A Survey of the Structures of US FDA Approved Combination Drugs.

Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this Perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018. Our database contains 419 combination drugs, which are represented by 328 unique small molecule structures. Breakdown of these drugs according to disease category, structure, combination composition, and year of approval is presented as well as the top 24 most commonly used small molecule combination drug components. For frequently used small molecule components, we present "relationship diagrams" to aid in the visualization of the many drug combinations these structures are part of. The main body contains 10 disease-focused sections wherein every small molecule component utilized as part of a combination for each disease category is displayed.

[1]  J. T. Njardarson,et al.  From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen Heterocycles. , 2018, Journal of medicinal chemistry.

[2]  P. Narciso,et al.  Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected patients: 96 week outcomes of a randomized trial , 2018, The Journal of antimicrobial chemotherapy.

[3]  J. T. Njardarson,et al.  Analysis of US FDA-Approved Drugs Containing Sulfur Atoms , 2018, Topics in Current Chemistry.

[4]  Jin Hwa Kim,et al.  Combination Therapy of Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus , 2017, Diabetes & metabolism journal.

[5]  C. Bailey,et al.  Metformin: historical overview , 2017, Diabetologia.

[6]  V. Prasad,et al.  Drugs that lack single-agent activity: are they worth pursuing in combination? , 2017, Nature Reviews Clinical Oncology.

[7]  Herman Yeger,et al.  Combination therapy in combating cancer , 2017, Oncotarget.

[8]  A. Chaudhury,et al.  Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management , 2017, Front. Endocrinol..

[9]  J. DiNicolantonio,et al.  Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes , 2016, Open Heart.

[10]  P. Richardson.  Fluorination methods for drug discovery and development , 2016, Expert opinion on drug discovery.

[11]  T. Talele.  The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. , 2016, Journal of medicinal chemistry.

[12]  N. Ghiotto,et al.  Recent advances in migraine therapy , 2016, SpringerPlus.

[13]  T. Yuraszeck,et al.  Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities , 2016, Clinical and translational science.

[14]  Robert K. Stuart,et al.  CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia , 2015 .

[15]  Sarah L. Greig,et al.  Memantine ER/Donepezil: A Review in Alzheimer’s Disease , 2015, CNS Drugs.

[16]  J. Shubrook,et al.  Use of oral combination therapy for type 2 diabetes in primary care: Meeting individualized patient goals , 2015, Postgraduate medicine.

[17]  G. Tiegs,et al.  Acetaminophen/paracetamol: A history of errors, failures and false decisions , 2015, European journal of pain.

[18]  Aimin Liu,et al.  What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? , 2015, Expert review of neurotherapeutics.

[19]  M. Totrov,et al.  Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. , 2015, Journal of medicinal chemistry.

[20]  J. Issa,et al.  Results of phase 2 randomized study of low‐dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia , 2015, Cancer.

[21]  V. Hatzimanikatis,et al.  Antihypertensive Drugs Metabolism: An Update to Pharmacokinetic Profiles and Computational Approaches , 2014, Current pharmaceutical design.

[22]  J. T. Njardarson,et al.  Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. , 2014, Journal of medicinal chemistry.

[23]  J. T. Njardarson,et al.  Beyond C, H, O, and N! Analysis of the elemental composition of U.S. FDA approved drug architectures. , 2014, Journal of medicinal chemistry.

[24]  P. Tchounwou,et al.  Cisplatin in cancer therapy: molecular mechanisms of action. , 2014, European journal of pharmacology.

[25]  Justin K H Liu.  The history of monoclonal antibody development – Progress, remaining challenges and future innovations , 2014, Annals of medicine and surgery.

[26]  H. Gallagher,et al.  Clotrimazole as a pharmaceutical: past, present and future. , 2014, Journal of applied microbiology.

[27]  Hyung Gyun Kim,et al.  Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. , 2014, Free radical biology & medicine.

[28]  E. Acosta,et al.  Pharmacokinetic Enhancers in HIV Therapeutics , 2014, Clinical Pharmacokinetics.

[29]  Hubert H. Kerschbaum,et al.  50 years of hormonal contraception—time to find out, what it does to our brain , 2014, Front. Neurosci..

[30]  S. Feldman,et al.  Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. , 2014, Journal of the American Academy of Dermatology.

[31]  M. Thase,et al.  Efficacy and Safety of Olanzapine/Fluoxetine Combination vs Fluoxetine Monotherapy Following Successful Combination Therapy of Treatment-Resistant Major Depressive Disorder , 2014, Neuropsychopharmacology.

