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Journal of Medicinal Chemistry Nov 2011A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O(6)-benzylguanine (O(6)-BG), conceived as prodrugs of O(6)-BG, an inhibitor of the resistance protein...
4-nitrobenzyloxycarbonyl derivatives of O(6)-benzylguanine as hypoxia-activated prodrug inhibitors of O(6)-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the O-6 position of DNA guanine.
A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O(6)-benzylguanine (O(6)-BG), conceived as prodrugs of O(6)-BG, an inhibitor of the resistance protein O(6)-alkylguanine-DNA alkyltransferase (AGT), were synthesized and evaluated for their ability to undergo bioreductive activation by reductase enzymes under oxygen deficiency. Three agents of this class, 4-nitrobenzyl (6-(benzyloxy)-9H-purin-2-yl)carbamate (1) and its monomethyl (2) and gem-dimethyl analogues (3), were tested for activation by reductase enzyme systems under oxygen deficient conditions. Compound 3, the most water-soluble of these agents, gave the highest yield of O(6)-BG following reduction of the nitro group trigger. Compound 3 was also evaluated for its ability to sensitize 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine)-resistant DU145 human prostate carcinoma cells, which express high levels of AGT, to the cytotoxic effects of this agent under normoxic and oxygen deficient conditions. While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O(6)-BG under hypoxia.
Topics: Animals; Antineoplastic Agents, Alkylating; Cell Hypoxia; Cell Line, Tumor; DNA; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Guanine; Humans; Hydrazines; Mice; NADPH-Ferrihemoprotein Reductase; O(6)-Methylguanine-DNA Methyltransferase; Prodrugs; Solubility; Structure-Activity Relationship; Sulfonamides; Xanthine Oxidase
PubMed: 21955333
DOI: 10.1021/jm201115f -
Chemical Research in Toxicology Aug 2014Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30...
Influence of glutathione and glutathione S-transferases on DNA interstrand cross-link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine.
Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine in DNA. These guanine O-6 alkylations are believed to be responsible for the therapeutic effects of 90CE and its prodrugs. Thus, 90CE demonstrates high selectivity toward tumors with diminished levels of O(6)-alkylguanine-DNA alkyltransferase (MGMT), the resistance protein responsible for O(6)-alkylguanine repair. The formation of O(6)-(2-chloroethyl)guanine lesions ultimately leads to the generation of highly cytotoxic 1-(N(3)-cytosinyl),-2-(N(1)-guaninyl)ethane DNA interstrand cross-links via N(1),O(6)-ethanoguanine intermediates. The anticancer activity arising from this sequence of reactions is thus identical to this component of the anticancer activity of the clinically used chloroethylnitrosoureas. Herein, we evaluate the ability of glutathione (GSH) and other low molecular weight thiols, as well as GSH coupled with various glutathione S-transferase enzymes (GSTs) to attenuate the final yields of cross-links generated by 90CE when added prior to or immediately following the initial chloroethylation step to determine the major point(s) of interaction. In contrast to studies utilizing BCNU as a chloroethylating agent by others, GSH (or GSH/GST) did not appreciably quench DNA interstrand cross-link precursors. While thiols alone offered little protection at either alkylation step, the GSH/GST couple was able to diminish the initial yields of cross-link precursors. 90CE exhibited a very different GST isoenzyme susceptibility to that reported for BCNU, this could have important implications in the relative resistance of tumor cells to these agents. The protection afforded by GSH/GST was compared to that produced by MGMT.
Topics: Alkylation; Animals; Antineoplastic Agents; Cell Line, Tumor; DNA; DNA Modification Methylases; DNA Repair Enzymes; Glutathione; Glutathione Transferase; Guanine; Hydrazines; Mice; Prodrugs; Recombinant Proteins; Sulfonamides; Tumor Suppressor Proteins
PubMed: 25012050
DOI: 10.1021/tx500197t -
Chemical Biology & Drug Design Aug 2012Cellular resistance to chemotherapeutics that alkylate the O-6 position of guanine residues in DNA correlates with their O(6)-alkylguanine-DNA alkyltransferase activity....
Cellular resistance to chemotherapeutics that alkylate the O-6 position of guanine residues in DNA correlates with their O(6)-alkylguanine-DNA alkyltransferase activity. In normal cells high [O(6)-alkylguanine-DNA alkyltransferase] is beneficial, sparing the host from toxicity, whereas in tumor cells high [O(6)-alkylguanine-DNA alkyltransferase] prevents chemotherapeutic response. Therefore, it is necessary to selectively inactivate O(6)-alkylguanine-DNA alkyltransferase in tumors. The oxygen-deficient compartment unique to solid tumors is conducive to reduction, and could be utilized to provide this selectivity. Therefore, we synthesized 2-nitro-6-benzyloxypurine, an analog of O(6)-benzylguanine in which the essential 2-amino group is replaced by a nitro moiety, and 2-nitro-6-benzyloxypurine is >2000-fold weaker than O(6)-benzylguanine as an O(6)-alkylguanine-DNA alkyltransferase inhibitor. We demonstrate oxygen concentration sensitive net reduction of 2-nitro-6-benzyloxypurine by cytochrome P450 reductase, xanthine oxidase, and EMT6, DU145, and HL-60 cells to yield O(6)-benzylguanine. We show that 2-nitro-6-benzyloxypurine treatment depletes O(6)-alkylguanine-DNA alkyltransferase in intact cells under oxygen-deficient conditions and selectively sensitizes cells to laromustine (an agent that chloroethylates the O-6 position of guanine) under oxygen-deficient but not normoxic conditions. 2-Nitro-6-benzyloxypurine represents a proof of concept lead compound; however, its facile reduction (E(1/2) - 177 mV versus Ag/AgCl) may result in excessive oxidative stress and/or the generation of O(6)-alkylguanine-DNA alkyltransferase inhibitors in normoxic regions in vivo.
