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[ { "id": "passage-300", "type": "abstract", "text": [ "Two rare cases of methotrexate-induced pneumonitis and pleurisy in patients with gestational trophoblastic neoplasms. BACKGROUND: Pneumonitis is a serious and unpredictable side-effect of treatment with methotrexate (MTX) that may result in a life-threatening outcome. Pulmonary toxicity of methotrexate in patients with a gestational trophoblastic neoplasm (GTN) has rarely been reported before. CASE REPORTS: For the first time two cases of methotrexate-induced pneumonitis and pleurisy in GTN patients of Chinese ethnicity are presented. Two patients were both categorized as the low-risk group, and underwent a single regimen therapy of methotrexate. Their symptoms, such as fever, chest pain, acute nonproductive cough, dyspnea and hypoxemia did not respond to antibiotics immediately. Treatment with corticosteroids may be helpful. CONCLUSION: Awareness of pneumonitis and pleurisy, potentially life-threatening complications of MTX, is very necessary and important to early recognition and treatment." ], "offsets": [ [ 0, 1008 ] ] } ]

[ { "id": "entity-300-0", "type": "ADVERSE", "text": [ "pneumonitis" ], "offsets": [ [ 39, 50 ] ], "normalized": [] }, { "id": "entity-300-1", "type": "ADVERSE", "text": [ "pleurisy" ], "offsets": [ [ 55, 63 ] ], "normalized": [] }, { "id": "entity-300-2", "type": "DISEASE", "text": [ "gestational trophoblastic neoplasms" ], "offsets": [ [ 81, 116 ] ], "normalized": [] }, { "id": "entity-300-3", "type": "ADVERSE", "text": [ "Pneumonitis" ], "offsets": [ [ 131, 142 ] ], "normalized": [] }, { "id": "entity-300-4", "type": "ADVERSE", "text": [ "Pulmonary toxicity" ], "offsets": [ [ 270, 288 ] ], "normalized": [] }, { "id": "entity-300-5", "type": "DISEASE", "text": [ "gestational trophoblastic neoplasm" ], "offsets": [ [ 324, 358 ] ], "normalized": [] }, { "id": "entity-300-6", "type": "DISEASE", "text": [ "GTN" ], "offsets": [ [ 360, 363 ] ], "normalized": [] }, { "id": "entity-300-7", "type": "ADVERSE", "text": [ "pneumonitis" ], "offsets": [ [ 465, 476 ] ], "normalized": [] }, { "id": "entity-300-8", "type": "ADVERSE", "text": [ "pleurisy" ], "offsets": [ [ 481, 489 ] ], "normalized": [] }, { "id": "entity-300-9", "type": "DISEASE", "text": [ "GTN" ], "offsets": [ [ 493, 496 ] ], "normalized": [] }, { "id": "entity-300-10", "type": "ADVERSE", "text": [ "fever" ], "offsets": [ [ 680, 685 ] ], "normalized": [] }, { "id": "entity-300-11", "type": "ADVERSE", "text": [ "chest pain" ], "offsets": [ [ 687, 697 ] ], "normalized": [] }, { "id": "entity-300-12", "type": "ADVERSE", "text": [ "acute nonproductive cough" ], "offsets": [ [ 699, 724 ] ], "normalized": [] }, { "id": "entity-300-13", "type": "ADVERSE", "text": [ "dyspnea" ], "offsets": [ [ 726, 733 ] ], "normalized": [] }, { "id": "entity-300-14", "type": "ADVERSE", "text": [ "hypoxemia" ], "offsets": [ [ 738, 747 ] ], "normalized": [] }, { "id": "entity-300-15", "type": "ADVERSE", "text": [ "pneumonitis" ], "offsets": [ [ 864, 875 ] ], "normalized": [] }, { "id": "entity-300-16", "type": "ADVERSE", "text": [ "pleurisy" ], "offsets": [ [ 880, 888 ] ], "normalized": [] } ]

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[ { "id": "passage-301", "type": "abstract", "text": [ "Effect of 2-hydroxyethyl-methacrylate (HEMA) on the phagocytic and respiratory burst activity of human neutrophils and monocytes. Neutrophils and monocytes/macrophages (M?), found in oral mucosa and gingival sulcus, phagocytose and kill bacteria using products produced during a respiratory burst. 2-Hydroxyethyl-methacrylate (HEMA) is a major component released from resin glass ionomer and dental adhesives. Hence, in pulp and gingiva, phagocytes can come into contact with unpolymerized HEMA monomers. The aim of this study was to examine the effects of exposure to HEMA on neutrophil and monocyte bactericidal function. Blood collected from five female volunteers was exposed in vitro to HEMA for 2 h and then phagocytosis, respiratory burst, and cellular integrity were measured using flow cytometry. Respiratory burst was quantified by measuring fluorescent rhodamine 123 generated via oxidation of dihydrorhodamine 123. Cellular membrane integrity was evaluated by staining with propidium iodide. The respiratory burst activity of the neutrophils was significantly decreased by exposure to 7.5 and 15 mM HEMA. No significant effect of HEMA was seen on the number of granulocytes or monocytes capable of performing respiratory burst. Furthermore, there was no significant effect of HEMA on the phagocytic activity of the monocytes or the granulocytes. In conclusion, HEMA did not affect the phagocytosis activity of neutrophils; however, the ability of the cells to kill internalized prey was significantly reduced." ], "offsets": [ [ 0, 1522 ] ] } ]

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[ { "id": "passage-302", "type": "abstract", "text": [ "Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. BACKGROUND: Small cell lung cancer (SCLC) is a very fast growing form of cancer and is characterised by early metastasis. As a result, chemotherapy is the mainstay of treatment. A number of different platinum-based chemotherapy regimens and non-platinum-based chemotherapy regimens have been used for the treatment of SCLC, with varying results. This review was conducted to analyse the data from these trials in order to compare their effectiveness. OBJECTIVES: To determine the effectiveness of platinum chemotherapy regimens compared with non-platinum chemotherapy regimens in the treatment of SCLC with respect to survival, tumour response, toxicity and quality of life. SEARCH STRATEGY: We searched the biomedical literature databases CENTRAL (The Cochrane Library 2007, Issue 2), MEDLINE, EMBASE and CINAHL from 1966 to April 2007. In addition, we handsearched reference lists from relevant resources. SELECTION CRITERIA: All randomised controlled trials involving patients with pathologically confirmed (cytological or histological) SCLC and the use of a platinum-based chemotherapy regimen in at least one treatment arm and a non-platinum-based chemotherapy regimen in a separate arm. DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results. We assessed included studies for methodological quality and recorded the following outcome data: survival, tumour response, toxicity and quality of life. We combined the results of the survival, tumour response and toxicity data in a meta-analysis. MAIN RESULTS: A total of 29 trials involving 5530 patients were included in this systematic review. There was no statistically significant difference between treatment groups in terms of survival at 6 months, 12 months and 24 months. There was also no statistically significant difference in terms of overall tumour response. However, platinum-based treatment regimens did have a significantly higher rate of complete response. Platinum-based chemotherapy regimens had significantly higher rates of nausea and vomiting, anaemia and thrombocytopenia toxicity. Three trials presented quality of life data but the data presented were not complete and therefore could not be combined in a meta-analysis. AUTHORS' CONCLUSIONS: Platinum-based chemotherapy regimens did not offer a statistically significant benefit in survival or overall tumour response compared with non-platinum-based regimens. However, platinum-based chemotherapy regimens did increase complete response rates, at the cost of higher adverse events including nausea and vomiting, anaemia and thrombocytopenia toxicity. These data suggest non-platinum chemotherapy regimens have a more advantageous risk-benefit profile. This systematic review highlights the lack of quality of life data in trials involving chemotherapy treatment for SCLC. With poor long-term survival associated with both treatment groups, the issue of the quality of the survival period takes on even more significance. It would be beneficial for future trials in this area to include a quality of life assessment." ], "offsets": [ [ 0, 3149 ] ] } ]

[ { "id": "entity-302-0", "type": "DISEASE", "text": [ "small cell lung cancer" ], "offsets": [ [ 55, 77 ] ], "normalized": [] }, { "id": "entity-302-1", "type": "DISEASE", "text": [ "Small cell lung cancer" ], "offsets": [ [ 92, 114 ] ], "normalized": [] }, { "id": "entity-302-2", "type": "DISEASE", "text": [ "SCLC" ], "offsets": [ [ 116, 120 ] ], "normalized": [] }, { "id": "entity-302-3", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 153, 159 ] ], "normalized": [] }, { "id": "entity-302-4", "type": "DISEASE", "text": [ "metastasis" ], "offsets": [ [ 190, 200 ] ], "normalized": [] }, { "id": "entity-302-5", "type": "DISEASE", "text": [ "SCLC" ], "offsets": [ [ 398, 402 ] ], "normalized": [] }, { "id": "entity-302-6", "type": "DISEASE", "text": [ "SCLC" ], "offsets": [ [ 677, 681 ] ], "normalized": [] }, { "id": "entity-302-7", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 708, 714 ] ], "normalized": [] }, { "id": "entity-302-8", "type": "DISEASE", "text": [ "SCLC" ], "offsets": [ [ 1120, 1124 ] ], "normalized": [] }, { "id": "entity-302-9", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 1461, 1467 ] ], "normalized": [] }, { "id": "entity-302-10", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 1549, 1555 ] ], "normalized": [] }, { "id": "entity-302-11", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 1912, 1918 ] ], "normalized": [] }, { "id": "entity-302-12", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 2102, 2108 ] ], "normalized": [] }, { "id": "entity-302-13", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 2113, 2121 ] ], "normalized": [] }, { "id": "entity-302-14", "type": "ADVERSE", "text": [ "anaemia" ], "offsets": [ [ 2123, 2130 ] ], "normalized": [] }, { "id": "entity-302-15", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 2135, 2151 ] ], "normalized": [] }, { "id": "entity-302-16", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 2435, 2441 ] ], "normalized": [] }, { "id": "entity-302-17", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 2625, 2631 ] ], "normalized": [] }, { "id": "entity-302-18", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 2636, 2644 ] ], "normalized": [] }, { "id": "entity-302-19", "type": "ADVERSE", "text": [ "anaemia" ], "offsets": [ [ 2646, 2653 ] ], "normalized": [] }, { "id": "entity-302-20", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 2658, 2674 ] ], "normalized": [] }, { "id": "entity-302-21", "type": "DISEASE", "text": [ "SCLC" ], "offsets": [ [ 2900, 2904 ] ], "normalized": [] } ]

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[ { "id": "passage-303", "type": "abstract", "text": [ "Choosing a skeletal muscle relaxant. Skeletal muscle relaxants are widely used in treating musculoskeletal conditions. However, evidence of their effectiveness consists mainly of studies with poor methodologic design. In addition, these drugs have not been proven to be superior to acetaminophen or nonsteroidal anti-inflammatory drugs for low back pain. Systematic reviews and meta-analyses support using skeletal muscle relaxants for short-term relief of acute low back pain when nonsteroidal anti-inflammatory drugs or acetaminophen are not effective or tolerated. Comparison studies have not shown one skeletal muscle relaxant to be superior to another. Cyclobenzaprine is the most heavily studied and has been shown to be effective for various musculoskeletal conditions. The sedative properties of tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms. Methocarbamol and metaxalone are less sedating, although effectiveness evidence is limited. Adverse effects, particularly dizziness and drowsiness, are consistently reported with all skeletal muscle relaxants. The potential adverse effects should be communicated clearly to the patient. Because of limited comparable effectiveness data, choice of agent should be based on side-effect profile, patient preference, abuse potential, and possible drug interactions." ], "offsets": [ [ 0, 1364 ] ] } ]

[ { "id": "entity-303-0", "type": "DISEASE", "text": [ "low back pain" ], "offsets": [ [ 341, 354 ] ], "normalized": [] }, { "id": "entity-303-1", "type": "DISEASE", "text": [ "acute low back pain" ], "offsets": [ [ 458, 477 ] ], "normalized": [] }, { "id": "entity-303-2", "type": "DISEASE", "text": [ "insomnia" ], "offsets": [ [ 862, 870 ] ], "normalized": [] }, { "id": "entity-303-3", "type": "DISEASE", "text": [ "muscle spasms" ], "offsets": [ [ 888, 901 ] ], "normalized": [] }, { "id": "entity-303-4", "type": "DISEASE", "text": [ "dizziness" ], "offsets": [ [ 1025, 1034 ] ], "normalized": [] }, { "id": "entity-303-5", "type": "DISEASE", "text": [ "drowsiness" ], "offsets": [ [ 1039, 1049 ] ], "normalized": [] }, { "id": "entity-303-6", "type": "DISEASE", "text": [ "abuse" ], "offsets": [ [ 1316, 1321 ] ], "normalized": [] } ]

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[ { "id": "passage-304", "type": "abstract", "text": [ "Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease. Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM." ], "offsets": [ [ 0, 1789 ] ] } ]

[ { "id": "entity-304-0", "type": "DISEASE", "text": [ "Glioblastoma multiforme" ], "offsets": [ [ 100, 123 ] ], "normalized": [] }, { "id": "entity-304-1", "type": "DISEASE", "text": [ "GBM" ], "offsets": [ [ 125, 128 ] ], "normalized": [] }, { "id": "entity-304-2", "type": "DISEASE", "text": [ "malignant brain tumor" ], "offsets": [ [ 150, 171 ] ], "normalized": [] }, { "id": "entity-304-3", "type": "DISEASE", "text": [ "GBM" ], "offsets": [ [ 519, 522 ] ], "normalized": [] }, { "id": "entity-304-4", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1039, 1044 ] ], "normalized": [] }, { "id": "entity-304-5", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1229, 1234 ] ], "normalized": [] }, { "id": "entity-304-6", "type": "DISEASE", "text": [ "GBM" ], "offsets": [ [ 1578, 1581 ] ], "normalized": [] }, { "id": "entity-304-7", "type": "DISEASE", "text": [ "GBM" ], "offsets": [ [ 1785, 1788 ] ], "normalized": [] } ]

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[ { "id": "passage-305", "type": "abstract", "text": [ "Inhibition of hydroxyapatite dissolution by whole casein: the effects of pH, protein concentration, calcium, and ionic strength. Formulating drinks with reduced erosive potential is one approach for reducing dental erosion. In this study, whole casein was added to citric acid solutions representative of soft drinks, and the hydroxyapatite dissolution rate was assessed. Adding 0.02% (w/v) casein to acid solutions significantly reduced the hydroxyapatite dissolution rate by 51 +/- 4% at pH values of 2.80, 3.00, 3.20, 3.40, and 3.60, although the baseline dissolution rates of course varied as a function of pH. The protein concentration [0.002, 0.02, and 0.2% (w/v) casein] had no significant effect on dissolution inhibition. Adding both casein and calcium to citric acid resulted in a further reduction in the dissolution rate at low and intermediate calcium concentrations (5 and 10 mM) but not at higher calcium concentrations (20 and 50 mM). Ionic strength had no significant impact on the efficacy of casein. Casein also significantly reduced the hydroxyapatite dissolution rate when the hydroxyapatite was coated with a salivary pellicle. The reduction in dissolution rate is ascribed to firmly adsorbed casein on the hydroxyapatite surface, which stabilizes the crystal surface and inhibits ion detachment." ], "offsets": [ [ 0, 1319 ] ] } ]

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[ { "id": "passage-306", "type": "abstract", "text": [ "Fragrance material review on sclareol. A toxicologic and dermatologic review of sclareol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 139 ] ] } ]

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[ { "id": "passage-307", "type": "abstract", "text": [ "Estimates of cancer potency of 2,3,4,7,8-pentachlorodibenzofuran using both nonlinear and linear approaches. Cancer potency estimates were derived for 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) using data collected from the recently published National Toxicology Program bioassay in female Sprague-Dawley rats. By using a toxicokinetic model for 4-PeCDF, the dose-response relationship for combined liver tumors (hepatocellular adenomas and cholangiocarcinomas) in rats was assessed in terms of lifetime average liver concentration and lifetime average adipose concentration with data from both the lifetime and the stop-exposure components of the bioassay. Benchmark dose modeling was performed to estimate tissue concentrations at two points of departure (EC(10) and EC(01) and their 95% upper and lower confidence limits). The same toxicokinetic model with human input values was then used to back-extrapolate human equivalent doses that corresponded to the internal tissue concentration measures at the points of departure. Information regarding the cancer mode of action was used to support the development of several toxicity criterion values based on a nonlinear method, e.g., reference dose or tolerable daily intake. Nonlinear estimates of toxicity criteria based on observed noncancer toxic events as possible precursors to tumor formation were also derived and were similar in value to those based on combined liver tumors. For comparison purposes, linear estimates of cancer potency were also derived." ], "offsets": [ [ 0, 1515 ] ] } ]

[ { "id": "entity-307-0", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 13, 19 ] ], "normalized": [] }, { "id": "entity-307-1", "type": "ADVERSE", "text": [ "Cancer" ], "offsets": [ [ 110, 116 ] ], "normalized": [] }, { "id": "entity-307-2", "type": "ADVERSE", "text": [ "liver tumors" ], "offsets": [ [ 401, 413 ] ], "normalized": [] }, { "id": "entity-307-3", "type": "ADVERSE", "text": [ "hepatocellular adenomas" ], "offsets": [ [ 415, 438 ] ], "normalized": [] }, { "id": "entity-307-4", "type": "ADVERSE", "text": [ "cholangiocarcinomas" ], "offsets": [ [ 443, 462 ] ], "normalized": [] }, { "id": "entity-307-5", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 1056, 1062 ] ], "normalized": [] }, { "id": "entity-307-6", "type": "ADVERSE", "text": [ "tumor" ], "offsets": [ [ 1336, 1341 ] ], "normalized": [] }, { "id": "entity-307-7", "type": "ADVERSE", "text": [ "liver tumors" ], "offsets": [ [ 1423, 1435 ] ], "normalized": [] }, { "id": "entity-307-8", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 1482, 1488 ] ], "normalized": [] } ]

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[ { "id": "passage-308", "type": "abstract", "text": [ "Effects of in vitro brevetoxin exposure on apoptosis and cellular metabolism in a leukemic T cell line (Jurkat). Harmful algal blooms (HABs) of the toxic dinoflagellate, Karenia brevis, produce red tide toxins, or brevetoxins. Significant health effects associated with red tide toxin exposure have been reported in sea life and in humans, with brevetoxins documented within immune cells from many species. The objective of this research was to investigate potential immunotoxic effects of brevetoxins using a leukemic T cell line (Jurkat) as an in vitro model system. Viability, cell proliferation, and apoptosis assays were conducted using brevetoxin congeners PbTx-2, PbTx-3, and PbTx-6. The effects of in vitro brevetoxin exposure on cell viability and cellular metabolism or proliferation were determined using trypan blue and MTT (1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan), respectively. Using MTT, cellular metabolic activity was decreased in Jurkat cells exposed to 5 - 10 microg/ml PbTx-2 or PbTx-6. After 3 h, no significant effects on cell viability were observed with any toxin congener in concentrations up to 10 microg/ml. Viability decreased dramatically after 24 h in cells treated with PbTx-2 or -6. Apoptosis, as measured by caspase-3 activity, was significantly increased in cells exposed to PbTx-2 or PbTx-6. In summary, brevetoxin congeners varied in effects on Jurkat cells, with PbTx-2 and PbTx-6 eliciting greater cellular effects compared to PbTx-3." ], "offsets": [ [ 0, 1484 ] ] } ]