[32]  J. T. Njardarson,et al.  Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. , 2014, Journal of medicinal chemistry.

[33]  P. Chanez,et al.  Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases , 2014, Therapeutic advances in chronic disease.

[34]  S. Al‐Thabaiti,et al.  Tetrazoles as carboxylic acid isosteres: chemistry and biology , 2014, Journal of Inclusion Phenomena and Macrocyclic Chemistry.

[35]  E. Deeks.  Cobicistat: A Review of Its Use as a Pharmacokinetic Enhancer of Atazanavir and Darunavir in Patients with HIV-1 Infection , 2014, Drugs.

[36]  G. Mor,et al.  Targeted cancer therapy--are the days of systemic chemotherapy numbered? , 2013, Maturitas.

[37]  J. T. Njardarson,et al.  An In-Pharm-ative Educational Poster Anthology Highlighting the Therapeutic Agents That Chronicle Our Medicinal History , 2013 .

[38]  T. Ritter,et al.  Introduction of fluorine and fluorine-containing functional groups. , 2013, Angewandte Chemie.

[39]  S. Sarkar,et al.  Lomotil (Diphenoxylate) Dependence in India , 2013, Indian journal of psychological medicine.

[40]  A. Kapoor,et al.  Dutasteride for the treatment of benign prostatic hyperplasia , 2013, Expert opinion on pharmacotherapy.

[41]  A. Harris,et al.  Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro , 2013, Journal of enzyme inhibition and medicinal chemistry.

[42]  J. Karlowsky,et al.  Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination , 2013, Drugs.

[43]  S. Frischbutter,et al.  Pharmacology of Antihistamines , 2011, Indian journal of dermatology.

[44]  P. A. Todd,et al.  Imipenem/Cilastatin , 1987, Drugs.

[45]  P. Sawaddiruk.  Tramadol hydrochloride/acetaminophen combination for the relief of acute pain. , 2011, Drugs of today.

[46]  K. Coleman.  Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. , 2011, Current opinion in microbiology.

[47]  S. Bangalore,et al.  Half a century of hydrochlorothiazide: facts, fads, fiction, and follies. , 2011, The American journal of medicine.

[48]  H. Osswald,et al.  Methylxanthines and the kidney. , 2011, Handbook of experimental pharmacology.

[49]  Neang S. Ly,et al.  Resurgence of Colistin: A Review of Resistance, Toxicity, Pharmacodynamics, and Dosing , 2010, Pharmacotherapy.

[50]  Nicholas A. McGrath,et al.  A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives , 2010 .

[51]  J. Rosenstock,et al.  Initial Combination Therapy With Alogliptin and Pioglitazone in Drug-Naïve Patients With Type 2 Diabetes , 2010, Diabetes Care.

[52]  M. A. van de Laar,et al.  Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks , 2010, Pharmaceuticals.

[53]  P. Keegan,et al.  FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. , 2010, The oncologist.

[54]  K. Williams,et al.  The introduction of ‘chemotherapy’ using arsphenamine – the first magic bullet , 2009, Journal of the Royal Society of Medicine.

[55]  L. Seeberger,et al.  Levodopa/carbidopa/entacapone in Parkinson’s disease , 2009, Expert review of neurotherapeutics.

[56]  A. Gottlieb,et al.  Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. , 2009, Journal of the American Academy of Dermatology.

[57]  D. Govil,et al.  Colistin and polymyxin B: A re-emergence , 2009, Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine.

[58]  P. Hunter.  Not boring at all , 2009, EMBO reports.

[59]  K. Simons,et al.  H1 Antihistamines: Current Status and Future Directions , 2008, The World Allergy Organization journal.

[60]  P. Home,et al.  Impact of the UKPDS—an overview , 2008, Diabetic medicine : a journal of the British Diabetic Association.

[61]  T. Strack.  Metformin: a review. , 2008, Drugs of today.

[62]  T. Macdonald,et al.  In vitro metabolism of a model cyclopropylamine to reactive intermediate: insights into trovafloxacin-induced hepatotoxicity. , 2008, Chemical research in toxicology.

[63]  M. Mitka.  Experts argue not all diuretics the same. , 2007, Journal of the American Medical Association (JAMA).

[64]  G. Kobal,et al.  Caffeine Accelerates Absorption and Enhances the Analgesic Effect of Acetaminophen , 2007, Journal of clinical pharmacology.

[65]  J. Armand,et al.  Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors , 2007, Therapeutics and clinical risk management.

[66]  K. Mann,et al.  Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. , 2007, Blood.

