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At least 145 records · Page 8Linked to original sources

PubMed2003

Role of poly(ADP-ribose)polymerase in cisplatin-induced injury in LLC-PK1 cells.

Acute renal failure is a dose-limiting factor during cisplatin chemotherapy. We have previously shown in rats that the hydroxyl radical scavenger edaravone reverses cisplatin-induced in vivo renal damage. In the present study, the role of poly(ADP-ribose) polymerase (PARP) in cisplatin nephrotoxicity was investigated in porcine tubular cells LLC-PK1. Cell injury was elicited by transient exposure to 500 microM cisplatin for 1 h or continuous exposure to 30 microM cisplatin for 24 h. Various hydroxyl radical scavengers reversed cell damage in a transient but not permanent model. The cell injury seemed to be necrosis and apoptosis in transient and permanent models, respectively, as assessed by TUNEL method and Annexin V stain. PARP inhibitors such as 3-aminobenzamide and benzamide inhibited cell damage in transient but not permanent model. PARP-dependent cell injury was also observed after transient exposure to hydroxyl radical-generating solution. We demonstrated for the first time the activation of PARP in renal tubular cells by transient cisplatin exposure, as determined by immunofluorescent stain with anti-poly(ADP-ribose) antibody. Moreover, ATP was depleted by transient exposure to cisplatin or hydroxyl radical, both of which were reversed by PARP inhibitors. These findings suggest that hydroxyl radical generation followed by PARP activation contributes to the necrotic cell injury caused by a transient exposure to cisplatin.

Adenosine Triphosphate↗

PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗

PubMed2026

Mechanisms of Hexavalent Chromium-Induced Reproductive Toxicity: A Focus on the Ovary and Placenta.

Hexavalent Chromium (Cr(VI)) is a Group A carcinogen, mutagen, and teratogen. Cr(VI) has been used by more than 50 industries, and its contamination of drinking water is widespread across the United States (U.S.). Epidemiological data of women who lived in Willits, California, U.S., indicate that environmental exposure to Cr(VI) adversely affects pregnancy outcomes and the health of their immediate offspring, resulting in a low birth rate, pregnancy loss, and spontaneous abortion, and their children (F1 offspring) experienced birth defects. However, the molecular mechanisms behind Cr(VI)-induced reproductive and developmental toxicity are poorly understood. Cr(VI) enters cells through anion transporters and is rapidly reduced to Cr(III) by endogenous antioxidants within the cell. Cr(III) forms adducts with DNA, which can block DNA replication and transcription; abnormal repair can lead to DNA double-strand breaks, mutations, micronucleus formation, chromosomal abnormalities, and increased genomic instability. Cr(VI) induces oxidative stress via the Fenton reaction, generating free radicals, and depleting antioxidants, thereby promoting apoptosis via p53-dependent and independent pathways, resulting in follicular atresia and accelerated reproductive aging. Antioxidant supplementation with resveratrol, vitamin C, and edaravone mitigates Cr(VI) toxicity in the ovary. Cr(VI) disrupts meiosis in metaphase II oocytes by causing DNA strand breaks, altering F-actin dynamics, disturbing microtubules, and leading to chromosome missegregation. Gestational exposure to Cr(VI) also disrupts placental function through multiple mechanisms by targeting trophoblast lineages. The current review focuses on genotoxicity, oxidative stress, and other mechanisms by which Cr(VI) disrupts the female reproductive and endocrine systems, with particular emphasis on the ovary and placenta.

Hexavalent chromium↗

PubMed2006

Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells.