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[ { "id": "passage-309", "type": "abstract", "text": [ "Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. Much debate has focused on whether antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the randomized, controlled clinical trial evidence evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. We performed a search of literature from 1966-October 2007 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting antioxidant-based mitigation of chemotherapy toxicity were included in the final tally. Searches were performed following a standardized protocol for systematic reviews. Only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione (11), melatonin (7), vitamin A (1), an antioxidant mixture (2), N-acetylcysteine (2), vitamin E (5), selenium (2), L-carnitine (1), Co-Q10 (1) and ellagic acid (1). The majority (24) of the 33 studies included reported evidence of decreased toxicities from the concurrent use of antioxidants with chemotherapy. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. Five studies reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. Statistical power and poor study quality were concerns with some studies. This review provides the first systematically reviewed evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. However, well-designed studies evaluating larger populations of patients given specific antioxidants defined by dose and schedule relative to chemotherapy are warranted." ], "offsets": [ [ 0, 1957 ] ] } ]

[ { "id": "entity-309-0", "type": "ADVERSE", "text": [ "chemotherapeutic toxicity" ], "offsets": [ [ 41, 66 ] ], "normalized": [] }, { "id": "entity-309-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 219, 225 ] ], "normalized": [] }, { "id": "entity-309-2", "type": "ADVERSE", "text": [ "chemotherapy toxicity" ], "offsets": [ [ 661, 682 ] ], "normalized": [] } ]

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[ { "id": "passage-310", "type": "abstract", "text": [ "The effect of QuYuHuaTanTongLuo Decoction on the non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis (NASH) is the most common cause of cryptogenic cirrhosis, is becoming more prevalent in China. However, there is as yet no clearly established therapy for reversing fatty liver. Our aim is to explore the effect of traditional Chinese herbs QuYuHuaTanTongLuo Decoction (QYHTTLD) on non-alcoholic steatohepatitis. Sixty-nine non-alcoholic steatohepatitis patients were randomly divided into two groups. One group of 35 patients were treated by QYHTTLD, another group of 34 patients were treated by Ursodeoxycholic acid (UDCA). The TNF-alpha, IL-8, MDA level, SOD activity and liver function, as well as B ultrasonic image were detected before and after being treated. The results showed: after 6 months treatment, MBI of the treatment group was obviously decreased (p<0.05). The levels of TC, TG and LDL-C were significantly decreased whereas the level of HDL-C increased (p<0.01, p<0.05, p<0.05, and p<0.05, respectively) in the treatment group, the levels of TC, TG, LDL-C and HDL-C had no significant difference in the control group (p>0.05). The levels of TNF-alpha, IL-8 and MDA were significantly decreased whereas SOD activity was significantly increased (p<0.01, p<0.05, p<0.01, and p<0.01, respectively) in the treatment group, the level of MDA was significantly decreased in the control group (p<0.05). B ultrasonic images were ameliorated in different degree (p<0.01 and p<0.01, respectively). Both QYHTTLD and UDCA had the effect in improving the scores of symptoms and signs of patients, however, the difference value of the scores in treatment group were significantly higher than that in control group after being treated for 6 months (p<0.05). Conclusion: QYHTTLD is effective for treating non-alcoholic steatohepatitis, and its effect seems to relate with the ways of QYHTTL down-regulating inflammation cytokine IL-8 level and relieving lipid peroxidation of liver." ], "offsets": [ [ 0, 1992 ] ] } ]

[ { "id": "entity-310-0", "type": "DISEASE", "text": [ "non-alcoholic steatohepatitis" ], "offsets": [ [ 49, 78 ] ], "normalized": [] }, { "id": "entity-310-1", "type": "DISEASE", "text": [ "Non-alcoholic steatohepatitis" ], "offsets": [ [ 81, 110 ] ], "normalized": [] }, { "id": "entity-310-2", "type": "DISEASE", "text": [ "cryptogenic cirrhosis" ], "offsets": [ [ 146, 167 ] ], "normalized": [] }, { "id": "entity-310-3", "type": "DISEASE", "text": [ "fatty liver" ], "offsets": [ [ 276, 287 ] ], "normalized": [] }, { "id": "entity-310-4", "type": "DISEASE", "text": [ "non-alcoholic steatohepatitis" ], "offsets": [ [ 392, 421 ] ], "normalized": [] }, { "id": "entity-310-5", "type": "DISEASE", "text": [ "non-alcoholic steatohepatitis" ], "offsets": [ [ 434, 463 ] ], "normalized": [] }, { "id": "entity-310-6", "type": "DISEASE", "text": [ "non-alcoholic steatohepatitis" ], "offsets": [ [ 1815, 1844 ] ], "normalized": [] }, { "id": "entity-310-7", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 1917, 1929 ] ], "normalized": [] } ]

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[ { "id": "passage-311", "type": "abstract", "text": [ "A high throughput in vitro analytical approach to screen for oxidative stress potential exerted by nanomaterials using a biologically relevant matrix: human blood serum. Limited studies have shown that selected nanomaterials (NMs) impart various forms of toxicity in biological systems; however, a common metric to screen for potential toxicity is needed. This study optimized and utilized a 'Ferric reducing ability of serum (FRAS)' assay as a screening tool to quantitate the degree of oxidative damage induced by NMs on human blood serum. Antioxidants in blood protect against oxidative damage caused by free radicals via chemical quenching and will decrease when exposed to oxidatively stressful materials. Using this approach, the antioxidant capacity of NM treated serum was significantly decreased by nano-silver, a series of nano-carbon blacks, fullerene soot, and nano-TiO(2) (anatase, p<0.05), but not with nano-alumina, fullerite, purified fullerene, fine TiO(2) (rutile) and Min-U-Sil 5. Particle surface area and not biological particle size was highly associated with the degree of oxidative stress observed. This approach appears responsive to multiple determinants of oxidative damage, including particle chemistry, surface area and impurities, and may be a valid screening method to determine oxidative damage imparted by nanomaterials." ], "offsets": [ [ 0, 1354 ] ] } ]

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[ { "id": "passage-312", "type": "abstract", "text": [ "Fragrance material review on ocimenol. A toxicologic and dermatologic review of ocimenol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 139 ] ] } ]

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[ { "id": "passage-313", "type": "abstract", "text": [ "Early-onset pancytopenia and skin ulcer following low-dose methotrexate therapy. Pancytopenia is a rare but serious adverse effect of low-dose methotrexate (MTX) sodium therapy, and this case report describes a very early-onset of pancytopenia and cutaneous lesions after three days of ingestion. A 64-year-old man was presented to Emergency Department with weakness, fever, poor appetite, nausea, and vomiting after he had had accidentally ingested MTX tablets (2.5 mg) twice a day for the last three days. On initial examination, several painful lesions in his oral mucosa and a cutaneous ulceration on his right foot were also observed. He had severe pancytopenia, poor kidney functions, and abnormal coagulation parameters. The blood level of MTX was found to be within therapeutic range. He was treated with leucovorine, intravenous antibiotics, and appropriate blood transfusions; he was discharged from hospital without any sequela. Pancytopenia associated with low-dose (cumulative dose of 15 mg in 3 days) MTX therapy had not been reported previously. The Naranjo probability scale showed pancytopenia and skin ulcer associated with low-dose MTX therapy as probable adverse reactions. Risk factors for pancytopenia such as renal insufficiency, hypoalbuminemia, low folate levels, concomitant infections, concomitant use of drugs, and folate supplementation were not identified in our patient. Although pancytopenia associated with low-dose MTX therapy is not expected as early as 3 days after initiation of the therapy, physicians should also be aware of this life threatening adverse effect during the very first days of MTX therapy for rheumatoid arthritis patients." ], "offsets": [ [ 0, 1678 ] ] } ]

[ { "id": "entity-313-0", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 12, 24 ] ], "normalized": [] }, { "id": "entity-313-1", "type": "ADVERSE", "text": [ "skin ulcer" ], "offsets": [ [ 29, 39 ] ], "normalized": [] }, { "id": "entity-313-2", "type": "ADVERSE", "text": [ "Pancytopenia" ], "offsets": [ [ 82, 94 ] ], "normalized": [] }, { "id": "entity-313-3", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 232, 244 ] ], "normalized": [] }, { "id": "entity-313-4", "type": "ADVERSE", "text": [ "cutaneous lesions" ], "offsets": [ [ 249, 266 ] ], "normalized": [] }, { "id": "entity-313-5", "type": "ADVERSE", "text": [ "weakness" ], "offsets": [ [ 359, 367 ] ], "normalized": [] }, { "id": "entity-313-6", "type": "ADVERSE", "text": [ "fever" ], "offsets": [ [ 369, 374 ] ], "normalized": [] }, { "id": "entity-313-7", "type": "ADVERSE", "text": [ "poor appetite" ], "offsets": [ [ 376, 389 ] ], "normalized": [] }, { "id": "entity-313-8", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 391, 397 ] ], "normalized": [] }, { "id": "entity-313-9", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 403, 411 ] ], "normalized": [] }, { "id": "entity-313-10", "type": "ADVERSE", "text": [ "painful lesions" ], "offsets": [ [ 541, 556 ] ], "normalized": [] }, { "id": "entity-313-11", "type": "ADVERSE", "text": [ "cutaneous ulceration" ], "offsets": [ [ 582, 602 ] ], "normalized": [] }, { "id": "entity-313-12", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 655, 667 ] ], "normalized": [] }, { "id": "entity-313-13", "type": "ADVERSE", "text": [ "abnormal coagulation" ], "offsets": [ [ 696, 716 ] ], "normalized": [] }, { "id": "entity-313-14", "type": "ADVERSE", "text": [ "Pancytopenia" ], "offsets": [ [ 941, 953 ] ], "normalized": [] }, { "id": "entity-313-15", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 1099, 1111 ] ], "normalized": [] }, { "id": "entity-313-16", "type": "ADVERSE", "text": [ "skin ulcer" ], "offsets": [ [ 1116, 1126 ] ], "normalized": [] }, { "id": "entity-313-17", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 1212, 1224 ] ], "normalized": [] }, { "id": "entity-313-18", "type": "ADVERSE", "text": [ "renal insufficiency" ], "offsets": [ [ 1233, 1252 ] ], "normalized": [] }, { "id": "entity-313-19", "type": "ADVERSE", "text": [ "hypoalbuminemia" ], "offsets": [ [ 1254, 1269 ] ], "normalized": [] }, { "id": "entity-313-20", "type": "ADVERSE", "text": [ "concomitant infections" ], "offsets": [ [ 1290, 1312 ] ], "normalized": [] }, { "id": "entity-313-21", "type": "ADVERSE", "text": [ "pancytopenia" ], "offsets": [ [ 1412, 1424 ] ], "normalized": [] }, { "id": "entity-313-22", "type": "DISEASE", "text": [ "rheumatoid arthritis" ], "offsets": [ [ 1648, 1668 ] ], "normalized": [] } ]

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[ { "id": "passage-314", "type": "abstract", "text": [ "Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients. PURPOSE: Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). METHODS: A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. RESULTS: The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. CONCLUSIONS: The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations." ], "offsets": [ [ 0, 2021 ] ] } ]

[ { "id": "entity-314-0", "type": "DISEASE", "text": [ "neutropenia" ], "offsets": [ [ 39, 50 ] ], "normalized": [] }, { "id": "entity-314-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 140, 146 ] ], "normalized": [] }, { "id": "entity-314-2", "type": "DISEASE", "text": [ "neutropenia" ], "offsets": [ [ 257, 268 ] ], "normalized": [] }, { "id": "entity-314-3", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 272, 278 ] ], "normalized": [] }, { "id": "entity-314-4", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 752, 768 ] ], "normalized": [] }, { "id": "entity-314-5", "type": "DISEASE", "text": [ "neutropenia" ], "offsets": [ [ 1979, 1990 ] ], "normalized": [] } ]

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[ { "id": "passage-315", "type": "abstract", "text": [ "Topical pyrethrin toxicity leading to acute-onset stuttering in a toddler. Pyrethrin compounds can cause neurotoxicity when used in an excessive dose. A case of stuttering and general clumsiness in a toddler associated with topical pyrethrin use is described." ], "offsets": [ [ 0, 260 ] ] } ]

[ { "id": "entity-315-0", "type": "ADVERSE", "text": [ "pyrethrin toxicity" ], "offsets": [ [ 8, 26 ] ], "normalized": [] }, { "id": "entity-315-1", "type": "ADVERSE", "text": [ "acute-onset stuttering" ], "offsets": [ [ 38, 60 ] ], "normalized": [] }, { "id": "entity-315-2", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 106, 119 ] ], "normalized": [] }, { "id": "entity-315-3", "type": "ADVERSE", "text": [ "stuttering" ], "offsets": [ [ 162, 172 ] ], "normalized": [] }, { "id": "entity-315-4", "type": "ADVERSE", "text": [ "clumsiness" ], "offsets": [ [ 185, 195 ] ], "normalized": [] } ]

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[ { "id": "passage-316", "type": "abstract", "text": [ "Efficient telomerase inhibition in human non-small cell lung cancer cells by liposomal delivery of 2'-O-methyl-RNA. The antisense oligonucleotide 2'-O-methyl-RNA is a selective telomerase inhibitor targeting the telomerase RNA component and represents a potential candidate for anticancer therapy. The poor cellular uptake of 2'-O-methyl-RNA is a limiting factor that may contribute to the lack of functional efficacy. To improve delivery of 2'-O-methyl-RNA and consequently antitumoral efficiency in human lung cancer cells, we have investigated several transfection reagents. The transfection reagents DOTAP, MegaFectin 60, SuperFect, FuGENE 6 and MATra-A were tested for intracellular delivery. A FAM-labeled 2'-O-methyl-RNA was used to assess the intracellular distribution by confocal laser scanning microscopy in A549 human non-small cell lung cancer cells. Telomerase activity was measured using the telomeric repeat amplification protocol. Cell viability after transfection was quantified by the MTT assay. All transfection reagents enhanced 2'-O-methyl-RNA uptake in A549 cells but the cationic lipid reagents DOTAP and MegaFectin 60 were most efficient in the delivery of 2'-O-methyl-RNA resulting in telomerase inhibition. Among both DOTAP exhibited the lowest cytotoxicity. Our experiments show that DOTAP is the most suitable transfection reagent for the delivery of 2'-O-methyl-RNA in human lung cancer cells according to its relatively low cytotoxicity and its ability to promote efficient uptake leading to the inhibition of telomerase." ], "offsets": [ [ 0, 1553 ] ] } ]

[ { "id": "entity-316-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1273, 1285 ] ], "normalized": [] }, { "id": "entity-316-1", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1456, 1468 ] ], "normalized": [] } ]

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[ { "id": "passage-317", "type": "abstract", "text": [ "How can biologically-based modeling of arsenic kinetics and dynamics inform the risk assessment process? - A workshop review. Quantitative biologically-based models describing key events in the continuum from arsenic exposure to the development of adverse health effects provide a framework to integrate information obtained across diverse research areas. For example, genetic polymorphisms in arsenic metabolizing enzymes can lead to differences in target tissue dosimetry for key metabolites causative in toxic and carcinogenic response. This type of variation can be quantitatively incorporated into pharmacokinetic (PK) models and used together with population-based modeling approaches to evaluate the impact of genetic variation in methylation capacity on dose of key metabolites to target tissue. The PK model is an essential bridge to the pharmacodynamic (PD) models. A particular benefit of PD modeling for arsenic is that alternative models can be constructed for multiple proposed modes of action for arsenicals. Genomics data will prove useful for identifying the key pathways involved in particular responses and aid in determining other types of data needed for quantitative modeling. These models, when linked with PK models, can be used to better understand and explain dose- and time-response behaviors. This in turn assists in prioritizing modes of action with respect to their risk assessment relevance and future research. This type of integrated modeling approach can form the basis for a highly informative mode-of-action directed risk assessment for inorganic arsenic (iAs). This paper will address both practical and theoretical aspects of integrating PK and PD data in a modeling framework, including practical barriers to its application." ], "offsets": [ [ 0, 1765 ] ] } ]

[ { "id": "entity-317-0", "type": "ADVERSE", "text": [ "carcinogenic response" ], "offsets": [ [ 518, 539 ] ], "normalized": [] } ]

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[ { "id": "passage-318", "type": "abstract", "text": [ "Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. ATP-binding drug efflux transporters decrease intracellular concentrations of cytotoxic drugs, causing multidrug resistance in cancer. In this study, we examined possible interactions of ABCG2 transporter with platinum cytotoxic drugs. We demonstrate here an interference of platinum drugs with enhanced green fluorescence protein (EGFP) in the cellular models, where EGFP was employed as a reporter gene. Cytotoxicity of cisplatin (CIP), carboplatin (CAP) and oxaliplatin (OXP) was significantly lowered in MDCKII cells transfected with ABCG2 transporter and EGFP reporter. The IC(50) values in MDCKII-ABCG2 were 25.7, 164 and 165 microM for CIP, CAP and OXP, respectively, whereas IC(50) for the same cytostatics in MDCKII cells were as follows: 15.4, 133 and 50.3 microM. Addition of fumitremorgin C (FTC), a potent ABCG2 inhibitor, significantly suppressed the resistance of MDCKII-ABCG2 to OXP, suggesting that OXP interacts with ABCG2. However, FTC did not change the sensitivity of the cells to CIP and CAP. We assume that EGFP rather than ABCG2 causes the diminished toxicity of the platinum cytostatics in the transfected cells. This hypothesis was confirmed in human Hep2 cells expressing EGFP: using MTT test, IC(50) of 30.0, 247 and 27.9 microM were obtained for CIP, CAP and OXP, respectively, while 12.3, 106 and 20.5 microM were observed in the parent Hep2 cells. Employing neutral red cytotoxicity assay, similar data were obtained (IC(50) 7.73, 685 and 112 microM for CIP, CAP, and OXP, respectively, in the Hep2-EGFP cells and 1.65, 79.4 and 24.5 microM in the parent Hep2 cells). Caspase-3/7 assay revealed lower susceptibility of EGFP expressing Hep2 cells to apoptosis induced by CIP when compared to the parent cell line. We therefore conclude that EGFP in transfected cells interferes with cytotoxicity of platinum drugs by hindering the drug induced apoptosis and could cause misinterpretation of results obtained in cytotoxicity studies." ], "offsets": [ [ 0, 2036 ] ] } ]

[ { "id": "entity-318-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 19, 31 ] ], "normalized": [] }, { "id": "entity-318-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 201, 207 ] ], "normalized": [] }, { "id": "entity-318-2", "type": "ADVERSE", "text": [ "Cytotoxicity" ], "offsets": [ [ 480, 492 ] ], "normalized": [] }, { "id": "entity-318-3", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1475, 1487 ] ], "normalized": [] }, { "id": "entity-318-4", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1887, 1899 ] ], "normalized": [] }, { "id": "entity-318-5", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 2015, 2027 ] ], "normalized": [] } ]

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[ { "id": "passage-319", "type": "abstract", "text": [ "Fragrance material review on tricyclodecanyl acetate. A toxicologic and dermatologic review of tricyclodecanyl acetate when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 169 ] ] } ]

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[ { "id": "passage-320", "type": "abstract", "text": [ "AIDS-related malignancies: state of the art and therapeutic challenges. Despite the impact of combination antiretroviral therapy (cART) on HIV-related mortality, malignancy remains an important cause of death in the current era. Although the advent of cART has resulted in reductions in the incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma, non-AIDS-defining malignancies present an increased risk for HIV-infected patients, characterized by some common clinical features, generally with a more aggressive behavior and a more advanced disease at diagnosis, which is responsible for poorer patient outcomes. Specific therapeutic recommendations are lacking for these new nonopportunistic malignancies, such as Hodgkin's lymphoma, anal cancer, lung cancer, hepatocarcinoma, and many others. Antiretroviral agents have a propensity for causing drug interactions as a result of their ability to either inhibit or induce the cytochrome P450 (CYP) enzyme system. Because many antineoplastic drugs are also metabolized by the CYP system, coadministration with cART could result in either drug accumulation with increased toxicity, or decreased efficacy of one or both classes of drugs. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary. Special considerations of these AIDS-related and non-AIDS-related malignancies and their clinical and therapeutic aspects constitute the subject of this review." ], "offsets": [ [ 0, 1478 ] ] } ]