[67]  P. Keegan,et al.  FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. , 2007, The oncologist.

[68]  R. Eccles.  Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse. , 2007, British journal of clinical pharmacology.

[69]  Vojo Deretic,et al.  Mechanisms of action of isoniazid , 2006, Molecular microbiology.

[70]  C. Borghi,et al.  Fixed combination of zofenopril plus hydrochlorothiazide in the management of hypertension: a review of available data , 2006, Vascular health and risk management.

[71]  L. Cantor.  Brimonidine in the treatment of glaucoma and ocular hypertension , 1997, Therapeutics and clinical risk management.

[72]  Jerome Goldstein,et al.  Acetaminophen, Aspirin, and Caffeine in Combination Versus Ibuprofen for Acute Migraine: Results From a Multicenter, Double‐Blind, Randomized, Parallel‐Group, Single‐Dose, Placebo‐Controlled Study , 2006, Headache.

[73]  H. Torok.  A Comprehensive Review of the Long-Term and Short-Term Treatment of Melasma with a Triple Combination Cream , 2006, American journal of clinical dermatology.

[74]  J. Greiner,et al.  A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model. , 2005, Clinical therapeutics.

[75]  A. Rubin,et al.  Review of local anaesthetic agents. , 2004, Minerva anestesiologica.

[76]  C. Perry,et al.  Emtricitabine , 2012, Drugs.

[77]  P. Kirkpatrick,et al.  Memantine hydrochloride , 2004, Nature Reviews Drug Discovery.

[78]  V. Fonseca.  Effect of thiazolidinediones on body weight in patients with diabetes mellitus. , 2003, The American journal of medicine.

[79]  Rationale for Combination Therapy in the Management of Hypertension , 2003, Journal of clinical hypertension.

[80]  S. Keam,et al.  Ethinylestradiol/Drospirenone , 2003 .

[81]  W. Sneader,et al.  The discovery of aspirin: a reappraisal , 2000, BMJ : British Medical Journal.

[82]  J. Spivak,et al.  Commentary on and reprint of Freireich EJ, Karon M, Frei E III, Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood, in Proceedings of the American Association for Cancer Research (1964) 5:20 , 2000 .

[83]  P R Saxena,et al.  Ergotamine in the acute treatment of migraine: a review and European consensus. , 2000, Brain : a journal of neurology.

[84]  C. Perry,et al.  Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. , 1997, Drugs.

[85]  R. Cady,et al.  Analgesic Rebound Headache in Clinical Practice: Data From a Physician Survey , 1996, Headache.

[86]  H. Sugimoto,et al.  Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. , 1995, Journal of medicinal chemistry.

[87]  J. Schoenen,et al.  Migraine and Cluster Headache-Their Management with Sumatriptan: A Critical Review of The Current Clinical Experience , 1995, Cephalalgia : an international journal of headache.

[88]  D. Phillips,et al.  Nitrogen mustard inhibits transcription and translation in a cell free system. , 1995, Nucleic acids research.

[89]  G. Koren,et al.  Bendectin/diclectin for morning sickness: a Canadian follow-up of an American tragedy. , 1995, Reproductive toxicology.

[90]  M. Ferrari,et al.  Clinical effects and mechanism of action of sumatriptan in migraine , 1992, Clinical Neurology and Neurosurgery.

[91]  M. Beck,et al.  Neomycin: a review with particular reference to dermatological usage , 1983, Clinical and experimental dermatology.

[92]  W. Frishman,et al.  Verapamil therapy for stable and unstable angina pectoris: calcium channel antagonists in perspective. , 1982, The American journal of cardiology.

[93]  D. Vidt.  Mechanism of Action, Pharmacokinetics, Adverse Effects, and Therapeutic Uses of Amiloride Hydrochloride, A New Potassium‐Sparing Diuretic , 1981, Pharmacotherapy.

[94]  J. Greenhouse,et al.  Combined bacitracin-neomycin ointment in treatment of pyogenic infections of the skin. , 1954, A.M.A. archives of dermatology and syphilology.

[95]  S. Waksman,et al.  Neomycin, a New Antibiotic Active against Streptomycin-Resistant Bacteria, including Tuberculosis Organisms. , 1949, Science.

[96]  F. Meleney,et al.  BACITRACIN: A NEW ANTIBIOTIC PRODUCED BY A MEMBER OF THE B. SUBTILIS GROUP , 1945, Science.

[97]  R. Dubos.  STUDIES ON A BACTERICIDAL AGENT EXTRACTED FROM A SOIL BACILLUS , 1939, The Journal of experimental medicine.