vitro, quite a remarkable result given the further simplification of the parent. The

next breakthrough was the replacement of a part of the fatty

acid side chain with 1,4-disubstituted phenyl ring to reduce

bond rotation (21684798)

LTS of NPs

Early 1990s

Optimization of a novel and potent NP with

new mechanism but poor PK

into the first oral

drug for the diseas with improved

potency and PK profiles

Mid 1990s

to 2010

Cabazitaxel; XRP-

62582010 ND Taxol Taxanes

Taxus baccata (120080

00); Corylus avellana (120080

00); Taxus

brevifolia

(18690825);

Taxus wallichia

na (161296

03); Seimatoantlerium tepuiense (120080

00)

Taxol was discovered in the mid 1960s by LTS. Cabazitaxel is a semisynthetic taxane that was

selected for development in 2002 on the basis of its poor affinity for P-gp

compared with docetaxel and paclitaxe (20811375, US6372780)

LTS of NPs

Mid 1960s

Optimization of a

potent NP with

undesired drug

resistance profile (MDR-

mediated) into a drug

against drug resistant cancers

Early 2000s

to 2010


Ceftaroline fosamil 2010 ND

Cephalospori

n

Cephalosporin

s

Acremonium

In 2000, some cephalosporin derivatives were generated and found to possess anti-MRSA

activities comparable to that of vancomycin, but with unsatisfactory

physicochemical and pharmacokinetic properties, only

one of them possess sufficient water-solubility but insufficient chemical stability for drug storage, in 2003

that compound was optimized into a potent drug lead with sufficident

stability (12735989)

LTS of NPs

Early 1950s

Optimization of a

potent NP derivative with poor stability

into a broad spectrum

drug against drug-

resistant pathogens

Early 2000s

to 2010

Artemether;lumefantr

ine2009 ND Artemi

sininTrioxan

esArtemisia annua

Artemisinin, discovered in 1971 from traditional Chinese medicinal

plants, has low solubility and stability because of its lactone ring,

In late 1970s to early 1980s, successful reduction of this lactone

ring was achieved with sodium borohydride, which lead to the

formation of dihydroartemisinin, which had a two-fold higher

antimalarial activity than its mother compound, is well tolerated, and its

production is easier and cheaper. Although hydroartemisinin was still poorly soluble, it was used for the

preparation of several first generation derivatives, Subsequent studies showed that the secondary

hydroxy group of dihydroartemisinin provides the

only site for derivatization without loss of antimalarial activity, in

1998, further optimization efforts led to the drug with improved drug delivery characteristics (3887571,

11772354)

Focused


medicinal

plants

Early 1970s

Optimization of a

potent NP drug with undesired

stability and PK profile into a drug

in combination of another drug as the first-line treatment options

against drug resistant

pathogens

Late 1970s

to 2010

(approved

outside US since 1987)

Telavancin 2009 ND Vancomycin

Glycopeptides

Amycolatopsis

orientalis

Vancomycin was discovered in mid 1950s, In 1989-1993, to design

drugs against vancomycin-resistant bacteria, vancomycin was modified by adding hydrophobic substituents,

which impart unfavorable ADME with prolonged elimination half life

and high tissue accumulation, subsequent optimization efforts by

adding hydrophilic group leading to the drug lead with improved

potency and ADME (15303493)

LTS of NPs

Mid 1950s

Optimization of an NP

drug ineffective

against drug-resistant

pathogens into a drug

with improved

potency and PK

Early 1990s

to 2009


Pitavastatin

HMG-CoA

reductase

inhibitor

2009 S*/NM

Mevastatin Statins

Pseudonocardia

autotrophica

(DB00175);

Penicillium

brevicompactum (108880

10); Penicilliu

m citrinum (167963

74)

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) (‘statins’), initially isolated from nature in mid 1970s, have been widely used clinically, but

some of them are metabolized by P450, making them prone to drug-drug interaction induced serious

adverse effects, in late 1990s Pitavastatin was derived based on the statin scaffold as a potent drug

with reduced P450 metabolism profile (11060827)

LTS of NPs

Mid 1960s

Optimization of a

potent NP with poor

metabolism profile into

a potent drug with improved

metabolism and

torability profile

Late 1990s

to 2009

Everolimus; RAD-

001; SDZ RAD

mTOR inhibitor 2009 ND

Sirolimus;