[ { "id": "entity-320-0", "type": "DISEASE", "text": [ "AIDS-related malignancies" ], "offsets": [ [ 0, 25 ] ], "normalized": [] }, { "id": "entity-320-1", "type": "DISEASE", "text": [ "Kaposi's sarcoma" ], "offsets": [ [ 305, 321 ] ], "normalized": [] }, { "id": "entity-320-2", "type": "DISEASE", "text": [ "non-Hodgkin's lymphoma" ], "offsets": [ [ 326, 348 ] ], "normalized": [] }, { "id": "entity-320-3", "type": "DISEASE", "text": [ "non-AIDS-defining malignancies" ], "offsets": [ [ 350, 380 ] ], "normalized": [] }, { "id": "entity-320-4", "type": "DISEASE", "text": [ "aggressive behavior" ], "offsets": [ [ 504, 523 ] ], "normalized": [] }, { "id": "entity-320-5", "type": "DISEASE", "text": [ "malignancies" ], "offsets": [ [ 696, 708 ] ], "normalized": [] }, { "id": "entity-320-6", "type": "DISEASE", "text": [ "Hodgkin's lymphoma" ], "offsets": [ [ 718, 736 ] ], "normalized": [] }, { "id": "entity-320-7", "type": "DISEASE", "text": [ "anal cancer" ], "offsets": [ [ 738, 749 ] ], "normalized": [] }, { "id": "entity-320-8", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 751, 762 ] ], "normalized": [] }, { "id": "entity-320-9", "type": "DISEASE", "text": [ "hepatocarcinoma" ], "offsets": [ [ 764, 779 ] ], "normalized": [] }, { "id": "entity-320-10", "type": "DISEASE", "text": [ "non-AIDS-related malignancies" ], "offsets": [ [ 1367, 1396 ] ], "normalized": [] } ]

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[ { "id": "passage-321", "type": "abstract", "text": [ "Should we abandon corticosteroids during septic shock? No. PURPOSE OF REVIEW: With the publication of the results of the recent CORTICUS trial, stress ('low') doses of corticosteroids for the treatment of vasopressor-dependent septic shock in adults can still be considered controversial. The purpose of this narrative review is to elaborate the pros and cons of this treatment in clinical practice and to formulate clinical and research directions. RECENT FINDINGS: The recent CORTICUS study only shows a beneficial effect of stress doses of corticosteroids in the time interval to shock reversal and not on mortality, potentially explained by an increased risk for superinfection. The mortality in the placebo arm was relatively low and lower than in earlier randomized studies in which stress doses of corticosteroids had a favorable hemodynamic effect and conferred a survival benefit in septic shock. SUMMARY: Treatment by stress doses of corticosteroids should not be abandoned during septic shock. Additional studies are needed, however, to better delineate the patient group with the highest likelihood to benefit from this therapy, as a function of severity of illness, response to adrenocorticotrophic hormone testing or both. For now, results of the CORTICUS study should not change current clinical practice of administering 200-300 mg of hydrocortisone daily (in divided doses) in case of fluid and vasopressor-insensitive septic shock and rapid tapering of this treatment on the basis of a hemodynamic response." ], "offsets": [ [ 0, 1526 ] ] } ]

[ { "id": "entity-321-0", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 41, 53 ] ], "normalized": [] }, { "id": "entity-321-1", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 228, 240 ] ], "normalized": [] }, { "id": "entity-321-2", "type": "ADVERSE", "text": [ "superinfection" ], "offsets": [ [ 668, 682 ] ], "normalized": [] }, { "id": "entity-321-3", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 893, 905 ] ], "normalized": [] }, { "id": "entity-321-4", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 992, 1004 ] ], "normalized": [] }, { "id": "entity-321-5", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 1437, 1449 ] ], "normalized": [] } ]

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[ { "id": "passage-322", "type": "abstract", "text": [ "Eosinophil-derived neurotoxin / RNase 2: connecting the past, the present and the future. The eosinophil-derived neurotoxin (EDN, also known as eosinophil protein-X) is best-known as one of the four major proteins found in the large specific granules of human eosinophilic leukocytes. Although it was named for its discovery and initial characterization as a neurotoxin, it is also expressed constitutively in human liver tissue and its expression can be induced in macrophages by proinflammatory stimuli. EDN and its divergent orthologs in rodents have ribonuclease activity, and are members of the extensive RNase A superfamily, although the relationship between the characterized physiologic functions and enzymatic activity remains poorly understood. Recent explorations into potential physiologic functions for EDN have provided us with some insights into its role in antiviral host defense, as a chemoattractant for human dendritic cells, and most recently, as an endogenous ligand for toll-like receptor (TLR)2." ], "offsets": [ [ 0, 1019 ] ] } ]

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[ { "id": "passage-323", "type": "abstract", "text": [ "Long-term clinical and surrogate marker effects of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients. OBJECTIVES: Subcutaneous administration of interleukin-2 (IL-2) has been shown to increase CD4 counts in HIV-infected patients. It remains unclear whether this effect is associated with a clinical benefit. PATIENTS AND METHODS: We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm(3) received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively. RESULTS: Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non-significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely. CONCLUSIONS: We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention." ], "offsets": [ [ 0, 1732 ] ] } ]

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[ { "id": "passage-324", "type": "abstract", "text": [ "Optimal timing for adjuvant radiation therapy in breast cancer: a comprehensive review and perspectives. PURPOSE: The optimal sequence of modalities involved in breast cancer treatment with respect to radiotherapy and the maximum acceptable interval between radiotherapy and surgery need to be determined. DESIGN: This review attempts a critical reading of the literature. RESULTS: A delay of radiotherapy more than 8-12 weeks after surgery adversely affects local recurrence. Radiotherapy should be administered within 7 months after surgery, when chemotherapy is administered first. Several chemotherapy regimens can be safely administered concurrently with radiotherapy. The concurrent use of tamoxifen with chemotherapy should be avoided, but not with radiotherapy. Data is insufficient with regard to concurrent use of aromatase inhibitors with radiotherapy. The use of trastuzumab concomitantly with radiotherapy may enhance toxicities but may also improve its efficacy. CONCLUSIONS: Although the issue of radiotherapy delay and that of sequence with chemotherapy or tamoxifen are clarified, the sequence of radiotherapy with aromatase inhibitors and trastuzumab needs to be defined. Individual radiosensitivity may influence toxicity. New biologic markers have to be determined in the future for tailoring radiotherapy in breast cancer." ], "offsets": [ [ 0, 1344 ] ] } ]

[ { "id": "entity-324-0", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 49, 62 ] ], "normalized": [] }, { "id": "entity-324-1", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 162, 175 ] ], "normalized": [] }, { "id": "entity-324-2", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1330, 1343 ] ], "normalized": [] } ]

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[ { "id": "passage-325", "type": "abstract", "text": [ "Risk assessment of khat use in the Netherlands: a review based on adverse health effects, prevalence, criminal involvement and public order. In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance." ], "offsets": [ [ 0, 2076 ] ] } ]

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[ { "id": "passage-326", "type": "abstract", "text": [ "Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans. Intramuscular injection of nerve growth factor (NGF) has been shown to induce long-term sensitisation and time-dependent hyperalgesia indicating potential involvement of both central and peripheral pain mechanisms. This double-blind placebo-controlled study was designed to describe the spatial distribution of muscle hyperalgesia over time (immediately after, 3 h, 1, 4, 7 and 21 days) after injecting NGF (5 mug) into the tibialis anterior (TA) muscle, to explore possibly involved central pain mechanisms and to investigate the effect of gender on development of hyperalgesia. Totally 20 healthy volunteers (10 men and 10 women) participated in the study. An isotonic saline injection into the contralateral TA muscle served as a control condition for the NGF injection. Pressure pain thresholds (PPT) were used to test for muscle hyperalgesia along the TA (seven sites) muscle at the extensor digitorum longus and at the web between 1st and 2nd metatarsal (central involvement). One day after the NGF/control injections, hypertonic saline (0.5 ml, 5.8%) was injected into the left and right TA to study the pain response to chemical stimulation of the hyperalgesic muscle tissue. Scores on a modified Likert scale were used to assess soreness during muscle function. An area of hyperalgesia was observed locally at the injected site 3 h after injection of NGF, which expanded both proximally and distally on day 1; this effect subsided on day 4. Decreased PPT was also found between 1st and 2nd metatarsal on day 1. Hypertonic saline evoked more pain in men when injected in the NGF treated TA compared to the control leg. Injection of NGF increased muscle soreness during muscle activity for 7 days. In this material there was no gender effect of NGF-induced muscle hyperalgesia. The expansion of muscle hyperalgesia to distant areas indicates that central mechanisms are involved." ], "offsets": [ [ 0, 1981 ] ] } ]

[ { "id": "entity-326-0", "type": "ADVERSE", "text": [ "muscle hyperalgesia" ], "offsets": [ [ 32, 51 ] ], "normalized": [] }, { "id": "entity-326-1", "type": "ADVERSE", "text": [ "hyperalgesia" ], "offsets": [ [ 216, 228 ] ], "normalized": [] }, { "id": "entity-326-2", "type": "ADVERSE", "text": [ "pain" ], "offsets": [ [ 293, 297 ] ], "normalized": [] }, { "id": "entity-326-3", "type": "ADVERSE", "text": [ "muscle hyperalgesia" ], "offsets": [ [ 406, 425 ] ], "normalized": [] }, { "id": "entity-326-4", "type": "ADVERSE", "text": [ "pain" ], "offsets": [ [ 587, 591 ] ], "normalized": [] }, { "id": "entity-326-5", "type": "ADVERSE", "text": [ "hyperalgesia" ], "offsets": [ [ 661, 673 ] ], "normalized": [] }, { "id": "entity-326-6", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 878, 882 ] ], "normalized": [] }, { "id": "entity-326-7", "type": "DISEASE", "text": [ "muscle hyperalgesia" ], "offsets": [ [ 922, 941 ] ], "normalized": [] }, { "id": "entity-326-8", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 1206, 1210 ] ], "normalized": [] }, { "id": "entity-326-9", "type": "ADVERSE", "text": [ "hyperalgesia" ], "offsets": [ [ 1377, 1389 ] ], "normalized": [] }, { "id": "entity-326-10", "type": "ADVERSE", "text": [ "pain" ], "offsets": [ [ 1645, 1649 ] ], "normalized": [] }, { "id": "entity-326-11", "type": "ADVERSE", "text": [ "muscle soreness" ], "offsets": [ [ 1749, 1764 ] ], "normalized": [] }, { "id": "entity-326-12", "type": "ADVERSE", "text": [ "muscle hyperalgesia" ], "offsets": [ [ 1859, 1878 ] ], "normalized": [] }, { "id": "entity-326-13", "type": "DISEASE", "text": [ "muscle hyperalgesia" ], "offsets": [ [ 1897, 1916 ] ], "normalized": [] } ]

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[ { "id": "passage-327", "type": "abstract", "text": [ "Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. BACKGROUND: An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women. METHODS: In session 1, participants received 35 microg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session. RESULTS: Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters. CONCLUSIONS: The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r." ], "offsets": [ [ 0, 1819 ] ] } ]

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[ { "id": "passage-328", "type": "abstract", "text": [ "Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. OBJECTIVES: The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE. METHODS: We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months. RESULTS: Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group. CONCLUSIONS: A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study." ], "offsets": [ [ 0, 1984 ] ] } ]

[ { "id": "entity-328-0", "type": "DISEASE", "text": [ "systemic lupus erythematosus" ], "offsets": [ [ 32, 60 ] ], "normalized": [] }, { "id": "entity-328-1", "type": "DISEASE", "text": [ "nephritis" ], "offsets": [ [ 79, 88 ] ], "normalized": [] }, { "id": "entity-328-2", "type": "DISEASE", "text": [ "lupus nephropathy" ], "offsets": [ [ 146, 163 ] ], "normalized": [] }, { "id": "entity-328-3", "type": "DISEASE", "text": [ "membranous nephritis" ], "offsets": [ [ 257, 277 ] ], "normalized": [] }, { "id": "entity-328-4", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 291, 294 ] ], "normalized": [] }, { "id": "entity-328-5", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "entity-328-6", "type": "DISEASE", "text": [ "lupus nephritis" ], "offsets": [ [ 411, 426 ] ], "normalized": [] }, { "id": "entity-328-7", "type": "DISEASE", "text": [ "proteinuria" ], "offsets": [ [ 606, 617 ] ], "normalized": [] }, { "id": "entity-328-8", "type": "DISEASE", "text": [ "proteinuria" ], "offsets": [ [ 1114, 1125 ] ], "normalized": [] }, { "id": "entity-328-9", "type": "DISEASE", "text": [ "proteinuria" ], "offsets": [ [ 1226, 1237 ] ], "normalized": [] }, { "id": "entity-328-10", "type": "ADVERSE", "text": [ "lupus flare" ], "offsets": [ [ 1534, 1545 ] ], "normalized": [] }, { "id": "entity-328-11", "type": "DISEASE", "text": [ "lupus nephritis" ], "offsets": [ [ 1727, 1742 ] ], "normalized": [] }, { "id": "entity-328-12", "type": "DISEASE", "text": [ "proteinuria" ], "offsets": [ [ 1849, 1860 ] ], "normalized": [] }, { "id": "entity-328-13", "type": "ADVERSE", "text": [ "lupus flare" ], "offsets": [ [ 1882, 1893 ] ], "normalized": [] } ]

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[ { "id": "passage-329", "type": "abstract", "text": [ "Antitumor properties of a sulfated polysaccharide from the red seaweed Champia feldmannii (Diaz-Pifferer). In recent years, much attention has been focused on polysaccharides isolated from natural sources. The aim of this study was to investigate the in vitro and in vivo antitumor properties of a sulfated polysaccharide isolated from the seaweed C. feldmannii (Cf-PLS). Hematological, biochemical and histopathological analyses were performed in order to evaluate the toxicological aspects related to Cf-PLS treatment. Its effects on the immunological system were also investigated. The Cf-PLS did not show any significant in vitro cytotoxicity at the experimental exposure levels that were used, but showed in vivo antitumor effect. The inhibition rates of sarcoma 180 tumor development were 48.62 and 48.16% at the doses of 10 and 25 mg kg(-1), respectively. In addition, Cf-PLS was also able to increase the response elicited by 5-fluorouracil (5-FU) from 48.66 to 68.32%. The histopathological analysis of liver and kidney showed that both organs were moderately affected by Cf-PLS-treatment. Neither enzymatic activity of alanine aminotransferase nor urea or creatinine levels were significantly altered. In hematological analysis, leucopeny was observed after 5-FU treatment, but this effect was prevented when the treatment was associated with the Cf-PLS. It was also demonstrated that Cf-PLS acts as an immunomodulatory agent, raising the production of specific antibodies, and increasing the production of OVA-specific antibodies. It also induced a discreet hyperplasia of lymphoid folicules of the white pulp in the spleen of treated mice. In conclusion, Cf-PLS has some interesting anticancer activity that could be associated with its immunostimulating properties." ], "offsets": [ [ 0, 1779 ] ] } ]

[ { "id": "entity-329-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 635, 647 ] ], "normalized": [] }, { "id": "entity-329-1", "type": "DISEASE", "text": [ "sarcoma" ], "offsets": [ [ 761, 768 ] ], "normalized": [] }, { "id": "entity-329-2", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 773, 778 ] ], "normalized": [] }, { "id": "entity-329-3", "type": "ADVERSE", "text": [ "leucopeny" ], "offsets": [ [ 1240, 1249 ] ], "normalized": [] }, { "id": "entity-329-4", "type": "ADVERSE", "text": [ "hyperplasia of lymphoid folicules" ], "offsets": [ [ 1570, 1603 ] ], "normalized": [] } ]

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[ { "id": "passage-330", "type": "abstract", "text": [ "Particulate matter inhibits DNA repair and enhances mutagenesis. Exposure to ambient air pollution has been associated with adverse health effects including lung cancer. A recent epidemiology study has established that each 10 microg/m3 elevation in long-term exposure to average PM2.5 ambient concentration was associated with approximately 8% of lung cancer mortality. The underlying mechanisms of how PM contributes to lung carcinogenesis, however, remain to be elucidated. We have recently found that transition metals such as nickel and chromium and oxidative stress induced lipid peroxidation metabolites such as aldehydes can greatly inhibit nucleotide excision repair (NER) and enhance carcinogen-induced mutations. Because PM is rich in metal and aldehyde content and can induce oxidative stress, we tested the effect of PM on DNA repair capacity in cultured human lung cells using in vitro DNA repair synthesis and host cell reactivation assays. We found that PM greatly inhibits NER for ultraviolet (UV) light and benzo(a)pyrene diol epoxide (BPDE) induced DNA damage in human lung cells. We further demonstrated that PM exposure can significantly increase both spontaneous and UV-induced mutagenesis. These results together suggest that the carcinogenicity of PM may act through its combined effect on suppression of DNA repair and enhancement of DNA replication errors." ], "offsets": [ [ 0, 1383 ] ] } ]

[ { "id": "entity-330-0", "type": "ADVERSE", "text": [ "lung cancer" ], "offsets": [ [ 158, 169 ] ], "normalized": [] }, { "id": "entity-330-1", "type": "ADVERSE", "text": [ "lung cancer" ], "offsets": [ [ 349, 360 ] ], "normalized": [] }, { "id": "entity-330-2", "type": "ADVERSE", "text": [ "carcinogenicity" ], "offsets": [ [ 1254, 1269 ] ], "normalized": [] } ]

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[ { "id": "passage-331", "type": "abstract", "text": [ "Novel therapeutic agents targeting the glucocorticoid receptor for inflammation and cancer. Glucocorticoids, through their interaction with the ubiquitous glucocorticoid receptor (GR), have extensive and disparate effects on different cells and tissues. They have long been used in the treatment of asthma, arthritis and autoimmune diseases based on their anti-inflammatory and immunosuppressive effects. For these reasons, as well as for their ability to induce massive apoptosis in hematological malignancies, they are also commonly used as cotreatment in cancers. Despite their wide usage, chronic glucocorticoid therapy has deleterious side effects, including weight gain, osteoporosis and diabetes mellitus, and has been shown to diminish the tumor toxicity of chemotherapy, preventing the full potential of glucocorticoid treatment from being realized. Technological advances have contributed to a better understanding of the mechanism of glucocorticoid action, prompting the development of tailored therapeutics targeting the desired outcomes of GR signaling. This review discusses recent advances in the development of novel therapeutic agents for inflammation and cancer through targeting the GR." ], "offsets": [ [ 0, 1206 ] ] } ]