Topics: Antineoplastic Agents; Cell Hypoxia; Cell Line; Enzyme Inhibitors; Guanine; HL-60 Cells; Humans; Hydrazines; Hydrogen Peroxide; O(6)-Methylguanine-DNA Methyltransferase; Oxidation-Reduction; Oxygen; Purines; Sulfonamides; Superoxides
PubMed: 22553921
DOI: 10.1111/j.1747-0285.2012.01401.x -
Neuro-oncology Jan 2007Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to...
Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.
Topics: Adult; Aged; Brain Neoplasms; Disease Progression; Female; Glioblastoma; Humans; Hydrazines; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Sulfonamides; Survival Rate; Time Factors; Treatment Outcome
PubMed: 17108065
DOI: 10.1215/15228517-2006-022 -
Methods and Findings in Experimental... May 2009(-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir...
(-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir sulfate, Azacitidine; Becatecarin, Belinostat, Bevacizumab, BMS-387032, BMS-690514, Bortezomib; Casopitant mesylate, Cetuximab, Choline fenofibrate, CK-1827452, Clofarabine, Conivaptan hydrochloride; Dabigatran etexilate, DADMe-Immucillin-H, Darbepoetin alfa, Darunavir, Dasatinib, DC-WT1, Decitabine, Deferasirox, Degarelix acetate, Denenicokin, Denosumab, Dienogest, Duloxetine hydrochloride; Ecogramostim, Eculizumab, Edoxaban tosilate, Elacytarabine, Elesclomol, Eltrombopag olamine, Enfuvirtide, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Etravirine; Flibanserin, Fludarabine, Fondaparinux sodium, Fosamprenavir calcium; Gefitinib, Genistein; I-131-L19-SIP, Idrabiotaparinux sodium, Imatinib mesylate, IMGN-901, Ipilimumab; Laromustine, Lenalidomide, Liposomal cisplatin, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Lopinavir/ritonavir; Maraviroc, MDV-3100, Mecasermin rinfabate, MP-470, Mycophenolic acid sodium salt; Naproxcinod, NB-002, Nesiritide, Nilotinib hydrochloride monohydrate, NK-012; Palonosetron hydrochloride, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Pitavastatin calcium, PL-3994, Plerixafor hydrochloride, Plitidepsin, PM-10450; Raltegravir potassium, Recombinant human soluble thrombomodulin, ReoT3D, RHAMM R3 peptide, Rivaroxaban, Romiplostim, Rosuvastatin calcium, Rozrolimupab; Sabarubicin hydrochloride, Salinosporamide A, Sirolimus-eluting stent, Smallpox (Vaccinia) Vaccine, Live, Sorafenib; Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Tipifarnib, Tipranavir, Trabectedin, Trifluridine/TPI; Vardenafil hydrochloride hydrate, Vinflunine, Volociximab, Vorinostat; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 19557204
DOI: 10.1358/mf.2009.31.4.1373959 -
Neuro-oncology Jul 2007VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of...
VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.
Topics: Animals; Brain Neoplasms; Female; Humans; Hydrazines; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Prodrugs; Sulfonamides; Xenograft Model Antitumor Assays
PubMed: 17522334
DOI: 10.1215/15228517-2007-011 -
Proceedings of the National Academy of... Jun 2005To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species...
To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) after bioreductive activation. We postulate that one of these agents, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119), requires enzymatic nitro reduction to produce 90CE, whereas another agent, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (PNBC), can also be activated by nucleophilic attack by thiols such as glutathione (GSH)/GST. We demonstrated that these agents selectively kill hypoxic EMT6 mouse mammary carcinoma and CHO cells. In hypoxia, 50 microM KS119 produced 5 logs of kill of EMT6 cells without discernable cytotoxicity in air; similar effects were observed with CHO cells. PNBC was less efficacious against hypoxic tumor cells and also had some toxicity to aerobic cells, presumably because of GST/thiol activation, making PNBC less interesting as a selective hypoxic-cell cytotoxin. BALB/c mice with established EMT6 solid tumors were used to demonstrate that KS119 could reach and kill hypoxic cells in solid tumors. To gain information on bioreductive enzymes involved in the activation of KS119, cytotoxicity was measured in CHO cell lines overexpressing NADH:cytochrome b5 reductase (NBR), NADPH:cytochrome P450 reductase (NPR), or NADPH: quinone oxidoreductase 1 (NQO1). Increased cytotoxicity occurred in cells overexpressing NBR and NPR, whereas overexpressed NQO1 had no effect. These findings were supported by enzymatic studies using purified NPR and xanthine oxidase to activate KS119. KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues.
