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Methods and Findings in Experimental... Apr 2002Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from... (Review)
Review
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, and provides information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abiciximab, acetylcholine chloride, acetylcysteine, alefacept, alemtuzumab, alicaforsen, alteplase, aminopterin, amoxicillin sodium, amphotericin B, anastrozole, argatroban monohydrate, arsenic trioxide, aspirin, atazanavir, atorvastatin, augmerosen, azathioprine; Benzylpenicillin, BMS-284756, botulinum toxin type A, botulinum toxin type B, BQ-123, budesonide, BXT-51072; Calcium folinate, carbamazepine, carboplatin, carmustine, ceftriaxone sodium, cefuroxime axetil, chorionic gonadotropin (human), cimetidine, ciprofloxacin hydrochloride, cisplatin, citalopram hydrobromide, cladribine, clarithromycin, clavulanic acid, clofarabine, clopidogrel hydrogensulfate, clotrimazole, CNI-1493, colesevelam hydrochloride, cyclophosphamide, cytarabine; Dalteparin sodium, daptomycin, darbepoetin alfa, debrisoquine sulfate, dexrazoxane, diaziquone, didanosine, docetaxel, donezepil, doxorubicin hydrochloride liposome injection, DX-9065a; Eberconazole, ecogramostim, eletriptan, enoxaparin sodium, epoetin, epoprostenol sodium, erlizumab, ertapenem sodium, ezetimibe; Fampridine, fenofibrate, filgrastim, fluconazole, fludarabine phosphate, fluorouracil, 5-fluorouracil/epinephrine, fondaparinux sodium, formoterol fumarate; Gabapentin, gemcitabine, gemfibrozil, glatiramer; Heparin sodium, homoharringtonine; Ibuprofen, iloprost, imatinib mesilate, imiquimod, interferon alpha-2b, interferon alpha-2c, interferon-beta; KW-6002; Lamotrigine, lanoteplase, metoprolol tartrate, mitoxantrone hydrochloride; Naproxen sodium, naratriptan, Natalizumab, nelfinavir mesilate, nevirapine, nifedipine, NSC-683864; Oral heparin; Paclitaxel, peginterferon alfa-2b, phenytoin, pimecrolimus, piperacillin, pleconaril, pramipexole hydrochloride, prednisone, pregabalin, progesterone; Rasburicase, ravuconazole, reteplase, ribavirin, rituximab, rizatriptan, rosiglitazone maleate, rotigotine; Semaxanib, sildenafil citrate, simvastatin, stavudine, sumatriptan; Tacrolimus, tamoxifen citrate, tanomastat, tazobactam, telithromycin, tenecteplase, tolafentrine, tolterodine tartrate, triamcinolone acetonide, trimetazidine, troxacitabine; Valproic acid, vancomycin hydrochloride, vincristine, voriconazole, Warfarin sodium; Ximelagatran, Zidovudine, zolmitriptan.
Topics: Clinical Trials as Topic; Drug Therapy; Humans
PubMed: 12087878
DOI: No ID Found -
Journal of Pharmaceutical Sciences Dec 1985In order to understand the redox properties of diaziquone (AZQ) and the reductive alkylation role of its one-electron reduced free radical anion AZQ- in biological...
In order to understand the redox properties of diaziquone (AZQ) and the reductive alkylation role of its one-electron reduced free radical anion AZQ- in biological systems, we investigated the electrochemical and structural properties of AZQ and its reduced species by cyclic voltammetry, controlled potential electrolysis, optical absorbance spectroscopy and 1H NMR. This study was carried out in aqueous media as well as in Me2SO. In aqueous media AZQ can be reduced by 2 electrons to the dianion AZQ2- which is oxidized back to AZQ- and AZQ. In Me2SO, 1 - e- reduction or oxidation steps are possible. This allowed the characterization of AZQ and its 1 or 2 - e- reduced species by UV-visible absorbance spectroscopy. The redox properties of the aziridine rings were observed by cycle voltammetry. Using 1H NMR, it was possible to follow the structural dependence of AZQ on the nature of the medium. Protonation of the aziridine rings at low pH may facilitate the opening of the ring leading to the carbonium ion, the required species for alkylation. Cyclic voltammetry data indicate that reduction of the quinone facilitates the aziridine ring opening.