[ { "id": "entity-331-0", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 67, 79 ] ], "normalized": [] }, { "id": "entity-331-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 84, 90 ] ], "normalized": [] }, { "id": "entity-331-2", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 300, 306 ] ], "normalized": [] }, { "id": "entity-331-3", "type": "DISEASE", "text": [ "arthritis" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "entity-331-4", "type": "DISEASE", "text": [ "autoimmune diseases" ], "offsets": [ [ 322, 341 ] ], "normalized": [] }, { "id": "entity-331-5", "type": "DISEASE", "text": [ "hematological malignancies" ], "offsets": [ [ 485, 511 ] ], "normalized": [] }, { "id": "entity-331-6", "type": "DISEASE", "text": [ "cancers" ], "offsets": [ [ 559, 566 ] ], "normalized": [] }, { "id": "entity-331-7", "type": "ADVERSE", "text": [ "osteoporosis" ], "offsets": [ [ 678, 690 ] ], "normalized": [] }, { "id": "entity-331-8", "type": "ADVERSE", "text": [ "diabetes mellitus" ], "offsets": [ [ 695, 712 ] ], "normalized": [] }, { "id": "entity-331-9", "type": "ADVERSE", "text": [ "tumor toxicity" ], "offsets": [ [ 749, 763 ] ], "normalized": [] }, { "id": "entity-331-10", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 1157, 1169 ] ], "normalized": [] }, { "id": "entity-331-11", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 1174, 1180 ] ], "normalized": [] } ]

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[ { "id": "passage-332", "type": "abstract", "text": [ "An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer. The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified." ], "offsets": [ [ 0, 1649 ] ] } ]

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[ { "id": "passage-333", "type": "abstract", "text": [ "Using dietary exposure and physiologically based pharmacokinetic/pharmacodynamic modeling in human risk extrapolations for acrylamide toxicity. The discovery of acrylamide (AA) in many common cooked starchy foods has presented significant challenges to toxicologists, food scientists, and national regulatory and public health organizations because of the potential for producing neurotoxicity and cancer. This paper reviews some of the underlying experimental bases for AA toxicity and earlier risk assessments. Then, dietary exposure modeling is used to estimate probable AA intake in the U.S. population, and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling is used to integrate the findings of rodent neurotoxicity and cancer into estimates of risks from human AA exposure through the diet. The goal of these modeling techniques is to reduce the uncertainty inherent in extrapolating toxicological findings across species and dose by comparing common exposure biomarkers. PBPK/PD modeling estimated population-based lifetime excess cancer risks from average AA consumption in the diet in the range of 1-4 x 10 (-4); however, modeling did not support a link between dietary AA exposure and human neurotoxicity because marginal exposure ratios were 50-300 lower than in rodents. In addition, dietary exposure modeling suggests that because AA is found in so many common foods, even big changes in concentration for single foods or groups of foods would probably have a small impact on overall population-based intake and risk. These results suggest that a more holistic analysis of dietary cancer risks may be appropriate, by which potential risks from AA should be considered in conjunction with other risks and benefits from foods." ], "offsets": [ [ 0, 1760 ] ] } ]

[ { "id": "entity-333-0", "type": "ADVERSE", "text": [ "acrylamide toxicity" ], "offsets": [ [ 123, 142 ] ], "normalized": [] }, { "id": "entity-333-1", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 381, 394 ] ], "normalized": [] }, { "id": "entity-333-2", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 399, 405 ] ], "normalized": [] }, { "id": "entity-333-3", "type": "ADVERSE", "text": [ "AA toxicity" ], "offsets": [ [ 472, 483 ] ], "normalized": [] }, { "id": "entity-333-4", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 730, 743 ] ], "normalized": [] }, { "id": "entity-333-5", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 748, 754 ] ], "normalized": [] }, { "id": "entity-333-6", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 1061, 1067 ] ], "normalized": [] }, { "id": "entity-333-7", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 1224, 1237 ] ], "normalized": [] }, { "id": "entity-333-8", "type": "ADVERSE", "text": [ "dietary cancer" ], "offsets": [ [ 1609, 1623 ] ], "normalized": [] } ]

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[ { "id": "passage-334", "type": "abstract", "text": [ "A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect. BACKGROUND: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. METHODS: Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. RESULTS: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). CONCLUSION: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo." ], "offsets": [ [ 0, 3061 ] ] } ]

[ { "id": "entity-334-0", "type": "DISEASE", "text": [ "attention-deficit hyperactivity disorder" ], "offsets": [ [ 94, 134 ] ], "normalized": [] }, { "id": "entity-334-1", "type": "DISEASE", "text": [ "attention-deficit hyperactivity disorder" ], "offsets": [ [ 232, 272 ] ], "normalized": [] }, { "id": "entity-334-2", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 274, 278 ] ], "normalized": [] }, { "id": "entity-334-3", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 788, 792 ] ], "normalized": [] }, { "id": "entity-334-4", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 1424, 1428 ] ], "normalized": [] }, { "id": "entity-334-5", "type": "ADVERSE", "text": [ "abdominal pain" ], "offsets": [ [ 2362, 2376 ] ], "normalized": [] }, { "id": "entity-334-6", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 2421, 2429 ] ], "normalized": [] }, { "id": "entity-334-7", "type": "ADVERSE", "text": [ "increased appetite" ], "offsets": [ [ 2477, 2495 ] ], "normalized": [] } ]

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[ { "id": "passage-335", "type": "abstract", "text": [ "A phase II study of oxaliplatin, pemetrexed, and bevacizumab in previously treated advanced non-small cell lung cancer. INTRODUCTION: Single agent chemotherapy is standard for second and third line treatment of non-small cell lung cancer (NSCLC). Combination therapy to date has not proven to be superior to single agents in this setting, often adding toxicity without any additional efficacy. We investigated the activity and tolerability of the combination of oxaliplatin, pemetrexed, and bevacizumab in patients with previously treated advanced NSCLC. METHODS: This multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (500 mg/m), oxaliplatin (120 mg/m), and bevacizumab (15 mg/kg), given every 21 days, in patients with previously treated advanced NSCLC. Eligibility criteria included performance status 0 to 1, nonsquamous histology, and at least one prior chemotherapy regimen. Patients with treated brain metastases were allowed. The primary end point was response rate, with secondary endpoints of progression-free survival and overall survival. RESULTS: Thirty-six patients were enrolled on this study. Treatment was well tolerated; the most common grade 3 toxicity was hypertension, which was easily managed with oral medications. The nine (25%) patients with treated brain metastases had no episodes of cerebral hemorrhage. Of the 34 patients evaluable for tumor response, none had complete response, nine (27%) had partial response, 15 (44%) had stable disease, and 10 (29%) had progressive disease. Median progression-free survival was 5.8 months (95% confidence interval 4.1-7.8 months) and median overall survival was 12.5 months (95% confidence interval 7.3-17 months). CONCLUSIONS: Treatment with oxaliplatin and pemetrexed in combination with the targeted antiangiogenic agent bevacizumab yielded promising efficacy with manageable toxicity in the previously treated advanced NSCLC population." ], "offsets": [ [ 0, 1953 ] ] } ]

[ { "id": "entity-335-0", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 92, 118 ] ], "normalized": [] }, { "id": "entity-335-1", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 212, 238 ] ], "normalized": [] }, { "id": "entity-335-2", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 240, 245 ] ], "normalized": [] }, { "id": "entity-335-3", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 549, 554 ] ], "normalized": [] }, { "id": "entity-335-4", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 794, 799 ] ], "normalized": [] }, { "id": "entity-335-5", "type": "DISEASE", "text": [ "brain metastases" ], "offsets": [ [ 948, 964 ] ], "normalized": [] }, { "id": "entity-335-6", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 1221, 1233 ] ], "normalized": [] }, { "id": "entity-335-7", "type": "DISEASE", "text": [ "brain metastases" ], "offsets": [ [ 1320, 1336 ] ], "normalized": [] }, { "id": "entity-335-8", "type": "DISEASE", "text": [ "cerebral hemorrhage" ], "offsets": [ [ 1356, 1375 ] ], "normalized": [] }, { "id": "entity-335-9", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1410, 1415 ] ], "normalized": [] }, { "id": "entity-335-10", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 1936, 1941 ] ], "normalized": [] } ]

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[ { "id": "passage-336", "type": "abstract", "text": [ "EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24." ], "offsets": [ [ 0, 1861 ] ] } ]

[ { "id": "entity-336-0", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 662, 677 ] ], "normalized": [] } ]

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[ { "id": "passage-337", "type": "abstract", "text": [ "Reduced weight gain with insulin detemir compared to NPH insulin is not explained by a reduction in hypoglycemia. BACKGROUND: Weight gain often occurs when insulin therapy is initiated. The long-acting insulin analog insulin detemir has been shown to be effective and well tolerated when used in basal-bolus regimens or as an add-on to oral antidiabetic drugs (OADs) and causes less weight gain than other insulins. The aim of this exploratory analysis was to investigate any correlations between weight change and occurrence of hypoglycemia with NPH insulin and insulin detemir. METHODS: The analysis was based on a 26-week, randomized, multicenter, open-label, parallel-group trial in which glycemic control, hypoglycemia, and weight change were compared between insulin detemir and NPH insulin. A total of 476 insulin-naive patients with type 2 diabetes treated with one or two OADs added insulin detemir (n=237) or NPH insulin (n=239) morning and evening to their current oral treatment. Weight gain data from this study were analyzed as a function of hypoglycemia frequency. RESULTS: Both groups achieved excellent glycosylated hemoglobin control (insulin detemir, 6.6%; NPH insulin, 6.5% [difference not significant]). Weight gain with insulin detemir was less than half that of NPH insulin (1.2 vs. 2.8 kg, respectively [P<0.001]), and the overall risk of hypoglycemia was 47% lower with insulin detemir (P<0.001). No significant relationship between hypoglycemia and weight gain was seen with insulin detemir (P=0.2), while a statistically significant correlation was found for NPH insulin (P=0.003). CONCLUSIONS: Hypoglycemia is predictive of weight gain with NPH insulin, but the same relationship is not seen with insulin detemir. It is therefore likely that the weight-sparing effect of insulin detemir involves other mechanisms." ], "offsets": [ [ 0, 1842 ] ] } ]

[ { "id": "entity-337-0", "type": "DISEASE", "text": [ "hypoglycemia" ], "offsets": [ [ 100, 112 ] ], "normalized": [] }, { "id": "entity-337-1", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 530, 542 ] ], "normalized": [] }, { "id": "entity-337-2", "type": "DISEASE", "text": [ "hypoglycemia" ], "offsets": [ [ 712, 724 ] ], "normalized": [] }, { "id": "entity-337-3", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 842, 857 ] ], "normalized": [] }, { "id": "entity-337-4", "type": "DISEASE", "text": [ "hypoglycemia" ], "offsets": [ [ 1057, 1069 ] ], "normalized": [] }, { "id": "entity-337-5", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 1364, 1376 ] ], "normalized": [] }, { "id": "entity-337-6", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 1459, 1471 ] ], "normalized": [] }, { "id": "entity-337-7", "type": "ADVERSE", "text": [ "Hypoglycemia" ], "offsets": [ [ 1623, 1635 ] ], "normalized": [] } ]

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[ { "id": "passage-338", "type": "abstract", "text": [ "Derivation of a chronic reference dose and reference concentration for trimethylbenzenes and C9 aromatic hydrocarbon solvents. Trimethylbenzenes (TMBs) and C9 aromatic hydrocarbon solvents are structurally similar and have similar toxicity. Based on a review of the entire TMB and C9 aromatic hydrocarbon solvents toxicology database, oral and inhalation studies were identified to serve as the basis for a Reference dose (RfD) and Reference concentrations (RfC). The RfD and RfC were derived using standard USEPA methods and assumptions. The RfD was calculated to be 0.4 mg/kg/day using a 90-day oral study that resulted in a NOAEL of 600 mg/kg/day, based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), along with a total uncertainty factor of 1000. For the RfC, three studies were considered based on different study designs and toxicological endpoints, including neurotoxicity, systemic toxicity, and potential developmental and reproductive toxicity. For all three studies, as the calculated RfCs were consistent (3-4 mg/m3), the most conservative RfC, 3mg/m3, was selected. The C9 aromatic hydrocarbon solvents referred to herein are based on chemistries assessed as part of the TSCA Section 4 Test Rule. These solvents contain primarily ethyl toluene and tri-methyl benzene isomers, but the specific compositions can vary based on feedstock and manufacturing process, thus, it is important to consider the composition of any specific solvent to assess similarity to that assessed in the TSCA Section 4 Test Rule program." ], "offsets": [ [ 0, 1628 ] ] } ]

[ { "id": "entity-338-0", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 968, 981 ] ], "normalized": [] }, { "id": "entity-338-1", "type": "ADVERSE", "text": [ "systemic toxicity" ], "offsets": [ [ 983, 1000 ] ], "normalized": [] }, { "id": "entity-338-2", "type": "ADVERSE", "text": [ "reproductive toxicity" ], "offsets": [ [ 1034, 1055 ] ], "normalized": [] } ]

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[ { "id": "passage-339", "type": "abstract", "text": [ "NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity. Clinical use of retinoic acids (RA) is hindered by toxicity possibly related to oxidative stress. Recently, RA at relatively low concentrations was shown to inhibit NRF2 and the expression of its target antioxidative genes. This raises the possibility that RA toxicity may result from cellular inability to cope with resultant oxidative stress. Using in vitro cell and in vivo mouse models, we report that RA, specifically all-trans-RA (atRA) at concentrations implicated in toxicity, can activate NRF2 and induce NRF2 target genes, particularly the subunits of the rate-limiting enzyme of glutathione biosynthesis, glutamate cysteine ligase (GCLM/GCLC). RNA interference-mediated silencing of NRF2, but not of retinoid X receptor-alpha and -beta, reduced basal and atRA-induced GCLM/GCLC gene expression. Moreover, RA increased nuclear accumulation of NRF2, antioxidant response element (ARE) reporter activity, and NRF2 occupancy at AREs. 4-Hydroxynonenal, a lipid peroxidation product, was increased by RA. Inhibition of MEK1/ERK mitogen-activated protein kinases significantly suppressed atRA-induced NRF2 activation and ARE-regulated gene expression, reducing cell resistance against toxic concentrations of RA. NRF2-silenced cells were vulnerable to atRA-induced mitochondrial toxicity and apoptosis. In conclusion, toxic RA activates NRF2, thereby triggering an adaptive response against the resultant oxidative stress. NRF2 enhancement as a therapeutic target of retinoid toxicity awaits further investigation." ], "offsets": [ [ 0, 1595 ] ] } ]

[ { "id": "entity-339-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 62, 74 ] ], "normalized": [] }, { "id": "entity-339-1", "type": "ADVERSE", "text": [ "RA toxicity" ], "offsets": [ [ 334, 345 ] ], "normalized": [] }, { "id": "entity-339-2", "type": "ADVERSE", "text": [ "mitochondrial toxicity" ], "offsets": [ [ 1346, 1368 ] ], "normalized": [] } ]

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[ { "id": "passage-340", "type": "abstract", "text": [ "Amended final report of the safety assessment of cocamidopropylamine oxide. Cocamidopropylamine Oxide is a tertiary amine oxide which functions as a hair-conditioning agent and as a surfactant, currently used in 60 cosmetic formulations at concentrations between 0.07% and 4.0%. In an earlier safety assessment, the Cosmetic Ingredient Review (CIR) Expert Panel had determined that the available data were insufficient to support the safety of this ingredient in cosmetic products. Additional data have now been provided and reviewed. Cocamidopropylamine Oxide was determined to have an acute oral LD(50) between 500 and 1000 mg/kg day(-1) using rats. The acute dermal LD(50) in rats was > 2174 mg/kg day(-1). A 28-day repeated oral dose toxicity study in rats found hemolytic anemia at 150 and 1000 mg/kg day(- 1), with a no observed effect level (NOEL) of 15 mg/kg day(- 1). At 5%, Cocamidopropylamine Oxide solution was not a primary dermal irritant. Application of 81.5% Cocamidopropylamine Oxide to rabbit skin caused moderate irritation under Draize classification scale, but 81.5% Cocamidopropylamine Oxide in rabbit eyes caused severe irritation. A maximization study classified Cocamidopropylamine Oxide as a nonsensitizer to guinea pig skin. Cocamidopropylamine Oxide was not mutagenic in an Ames test, with and without metabolic activation. No evidence of increased chromosomal aberrations were noted in human lymphocytes treated with 81.5% Cocamidopropylamine Oxide. In a clinical study, 7.5% Cocamidopropylamine Oxide was not a sensitizer, although it did produce some reactions typical of mild irritation. Although the impurities, amidoamine and dimethylaminopropylamine, have been implicated in contact allergy reactions to products containing cocamidopropylamine betaine, clinical testing of a product with cocamidopropylamine betaine containing these impurities, at levels comparable to those found in Cocamidopropylamine Oxide, failed to produce a reaction in 10 individuals known to be sensitive to cocamidopropylamine betaine. Two repeat-insult patch tests using a facial wash with 1% raw material containing 35% to 36.5% Cocamidopropylamine Oxide did not find evidence of dermal sensitization. Tests for dermal phototoxicity and photoallergenicity with the same facial wash product also did not produce evidence of effect. The CIR Expert Panel recognizes that there are data gaps regarding the use and concentration of this ingredient. However, the overall information available on types of products in which this ingredient is used and at what concentration indicate a pattern of use, which was considered by the Expert Panel in assessing safety. Overall, these data demonstrate that Cocamidopropylamine Oxide has low toxicity in animal and in vitro tests. Although there are no available carcinogenicity data, the available genotoxicity data, combined with the absence of any structural alerts, suggest no carcinogenic potential. The Panel noted the absence of reproductive and developmental toxicity data. Because this ingredient has a highly polarized molecular structure, the Panel considered that it would be, at most, slowly absorbed. Given that most of the uses and the highest use concentration of 4% is found in rinse-off products, the Panel determined that the available data suggest that Cocamidopropylamine Oxide is safe as used in rinse-off products. Although dermal penetration may be slow, data on the extent of dermal penetration of Cocamidopropylamine Oxide are needed to support the safety of leave-on uses. If there is significant dermal absorption, dermal reproductive and developmental toxicity data may be needed." ], "offsets": [ [ 0, 3658 ] ] } ]

[ { "id": "entity-340-0", "type": "ADVERSE", "text": [ "dose toxicity" ], "offsets": [ [ 734, 747 ] ], "normalized": [] }, { "id": "entity-340-1", "type": "ADVERSE", "text": [ "hemolytic anemia" ], "offsets": [ [ 768, 784 ] ], "normalized": [] }, { "id": "entity-340-2", "type": "ADVERSE", "text": [ "irritation" ], "offsets": [ [ 1033, 1043 ] ], "normalized": [] }, { "id": "entity-340-3", "type": "ADVERSE", "text": [ "irritation" ], "offsets": [ [ 1144, 1154 ] ], "normalized": [] }, { "id": "entity-340-4", "type": "ADVERSE", "text": [ "irritation" ], "offsets": [ [ 1609, 1619 ] ], "normalized": [] }, { "id": "entity-340-5", "type": "ADVERSE", "text": [ "contact allergy" ], "offsets": [ [ 1711, 1726 ] ], "normalized": [] }, { "id": "entity-340-6", "type": "ADVERSE", "text": [ "dermal sensitization" ], "offsets": [ [ 2194, 2214 ] ], "normalized": [] }, { "id": "entity-340-7", "type": "ADVERSE", "text": [ "dermal phototoxicity" ], "offsets": [ [ 2226, 2246 ] ], "normalized": [] }, { "id": "entity-340-8", "type": "ADVERSE", "text": [ "photoallergenicity" ], "offsets": [ [ 2251, 2269 ] ], "normalized": [] }, { "id": "entity-340-9", "type": "ADVERSE", "text": [ "carcinogenicity" ], "offsets": [ [ 2812, 2827 ] ], "normalized": [] }, { "id": "entity-340-10", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 2848, 2860 ] ], "normalized": [] }, { "id": "entity-340-11", "type": "ADVERSE", "text": [ "developmental toxicity" ], "offsets": [ [ 3002, 3024 ] ], "normalized": [] }, { "id": "entity-340-12", "type": "ADVERSE", "text": [ "developmental toxicity" ], "offsets": [ [ 3616, 3638 ] ], "normalized": [] } ]