Oxidative stress is central to ischemia-reperfusion injury. The role of the endoplasmic reticulum (ER) in this process is uncertain. In ER signaling, PERK-Nrf2 and Ire-CHOP are two pathways that determine cell fate under stress. PERK-Nrf2 up-regulates antioxidant enzyme expression whereas Ire-CHOP promotes apoptosis. We have identified a novel pathway in ER stress-induced apoptosis after ischemia-reperfusion in vitro involving translational suppression of the survival kinase PKB/Akt (Akt), and elucidated an alternative protective role of antioxidants in the regulation of Akt activity. Using human choriocarcinoma JEG-3 cells, we found that sustained activation of ER stress by tunicamycin or thapsigargin exacerbated apoptosis in oxygen-glucose-deprived cells during reoxygenation. This was mediated via a reduction in phosphorylated Akt secondary to down-regulation of protein translation rather than suppression of phosphorylation. Transient overexpression of wild-type Akt, but not kinase-dead Akt, in JEG-3 cells diminished tunicamycin-OGD reoxygenation-induced apoptosis. The antioxidants Trolox and Edaravone reduced apoptosis, but the protective effect of Trolox was abrogated by the PI3K inhibitor, LY294002. We speculate that sustained ER stress may contribute to the placental dysfunction seen in human pregnancy complications.

Apoptosis↗

PubMed2003

Arachidonic acid metabolites contribute to the irreversible depolarization induced by in vitro ischemia.

Intracellular recordings were made from hippocampal CA1 neurons in rat slice preparations. Superfusion with oxygen- and glucose-deprived medium (in vitro ischemia) produced a rapid depolarization approximately 5 min after the onset of the superfusion. Even when oxygen and glucose were reintroduced immediately after rapid depolarization, the membrane depolarized further (persistent depolarization) and reached 0 mV (irreversible depolarization) after 5 min from the reintroduction. The pretreatment of the slice preparation with a phospholipase A2 (PLA2) inhibitor, para-bromophenacyl bromide, or a cytochrome p-450 inhibitor, 17-octadecynoic acid, significantly restored the membrane to the preexposure potential level after the reintroduction of oxygen and glucose. The administration of 14,15-epoxyeicosatrienoic acid or 20-hydroxyeicosatetraenoic acid did not change the latency of the rapid depolarization and did not allow the membrane potential to recover after the ischemic exposure. In contrast, after pretreatment with cyclooxygenase or lipoxygenase inhibitors, such as indomethacin, resveratrol, Dup-697, nordihydroguaiaretic acid, and 3,4-dihydrophenyl ethanol, a minority of neurons tested showed postischemic recovery from the persistent depolarization. Improved recovery was also seen after treatment with the free radical scavengers, edaravone and alpha-tocopherol. These results suggest that the activation of the arachidonic acid cascade via PLA2 and the free radicals produced by arachidonic acid metabolism contribute to the irreversible depolarization produced by in vitro ischemia.

Action Potentials↗

PubMed2003

Hospital-based study of the care and cost of acute ischemic stroke in Japan.

BACKGROUND AND PURPOSE: To evaluate the current status of care and cost of acute ischemic stroke in Japan, we performed a hospital-based analysis at a tertiary emergency hospital with a 24-hour neurology-neurosurgery team and care unit. METHODS: During the 12-month period of October 2000 to September 2001, we collected data on 179 patients consecutively hospitalized with acute ischemic stroke within 7 days of onset. We examined demographic data, in-hospital care, length of hospital stay, outcome at discharge, and hospital costs. The medical cost data were collected from official hospital medical cost charts, which calculated direct medical costs for beds, staff, examinations, medications, and rehabilitation. RESULTS: The mean age was 70 years, and 69% were male. Hospital arrival was within 3 hours of onset in 30% of the patients. A history of stroke was present in 37%. The mean initial National Institutes of Health Stroke Scale score was 8.3 points (median, 6 points). Using the Trial of Org 10172 in Acute Stroke Treatment classification, 25% were lacunar, 27% were atherothrombotic, 33% were cardioembolic, and 15% were of unknown origin. All patients underwent neuroimaging studies during hospitalization; 96% and 92% underwent CT and MRI with MR angiography, respectively. Antithrombotic medications were given in 94%, none of whom received thrombolysis. A newly licensed neuroprotective agent, edaravone, was given in 16%. More than half of the patients (55%) were initially admitted to the neurological intensive care unit. Overall, 64% received in-hospital rehabilitation. Mean length of stay was 33 days. In-hospital mortality rate was 3%. On the modified Rankin Scale (mRS), 63% were independent (mRS, 0 to 2) and 34% were dependent (mRS, 3 to 5) at discharge. Two thirds of the patients (65%) went directly back home. The mean hospital cost per patient was $6887 ($209/d), of which 69% was attributable to the costs for beds and staff, 12% for medications, 7% for rehabilitation, 6% for imaging studies, 5% for laboratory examinations, and 1% for other costs. CONCLUSIONS: Despite the single hospital-based analysis, this study provided current, precise data on short-term inpatient care and costs of acute ischemic stroke in Japan. Because stroke often carries a permanent dependence, long-term cost-effective stroke care should be established.