Rapamycin

Macrolides

Streptomyces

hygroscopicus

(18497896)

The NP rapamycin, isolated in 1975 and found to have anticancer effect in 1984, binds to FK506-binding

protein 12 (FKBP12), and the resultant protein–drug complex inhibits the kinase activity of

mTOR4. Rapamycin has immunosuppressive, antifungal and

anticancer activity, but its development as an

immunosuppressant was prioritized, and it was approved by the FDA for

the prevention of transplant rejection in 1999. Multiple

derivatives of rapamycin have been synthesized and evaluated with the

aim of improving its pharmaceutical properties, and such efforts led to the discovery and development of

temsirolimus (which is administered intravenously) for RCC and

everolimus (which can be orally administered). In 2003, everolimus was approved for the prevention of

transplant rejection in Europe, where it is marketed as Certican

(1956828)

LTS of NPs

Mid 1980s

Optimization of a

potent NP with

undesired pharmacolo

gical property

into a potent drug

with improved

PK for oral delivery

Late 1990s

to 2009

(approved

outside US since 2003)


Pazopanib; GW-

786034

Kinase inhibitor

s2009 S/N

M

Zeatin; Cytoki

nins

Purine analogu

es adenine-

type

Spinacia oleracea (15153188); Zea

mays (151531

88); Pisum

sativum (151531

88); Cocos

nucifera (151531

88)

In late 1990s, A compound screening campaign against

VEGFR2 kinase was conducted using kinase - focused screening

sets comprised of compounds from (1) prior and ongoing kinase

programs, (2) literature - based kinase hemotypes, and (3)

chemotypes that originated through structure - based design, which

identified an olomocine derivative (olomocine is a zeatin derivative) as a potent inhibitor, which is further

optimized into potent drug with good PK (4348261, 8080438,

7925396, 8691423, 18620382)

Screening of focuse

d librarie

s talored

to target class

Late 1990s

Structure-based

optimization of a

moderately potent NP derivative

incorporating structural elements of

another potent lead

into a potent first-

line drug with good PK profile

Late 1990s

to 2009

Vigabatrin

GABA-transami

nase inhibitor

2009 ND

Gamma-

aminobutyric

acid (GAB

A)

Mmino acids with

acyclic hydroxyl side

chain & derivati

ves

Homo sapiens (173093

02)

In 1975, based on the hypothesis of that substrate analogs may be

inhibitors, a GABA analog was found to selectively inhibit GABA-

transaminase (856582)

Natural

substrate

analogs as

starting point


Mid 1970s

Development of a

selective and

irreversiblly acting NP derivative into a first-line drug

Mid 1970s

to 2009

(approved

outside US since late

1980s)

Romidepsin

HDAC inhibitor 2009 N .

Depsipeptide cyclic

structure

Chromobacterium violaceu

m

In 1993, in screening of anticancer NPs, an NP was found to show

anticancer acvitity, subsequently, it was found to inhibit multiple cell-

lines in NCI60 screening, in 1998, it was found to be a potent HDAC

inhibitor with novel structure

LTS of NPs

Early 1990s

Development of a

novel and potent NP into a drug

Late 1990s

to 2009

Pralatrexate 2009 ND Folic

acidFolate

analogs

In the late 1970s, it was that cancerous cells take in natural folate

through a protein RFC-1. Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to

ensure they get enough folate, reported in 1993, potent NP

derivatives (folate analogs) were optimized for deriving an antifolate agent that could be more effectively internalized into tumors (transported into the cells through RFC-1) led to

the discovey of the drug that is 5 times more potent than MTX

aganist cancer cells (8340923)

Natural

substrate

analogs as

starting point


Early 1990s

Optimization of a

potent NP derivative with novel

cell-selective delivery

profile into a more

potent drug for selective targeting of

specific cancer

subtypes

Early 1990s

to 2009


Desvenlafaxine

Serotonin

reuptake,

noradrenaline

reuptake

2008 ND Benzylamine

Monoamine

alkaloids

Remove (Acacia

Rigidula)