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[ { "id": "passage-341", "type": "abstract", "text": [ "Determinants of negative white-coat effect in treated hypertensive patients: the Jichi Morning Hypertension Research (J-MORE) study. BACKGROUND: The negative white-coat effect (WCE), a phenomenon in which out-of-office blood pressure (BP) is higher than clinic BP, has not been well examined, unlike the WCE. METHODS: As part of the Jichi Morning Hypertension Research study, in which clinic and home BP were measured in 969 hypertensive outpatients, 405 patients with normal clinic BP were separately analyzed. Clinic BP was measured on two different occasions, and home BP was measured twice in the morning and twice in the evening for three consecutive days. Clinic and home BP were each averaged from all readings, and negative WCE was defined as clinic systolic BP (SBP) lower than home SBP. RESULTS: Negative WCE was observed in 324 (33%) of the patients overall and in 173 (42%) of the patients with controlled BP (clinic BP < 140/90 mm Hg). In multiple logistic regression analysis adjusting for covariates including home SBP and pulse rate, negative WCE was correlated with older age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06) and male gender (OR 1.08, 95% CI 1.01-1.14) in overall subjects. Among patients with well-controlled clinic BP, negative WCE was significantly correlated with the presence of ischemic heart disease (OR 1.17, 95% CI 1.04-1.31). The association of negative WCE with age and male gender remained significant under stringent criteria (negative WCE < -10.2 mm Hg (the mean -1 s.d.)). CONCLUSIONS: Negative WCE remaining even after clinic BP is controlled may be related to cardiovascular risk factors such as older age, male gender, and a history of ischemic heart disease." ], "offsets": [ [ 0, 1725 ] ] } ]

[ { "id": "entity-341-0", "type": "DISEASE", "text": [ "Hypertension" ], "offsets": [ [ 95, 107 ] ], "normalized": [] }, { "id": "entity-341-1", "type": "DISEASE", "text": [ "Hypertension" ], "offsets": [ [ 348, 360 ] ], "normalized": [] }, { "id": "entity-341-2", "type": "DISEASE", "text": [ "ischemic heart disease" ], "offsets": [ [ 1332, 1354 ] ], "normalized": [] }, { "id": "entity-341-3", "type": "DISEASE", "text": [ "ischemic heart disease" ], "offsets": [ [ 1702, 1724 ] ], "normalized": [] } ]

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[ { "id": "passage-342", "type": "abstract", "text": [ "Amiodarone pulmonary toxicity after lung transplantation. Atrial fibrillation occurs frequently after lung transplantation and is commonly treated with amiodarone. Pulmonary toxicity may result from amiodarone exposure and is characterized by non-specific respiratory manifestations. To our knowledge, there are no reports of this complication occurring after lung transplantation. We present a patient who developed radiologic evidence of amiodarone deposition in the lungs after bilateral lung transplantation." ], "offsets": [ [ 0, 513 ] ] } ]

[ { "id": "entity-342-0", "type": "ADVERSE", "text": [ "pulmonary toxicity" ], "offsets": [ [ 11, 29 ] ], "normalized": [] }, { "id": "entity-342-1", "type": "ADVERSE", "text": [ "Atrial fibrillation" ], "offsets": [ [ 59, 78 ] ], "normalized": [] }, { "id": "entity-342-2", "type": "ADVERSE", "text": [ "Pulmonary toxicity" ], "offsets": [ [ 165, 183 ] ], "normalized": [] } ]

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[ { "id": "passage-343", "type": "abstract", "text": [ "Predicting and preventing acute kidney injury after cardiac surgery. PURPOSE OF REVIEW: Acute kidney injury (AKI) after cardiac surgery is associated with significant morbidity and mortality. Despite the proliferation of predictive clinical scoring models of renal risk after cardiac surgery, limitations in preventing AKI through the use of pharmacological agents remain. Here we review the evolution of predictive models of renal risk after cardiac surgery, and highlight the important gains made in preventing its occurrence. RECENT FINDINGS: Simple risk indices predicting AKI after cardiac surgery have been developed and can now be readily applied clinically. However, studies focusing on preventing AKI after surgery have yet to demonstrate any consistent renoprotective effect. SUMMARY: Clinical scoring systems predicting AKI risk after cardiac surgery are available and should be employed in the preoperative assessment. Elucidation of beneficial preventive strategies of AKI after cardiac surgery requires ongoing research." ], "offsets": [ [ 0, 1035 ] ] } ]

[ { "id": "entity-343-0", "type": "ADVERSE", "text": [ "acute kidney injury" ], "offsets": [ [ 26, 45 ] ], "normalized": [] }, { "id": "entity-343-1", "type": "ADVERSE", "text": [ "Acute kidney injury" ], "offsets": [ [ 89, 108 ] ], "normalized": [] }, { "id": "entity-343-2", "type": "ADVERSE", "text": [ "AKI" ], "offsets": [ [ 110, 113 ] ], "normalized": [] } ]

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[ { "id": "passage-344", "type": "abstract", "text": [ "Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitis. BACKGROUND: Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa. AIM: To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC. METHODS: Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years. RESULTS: 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations,and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator activated receptor-gamma (PPAR-gamma) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-gamma agonists. CONCLUSION: The evolution of novel oral 5-ASA formulations and dosage regimens,and recent development of new molecules have expanded the therapeutic armamentarium of UC." ], "offsets": [ [ 0, 1860 ] ] } ]

[ { "id": "entity-344-0", "type": "DISEASE", "text": [ "ulcerative colitis" ], "offsets": [ [ 106, 124 ] ], "normalized": [] }, { "id": "entity-344-1", "type": "DISEASE", "text": [ "ulcerative colitis" ], "offsets": [ [ 161, 179 ] ], "normalized": [] }, { "id": "entity-344-2", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 181, 183 ] ], "normalized": [] }, { "id": "entity-344-3", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 336, 338 ] ], "normalized": [] }, { "id": "entity-344-4", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 634, 636 ] ], "normalized": [] }, { "id": "entity-344-5", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 683, 685 ] ], "normalized": [] }, { "id": "entity-344-6", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 925, 927 ] ], "normalized": [] }, { "id": "entity-344-7", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 1396, 1398 ] ], "normalized": [] }, { "id": "entity-344-8", "type": "ADVERSE", "text": [ "systemic toxicity" ], "offsets": [ [ 1462, 1479 ] ], "normalized": [] }, { "id": "entity-344-9", "type": "DISEASE", "text": [ "UC" ], "offsets": [ [ 1857, 1859 ] ], "normalized": [] } ]

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[ { "id": "passage-345", "type": "abstract", "text": [ "The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM." ], "offsets": [ [ 0, 1557 ] ] } ]

[ { "id": "entity-345-0", "type": "DISEASE", "text": [ "lymphoplasmacytic lymphoma" ], "offsets": [ [ 155, 181 ] ], "normalized": [] }, { "id": "entity-345-1", "type": "DISEASE", "text": [ "Lymphoma" ], "offsets": [ [ 237, 245 ] ], "normalized": [] }, { "id": "entity-345-2", "type": "DISEASE", "text": [ "Lymphoplasmacytic lymphoma" ], "offsets": [ [ 267, 293 ] ], "normalized": [] }, { "id": "entity-345-3", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 295, 298 ] ], "normalized": [] }, { "id": "entity-345-4", "type": "DISEASE", "text": [ "lymphoma" ], "offsets": [ [ 315, 323 ] ], "normalized": [] }, { "id": "entity-345-5", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 493, 496 ] ], "normalized": [] }, { "id": "entity-345-6", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 517, 520 ] ], "normalized": [] }, { "id": "entity-345-7", "type": "DISEASE", "text": [ "Waldenstroem's macroglobulinemia" ], "offsets": [ [ 557, 589 ] ], "normalized": [] }, { "id": "entity-345-8", "type": "DISEASE", "text": [ "WM" ], "offsets": [ [ 591, 593 ] ], "normalized": [] }, { "id": "entity-345-9", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "entity-345-10", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 750, 753 ] ], "normalized": [] }, { "id": "entity-345-11", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 1024, 1027 ] ], "normalized": [] }, { "id": "entity-345-12", "type": "DISEASE", "text": [ "WM" ], "offsets": [ [ 1048, 1050 ] ], "normalized": [] }, { "id": "entity-345-13", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 1272, 1275 ] ], "normalized": [] }, { "id": "entity-345-14", "type": "DISEASE", "text": [ "WM" ], "offsets": [ [ 1307, 1309 ] ], "normalized": [] }, { "id": "entity-345-15", "type": "ADVERSE", "text": [ "treatment-associated toxicity" ], "offsets": [ [ 1364, 1393 ] ], "normalized": [] }, { "id": "entity-345-16", "type": "DISEASE", "text": [ "LPL" ], "offsets": [ [ 1547, 1550 ] ], "normalized": [] }, { "id": "entity-345-17", "type": "DISEASE", "text": [ "WM" ], "offsets": [ [ 1554, 1556 ] ], "normalized": [] } ]

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[ { "id": "passage-346", "type": "abstract", "text": [ "Fluctuating functions related to quality of life in advanced Parkinson disease: effects of duodenal levodopa infusion. OBJECTIVE: To assess fluctuations in quality of life (QoL) and motor performance in patients with advanced Parkinson disease (PD) treated with continuous daytime duodenal levodopa/carbidopa infusion or conventional therapy. METHODS: Of 18 patients completing a 6-week trial (DIREQT), 12 were followed for up to 6 months and assessed using electronic diaries and the PD Questionnaire-39 (PDQ-39). RESULTS: During the trial and follow-up, major diurnal fluctuations were observed, especially for hyperkinesia, 'off' time, ability to walk and depression. Duodenal infusion was associated with significantly more favourable outcomes compared with conventional treatment for satisfaction with overall functioning, 'off' time and ability to walk, with improved outcomes with PDQ-39. CONCLUSIONS: Relative to conventional treatment, infusion therapy may stabilize and significantly improve motor function and patient's QoL. The potential for daily fluctuation in PD symptoms means single measures of treatment effectiveness can result in bias in effect estimates and hence repeated measures are recommended." ], "offsets": [ [ 0, 1220 ] ] } ]

[ { "id": "entity-346-0", "type": "DISEASE", "text": [ "hyperkinesia" ], "offsets": [ [ 614, 626 ] ], "normalized": [] }, { "id": "entity-346-1", "type": "DISEASE", "text": [ "depression" ], "offsets": [ [ 660, 670 ] ], "normalized": [] } ]

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[ { "id": "passage-347", "type": "abstract", "text": [ "Methods in safety pharmacology in focus. This focused issue of the Journal of Pharmacological and Toxicological Methods is the fifth to highlight Methods in Safety Pharmacology and includes a number of articles from the 7th Annual Safety Pharmacology Society (SPS) meeting that was held in Edinburgh, Scotland, September 19-21, 2007. However, unlike issues of the past, in which content predominantly focused on cardiovascular issues (specifically QT interval prolongation, QT-HR correction methods and validation of non-clinical cardiovascular models) this issue is composed of a number of non-cardiovascular methods papers and review articles. Of particular interest to readers will be articles related to CNS studies, in particular neurobehavioral assessments in non-human primates and the effects of drugs in juvenile and adult rats (an article that may be relevant in light of recent EU/US pediatric legislation). While cardiovascular function may not dominate there are several useful methodological papers including an assessment of cardiovascular sensitivity of drugs in conscious and anesthetized non-human primates, and a mathematical model (fractal analysis) applied to canine heartbeat dynamics. A first for the journal is a paper by Vargas et al., (2008-this issue) in which members of the SPS formed a working group in order to assess and review safety pharmacology testing of biological therapeutic agents (specifically monoclonal antibodies, mAbs). The group provides recommendations that will likely shape regulatory strategy and discussions in the yet to be fully discussed area of biological safety testing. In the tradition of obtaining a perspective on industry safety pharmacology program practices Lindgren et al., (2008-this issue) provide the results of a recent SPS survey that examines ICH S7A and S7B trends, aspects of early 'frontloading' safety studies, abuse and dependence liability and Contract Research Organization (CRO) tests/assays used in safety assessment of core battery and supplementary organ systems. In keeping with the translation track aspect of the 2007 meeting is an overview of the Distinguished Service Award lecture to Dr. T. Hammond that discusses many aspects of safety pharmacology including its evolution, impact, value and translation of non-clinical findings to humans. Finally, perspectives are presented on the use of the zebrafish as an early safety pharmacology-screening assay." ], "offsets": [ [ 0, 2441 ] ] } ]

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[ { "id": "passage-348", "type": "abstract", "text": [ "Lung fibrosis 10 years after cessation of bleomycin therapy. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of several types of malignancy, including germ cell tumors, lymphoma, and certain types of squamous-cell carcinoma. The common adverse effect of BLM is interstitial pneumonitis, followed by pulmonary fibrosis. BLM-induced pneumonitis occurs in up to 46% of patients treated with BLM-containing chemotherapy and lung toxicity usually appears during treatment. Here we describe a patient with lung fibrosis, who presented with slow progressive breathlessness and pneumothorax more than 10 years after cessation of BLM therapy. A 15 year-old girl presented with abnormal shadows on chest X-ray. The patient had a yolk sac carcinoma in the sacral region at 1 year of age and obtained complete remission after being treated with tumor resection, radiation, and several anti-cancer drugs including BLM. There were no abnormal findings in chest X-ray until she reached 3 years of age, when she had developed respiratory distress that worsened with age. The patient had experienced an episode of pneumothorax at 13 years of age. Chest CT at the time revealed interstitial reticular opacities. Radiological findings and pathological examination of the lung tissue obtained during bullectomy with video-assisted thoracic surgery were compatible with BLM-induced pneumonitis. The present study suggests that lung fibrosis may surface more than 10 years after cessation of BLM therapy at the age of 1 year, with no chest radiographic findings 1 year after completion of chemotherapy. The use of BLM in infants requires strict supervision and observation and careful long-term follow up." ], "offsets": [ [ 0, 1703 ] ] } ]

[ { "id": "entity-348-0", "type": "ADVERSE", "text": [ "Lung fibrosis" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "entity-348-1", "type": "DISEASE", "text": [ "germ cell tumors" ], "offsets": [ [ 171, 187 ] ], "normalized": [] }, { "id": "entity-348-2", "type": "DISEASE", "text": [ "lymphoma" ], "offsets": [ [ 189, 197 ] ], "normalized": [] }, { "id": "entity-348-3", "type": "DISEASE", "text": [ "squamous-cell carcinoma" ], "offsets": [ [ 220, 243 ] ], "normalized": [] }, { "id": "entity-348-4", "type": "ADVERSE", "text": [ "interstitial pneumonitis" ], "offsets": [ [ 281, 305 ] ], "normalized": [] }, { "id": "entity-348-5", "type": "ADVERSE", "text": [ "pulmonary fibrosis" ], "offsets": [ [ 319, 337 ] ], "normalized": [] }, { "id": "entity-348-6", "type": "ADVERSE", "text": [ "pneumonitis" ], "offsets": [ [ 351, 362 ] ], "normalized": [] }, { "id": "entity-348-7", "type": "ADVERSE", "text": [ "lung toxicity" ], "offsets": [ [ 440, 453 ] ], "normalized": [] }, { "id": "entity-348-8", "type": "DISEASE", "text": [ "lung fibrosis" ], "offsets": [ [ 520, 533 ] ], "normalized": [] }, { "id": "entity-348-9", "type": "ADVERSE", "text": [ "progressive breathlessness" ], "offsets": [ [ 559, 585 ] ], "normalized": [] }, { "id": "entity-348-10", "type": "ADVERSE", "text": [ "pneumothorax" ], "offsets": [ [ 590, 602 ] ], "normalized": [] }, { "id": "entity-348-11", "type": "DISEASE", "text": [ "yolk sac carcinoma" ], "offsets": [ [ 739, 757 ] ], "normalized": [] }, { "id": "entity-348-12", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 853, 858 ] ], "normalized": [] }, { "id": "entity-348-13", "type": "ADVERSE", "text": [ "respiratory distress" ], "offsets": [ [ 1030, 1050 ] ], "normalized": [] }, { "id": "entity-348-14", "type": "ADVERSE", "text": [ "pneumothorax" ], "offsets": [ [ 1117, 1129 ] ], "normalized": [] }, { "id": "entity-348-15", "type": "ADVERSE", "text": [ "pneumonitis" ], "offsets": [ [ 1381, 1392 ] ], "normalized": [] }, { "id": "entity-348-16", "type": "DISEASE", "text": [ "lung fibrosis" ], "offsets": [ [ 1426, 1439 ] ], "normalized": [] } ]

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[ { "id": "passage-349", "type": "abstract", "text": [ "Hyperthermia adds to chemotherapy. The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy. Preclinical research reveals that for heat killing and synergistic effects the thermal dose is most critical. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. The induction of genetically defined stress responses can deliver danger signals to activate the host's immune system. The positive results of randomised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer. Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity. In specific clinical settings regional hyperthermia (RHT) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies. In Europe, more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology." ], "offsets": [ [ 0, 1107 ] ] } ]

[ { "id": "entity-349-0", "type": "DISEASE", "text": [ "Hyperthermia" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "entity-349-1", "type": "DISEASE", "text": [ "hyperthermia" ], "offsets": [ [ 53, 65 ] ], "normalized": [] }, { "id": "entity-349-2", "type": "ADVERSE", "text": [ "drug cytotoxicity" ], "offsets": [ [ 279, 296 ] ], "normalized": [] }, { "id": "entity-349-3", "type": "DISEASE", "text": [ "hyperthermia" ], "offsets": [ [ 576, 588 ] ], "normalized": [] }, { "id": "entity-349-4", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 672, 678 ] ], "normalized": [] }, { "id": "entity-349-5", "type": "DISEASE", "text": [ "Hyperthermia" ], "offsets": [ [ 680, 692 ] ], "normalized": [] }, { "id": "entity-349-6", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 746, 752 ] ], "normalized": [] }, { "id": "entity-349-7", "type": "ADVERSE", "text": [ "systemic toxicity" ], "offsets": [ [ 778, 795 ] ], "normalized": [] }, { "id": "entity-349-8", "type": "DISEASE", "text": [ "regional hyperthermia" ], "offsets": [ [ 827, 848 ] ], "normalized": [] }, { "id": "entity-349-9", "type": "DISEASE", "text": [ "RHT" ], "offsets": [ [ 850, 853 ] ], "normalized": [] }, { "id": "entity-349-10", "type": "DISEASE", "text": [ "hyperthermia" ], "offsets": [ [ 1069, 1081 ] ], "normalized": [] } ]

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[ { "id": "passage-350", "type": "abstract", "text": [ "Breakthrough cryptococcosis in a patient with systemic lupus erythematosus (SLE) receiving micafungin. A 67-year-old woman with systemic lupus erythematosus (SLE) was admitted to our hospital because of lupus nephritis. Methylprednisolone minipulse therapy dramatically reduced her proteinuria; however; she then complained of general fatigue with low-grade fever. Radiological and culture studies revealed no infectious focus, but she was treated with meropenem and micafungin, considering her immunosuppressive state. Cytomegalovirus antigenemia was later determined and ganciclovir was added. She became afebrile, but complained of nausea and headache, and disorientation, without meningeal signs. Because a brain computed tomography (CT) scan showed no abnormality, we initially suspected some kind of drug interaction. Despite the discontinuation of all drugs, however, she still suffered from disturbance of consciousness. A lumbar puncture revealed yeast cells stained by India ink. A diagnosis of cryptococcal meningitis was confirmed. Though fluconazole and meropenem were administered, the patient died. Autopsy findings revealed disseminated cryptococcosis concomitant with pulmonary aspergillosis. Micafungin is a recently approved echinocandin-class antifungal agent that is now widely used in Japan because of its minimal toxicity and broadspectrum activity. However, such echinocandins have limited activity against a number of fungi. Indeed, breakthrough trichosporonosis is becoming a significant problem in patients with hematological malignancies who are receiving echinocandins. To the best of our knowledge, breakthrough cryptococcosis, as seen in our patient, has not been reported previously in patients who were receiving micafungin as an empiric antifungal therapy. This case highlights that cryptococcosis should be kept in mind as a possible breakthrough infection during the administration of echinocandins, especially in patients with cellular immunodeficiency." ], "offsets": [ [ 0, 1991 ] ] } ]