Acute Disease↗

PubMed2002

Treatment of acute ischemic stroke: recent progress.

Intravenous thrombolysis with tissue plasminogen activator is currently the most effective treatment of acute ischemic stroke if administerd within 3 hours after symptom onset. Intraarterial thrombolysis by prourokinase is the another choise if the middle cerebral artery is occluded and within less than 6 hours after onset. Although heparin especially a moderate dose is not proved to be effective, a randomized, placebo-controlled trial to determine the safety and efficacy of argatroban (a selective thrombin inhibitor) in patients with acute ischemic stroke was started in USA. Aspirin provides some benefit to patients with acute stroke. However, its effect is not fully satisfactory. Although reports of numerous trials for neuroprotective drugs have been disappointing, edaravone (free radical scavenger) was approved for the treatment of acute ischemic stroke in Japan. In the future, thrombolytic and neuroprotective drugs will be used in combination.

Anticoagulants↗

PubMed2004

Differences in diffusion-weighted and T2-weighted magnetic resonance imaging findings in the acute and chronic stages of ischemic cerebrovascular disease--two case reports.

A 71-year-old man presented with sudden onset of vertigo and a 77-year-old man suffered consciousness disturbance. Diffusion-weighted magnetic resonance (MR) imaging on admission showed hyperintense areas in the left cerebellar hemisphere in the first patient and in the brainstem in the second patient. Both patients were treated with argatroban and edaravone, and the neurological deficits markedly improved one month after admission. T2-weighted MR imaging one month after the onset showed much smaller hyperintense areas compared with the findings on admission in both patients. These results indicate that findings of hyperintense areas by diffusion-weighted MR imaging in the acute stage of ischemic cerebrovascular disease indicate not only the ischemic core but also parts of the reversible incomplete ischemic lesion and suggest that intensive treatment in the acute stage might reverse ischemic brain damage in some patients.

Acute Disease↗

PubMed2001

[Targets of treatment in the acute phase of cerebral infarction].

In the acute phase of cerebral infarction, many experimental data suggest that free radicals including superoxide, hydroxy radical and nitric oxide are one of the most important factors to cause brain damage. We have clearly detected nitrotyrosine (a marker of endogenous production of peroxynitrite, which is readily produced from superoxide and nitric oxide) in neurons and intraparenchymal vascular walls during post-ischemic reperfusion. Free radical scavengers thus seem to be very promising tools of treatment, and one of them (edaravone) has recently been approved for clinical use in Japan. CREB (cyclic AMP response element binding protein) is a DNA-binding transcription factor, and its function is activated by phosphorylation of Ser133 residue. CREB plays important roles in neuronal development, synaptic plasticity and regeneration. We have found that phosphorylation of CREB is significantly and persistently increased in surviving neurons and oligodendrocytes in post-ischemic brain, while this phosphorylation is only transiently increased in neurons and oligodendrocytes which eventually die. These data suggest that CREB phosphorylation plays an important role in protection of ischemic brain tissue. Oligodendrocyte progenitor cells (OPC) remain abundant throughout the adult brain, and retain their ability to become not only mature oligodendrocytes, but also neurons. We have recently found that OPC are significantly activated and proliferate in the peri-infarct area at 1-2 weeks after ischemia, suggesting that OPC may be involved in the repair mechanisms of ischemic brain. Future targets of stroke treatment should include enhancement of intrinsic protection mechanisms such as CREB phosphorylation and activation of progenitors cells.