Antidepressant drug discovery effort was focused on the multi-targeting of (1)reuptakes and (2) the down-

regulation of 8-adrenoceptors caused by chronic antidepressant therapy. Natural product alkaloid

libraries such as benzylamines have been generated and evaluated as

sources for drug discovery, some of these benzylamines have been found to produce analgic effect, based on

which benzylamine derivatives were derived, in particular, ciramadol was derived in 1975 that showed potent analgesic activity due to its opioid

agonist and antagonist activity. Reported in 1990, because of its

structural similarity to an antidepressant compound,

ciramadol derivatives were derived for finding antidepressant agents

with the ability to both inhibit neurotransmitter uptake inhibitory and desensitize 6-adrenoceptors,

which derived venlafaxine, further optimization for reducing

interaction with CYP and Pgp to improve PK (metabolism and BBB crossing) lead to Desvenlafaxine (1976813, 19084064, 720500)

NP deriivatives

structurally

similar to

active compounds

as starting point


Late 1980s

Optimization of an NP derivative with multi-

target potential

into a potent drug

with improved

PK

Late 1980s

to 2009


Methylnaltrexone

bromide

μ -opioid

receptor2008 ND Morph

ine

Benzylisoquino

line alkaloid

s

Papaver somnifer

um

Methylnaltrexone (MNTX) is one of the newer agents of peripherally-acting μ-opioid antagonists with

ability to reverse some of the side effects of opioid drugs such as constipation without affecting

analgesia or precipitating withdrawals. Thousands of opioid-

like molecules had been synthesized by pharmaceutical companies

looking for the better analgesic , in 1963, screening these compounds led to the examination of putative antagonists which when modified

might not readily cross the blood–brain barrier based on their

size and charge, MNTX looked promising and passed initial

screening in which rodents were given opioids along with charcoal meals to track GI transit, and were

tested for analgesia in the late 1970s, In December 2005, Wyeth

and Progenics entered into an exclusive, worldwide agreement for

the joint development and commercialization of

methylnaltrexone for the treatment of opioid-induced side effects (US

patent 3101339, US patent 4176186, PMID 7200037)

Screening of focuse

d librarie

s structurally

similar to

natural ligands

Early 1960s

Development of a

novel and potent NP derivative

with desired BBB profile into the first peripheral

tissue selective

drug for the disease

late 1970s

to 2008

Degarelix

Gonadotropin-

releasing

hormone

receptor

2008 NM

Gonadotropi

n-releasi

ng hormo

ne (GnR

H decapeptide)

GPCR targetin

g peptide homone

s & analogs

Homo sapiens

Peptide and mimetic GnRH antagnosts have been derived since the early 1970s. Reported in 2000, GnRH decapeptide mimetics have

low solubility that affect bioavailability and formulation, these were further optimized for improved solubility and half-life (metabolic stability and delayed

elimination), which lead to Degarelix (6774418, 11462984)

Natural

substrate

analogs as

starting point


Early 1970s

Optimization of a potent natural

substrate analog with

low solubility

into a first-line drug

with improved

PK profiles

Late 1990s

to 2008


Ceftobiprole

medocaril2008 ND

Cephalospori

n nucleus; 7-

aminocephalospora

nic acid; 7-ACA

Cephalosporin

s

Emericellopsis

minima (162901

71); Amycola

topsis lactamdu

rans (162901

71); Streptom

yces clavulige

rus (162901

71); Acremon

ium chrysoge

num (162901

71)

In 2000, Ro 63-9141 was derived as a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins, and found to have

potent antibacterial activity. It differs from older, broad-spectrum

cephalosporins in that it has antibacterial activity against MRS

isolates

LTS of NPs

Early 1950s

Optimization of an NP

drug ineffective


pathogens into a drug effective


pathogens

Late 1990s

to 2008

Artesunate;

amodiaquine; ASAQ

2008 ND

Artemisinin;

Quinine

Trioxanes

Cinchona officinali

s (%Drugs

from nature past

achievements

future prospects 2002 by Gordon

M Cragg, David J Newman

%); Artemisia annua (184978

96); Cinchona (184545

80)

The NP drug artemisinin has low solubility and stability because of its lactone ring, In late 1970s to early 1980s, a water soluble derivative

Artesunate was derived and subsequently developed into an

approved drug (3887571)

Focused


medicinal

plants

Early 1970s

Optimization of an NP drug with

low solubility

into soluble drug that

can be given by injection

Late 1970s

to early 1980s


trends in exploration of therapeutic targets · s/nm made by total synthesis inspired by a natural...

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