[ { "id": "entity-350-0", "type": "ADVERSE", "text": [ "cryptococcosis" ], "offsets": [ [ 13, 27 ] ], "normalized": [] }, { "id": "entity-350-1", "type": "DISEASE", "text": [ "systemic lupus erythematosus" ], "offsets": [ [ 46, 74 ] ], "normalized": [] }, { "id": "entity-350-2", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 76, 79 ] ], "normalized": [] }, { "id": "entity-350-3", "type": "DISEASE", "text": [ "systemic lupus erythematosus" ], "offsets": [ [ 129, 157 ] ], "normalized": [] }, { "id": "entity-350-4", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 159, 162 ] ], "normalized": [] }, { "id": "entity-350-5", "type": "DISEASE", "text": [ "lupus nephritis" ], "offsets": [ [ 204, 219 ] ], "normalized": [] }, { "id": "entity-350-6", "type": "DISEASE", "text": [ "proteinuria" ], "offsets": [ [ 283, 294 ] ], "normalized": [] }, { "id": "entity-350-7", "type": "ADVERSE", "text": [ "fatigue" ], "offsets": [ [ 336, 343 ] ], "normalized": [] }, { "id": "entity-350-8", "type": "ADVERSE", "text": [ "fever" ], "offsets": [ [ 359, 364 ] ], "normalized": [] }, { "id": "entity-350-9", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 636, 642 ] ], "normalized": [] }, { "id": "entity-350-10", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 647, 655 ] ], "normalized": [] }, { "id": "entity-350-11", "type": "ADVERSE", "text": [ "disorientation" ], "offsets": [ [ 661, 675 ] ], "normalized": [] }, { "id": "entity-350-12", "type": "ADVERSE", "text": [ "meningeal signs" ], "offsets": [ [ 685, 700 ] ], "normalized": [] }, { "id": "entity-350-13", "type": "DISEASE", "text": [ "cryptococcal meningitis" ], "offsets": [ [ 1006, 1029 ] ], "normalized": [] }, { "id": "entity-350-14", "type": "DISEASE", "text": [ "disseminated cryptococcosis" ], "offsets": [ [ 1141, 1168 ] ], "normalized": [] }, { "id": "entity-350-15", "type": "DISEASE", "text": [ "pulmonary aspergillosis" ], "offsets": [ [ 1186, 1209 ] ], "normalized": [] }, { "id": "entity-350-16", "type": "DISEASE", "text": [ "hematological malignancies" ], "offsets": [ [ 1540, 1566 ] ], "normalized": [] }, { "id": "entity-350-17", "type": "ADVERSE", "text": [ "cryptococcosis" ], "offsets": [ [ 1643, 1657 ] ], "normalized": [] }, { "id": "entity-350-18", "type": "ADVERSE", "text": [ "cryptococcosis" ], "offsets": [ [ 1818, 1832 ] ], "normalized": [] }, { "id": "entity-350-19", "type": "ADVERSE", "text": [ "infection" ], "offsets": [ [ 1883, 1892 ] ], "normalized": [] }, { "id": "entity-350-20", "type": "DISEASE", "text": [ "cellular immunodeficiency" ], "offsets": [ [ 1965, 1990 ] ], "normalized": [] } ]

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[ { "id": "passage-351", "type": "abstract", "text": [ "Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. OBJECTIVE: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel. RESEARCH DESIGN AND METHODS: In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7 days; n = 23) or clopidogrel (600-mg LD, 75-mg MD for 7 days; n = 24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150 mg twice daily, starting 1 day before the LD). Pharmacokinetic parameter estimates (AUC(0-t last), C(max), and t(max)) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD. RESULTS: Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to C(max) (t(max)) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (C(max)) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5 h from 67.4 to 55.1% (p < 0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine. CONCLUSIONS: Results from this study suggest that there is no significant drug-drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel." ], "offsets": [ [ 0, 2538 ] ] } ]

[ { "id": "entity-351-0", "type": "DISEASE", "text": [ "acute coronary syndrome" ], "offsets": [ [ 237, 260 ] ], "normalized": [] }, { "id": "entity-351-1", "type": "DISEASE", "text": [ "interaction" ], "offsets": [ [ 2438, 2449 ] ], "normalized": [] } ]

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[ { "id": "passage-352", "type": "abstract", "text": [ "Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects. BACKGROUND: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the plasma CETP level. We questioned whether the plasma CETP level would affect RAAS responsiveness to low sodium diet and the blood pressure response to angiotensin-II infusion in healthy subjects. METHODS: RAAS parameters and blood pressure were determined during liberal sodium diet (200 mmol/24 h) and low sodium diet (50 mmol/24 h) in 67 healthy men. Blood pressure response to incremental angiotensin-II infusion was assessed in 34 subjects during liberal sodium diet. Correlation analysis was performed to test whether RAAS responsiveness and blood pressure were related to plasma CETP mass, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I measured during liberal sodium diet. RESULTS: CETP mass ranged from 1.29 to 2.95 mg/l. No significant differences in (changes) in mean arterial pressure, aldosterone and active plasma renin concentration in response to low sodium were observed between the lowest and highest tertiles of CETP mass, HDL-C and apolipoprotein A-I. These outcome variables were also not significantly correlated with CETP, HDL-C and apolipoprotein A-I, except for a modest relation of aldosterone measured during low sodium with apolipoprotein A-I (r = 0.28, p = 0.022). Blood pressure response to angiotensin-II was similar between CETP tertiles. CONCLUSIONS: Mineralocorticoid and blood pressure responsiveness to dietary salt intake are not significantly related to physiological interindividual differences in plasma CETP. We suggest that a lower CETP mass does not exert adverse effects on blood pressure regulation." ], "offsets": [ [ 0, 2046 ] ] } ]

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[ { "id": "passage-353", "type": "abstract", "text": [ "Riluzole in psychiatry: a systematic review of the literature. BACKGROUND: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent. OBJECTIVE: To assess the potential risks and benefits of riluzole treatment in psychiatric patients. METHODS: A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients. RESULTS/CONCLUSION: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging." ], "offsets": [ [ 0, 970 ] ] } ]

[ { "id": "entity-353-0", "type": "DISEASE", "text": [ "anxiety disorders" ], "offsets": [ [ 169, 186 ] ], "normalized": [] }, { "id": "entity-353-1", "type": "DISEASE", "text": [ "anxiety disorders" ], "offsets": [ [ 284, 301 ] ], "normalized": [] }, { "id": "entity-353-2", "type": "DISEASE", "text": [ "amyotrophic lateral sclerosis" ], "offsets": [ [ 398, 427 ] ], "normalized": [] }, { "id": "entity-353-3", "type": "DISEASE", "text": [ "ALS" ], "offsets": [ [ 429, 432 ] ], "normalized": [] }, { "id": "entity-353-4", "type": "DISEASE", "text": [ "anxiety" ], "offsets": [ [ 922, 929 ] ], "normalized": [] }, { "id": "entity-353-5", "type": "DISEASE", "text": [ "impulsive disorders" ], "offsets": [ [ 934, 953 ] ], "normalized": [] } ]

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[ { "id": "passage-354", "type": "abstract", "text": [ "Effect of calpain and proteasome inhibition on Ca2+-dependent proteolysis and muscle histopathology in the mdx mouse. Dystrophin deficiency is the underlying molecular cause of progressive muscle weakness observed in Duchenne muscular dystrophy (DMD). Loss of functional dystrophin leads to elevated levels of intracellular Ca(2+), a key step in the cellular pathology of DMD. The cysteine protease calpain is activated in dystrophin-deficient muscle, and its inhibition is regarded as a potential therapeutic approach. In addition, previous work has shown that the ubiquitin-proteasome system also contributes to muscle protein breakdown in dystrophic muscle and, therefore, also qualifies as a potential target for therapeutic intervention in DMD. The relative contribution of calpain- and proteasome-mediated proteolysis induced by increased Ca(2+) levels was characterized in cultured muscle cells and revealed initial Ca(2+) influx-dependent calpain activity and subsequent Ca(2+)-independent activity of the ubiquitin-proteasome system. We then set out to optimize novel small-molecule inhibitors that inhibit both calpain as well as the 20S proteasome in a cellular system with impaired Ca(2+) homeostasis. On administration of such inhibitors to mdx mice, quantitative histological parameters improved significantly, in particular with compounds strongly inhibiting the 20S proteasome. To investigate the role of calpain inhibition without interfering with the ubiquitin-proteasome system, we crossed mdx mice with transgenic mice, overexpressing the endogenous calpain inhibitor calpastatin. Although our data show that proteolysis by calpain is strongly inhibited in the transgenic mdx mouse, this calpain inhibition did not ameliorate muscle histology. Our results indicate that inhibition of the proteasome rather than calpain is required for histological improvement of dystrophin-deficient muscle. In conclusion, we have identified novel proteasome inhibitors that qualify as potential candidates for pharmacological intervention in muscular dystrophy." ], "offsets": [ [ 0, 2067 ] ] } ]

[ { "id": "entity-354-0", "type": "DISEASE", "text": [ "progressive muscle weakness" ], "offsets": [ [ 178, 205 ] ], "normalized": [] }, { "id": "entity-354-1", "type": "DISEASE", "text": [ "Duchenne muscular dystrophy" ], "offsets": [ [ 218, 245 ] ], "normalized": [] }, { "id": "entity-354-2", "type": "DISEASE", "text": [ "DMD" ], "offsets": [ [ 247, 250 ] ], "normalized": [] }, { "id": "entity-354-3", "type": "DISEASE", "text": [ "DMD" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "entity-354-4", "type": "DISEASE", "text": [ "DMD" ], "offsets": [ [ 746, 749 ] ], "normalized": [] }, { "id": "entity-354-5", "type": "DISEASE", "text": [ "muscular dystrophy" ], "offsets": [ [ 2048, 2066 ] ], "normalized": [] } ]

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[ { "id": "passage-355", "type": "abstract", "text": [ "7-Deaza-6-benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities. Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-benzylthioinosines act as subversive substrates of T. gondii, but not human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Moreover, 7-deazaadenosine (tubercidin) was shown to be an excellent ligand of T. gondii adenosine kinase. Therefore, we synthesized 7-deaza-6-benzylthioinosine, and analogues with various substitutions at their phenyl ring, to increase the binding affinity of the 6-benzylthioinosines to T. gondii adenosine kinase. Indeed, the 7-deaza-6-benzylthioinosine analogues were better ligands of T. gondii adenosine kinase than the parent compounds, 6-benzylthioinosine and 7-deazainosine. Herein, we report the testing of the metabolism of these newly synthesized 7-deaza-6-benzylthioinosines, as well as their efficacy as anti-toxoplasmic agents in cell culture. All the 7-deaza-6-benzylthioinosine analogues were metabolized to their 5'-monophosphate derivatives, albeit to different degrees. These results indicate that these compounds are not only ligands but also substrates of T. gondii adenosine kinase. All the 7-deaza-6-benzylthioinosine analogues showed a selective antitoxoplasmic effect against wild type parasites, but not mutants lacking adenosine kinase. The efficacy of these compounds varied with the position and nature of the substitution on their phenyl ring. Moreover, none of these analogues exhibited host toxicity. The best compounds were 7-deaza-6-(p-methoxybenzylthio)inosine (IC(50)=4.6 microM), 7-deaza-6-(p-methoxycarbonylbenzylthio)inosine (IC(50)=5.0 microM), and 7-deaza-6-(p-cyanobenzylthio)inosine (IC(50)=5.3 microM). These results further confirm that T. gondii adenosine kinase is an excellent target for chemotherapy and that 7-deaza-6-benzylthioinosines are potential antitoxoplasmic agents." ], "offsets": [ [ 0, 2337 ] ] } ]

[ { "id": "entity-355-0", "type": "DISEASE", "text": [ "toxoplasmosis" ], "offsets": [ [ 431, 444 ] ], "normalized": [] } ]

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[ { "id": "passage-356", "type": "abstract", "text": [ "Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Increased plasma and hepatic TNF-alpha expression is well documented in patients with alcoholic hepatitis and is implicated in the pathogenesis of alcoholic liver disease. We have previously shown that monocytes from patients with alcoholic hepatitis show increased constitutive and LPS-induced NF-kappaB activation and TNF-alpha production. Our recent studies showed that chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes and Kupffer cells, leading to an increase in LPS-inducible TNF-alpha production by affecting NF-kappaB activation and induction of TNF mRNA expression. Accordingly, the mechanisms underlying this ethanol-induced decrease in cellular cAMP leading to an increase in TNF expression were examined in monocytes/macrophages. In this study, chronic ethanol exposure was observed to significantly increase LPS-inducible expression of cAMP-specific phosphodiesterase (PDE)4B that degrades cellular cAMP. Increased PDE4B expression was associated with enhanced NF-kappaB activation and transcriptional activity and subsequent priming of monocytes/macrophages leading to enhanced LPS-inducible TNF-alpha production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-alpha expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-kappaB activation but significantly decreased NF-kappaB transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanol-mediated priming of monocytes/macrophages and increased LPS-inducible TNF production and the subsequent development of alcoholic liver disease (ALD). Since enhanced TNF expression plays a significant role in the evolution of clinical and experimental ALD, its downregulation via selective PDE4B inhibitors could constitute a novel therapeutic approach in the treatment of ALD." ], "offsets": [ [ 0, 2076 ] ] } ]

[ { "id": "entity-356-0", "type": "DISEASE", "text": [ "alcoholic liver disease" ], "offsets": [ [ 106, 129 ] ], "normalized": [] }, { "id": "entity-356-1", "type": "DISEASE", "text": [ "alcoholic hepatitis" ], "offsets": [ [ 218, 237 ] ], "normalized": [] }, { "id": "entity-356-2", "type": "DISEASE", "text": [ "alcoholic liver disease" ], "offsets": [ [ 279, 302 ] ], "normalized": [] }, { "id": "entity-356-3", "type": "DISEASE", "text": [ "alcoholic hepatitis" ], "offsets": [ [ 363, 382 ] ], "normalized": [] }, { "id": "entity-356-4", "type": "DISEASE", "text": [ "alcoholic liver disease" ], "offsets": [ [ 1819, 1842 ] ], "normalized": [] }, { "id": "entity-356-5", "type": "DISEASE", "text": [ "ALD" ], "offsets": [ [ 1844, 1847 ] ], "normalized": [] }, { "id": "entity-356-6", "type": "DISEASE", "text": [ "ALD" ], "offsets": [ [ 1951, 1954 ] ], "normalized": [] }, { "id": "entity-356-7", "type": "DISEASE", "text": [ "ALD" ], "offsets": [ [ 2072, 2075 ] ], "normalized": [] } ]

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[ { "id": "passage-357", "type": "abstract", "text": [ "The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. RATIONALE: Inhaled long-acting beta-agonists (LABAs), when used as monotherapy in asthma, may increase asthma-related hospitalizations, life threatening events requiring intubation/mechanical ventilation, and asthma-related deaths, but concomitant use of inhaled corticosteroids (ICS) may modify this effect. Objectives: To determine the safety of long-acting beta-agonists among patients with asthma using corticosteroids. METHODS: We conducted a systematic review and metaanalysis of parallel-group, blinded, randomized, controlled trials with at least 12 weeks of treatment addressing the impact of LABA on asthma-related and total morbidity and mortality in patients concomitantly using ICS. We searched MEDLINE, EMBASE, ACPJC, and Cochrane (Central) databases, and contacted authors and sponsors. MEASUREMENTS AND MAIN RESULTS: We used a random effects model to pool results from different studies as odds ratios (ORs) (95% confidence interval [CI]) (OR < 1.0 favors LABA). The search yielded 62 relevant studies included in this analysis. Among over 29,000 participants (15,710 taking LABA, with over 8,000 patient-years observed in the LABA groups), there were three asthma-related deaths and two asthma-related, nonfatal intubations (all in LABA groups; <or= one event per study). Differences in asthma-related hospitalizations (OR, 0.74; 95% CI, 0.53-1.03) and asthma-related serious adverse events (mostly hospitalizations; OR, 0.75; 95% CI, 0.54-1.03) failed to reach statistical significance. The OR for total mortality was 1.26 (95% CI, 0.58-2.74), reflecting 14 deaths in LABA groups and eight deaths in control groups, respectively. CONCLUSIONS: In patients with asthma using ICS, LABA did not increase the risk of asthma-related hospitalizations. There were very few asthma-related deaths and intubations, and events were too infrequent to establish LABA's relative effect on these outcomes." ], "offsets": [ [ 0, 2042 ] ] } ]

[ { "id": "entity-357-0", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 60, 66 ] ], "normalized": [] }, { "id": "entity-357-1", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 217, 223 ] ], "normalized": [] }, { "id": "entity-357-2", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 529, 535 ] ], "normalized": [] }, { "id": "entity-357-3", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 745, 751 ] ], "normalized": [] }, { "id": "entity-357-4", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 1309, 1315 ] ], "normalized": [] }, { "id": "entity-357-5", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 1339, 1345 ] ], "normalized": [] }, { "id": "entity-357-6", "type": "DISEASE", "text": [ "asthma" ], "offsets": [ [ 1813, 1819 ] ], "normalized": [] } ]

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[ { "id": "passage-358", "type": "abstract", "text": [ "Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime. Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure." ], "offsets": [ [ 0, 1283 ] ] } ]

[ { "id": "entity-358-0", "type": "ADVERSE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 6, 32 ] ], "normalized": [] }, { "id": "entity-358-1", "type": "ADVERSE", "text": [ "granulocytopenia" ], "offsets": [ [ 44, 60 ] ], "normalized": [] }, { "id": "entity-358-2", "type": "ADVERSE", "text": [ "Toxic epidermal necrolysis" ], "offsets": [ [ 97, 123 ] ], "normalized": [] }, { "id": "entity-358-3", "type": "ADVERSE", "text": [ "TEN" ], "offsets": [ [ 125, 128 ] ], "normalized": [] }, { "id": "entity-358-4", "type": "ADVERSE", "text": [ "TEN" ], "offsets": [ [ 231, 234 ] ], "normalized": [] }, { "id": "entity-358-5", "type": "ADVERSE", "text": [ "granulocytopenia" ], "offsets": [ [ 246, 262 ] ], "normalized": [] }, { "id": "entity-358-6", "type": "ADVERSE", "text": [ "TEN" ], "offsets": [ [ 358, 361 ] ], "normalized": [] }, { "id": "entity-358-7", "type": "DISEASE", "text": [ "urinary tract infection" ], "offsets": [ [ 442, 465 ] ], "normalized": [] }, { "id": "entity-358-8", "type": "DISEASE", "text": [ "chronic renal failure" ], "offsets": [ [ 494, 515 ] ], "normalized": [] }, { "id": "entity-358-9", "type": "DISEASE", "text": [ "allergic diathesis" ], "offsets": [ [ 543, 561 ] ], "normalized": [] }, { "id": "entity-358-10", "type": "ADVERSE", "text": [ "granulocytopenia" ], "offsets": [ [ 604, 620 ] ], "normalized": [] }, { "id": "entity-358-11", "type": "ADVERSE", "text": [ "gastrointestinal hemorrhage" ], "offsets": [ [ 637, 664 ] ], "normalized": [] }, { "id": "entity-358-12", "type": "ADVERSE", "text": [ "sepsis" ], "offsets": [ [ 673, 679 ] ], "normalized": [] }, { "id": "entity-358-13", "type": "ADVERSE", "text": [ "multiple organ failure syndrome" ], "offsets": [ [ 684, 715 ] ], "normalized": [] }, { "id": "entity-358-14", "type": "ADVERSE", "text": [ "TEN" ], "offsets": [ [ 907, 910 ] ], "normalized": [] }, { "id": "entity-358-15", "type": "ADVERSE", "text": [ "granulocytopenia" ], "offsets": [ [ 922, 938 ] ], "normalized": [] }, { "id": "entity-358-16", "type": "DISEASE", "text": [ "chronic renal failure" ], "offsets": [ [ 1003, 1024 ] ], "normalized": [] }, { "id": "entity-358-17", "type": "DISEASE", "text": [ "chronic renal failure" ], "offsets": [ [ 1261, 1282 ] ], "normalized": [] } ]