Acute-Phase Reaction↗

PubMed2003

Gateways to clinical trials.

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 drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abetimus sodium, adefovir dipivoxil, AGI-1067, alefacept, alemtuzumab, ALVAC-p53, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, Anti-CTLA-4 Mab, AOD-9604, apafant, aprinocarsen sodium, arsenic trioxide; Balaglitazone, BIM-23190, bimatoprost, bortezomib, bosentan, BR-1; Canertinib dihydrochloride, CDP-850, cevimeline hydrochloride, cinacalcet hydrochloride, clenoliximab, clevudine, CN-787; D-003, darusentan, deferasirox, desloratadine dexanabinol, duloxetine hydrochloride; E-5564, edaravone, efaproxiral sodium, elvucitabine emfilermin, EN-101, enfuvirtide, entecavir, epithalon, eplerenone, erlotinib hydrochloride, escitalopram oxalate, esomeprazole magnesium, eszopiclone, etilefrine pivalate hydrochloride etoricoxib, everolimus, exenatide; Fidarestat, fondaparinux sodium; Ganstigmine hydrochloride; Homoharringtonine, HuMax-IL-15, hyperimmune IVIG; Imatinib mesylate, IMC-1C11, Inhaled insulin, irofulven, iseganan hydrochloride, ISIS-14803, ISIS-5132, ivabradine hydrochloride; Keratinocyte growth factor; Lafutidine, lanthanum carbonate, LAS-34475, levocetirizine, liraglutide, LY-307161 SR; Magnesium sulfate, maribavir, melatonin, mycobacterium cell wall complex; NN-414, NO-aspirin, nociceptin, nolomirole hydrochloride; Olmesartan medoxomil oral insulin, ospemifene; PDX, perillyl alcohol, pimecrolimus, pitavastatin calcium, pramlintide acetate, prasterone, pregabalin, PRO-542, PV-701, pyrazoloacridine; R-744, ranelic acid distrontium salt, rasburicase, rDNA insulin, resiniferatoxin, reslizumab, ridogrel, riplizumab ropivacaine, rosuvastatin calcium, roxifiban acetate, ruboxistaurin mesilate hydrate; Satraplatin, Sch-58500, semaxanib, sitaxsentan sodium, SMP-114, SU-6668; Teriparatide, tetrathiomolybdate, tipifarnib, tolvaptan, travoprost, treprostinil sodium; Valdecoxib, valganciclovir hydrochloride, vardenafil hydrochloride hydrate, vatalanib succinate; Ximelagatran; Z-335, ziprasidone hydrochloride, zoledronic acid monohydrate, ZYC-00101.

Clinical Trials as Topic↗

PubMed2005

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, pirfenidone, posaconazole, prasterone, pregabalin; R-112, ramelteon, ranolazine, rasagiline mesilate, rebimastat, roflumilast, rosuvastatin calcium, rotigotine hydrochloride, rupatadine fumarate; S-3013, S-3304, semustine, sitaxsentan sodium, St. John's Wort extract; Tadalafil, tamoxifen, Taxus, Tc-99m-EDDA-HYNIC-TOC, TH-9507, tiotropium bromide, tipifarnib, tocilizumab, tolvaptan, torcetrapib, TR-14035, tramadol hydrochloride/acetaminophen, treprostinil diethanolamine, troglitazone, troxacitabine; Valdecoxib, valganciclovir hydrochloride, vandetanib, vardenafil hydrochloride hydrate, VAS-991, veglin, vinflunine, voriconazole; White sweet potato extract; Ximelagatran.

Clinical Trials as Topic↗

PubMed2005

[Anesthetic management of a patient undergoing PTA stent placement for right common carotid artery stenosis].