Topics: Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Biotransformation; Dimethyl Sulfoxide; Electrochemistry; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Solvents; Spectrophotometry, Ultraviolet
PubMed: 4087189
DOI: 10.1002/jps.2600741202 -
Drug Safety Jan 2001Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia... (Review)
Review
Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease, renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renal tubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities, such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes to cisplatin-induced nephrotoxicity include amifostine, sodium thiosulfate and diethyldithiocarbamate. Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have occurred with ifosfamide treatment. High dose azacitidine causes renal dysfunction manifested by tubular acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids. Haemolytic uraemia is a rare adverse effect of gemcitabine. Methotrexate can cause increased serum creatinine levels, uraemia and haematuria. Acute renal failure is reported following administration of high dose methotrexate. Urinary alkalisation and hydration confer protection against methotrexate-induced renal dysfunction. Dose-related nephrotoxicity, including acute renal failure, are reported subsequent to treatment with pentostatin and diaziquone. Acute renal failure is a rare adverse effect of treatment with interferon-alpha. Haemolytic uraemic syndrome occurs with mitomycin administration. A mortality rate of 50 to 100% is reported in patients developing mitomycin-induced haemolytic uraemic syndrome. Capillary leak syndrome occurring with aldesleukin therapy can cause renal dysfunction. Infusion-related hypotension during infusion of high dose carmustine can precipitate renal dysfunction.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Aziridines; Benzoquinones; Humans; Interferon-alpha; Renal Insufficiency
PubMed: 11219485
DOI: 10.2165/00002018-200124010-00003 -
Cancer Treatment Reports Oct 1984Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on...
Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on six cases of hypersensitivity attributable to diaziquone. In five patients an acute reaction characterized by hypotension, bronchospasm, and urticaria was observed. In one patient a delayed urticarial rash was noted. Resolution was rapid in all patients but one, who responded to standard treatment over a period of hours. No reaction was fatal. Approximately 2000 patients have been treated with diaziquone in clinical trials sponsored by the National Cancer Institute. It is suggested that the reaction may not be to the drug itself but to the vehicle (dimethylacetamide) in which diaziquone is formulated. Studies to elucidate the relative contribution of drug and vehicle are warranted.
Topics: Aged; Anaphylaxis; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Urticaria
PubMed: 6525594
DOI: No ID Found -
Biochemical Pharmacology Apr 1992The flavoenzyme thioredoxin reductase (TR) is an important enzyme for many aspects of cellular function. The antitumor quinones diaziquone and doxorubicin have been... (Comparative Study)
Comparative Study
Inhibition of cellular thioredoxin reductase by diaziquone and doxorubicin. Relationship to the inhibition of cell proliferation and decreased ribonucleotide reductase activity.
The flavoenzyme thioredoxin reductase (TR) is an important enzyme for many aspects of cellular function. The antitumor quinones diaziquone and doxorubicin have been shown to produce a time- and concentration-dependent inhibition of TR when incubated for up to 24 hr with intact A204 human rhabdomyosarcoma cells. There was a positive correlation between the inhibition of TR and the inhibition of cell colony formation measured 7 days later for diaziquone (r = 0.84, P less than 0.01), and for doxorubicin (r = 0.87, P less than 0.01). 2,6-Dichloroindophenol, which in previous studies was shown to be a good inhibitor of TR in vitro, was a poor inhibitor of TR in intact A204 cells and there was no significant correlation with inhibition of colony formation. The activity of ribonucleotide reductase, which catalyzes the first unique step of DNA synthesis and which obtains its reducing equivalents from TR through thioredoxin, was decreased in diaziquone- and doxorubicin treated A204 cells. We suggest that the inhibition of TR by some antitumor quinones leading to a decreased activity of TR and, consequently, a decreased activity of thioredoxin-dependent enzymes including ribonucleotide reductase may contribute to the growth inhibitory activity of these quinones.
Topics: Antineoplastic Agents; Aziridines; Benzoquinones; Cell Division; Dose-Response Relationship, Drug; Doxorubicin; Humans; Ribonucleotide Reductases; Thioredoxin-Disulfide Reductase; Tumor Cells, Cultured
PubMed: 1567483
DOI: No ID Found -
BMC Psychiatry Aug 2023Depression is a common mental health problem among veterans, with high mortality. Despite the numerous conducted investigations, the prediction and identification of...
BACKGROUND
Depression is a common mental health problem among veterans, with high mortality. Despite the numerous conducted investigations, the prediction and identification of risk factors for depression are still severely limited. This study used a deep learning algorithm to identify depression in veterans and its factors associated with clinical manifestations.
METHODS
Our data originated from the National Health and Nutrition Examination Survey (2005-2018). A dataset of 2,546 veterans was identified using deep learning and five traditional machine learning algorithms with 10-fold cross-validation. Model performance was assessed by examining the area under the subject operating characteristic curve (AUC), accuracy, recall, specificity, precision, and F1 score.