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[ { "id": "passage-359", "type": "abstract", "text": [ "Hepatic protection by noni fruit juice against CCl(4)-induced chronic liver damage in female SD rats. Morinda citrifolia L. (noni) has been used throughout the Pacific, Southeast Asia, Central America, and the Caribbean for a variety of health conditions, including heart and liver ailments. In this study, we examined the hepatoprotective effects of TAHITIAN NONI Juice (TNJ) against CCl(4)-induced chronic liver damage in female Sprague Dawley (SD) rats. Twelve female SD rats were divided into control, placebo and TNJ (6 mL/rat/day) groups. On day 15, animals in the placebo and TNJ groups received 0.25 mL/kg CCl(4) in corn oil once a week for 12 successive weeks. All animals were sacrificed at week 16. Blood and liver were collected for liver function, lipid panel tests, and histological observation. Histopathological examination revealed that liver sections from the TNJ + CCl(4) appeared similar to controls, whereas typical hepatic steatosis was observed in the placebo + CCl(4) group. Serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) levels were increased in the placebo group compared with the TNJ group. In contrast, high-density lipoprotein (HDL) was increased in the TNJ group and decreased in the placebo group. Thus, TNJ juice appears to protect the liver from chronic exogenous CCl(4) exposures. Such protective mechanisms are supportive evidence for the utility of noni in traditional medicine for liver ailments." ], "offsets": [ [ 0, 1598 ] ] } ]

[ { "id": "entity-359-0", "type": "ADVERSE", "text": [ "chronic liver damage" ], "offsets": [ [ 62, 82 ] ], "normalized": [] }, { "id": "entity-359-1", "type": "ADVERSE", "text": [ "chronic liver damage" ], "offsets": [ [ 401, 421 ] ], "normalized": [] }, { "id": "entity-359-2", "type": "ADVERSE", "text": [ "hepatic steatosis" ], "offsets": [ [ 938, 955 ] ], "normalized": [] } ]

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[ { "id": "passage-360", "type": "abstract", "text": [ "Occupational hazard: treating cocaine body packers in Caribbean countries. Body packing is a common method of smuggling cocaine where individuals ingest several drug-filled parcels for transport. When identified by the authorities, body packers are usually taken to hospital for evaluation. There are several points during management of these patients when the health care team may be placed at risk. We explore the hazards encountered during the management of these patients in developing Caribbean nations." ], "offsets": [ [ 0, 509 ] ] } ]

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[ { "id": "passage-361", "type": "abstract", "text": [ "A multi-centre dose-escalation and pharmacokinetic study of diflomotecan in patients with advanced malignancy. PURPOSE: Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of diflomotecan doses administered intravenously. METHODS: Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups-2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to diflomotecan administration in cycles 1 and 2. RESULTS: Thirteen patients, were treated with a starting dose of either 2 mg (n = 8) or 4 mg (n = 5) of diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer. CONCLUSIONS: Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials." ], "offsets": [ [ 0, 2316 ] ] } ]

[ { "id": "entity-361-0", "type": "DISEASE", "text": [ "malignancy" ], "offsets": [ [ 99, 109 ] ], "normalized": [] }, { "id": "entity-361-1", "type": "ADVERSE", "text": [ "dose limiting toxicity" ], "offsets": [ [ 248, 270 ] ], "normalized": [] }, { "id": "entity-361-2", "type": "DISEASE", "text": [ "malignant tumours" ], "offsets": [ [ 460, 477 ] ], "normalized": [] }, { "id": "entity-361-3", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1346, 1357 ] ], "normalized": [] }, { "id": "entity-361-4", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1457, 1468 ] ], "normalized": [] }, { "id": "entity-361-5", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1490, 1501 ] ], "normalized": [] }, { "id": "entity-361-6", "type": "DISEASE", "text": [ "oesophageal cancer" ], "offsets": [ [ 1964, 1982 ] ], "normalized": [] } ]

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[ { "id": "passage-362", "type": "abstract", "text": [ "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD. METHODS: We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233. FINDINGS: 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated. INTERPRETATION: Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD." ], "offsets": [ [ 0, 2037 ] ] } ]

[ { "id": "entity-362-0", "type": "DISEASE", "text": [ "chronic obstructive pulmonary disease" ], "offsets": [ [ 49, 86 ] ], "normalized": [] }, { "id": "entity-362-1", "type": "DISEASE", "text": [ "Chronic obstructive pulmonary disease" ], "offsets": [ [ 154, 191 ] ], "normalized": [] }, { "id": "entity-362-2", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 193, 197 ] ], "normalized": [] }, { "id": "entity-362-3", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 510, 514 ] ], "normalized": [] }, { "id": "entity-362-4", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "entity-362-5", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 949, 953 ] ], "normalized": [] }, { "id": "entity-362-6", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 1764, 1768 ] ], "normalized": [] }, { "id": "entity-362-7", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 2032, 2036 ] ], "normalized": [] } ]

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[ { "id": "passage-363", "type": "abstract", "text": [ "Altered first-pass effects in a liver transplant recipient explained intraindividual variation in calcineurin inhibitor concentrations: a case report. BACKGROUND: The significant interindividual and intraindividual variability in the blood concentrations of the most commonly used calcineurin inhibitors such as tacrolimus and cyclosporine makes the exact dosing of these agents in transplant recipients very challenging. As both of these drugs have narrow therapeutic index and are metabolized by hepatic and intestinal cytochrome P450 3A, we tested the hypothesis that these variations are secondary to varying first-pass effects in the gut and the liver over a period of time. CASE REPORT: A liver transplant recipient, who had previously presented with tacrolimus toxicity on his usual dosing regimen and intolerant to standard doses of cyclosporine, was selected to undergo the study. Oral and intravenous midazolam was used as the probe to measure hepatic and intestinal CYP3A4 activities at two different time points (phases one and two). Small intestinal biopsies were also obtained for measuring CYP3A4 activity for in vitro studies. On serially determining the patient's hepatic and intestinal CYP3A activities, we concluded that the variability in the dosing requirements is due to altered first-pass effects in the intestine. DISCUSSION: Transplant recipients receive multiple medications that may inhibit or induce these metabolizing enzymes, which eventually determine the concentrations of these narrow therapeutic agents. If no obvious etiology of intolerance to calcineurin inhibitors in a transplant recipient is identified, one should consider altered first-pass effects in the gut and the liver contributing to intraindividual variations in the blood concentrations." ], "offsets": [ [ 0, 1787 ] ] } ]

[ { "id": "entity-363-0", "type": "ADVERSE", "text": [ "tacrolimus toxicity" ], "offsets": [ [ 758, 777 ] ], "normalized": [] } ]

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[ { "id": "passage-364", "type": "abstract", "text": [ "Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10-50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15-290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells." ], "offsets": [ [ 0, 1372 ] ] } ]

[ { "id": "entity-364-0", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 39, 44 ] ], "normalized": [] }, { "id": "entity-364-1", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 541, 546 ] ], "normalized": [] }, { "id": "entity-364-2", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 929, 934 ] ], "normalized": [] }, { "id": "entity-364-3", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [] }, { "id": "entity-364-4", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 1292, 1297 ] ], "normalized": [] } ]

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[ { "id": "passage-365", "type": "abstract", "text": [ "Clostridium perfringens enterotoxin in antibiotic-associated diarrhea. Clostridium perfringens type A is associated with 5-20% cases of antibiotic-associated diarrhea (AAD) even though Clostridium difficile is implicated in the most severe cases. Fecal specimens from one hundred hospitalized patients, who developed diarrhea regardless of antibiotic intake and who were negative for C. difficile toxin assay, were investigated for C. perfringens enterotoxin (CPE). Simultaneously, cultures were set up for other possible aetiological factors. Ten healthy controls were also similarly investigated. CPE was positive in 2/100 (2%) of the patients and the samples were also positive for the organism in culture. Other organisms isolated were non-toxigenic C. difficile (4%), staphylococci (6%), Candida (18%) and Klebsiella pneumoniae (1%). Stool samples from healthy controls grew mixed growth of no significance and CPE was negative in all of them. Detection of CPE is not part of routine laboratory investigation due to resource implication. Criteria for initiating investigations have to be therefore established by understanding the true burden of C. perfringens-associated AAD by further research." ], "offsets": [ [ 0, 1202 ] ] } ]

[ { "id": "entity-365-0", "type": "DISEASE", "text": [ "antibiotic-associated diarrhea" ], "offsets": [ [ 39, 69 ] ], "normalized": [] }, { "id": "entity-365-1", "type": "DISEASE", "text": [ "antibiotic-associated diarrhea" ], "offsets": [ [ 137, 167 ] ], "normalized": [] }, { "id": "entity-365-2", "type": "DISEASE", "text": [ "diarrhea" ], "offsets": [ [ 318, 326 ] ], "normalized": [] }, { "id": "entity-365-3", "type": "DISEASE", "text": [ "Ten" ], "offsets": [ [ 545, 548 ] ], "normalized": [] } ]

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[ { "id": "passage-366", "type": "abstract", "text": [ "Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. PURPOSE: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate. RESULTS: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. CONCLUSION: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC." ], "offsets": [ [ 0, 1935 ] ] } ]

[ { "id": "entity-366-0", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 128, 154 ] ], "normalized": [] }, { "id": "entity-366-1", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 354, 380 ] ], "normalized": [] }, { "id": "entity-366-2", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 382, 387 ] ], "normalized": [] }, { "id": "entity-366-3", "type": "ADVERSE", "text": [ "Drug-related toxicity" ], "offsets": [ [ 1205, 1226 ] ], "normalized": [] }, { "id": "entity-366-4", "type": "ADVERSE", "text": [ "neutrophil count decreased" ], "offsets": [ [ 1395, 1421 ] ], "normalized": [] }, { "id": "entity-366-5", "type": "ADVERSE", "text": [ "alanine aminotransferase (glutamine pyruvic transaminase) increased" ], "offsets": [ [ 1434, 1501 ] ], "normalized": [] }, { "id": "entity-366-6", "type": "ADVERSE", "text": [ "neutrophil count decreased" ], "offsets": [ [ 1522, 1548 ] ], "normalized": [] }, { "id": "entity-366-7", "type": "ADVERSE", "text": [ "WBC count decreased" ], "offsets": [ [ 1558, 1577 ] ], "normalized": [] }, { "id": "entity-366-8", "type": "ADVERSE", "text": [ "lymphocyte count decreased" ], "offsets": [ [ 1591, 1617 ] ], "normalized": [] }, { "id": "entity-366-9", "type": "ADVERSE", "text": [ "interstitial lung disease" ], "offsets": [ [ 1664, 1689 ] ], "normalized": [] }, { "id": "entity-366-10", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 1843, 1848 ] ], "normalized": [] }, { "id": "entity-366-11", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 1929, 1934 ] ], "normalized": [] } ]

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[ { "id": "passage-367", "type": "abstract", "text": [ "Disparities in the use of chemotherapy and monoclonal antibody therapy for elderly advanced colorectal cancer patients in the community oncology setting. BACKGROUND: The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. METHODS: A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age <or=65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. RESULTS: Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). CONCLUSION: Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival." ], "offsets": [ [ 0, 1947 ] ] } ]

[ { "id": "entity-367-0", "type": "DISEASE", "text": [ "colorectal cancer" ], "offsets": [ [ 92, 109 ] ], "normalized": [] }, { "id": "entity-367-1", "type": "DISEASE", "text": [ "colorectal" ], "offsets": [ [ 222, 232 ] ], "normalized": [] }, { "id": "entity-367-2", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 234, 237 ] ], "normalized": [] }, { "id": "entity-367-3", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 375, 378 ] ], "normalized": [] }, { "id": "entity-367-4", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 439, 442 ] ], "normalized": [] }, { "id": "entity-367-5", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 639, 642 ] ], "normalized": [] }, { "id": "entity-367-6", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 741, 744 ] ], "normalized": [] } ]

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[ { "id": "passage-368", "type": "abstract", "text": [ "Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study. BACKGROUND AND OBJECTIVES: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. METHODS: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. RESULTS: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. CONCLUSION: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r." ], "offsets": [ [ 0, 2747 ] ] } ]

[ { "id": "entity-368-0", "type": "DISEASE", "text": [ "erectile dysfunction" ], "offsets": [ [ 442, 462 ] ], "normalized": [] } ]

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[ { "id": "passage-369", "type": "abstract", "text": [ "Dielectrophoretic field-flow fractionation system for detection of aquatic toxicants. Dielectrophoretic field-flow fractionation (dFFF) was applied as a contact-free way to sense changes in the plasma membrane capacitances and conductivities of cultured human HL-60 cells in response to toxicant exposure. A micropatterned electrode imposed electric forces on cells in suspension in a parabolic flow profile as they moved through a thin chamber. Relative changes in the dFFF peak elution time, reflecting changes in cell membrane area and ion permeability, were measured as indices of response during the first 150 min of exposure to eight toxicants having different single or mixed modes of action (acrylonitrile, actinomycin D, carbon tetrachloride, endosulfan, N-nitroso- N-methylurea (NMU), paraquat dichloride, puromycin, and styrene oxide). The dFFF method was compared with the cell viability assay for all toxicants and with the mitochondrial potentiometric dye assay or DNA alkaline comet assay according to the mode of action of the specific agents. Except for low doses of nucleic acid-targeting agents (actinomycin D and NMU), the dFFF method detected all toxicants more sensitively than other assays, in some cases up to 10 (5) times more sensitively than the viability approach. The results suggest the dFFF method merits additional study for possible applicability in toxicology." ], "offsets": [ [ 0, 1395 ] ] } ]

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[ { "id": "passage-370", "type": "abstract", "text": [ "Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans. Prioritization of compounds based on human hepatotoxicity potential is currently a key unmet need in drug discovery, as it can become a major problem for several lead compounds in later stages of the drug discovery pipeline. The authors report the validation and implementation of a high-content multiparametric cytotoxicity assay based on simultaneous measurement of 8 key cell health indicators associated with nuclear morphology, plasma membrane integrity, mitochondrial function, and cell proliferation. Compounds are prioritized by (a) computing an in vitro safety margin using the minimum cytotoxic concentration (IC(20)) across all 8 indicators and cell-based efficacy data and (b) using the minimal cytotoxic concentration alone to take into account concentration of drug in tissues. Feasibility data using selected compounds, including quinolone antibiotics, thiazolidinediones, and statins, suggest the viability of this approach. To increase overall throughput of compound prioritization, the authors have identified the higher throughput, plate reader-based CyQUANT assay that is similar to the high-content screening (HCS) assay in sensitivity of measuring inhibition of cell proliferation. It is expected that the phenotypic output from the multiparametric HCS assay in combination with other highly sensitive approaches, such as microarray-based expression analysis of toxic signatures, will contribute to a better understanding and predictivity of human hepatotoxicity potential." ], "offsets": [ [ 0, 1623 ] ] } ]

[ { "id": "entity-370-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 45, 57 ] ], "normalized": [] }, { "id": "entity-370-1", "type": "ADVERSE", "text": [ "hepatotoxicity" ], "offsets": [ [ 171, 185 ] ], "normalized": [] }, { "id": "entity-370-2", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 440, 452 ] ], "normalized": [] }, { "id": "entity-370-3", "type": "ADVERSE", "text": [ "hepatotoxicity" ], "offsets": [ [ 1598, 1612 ] ], "normalized": [] } ]

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[ { "id": "passage-371", "type": "abstract", "text": [ "Induction of the multixenobiotic/multidrug resistance system in various cell lines in response to perfluorinated carboxylic acids. The multixenobiotic resistance (closely related to multidrug resistance) system controls transport across the plasma membrane as a defense against toxic molecules. Multixenobiotic resistance system consists of an efflux pump, ABCB1 (also named P-glycoprotein, P-gp), and/or a molecule of the ABCC family (also named multiple resistance associated protein, MRP). ABCB1 is able to increase efflux of many low-molecular foreign molecules. Measuring system induction may be used as a biomarker of cell/organism exposure to foreign substances. Various established cell lines were tested for constitutive and induced multixenobiotic resistance proteins by Western blotting immunodetection. The pumping function was indirectly assayed with Rhodamine B by visualization of cell fluorescence in the presence of verapamil. Changes in ABC proteins were measured by flow cytometry after exposition to various perfluorinated carboxylic acids. MCF7 and HeLa cells were found to contain the highest constitutive level of both ABCB1 and ABCC1. HEK293 exhibited much less ABCB1 and no activity of pumping out Rhodamine B. The pumping activity was found to be related to the amount of the cell-type specific 170 kDa ABCB1 protein. An 8-day exposure to 10(-4) M perfluorononanoic acid resulted in about 2-2.5-fold increase of ABCB1 level. That was confirmed also for short times by flow cytometry of cells exposed to perfluorinated acids and its natural congeners. Both ABCB1- and ABCC1-related fluorescence increased along with the carbon chain in acids from C(6) up to C(9) and decreased for C(10). Measuring of multixenobiotic resistance changes in vitro induced by chemicals may be a convenient test for screening for their potential toxicity." ], "offsets": [ [ 0, 1860 ] ] } ]

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[ { "id": "passage-372", "type": "abstract", "text": [ "Capecitabine: have we got the dose right? In the past 5-10 years there has been a growing trend for substituting conventional 5-fluorouracil with the oral prodrug of 5-fluorouracil, capecitabine, in chemotherapy regimens. This regimen change is based on evidence of the efficacy equivalence of these two drugs and the lack of an increase in overall toxic effects when capecitabine is used. Many investigators in different parts of the world have determined their own starting dose for capecitabine, usually based on their experience of toxic events within the population of patients they treat. This starting dose is usually between 1,000-1,250 mg/m(2), which is generally administered twice daily for 14 days followed by 7 days rest. This Review summarizes why there may indeed not be a universally applicable starting dose for capecitabine because of interpatient differences in basic physiology, pharmacogenomics and diet. This article also explores which of these factors contribute to the observed inter-regional geographical variation in capecitabine toxicity, and explains why even within a region various factors should prompt a clinician to modify the starting dose." ], "offsets": [ [ 0, 1176 ] ] } ]