A 60-year-old man underwent percutaneous transluminal angioplasty (PTA) stent replacement of the right common carotid artery. Preoperative angiogram revealed bilateral vertebral artery occlusion and 50% stenosis in contralateral internal carotid artery. Anesthesia was induced and maintained with fentanyl and propofol by TCI. rSO2, BIS and EEG were monitored. Moderate hypothermia (33-35 degrees C) was induced by concomitant use of milrinone. Edaravone, a novel free radical scavenger, and Sendai cocktail were administered before interruption of carotid flow. During 5 minutes of test occlusion by balloon, right rSO2 decreased from 61% to 49% and EEG showed slow waves with decreased amplitude. Therefore we decided to perform PTA and stenting separately. Right rSO2 decreased from 62% to 48% during PTA (6 min occlusion), while rSO2 decreased from 66% to 50% during stenting (7.5 min occlusion). EEG also showed the similar changes as observed during test occlusion. After the procedures, rSO2 and EEG recovered in a short time. Postoperative angiogram showed an improvement of carotid artery stenosis and intracranial vessels showed no branch occlusion. Patient was maintained hypothermic (35 degrees C) for 2 days after surgery. He recovered without additional neurological complications. We found that rSO2 was a useful, real-time and non-invasive method for evaluation of cerebral ischemia in our patient.

Angioplasty, Balloon↗

PubMed2006

[An 80-year-old woman with progressive stroke, who had rheumatoid arthritis and antiphospholipid syndrome].

We report an 80-year-old woman who had rheumatoid arthritis and antiphospholipid syndrome. She was treated for rheumatoid arthritis since her thirties. At 76 years of age, she was diagnosed antiphospholipid syndrome serologically. She felt It. limb weakness and dysarthria and was admitted to the hospital on July 18, 2003. The brain MRI showed T2 hyperintensity signal on the rt. pre-central lobe. She was treated by the argatroban, edaravone, glycerol, and aspirin. However, she became bedridden and fed by NG-tube because her symptoms progressed in spite of the therapy. Progression of stroke stopped by adding heparin at last. After that, she repeated pneumonia. She was found dead on the bed August 2, 2003. The patient was discussed in a CPC. The chief discussant arrived at a conclusion that the cause of infarction was angitis due to rheumatoid arthritis. Other possibilities were multiple thrombus due to antiphospholipid syndrome, amyloid angiopathy, and atherosclerotic infarction. Post-mortem study revealed sputum obstruction in her bronchus, string deposition in her organs. The brain showed infarction on the rt. pre-central lobe. There were multiple thrombus in the leptomeningeal artery, but few atherosclerotic changes of the small arteries. Amyloid didn't deposit in the brain artery and the parenchyma. Pathologist concluded that her infarction was induced with multiple thrombus due to antiphospholipid syndrome.

Aged, 80 and over↗

PubMed2006

Gateways to clinical trials.

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com This issue focuses on the following selection of drugs: A-007, A6, adalimumab, adenosine triphosphate, alefacept, alemtuzumab, AllerVax Ragweed, amphora, anakinra, angiotensin-(1-7), anidulafungin, apomine, aripiprazole, atomoxetine hydrochloride, avanafil; BAL-8557, becatecarin, bevacizumab, biphasic insulin aspart, BMS-188797, bortezomib, bosentan, botulinum toxin type B, brivudine; Calcipotriol/betamethasone dipropionate, caspofungin acetate, catumaxomab, certolizumab pegol, cetuximab, CG-0070, ciclesonide, cinacalcet hydrochloride, clindamycin phosphate/benzoyl peroxide, cryptophycin 52, Cypher; Dabigatran etexilate, darapladib, darbepoetin alfa, decitabine, deferasirox, desloratadine, dexanabinol, dextromethorphan/quinidine sulfate, DMF, drotrecogin alfa (activated), duloxetine hydrochloride; E-7010, edaravone, efalizumab, emtricitabine, entecavir, eplerenone, erlotinib hydrochloride, escitalopram oxalate, estradiol valerate/dienogest, eszopiclone, exenatide, ezetimibe; Fondaparinux sodium, fulvestrant; Gefitinib, gestodene, GYKI-16084; Hyaluronic acid, hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, indiplon, insulin glargine; Juzen-taiho-to; Lamivudine/zidovudine/abacavir sulfate, L-arginine hydrochloride, lasofoxifene tartrate, L-BLP-25, lenalidomide, levocetirizine, levodopa/carbidopa/entacapone, lexatumumab, lidocaine/prilocaine, lubiprostone, lumiracoxib; MAb-14.18, mitoquidone; Natalizumab, neridronic acid, neuradiab; Olpadronic acid sodium salt, omalizumab; p53-DC vaccine, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, perifosine, pimecrolimus, prasterone, prasugrel, PRO-2000, Pseudostat; R24, rasburicase, RHAMM R3 peptide, rilonacept, rosuvastatin calcium, rotavirus vaccine, rufinamide; Sabarubicin hydrochloride, SHL-749, sirolimus-eluting stent, SLx-2101, sodium butyrate, sorafenib, SU-6668; TachoSil, tadalafil, taxus, tegaserod maleate, telbivudine, tenofovir disoproxil fumarate, teriparatide, tetramethylpyrazine, teverelix, tiotropium bromide, tipifarnib, tirapazamine, tolvaptan, TransvaxTM hepatitis C vaccine, treprostinil sodium; Valganciclovir hydrochloride, valsartan/amlodipine, vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, veglin, voriconazole; Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zotarolimus, zotarolimus-eluting stent.