RESULTS
Deep learning had the highest AUC (0.891, 95%CI 0.869-0.914) and specificity (0.906) in identifying depression in veterans. Further study on depression among veterans of different ages showed that the AUC values for deep learning were 0.929 (95%CI 0.904-0.955) in the middle-aged group and 0.924(95%CI 0.900-0.948) in the older age group. In addition to general health conditions, sleep difficulties, memory impairment, work incapacity, income, BMI, and chronic diseases, factors such as vitamins E and C, and palmitic acid were also identified as important influencing factors.
CONCLUSIONS
Compared with traditional machine learning methods, deep learning algorithms achieved optimal performance, making it conducive for identifying depression and its risk factors among veterans.
Topics: Middle Aged; Humans; Aged; Deep Learning; Depression; Nutrition Surveys; Veterans; Algorithms
PubMed: 37612646
DOI: 10.1186/s12888-023-05109-9 -
Free Radical Biology & Medicine 1991The participation of DT-diaphorase or NAD(P)H:(quinone acceptor) oxidoreductase (E.C. 1.6.99.2) in metabolism or in events leading to toxicity is often implied on the... (Review)
Review
The participation of DT-diaphorase or NAD(P)H:(quinone acceptor) oxidoreductase (E.C. 1.6.99.2) in metabolism or in events leading to toxicity is often implied on the basis of the inhibitory effects of dicoumarol. DT-diaphorase functions via a ping pong bi-bi kinetic mechanism involving oxidized and reduced flavin forms of the free enzyme. Dicoumarol, a potent (Ki = 10 nM) inhibitor, binds to the oxidized form of the enzyme, competitively versus reduced pyridine nucleotide. Inhibition is effectively complete at 1 microM dicoumarol in typical studies using DCPIP, one of the best known substrates for the enzyme, as electron acceptor. The antitumor quinone Diaziquone (AZQ) is a poor substrate for DT-diaphorase relative to DCPIP, but effective inhibition of its reduction requires ten-fold higher concentrations of dicoumarol than for inhibition of DCPIP reduction under otherwise similar conditions. The variable inhibition of DT-diaphorase by dicoumarol dependent on the efficiency of the electron acceptor can be explained on the basis of the complete rate equation describing its ping pong type kinetic mechanism. Thus, the concentration of dicoumarol used to inhibit DT-diaphorase must be chosen carefully and consideration should be given to the efficiency of the electron acceptor. The absence of an inhibitory effect using low doses of dicoumarol cannot rule out a reaction mediated by DT-diaphorase. Although higher doses of dicoumarol may be required to inhibit DT-diaphorase mediated metabolism of less efficient electron acceptors, the use of such doses in cells may also affect biochemical processes other than DT-diaphorase and should be approached with caution.
Topics: Animals; Dicumarol; Free Radicals; Humans; NAD(P)H Dehydrogenase (Quinone); Substrate Specificity
PubMed: 1718826
DOI: 10.1016/0891-5849(91)90191-5 -
Biochemical and Biophysical Research... Oct 1985When diaziquone was irradiated with 500 nm visible light, hydroxyl free radicals as well as the diaziquone semiquinone were produced. The diaziquone semiquinone is a...
When diaziquone was irradiated with 500 nm visible light, hydroxyl free radicals as well as the diaziquone semiquinone were produced. The diaziquone semiquinone is a stable free radical that exhibits a characteristic 5-line electron spin resonance (ESR) spectrum. Since hydroxyl free radicals are short lived, and not observable by conventional ESR, the nitrone spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) was used to convert hydroxyl radicals into longer lived ESR detectable spin adducts. The formation of hydroxyl radicals was further confirmed by investigating reactions in which hydroxyl radical scavangers, sodium formate and dimethylsulfoxide, compete with the spin traps DMPO or POBN (alpha-(4-Pyridyl-1-oxide)-N- tert-butylnitrone) for hydroxyl free radicals. The products of these scavenging reactions were also trapped with DMPO or POBN. If drug free radicals and hydroxyl free radicals are important in the activity of quinone-containing antitumor agents, AZQ may have a potential in photoirradiation therapy or photodynamic therapy.