Topics: Animals; Antineoplastic Agents; CHO Cells; Cell Survival; Chromatography, High Pressure Liquid; Cricetinae; Cross-Linking Reagents; Cytochrome-B(5) Reductase; DNA; Dose-Response Relationship, Drug; Edetic Acid; Glutathione; Glutathione Transferase; Hydrazines; Hypoxia; Mice; Mice, Inbred BALB C; Models, Chemical; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Neoplasm Transplantation; Neoplasms; Nitrogen; Oxygen; Sulfhydryl Compounds; Sulfonamides; Time Factors; Treatment Outcome; Xanthine Oxidase; Zinc
PubMed: 15964988
DOI: 10.1073/pnas.0409013102 -
Molecular Cancer Therapeutics Apr 2006Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The cytotoxic potency of these species was...
Cloretazine is an antitumor sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species. The cytotoxic potency of these species was analyzed in L1210 leukemia cells using analogues with chloroethylating or carbamoylating function only. Clonogenic assays showed that the chloroethylating-only agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) produced marked differential cytotoxicity against wild-type and O6-alkylguanine-DNA alkyltransferase-transfected L1210 cells (LC10, 1.4 versus 31 micromol/L), indicating that a large portion of the cytotoxicity was due to alkylation of DNA at the O-6 position of guanine. Consistent with the concept that O-6 chloroethylation of DNA guanine progresses to interstrand cross-links, the comet assay, in which DNA cross-links were measured by a reduction in DNA migration induced by strand breaks, showed that cloretazine and 90CE, but not the carbamoylating-only agent 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), produced DNA cross-links and that cloretazine caused more DNA cross-links than 90CE at equimolar concentrations. Cell cycle analyses showed that 90CE and 101MDCE at concentrations of 5 and 80 micromol/L, respectively, produced similar degrees of G2-M arrest. 90CE produced selective inhibition of DNA synthesis after overnight incubation, whereas 101MDCE caused rapid and nonselective inhibition of RNA, DNA, and protein syntheses. Both 90CE and 101MDCE induced phosphorylation of histone H2AX, albeit with distinct kinetics. These results indicate that (a) differential expression of O6-alkylguanine-DNA alkyltransferase in tumor and host cells seems to be responsible for tumor selectivity exerted by cloretazine; (b) 101MDCE enhances DNA cross-linking activity; and (c) 90CE induces cell death at concentrations lower than those causing alterations in the cell cycle and macromolecular syntheses.
Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Survival; Comet Assay; Histones; Hydrazines; Leukemia L1210; Mice; O(6)-Methylguanine-DNA Methyltransferase; Phosphorylation; Prodrugs; Sulfonamides; Transfection
PubMed: 16648568
DOI: 10.1158/1535-7163.MCT-05-0532 -
Leukemia & Lymphoma Apr 2008This study evaluated combination drug partners for CP-4055, the C18:1(Delta9,trans) unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition...
Anti proliferative activity of ELACY (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells.
This study evaluated combination drug partners for CP-4055, the C18:1(Delta9,trans) unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition was assessed by ATP assay and drug interaction by the combination index and three dimensional methods. Synergy was observed in HL-60 cells for simultaneous combinations of CP-4055 with gemcitabine, irinotecan and topotecan, while combinations with cloretazine (VNP40101M) and idarubicin were additive. In U937 cells, synergy was observed with gemcitabine and additivity for the other drugs. In HL-60, the IC50 concentration of CP-4055 could be reduced 10-fold and that of gemcitabine 3-fold in combination versus the agents alone, an interaction that was independent of drug sequence, ratio and exposure time. In contrast, interactions of CP-4055 with the topoisomerase inhibitors became antagonistic when the drugs were administered 24 h prior to CP-4055 and at certain drug ratios, particularly in U937 cells. In summary, CP-4055 produced additive to synergistic anti proliferative activity when combined simultaneously with drugs from four mechanistic classes in cell culture models of human leukemia and lymphoma. The impact of drug sequence and ratio on the interactions argues for incorporation of these parameters into the design of combination chemotherapy regimens.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Cytarabine; Deoxycytidine; Drug Interactions; Drug Screening Assays, Antitumor; Humans; Hydrazines; Idarubicin; Irinotecan; Leukemia; Lymphoma; Sulfonamides; Topotecan; Gemcitabine
PubMed: 18398748
DOI: 10.1080/10428190801935752 -
Methods and Findings in Experimental... Jun 2010[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod...
[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 20664824
DOI: 10.1358/mf.2010.32.5.1520420