Clinical Trials as Topic↗

PubMed2006

Gateways to clinical trials.

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; LA-419, lacosamide, landiolol, lanthanum carbonate, lidocaine/prilocaine, liposomal cisplatin, lutropin alfa; Matuzumab, MBP(82-98), mecasermin, MGCD-0103, MMR-V, morphine hydrochloride, mycophenolic acid sodium salt; Natalizumab, NCX-4016, neridronic acid, nesiritide, nilotinib, NSC-330507; O6-benzylguanine, olanzapine/fluoxetine hydrochloride, omalizumab; Panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pemetrexed disodium, perospirone hydrochloride, pexelizumab, phorbol 12-myristate 13-acetate, pneumococcal 7-valent conjugate vaccine, posaconazole, pramiconazole, prasugrel, pregabalin, prilocaine; rAAV-GAD65, raclopride, rasagiline mesilate, retapamulin, rosuvastatin calcium, rotigotine, rufinamide; SarCNU, SB-743921, SHL-749, sirolimus-eluting stent, sitaxsentan sodium, sorafenib; TachoSil, tadalafil, talampanel, Taxus, tegaserod maleate, telithromycin, telmisartan/hydrochlorothiazide, temsirolimus, tenatoprazole, teriflunomide, tetrathiomolybdate, ticilimumab, timcodar dimesilate, tipifarnib, tirapazamine, TPI, tramiprosate, trifluridine/TPI, trimethoprim; Ularitide, Urocortin 2; Valdecoxib, valganciclovir hydrochloride, valproate magnesium, valspodar, vardenafil hydrochloride hydrate, vitespen, vofopitant hydrochloride, volociximab, vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, zotarolimus, zotarolimus-eluting stent.

Clinical Trials as Topic↗

PubMed1999

Electrospray ionization mass spectrometry of 1-phenyl-3-methyl-5-pyrazolone derivatives of neutral and N-acetylated oligosaccharides.

Derivatization using 1-phenyl-3-methyl-5-pyrazolone (PMP) was selected among a number of reported methods for labeling carbohydrates, since it gives a quantitative yield, proceeds through a rapid reaction and involves a simple clean-up procedure. Moreover, PMP derivatives provide an increase in sensitivity with ultraviolet and mass spectrometric detection relative to native neutral sugars. Sensitivity studies were carried out using a standard oligosaccharide, tetraglucose. One of the aims of these studies was to determine the minimum amounts of PMP-tetraglucose necessary to generate informative full-scan electrospray ionization (ESI) mass spectra and collision-induced dissociation tandem mass spectra. Another aim was to characterize the fragmentation pattern of PMP derivatives. Quantitative and qualitative studies were also carried out with a typical N-linked oligosaccharide obtained commercially. The PMP-labeled compound underwent directed cleavages which produced fragments containing the reducing end. The native N-linked sugar yielded fragments corresponding to cleavages from both ends of the molecule. Under the same ESI conditions, the N-linked oligosaccharide exhibited more lability, or tendency to fragment, than neutral tetraglucose, in both the derivatized and native forms. Also, PMP labeling was shown to enhance sensitivity in the case of a neutral oligosaccharide, i.e. tetraglucose, whereas the labeling of an N-acetylated oligosaccharide, NGA3, did not yield a noticeable improvement in sensitivity.