Topics: Aziridines; Azirines; Benzoquinones; Cyclic N-Oxides; Dimethyl Sulfoxide; Electron Spin Resonance Spectroscopy; Hydroxides; Hydroxyl Radical; Light; Nitrogen Oxides; Phototherapy; Pyridines; Quinones
PubMed: 2998365
DOI: 10.1016/0006-291x(85)91042-3 -
Journal of Neurosurgery May 1984Diaziquone (also called "aziridinyl benzoquinone," or AZQ), an antitumor drug designed to penetrate the blood-brain barrier, has demonstrated activity against central...
Diaziquone (also called "aziridinyl benzoquinone," or AZQ), an antitumor drug designed to penetrate the blood-brain barrier, has demonstrated activity against central nervous system (CNS) neoplasms. Four-hour infusions of carbon-14 (14C)-labeled AZQ (0.8 mg/kg) were given via the left common carotid artery or left brachial vein to two groups of puppies. A third group, harboring a transplantable canine glioma, received 14C-AZQ by intravenous infusion. Levels of chloroform (CHCl3)-extractable 14C (AZQ only) and total 14C (AZQ and metabolites) were determined in serial samples of plasma and cerebrospinal fluid (CSF). At the end of the infusion time, total and CHCl3-extractable 14C levels were determined in brain and tumor. Intra-arterial infusion of AZQ caused no histological abnormalities in the retina or brain. For the intravenous infusion group, the concentrations of CHCl3-extractable 14C (in nmol/ml or nmol/gm) were 0.68, 0.35, and 0.84 for plasma, brain, and CSF, respectively. For the intra-arterial infusion group, the concentrations were 0.25, 0.13, and 0.32 for plasma, brain, and CSF, respectively. Comparison of right and left hemispheres following intra-arterial infusion showed a slightly higher concentration of 14C in the ipsilateral (left) hemisphere, with concentrations (nmol/gm) of CHCl3-extractable 14C/total of 14C of 0.15/0.87 on the left and 0.12/0.65 on the right. Concentrations (nmol/gm) of CHCl3-extractable 14C/total 14C in brain and tumor were 0.60/1.24 and 0.58/1.65, respectively. In tumor-bearing animals, tumor and surrounding brain contained similar concentrations of AZQ, but there were higher concentrations of metabolites in tumor. This may reflect different metabolism of AZQ within brain and tumor or different permeability to metabolites. This study revealed that AZQ enters the CNS and brain-tumor tissue in substantial concentrations and that there is no significant advantage to intracarotid infusion of AZQ.
Topics: Animals; Aziridines; Azirines; Benzoquinones; Brain Neoplasms; Carotid Arteries; Dogs; Glioma; Infusions, Parenteral; Kinetics
PubMed: 6716135
DOI: 10.3171/jns.1984.60.5.1005 -
Cancer Research Nov 1990Reduction of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone; AZQ) by purified rat hepatic DT-diaphorase was NADH and enzyme dependent and was...
Metabolism of diaziquone by NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase): role in diaziquone-induced DNA damage and cytotoxicity in human colon carcinoma cells.
Reduction of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone; AZQ) by purified rat hepatic DT-diaphorase was NADH and enzyme dependent and was inhibited by prior boiling of the enzyme or by dicumarol. Under aerobic conditions some of the hydroquinone (AZQH2) formed by reduction oxidized to regenerate AZQ and an approximate 1:1 stoichiometry was observed between AZQH2 reoxidized and oxygen consumed. The steady state kinetics of AZQ reduction were consistent with a ping-pong mechanism and a high Km for AZQ. There was no evidence for saturation in the range of 25-200 microM AZQ at 200 microM NADH. AZQ (0-20 microM) induced dicumarol-inhibitable DNA interstrand cross-linking and cytotoxicity in HT-29 human colon carcinoma cells which have high DT-diaphorase activity but not in BE cells which have low DT-diaphorase activity. Extensive metabolism (greater than 90%) of AZQ (100 microM) in HT-29 cytosol occurred, which was either NADH or NADPH dependent and could be inhibited by dicumarol. Little metabolism of AZQ could be detected in BE cell cytosols. DT-diaphorase was purified from HT-29 cells and metabolism of AZQ by this enzyme was confirmed. These data show that AZQ can be metabolized by purified rat hepatic and human HT-29 DT-diaphorase and suggest that in HT-29 cells, DT-diaphorase catalyzed reduction of AZQ represents a bioactivation process leading to the production of genotoxic and cytotoxic metabolites.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Carcinoma; Cell Division; Chromatography, High Pressure Liquid; Colonic Neoplasms; Glutathione; Humans; In Vitro Techniques; Kinetics; Liver; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Quinone Reductases; Rats; Spectrum Analysis; Tumor Cells, Cultured
PubMed: 2121335
DOI: No ID Found