Acetylation↗

PubMed1999

Effect of 1-phenyl-3-methyl-5-pyrazolone labeling on the fragmentation behavior of asialo and sialylated N-linked glycans under electrospray ionization conditions.

The advantages of labeling free N-linked oligosaccharides with 1-phenyl-3-methyl-5-pyrazolone (PMP), for high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) are discussed. The study focuses on some asialo and sialylated sugars, and compares the HPLC and ESI-MS behaviors of the PMP-labeled substances vs. the native compounds. It is pointed out that native free N-linked carbohydrates have very low affinities for the C18 reversed phases commonly used in HPLC. Native asialo oligosaccharides yield good ESI-MS sensitivity, although they are very susceptible to in-source collision-induced dissociation (CID), and the fragments are produced from any of the branches of the molecules, i.e. do not give specific structural information. Native N-linked standards bearing one sialic acid residue yield a 10-fold loss of ESI-MS sensitivity vs. asialo compounds, and native sugars with two sialic acid moieties were not detectable. The PMP labeling of asialo and sialylated sugars yielded higher affinities for HPLC C18 columns and, even at the early stages of method development, it was possible to separate three PMP-labeled standards to a useful extent. In ESI-MS, PMP-asialo sugars did not yield a significant increase in sensitivity vs. the native species; however, fragmentation produced by in-source CID was more directed as all predominant fragment ions contained the bis-PMP label. This feature is particularly useful when structural determination of an unknown sugar is required. PMP-sialylated sugars gave rise to very clean and informative ESI mass spectra. The monosialo sugar yielded a 100-fold sensitivity improvement vs. its native analog and, in the case of the disialylated compound, a 100% improvement was obtained in the positive mode. Most fragment ions were informative and contained the reducing end on the molecules, thus facilitating spectral interpretation. The combination of PMP derivatization with on-line HPLC/ESI-MS is a promising method for the analysis of asialo and sialylated carbohydrate mixtures.

Antipyrine↗

PubMed2004

The hydroxyl radical scavenger MCI-186 protects the liver from experimental cold ischaemia-reperfusion injury.

BACKGROUND: Oxidative stress contributes to hepatic ischaemia-reperfusion (IR) injury in a biphasic pattern. In addition to direct cytotoxic effects, oxidative stress also initiates the signal transduction processes that promote second-phase liver injury. The present study investigated the effects of the hydroxyl radical scavenger MCI-186 on the biphasic process of hepatic cold IR injury. METHODS: After cold preservation for 16 h, rat livers were reperfused on an isolated liver perfusion system for 120 min with oxygenated Krebs-Henseleit bicarbonate buffer. Perfusate samples were obtained serially, and portal flow rates were also recorded. To determine whether MCI-186 affected cytokine levels that control the second-phase injury, levels of interleukin (IL) 10 and tumour necrosis factor (TNF) alpha were measured in the perfusate. RESULTS: Addition of MCI-186 1 mg/l into the perfusate significantly improved portal flow (P<0.050), hepatic enzyme release into the perfusate (P=0.038), total bile production (P=0.029) and malondialdehyde concentration (P=0.038). Furthermore, treatment with MCI-186 led to a substantial increase in IL-10 release (P=0.032). TNF-alpha levels were not affected. CONCLUSIONS: MCI-186, an agent ready for clinical use, appears to have direct and indirect protective effects against hepatic cold IR injury.

Animals↗