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[ { "id": "passage-373", "type": "abstract", "text": [ "Pharmacological profile, efficacy and safety of rupatadine in allergic rhinitis. Allergic rhinitis (AR) is a disease with high prevalence. In AR, exposure to airborne allergens elicits an allergic response which involves epithelial accumulation of effector cells - e.g. mast cells and basophils - and subsequent inflammation. During the early response in AR, histamine has been found to be the most abundant mediator and it is associated with many symptoms of this disease mediated through the histamine H1 receptor. Therefore, anti-histamines have a role to play in the management of AR. However, the available antihistamines have certain well-known side effects like sedation and potential pro-arrythmic effects owing to their interactions with other drugs, as well as having poor or no effect on platelet activating factor (PAF) which also plays an important role in AR. This article is a qualitative systematic literature review on the pharmacological profile of rupatadine in order to evaluate its safety and efficacy in AR as compared to other anti-histamines. Rupatadine is a once-daily non-sedative, selective, long-acting H1 anti-histamine with antagonistic PAF effects through its interaction with specific receptors. Rupatadine significantly improves nasal symptoms in patients with AR. It has a good safety profile and is devoid of arrythmogenic effects. These properties make rupatadine a suitable first line anti-histamine for the treatment of AR." ], "offsets": [ [ 0, 1462 ] ] } ]

[ { "id": "entity-373-0", "type": "DISEASE", "text": [ "allergic rhinitis" ], "offsets": [ [ 62, 79 ] ], "normalized": [] }, { "id": "entity-373-1", "type": "DISEASE", "text": [ "Allergic rhinitis" ], "offsets": [ [ 82, 99 ] ], "normalized": [] }, { "id": "entity-373-2", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 101, 103 ] ], "normalized": [] }, { "id": "entity-373-3", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 143, 145 ] ], "normalized": [] }, { "id": "entity-373-4", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 313, 325 ] ], "normalized": [] }, { "id": "entity-373-5", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 356, 358 ] ], "normalized": [] }, { "id": "entity-373-6", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 586, 588 ] ], "normalized": [] }, { "id": "entity-373-7", "type": "ADVERSE", "text": [ "sedation" ], "offsets": [ [ 670, 678 ] ], "normalized": [] }, { "id": "entity-373-8", "type": "ADVERSE", "text": [ "pro-arrythmic effects" ], "offsets": [ [ 693, 714 ] ], "normalized": [] }, { "id": "entity-373-9", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 871, 873 ] ], "normalized": [] }, { "id": "entity-373-10", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 1027, 1029 ] ], "normalized": [] }, { "id": "entity-373-11", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 1295, 1297 ] ], "normalized": [] }, { "id": "entity-373-12", "type": "ADVERSE", "text": [ "arrythmogenic effects" ], "offsets": [ [ 1345, 1366 ] ], "normalized": [] }, { "id": "entity-373-13", "type": "DISEASE", "text": [ "AR" ], "offsets": [ [ 1459, 1461 ] ], "normalized": [] } ]

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[ { "id": "passage-374", "type": "abstract", "text": [ "Nitrate-induced toxicity and preconditioning: a rationale for reconsidering the use of these drugs. Although organic nitrates have been clinically used for more than a century, findings in the last decade have radically challenged our traditional view concerning the mechanism(s) of their clinical effects and implications. While their hemodynamic properties are well known, the knowledge that nitrates possess previously unexpected nonhemodynamic effects is a unique opportunity of which clinicians should be aware but, at the same time, it also provides a rationale to worry about previously unanticipated clinical consequences of long-term treatment with these drugs." ], "offsets": [ [ 0, 671 ] ] } ]

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[ { "id": "passage-375", "type": "abstract", "text": [ "Adjuvant treatment with vindesine in comparison to observation alone in patients with metastasized melanoma after complete metastasectomy: a randomized multicenter trial of the German Dermatologic Cooperative Oncology Group. To evaluate the efficacy and safety of vindesine in patients with metastatic melanoma after complete metastasectomy. One hundred and forty-two patients with metastatic spread to regional sites, lymph nodes, and distant sites after complete metastasectomy were randomized to receive either treatment with vindesine for 2 years or observation alone. Vindesine 3 mg/m intravenously was administered biweekly for the first 26 weeks following 3-week intervals for an additional 26 weeks and thereafter every 4 weeks for 52 weeks. One hundred and thirty-nine patients were eligible for intent-to-treat analysis. Median follow-up time was 46 months. Median recurrence free survival was 7.9 months in the vindesine group and 7.6 months in the observational group (P=0.40). Three-year overall survival rate was 54.9% (37 patients) for patients receiving vindesine in comparison to 43.6% (31 patients) in the observation arm (P=0.07). No grade IV toxicity was observed. The two major side effects in the vindesine group were alopecia and peripheral neuropathy. Ten patients went off treatment because of grade III toxicity. Adjuvant treatment with vindesine did not significantly prolong disease free or overall survival in high-risk melanoma patients. Thus, this randomized trial did not confirm earlier reports of beneficial effects of adjuvant vindesine and can therefore not be recommended." ], "offsets": [ [ 0, 1610 ] ] } ]

[ { "id": "entity-375-0", "type": "DISEASE", "text": [ "metastasized melanoma" ], "offsets": [ [ 86, 107 ] ], "normalized": [] }, { "id": "entity-375-1", "type": "DISEASE", "text": [ "metastatic melanoma" ], "offsets": [ [ 292, 311 ] ], "normalized": [] }, { "id": "entity-375-2", "type": "ADVERSE", "text": [ "alopecia" ], "offsets": [ [ 1241, 1249 ] ], "normalized": [] }, { "id": "entity-375-3", "type": "ADVERSE", "text": [ "peripheral neuropathy" ], "offsets": [ [ 1254, 1275 ] ], "normalized": [] }, { "id": "entity-375-4", "type": "DISEASE", "text": [ "melanoma" ], "offsets": [ [ 1450, 1458 ] ], "normalized": [] } ]

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[ { "id": "passage-376", "type": "abstract", "text": [ "The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Vascular Endothelial Growth Factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a new key target in anti-cancer treatment. Various clinical trials have validated the clinical importance of anti-VEGF or anti-VEGF receptor (VEGFR) therapy. Currently the humanized monoclonal antibody bevacizumab (blocks VEGF-A), and the tyrosine kinase inhibitors sunitinib and sorafenib (inhibit VEGFRs) are approved for patients with various malignancies and several others are expected in the coming years. Unfortunately, anti-VEGF/VEGFR treatment is not void of side effects. An array of unexpected side effects is now seen in clinical practice. Management of these side effects is extremely important in the development of the various anti-VEGF/VEGFR therapies and their optimal use. This review provides an overview of the toxicity profile of this class of agents, the molecular basis behind these side effects and indicates potential options for management. VEGF and its receptors play an important role in normal tissues and are widely expressed. It is likely that interference with this pathway induces an array of side effects due to the lack of normal function of VEGF. A consistent pattern of side effects is now emerging. Hypertension, gastro-intestinal toxicity, hypothyroidism, proteinuria, coagulation disorders and neurotoxicity are side effects observed with both anti-VEGF and anti-VEGFR inhibitors. For these side effects the role of VEGF/VEGFR pathway in normal tissue was reviewed in order to provide a molecular mechanism that linked side effect with physiological activity of VEGF/VEGFR. Insight into the molecular basis may aid specific supportive care measures to ensure optimal use of this class of agents. Conclusion: Inhibiting the VEGF/VEGFR pathway is an effective approach to treat cancer. It has also provided new insight into the physiological role of this pathway in various organs. Integrating the knowledge in daily oncological practice will be a challenge for the future." ], "offsets": [ [ 0, 2133 ] ] } ]

[ { "id": "entity-376-0", "type": "DISEASE", "text": [ "malignancies" ], "offsets": [ [ 568, 580 ] ], "normalized": [] }, { "id": "entity-376-1", "type": "ADVERSE", "text": [ "Hypertension" ], "offsets": [ [ 1359, 1371 ] ], "normalized": [] }, { "id": "entity-376-2", "type": "ADVERSE", "text": [ "gastro-intestinal toxicity" ], "offsets": [ [ 1373, 1399 ] ], "normalized": [] }, { "id": "entity-376-3", "type": "ADVERSE", "text": [ "hypothyroidism" ], "offsets": [ [ 1401, 1415 ] ], "normalized": [] }, { "id": "entity-376-4", "type": "ADVERSE", "text": [ "proteinuria" ], "offsets": [ [ 1417, 1428 ] ], "normalized": [] }, { "id": "entity-376-5", "type": "ADVERSE", "text": [ "coagulation disorders" ], "offsets": [ [ 1430, 1451 ] ], "normalized": [] }, { "id": "entity-376-6", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 1456, 1469 ] ], "normalized": [] }, { "id": "entity-376-7", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 1938, 1944 ] ], "normalized": [] } ]

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[ { "id": "passage-377", "type": "abstract", "text": [ "Novel roles for ceramides, calpains and caspases in kidney proximal tubule cell apoptosis: lessons from in vitro cadmium toxicity studies. Apoptosis is a tightly regulated physiological process, which can be initiated by toxic stimuli, such as cadmium (Cd2+). Cd2+ (10-50 microM) induces a rapid increase in reactive oxygen species (ROS) (> or = 30 min) in a cell line derived from the S1 segment of rat kidney proximal tubule, without any apparent mitochondrial dysfunction. The sphingolipid ceramide is an important second messenger in apoptosis. Short exposure to Cd2+ (3h) causes an increase in ceramides, which occurs downstream of ROS formation, and may interact with cellular components, such as endoplasmic reticulum and mitochondria. Following apoptosis initiation, execution must take place. The classical executioners of apoptosis are caspases, a family of cysteine proteases. However, increasing studies report caspase-independent apoptosis, which questions the essentiality of caspases for apoptosis implementation. With low micromolar Cd2+ concentrations (< 10 microM), caspases are only activated after 24h and not at earlier time points, which supports the notion of caspase-independent apoptosis. Due to increased cytosolic Ca(2+) under pathological conditions, a role for the Ca2+-dependent proteases, calpains, has emerged. Calpain activation by Cd2+ (3-6h) seems to be regulated by ceramide levels, in order to induce apoptosis. Calpain and caspase substrates overlap but yield different fragments, which may explain their diverse downstream targets. Furthermore, calpains and caspases may interact with one another to enhance, as seen by Cd2+, or diminish apoptosis. In this review, we discuss novel roles for ceramides, calpains and caspases as part of Cd2+-induced apoptotic signalling pathways in the kidney proximal tubule and their in vivo relevance to Cd2+-induced nephrotoxicity." ], "offsets": [ [ 0, 1908 ] ] } ]

[ { "id": "entity-377-0", "type": "ADVERSE", "text": [ "cadmium toxicity" ], "offsets": [ [ 113, 129 ] ], "normalized": [] }, { "id": "entity-377-1", "type": "ADVERSE", "text": [ "nephrotoxicity" ], "offsets": [ [ 1893, 1907 ] ], "normalized": [] } ]

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[ { "id": "passage-378", "type": "abstract", "text": [ "Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies. PURPOSE: This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. PATIENTS AND METHODS: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m(2) intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m(2)/day which was escalated by 250 mg/m(2)/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. RESULTS: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m(2), two DLT of prolonged neutropenia of grade > or =3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m(2)/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. CONCLUSIONS: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts." ], "offsets": [ [ 0, 2371 ] ] } ]

[ { "id": "entity-378-0", "type": "DISEASE", "text": [ "solid malignancies" ], "offsets": [ [ 101, 119 ] ], "normalized": [] }, { "id": "entity-378-1", "type": "DISEASE", "text": [ "solid malignancies" ], "offsets": [ [ 312, 330 ] ], "normalized": [] }, { "id": "entity-378-2", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1631, 1642 ] ], "normalized": [] }, { "id": "entity-378-3", "type": "ADVERSE", "text": [ "Fatigue" ], "offsets": [ [ 1744, 1751 ] ], "normalized": [] }, { "id": "entity-378-4", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1756, 1764 ] ], "normalized": [] }, { "id": "entity-378-5", "type": "ADVERSE", "text": [ "hematologic toxicity" ], "offsets": [ [ 1850, 1870 ] ], "normalized": [] }, { "id": "entity-378-6", "type": "DISEASE", "text": [ "solid malignancies" ], "offsets": [ [ 2201, 2219 ] ], "normalized": [] } ]

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[ { "id": "passage-379", "type": "abstract", "text": [ "Endogenous alpha-calcitonin gene-related peptide mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A. BACKGROUND: Alpha-calcitonin gene-related peptide (alphaCGRP) is a 37-amino acid pleiotropic peptide that we previously showed to exert a hepatoprotective effect during concanavalin A (Con A)-induced acute hepatitis. In the present study, we used alphaCGRP(-/-) mice to further investigate the antifibrogenic and hepatoprotective effects of endogenous alphaCGRP in Con A-induced chronic hepatitis. METHODS: Chronic hepatitis was induced in alphaCGRP(-/-) and wild-type mice by repeated administration of Con A. Serum transaminases were measured to assess hepatic injury. The severity of fibrosis and the activation of hepatic stellate cells (HSCs) were analysed by Masson trichrome staining and immunohistochemical staining of alpha-smooth muscle actin (alpha-SMA) respectively. Altered expression of fibrosis- and inflammation-related genes was evaluated using a quantitative real-time polymerase chain reaction. Activation and proliferation of HSCs were analysed using both primary cultured HSCs from the mice and the LI90 HSC cell line. RESULTS: alphaCGRP(-/-) mice showed more severe liver fibrosis than wild-type mice in a Con A-induced chronic hepatitis model. In histological and gene expression analyses, alphaCGRP(-/-) mice showed greater inflammatory and fibrotic changes, greater HSC activation and a higher incidence of apoptosis among nonparenchymal cells than wild-type mice. CONCLUSIONS: Endogenous alphaCGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of Con A. alphaCGRP could be a useful therapeutic target for the treatment of chronic hepatitis." ], "offsets": [ [ 0, 1751 ] ] } ]

[ { "id": "entity-379-0", "type": "DISEASE", "text": [ "liver fibrosis" ], "offsets": [ [ 59, 73 ] ], "normalized": [] }, { "id": "entity-379-1", "type": "DISEASE", "text": [ "chronic hepatitis" ], "offsets": [ [ 77, 94 ] ], "normalized": [] }, { "id": "entity-379-2", "type": "DISEASE", "text": [ "A (Con A)-induced acute hepatitis" ], "offsets": [ [ 332, 365 ] ], "normalized": [] }, { "id": "entity-379-3", "type": "DISEASE", "text": [ "chronic hepatitis" ], "offsets": [ [ 529, 546 ] ], "normalized": [] }, { "id": "entity-379-4", "type": "DISEASE", "text": [ "Chronic hepatitis" ], "offsets": [ [ 557, 574 ] ], "normalized": [] }, { "id": "entity-379-5", "type": "DISEASE", "text": [ "injury" ], "offsets": [ [ 713, 719 ] ], "normalized": [] }, { "id": "entity-379-6", "type": "DISEASE", "text": [ "fibrosis" ], "offsets": [ [ 737, 745 ] ], "normalized": [] }, { "id": "entity-379-7", "type": "DISEASE", "text": [ "liver fibrosis" ], "offsets": [ [ 1238, 1252 ] ], "normalized": [] }, { "id": "entity-379-8", "type": "DISEASE", "text": [ "chronic hepatitis" ], "offsets": [ [ 1292, 1309 ] ], "normalized": [] }, { "id": "entity-379-9", "type": "DISEASE", "text": [ "apoptosis" ], "offsets": [ [ 1482, 1491 ] ], "normalized": [] }, { "id": "entity-379-10", "type": "DISEASE", "text": [ "liver fibrosis" ], "offsets": [ [ 1584, 1598 ] ], "normalized": [] }, { "id": "entity-379-11", "type": "DISEASE", "text": [ "chronic hepatitis" ], "offsets": [ [ 1602, 1619 ] ], "normalized": [] }, { "id": "entity-379-12", "type": "DISEASE", "text": [ "chronic hepatitis" ], "offsets": [ [ 1733, 1750 ] ], "normalized": [] } ]

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[ { "id": "passage-380", "type": "abstract", "text": [ "D-chiro-inositol-enriched tartary buckwheat bran extract lowers the blood glucose level in KK-Ay mice. D-chiro-inositol (DCI) is an active compound in tartary buckwheat [Fagopyrum tataricum (L.) Gaench] with an insulin-like bioactivity. The present study was performed to (i) prepare DCI-enriched tartary buckwheat bran extract (TBBE), (ii) evaluate its acute toxicity in mice, and (iii) examine its blood glucose lowering activity in diabetic mice. It was found that steaming buckwheat bran in an autoclave at 1.6 MPa and 120 degrees C for 60 min could significantly enrich the DCI level in TBBE from 0.03 to 0.22% and further to 22% after passage of the TBBE through activated carbon and ion exchange resins. An acute toxicity test demonstrated that the LD 50 of TBBE was >20 g/kg of body weight in mice, suggesting that TBBE was in general nontoxic and safe in mice. Male KK-A(y) mice (type 2 diabetic) and C57BL/6 mice (the control) were used to investigate the antidiabetic activity of TBBE. In KK-A(y) mice, the blood glucose, plasma C-peptide, glucagon, total cholesterol, triglyceride, and blood urea nitrogen (BUN) levels were significantly higher than those in the C57BL/6 mice. In addition, KK-A(y) mice showed an obvious decrease in insulin immunoreactivity in the pancreas. The present study clearly demonstrated that oral administration of DCI-enriched TBBE could lower plasma glucose, C-peptide, glucagon, triglyceride, and BUN, improve glucose tolerance, and enhance insulin immunoreactivity in KK-A(y) mice." ], "offsets": [ [ 0, 1525 ] ] } ]

[ { "id": "entity-380-0", "type": "ADVERSE", "text": [ "acute toxicity" ], "offsets": [ [ 355, 369 ] ], "normalized": [] }, { "id": "entity-380-1", "type": "ADVERSE", "text": [ "acute toxicity" ], "offsets": [ [ 715, 729 ] ], "normalized": [] }, { "id": "entity-380-2", "type": "DISEASE", "text": [ "type 2 diabetic" ], "offsets": [ [ 890, 905 ] ], "normalized": [] }, { "id": "entity-380-3", "type": "DISEASE", "text": [ "tolerance" ], "offsets": [ [ 1461, 1470 ] ], "normalized": [] } ]

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[ { "id": "passage-381", "type": "abstract", "text": [ "Evidence for altered hippocampal volume and brain metabolites in workers occupationally exposed to lead: a study by magnetic resonance imaging and (1)H magnetic resonance spectroscopy. Environmental and occupational exposure to lead (Pb) remains to be a major public health issue. The purpose of this cross-sectional study was to use non-invasive magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) techniques to investigate whether chronic exposure to Pb in an occupational setting altered brain structure and function of Pb-exposed workers. The Pb-exposed group consisted of 15 workers recruited from either a Pb-smelting factory or a Pb-battery manufacturer. The control group had 19 healthy volunteers who had no history of Pb exposure in working environment or at home. The average airborne Pb concentrations in fume and dust were 0.43 and 0.44 mg/m(3), respectively, in the smeltery, and 0.10 and 1.06 mg/m(3), respectively, in the Pb battery workshop. The average blood Pb concentrations (BPb) in Pb-exposed and control workers were 63.5 and 8.7 microg/dL, respectively. The MRI examination showed that brain hippocampal volume among Pb-exposed workers was significantly diminished in comparison to age-matched control subjects (p < 0.01), although the extent of this reduction was relatively small (5-6% of the control values). Linear regression analyses revealed significant inverse associations between BPb and the decreased hippocampal volume on both sides of brain hemisphere. Among five brain metabolites investigated by MRS, i.e., N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), inosine (mI), glutamate/glutamine (Glx) and lipids (Lip), a significant decrease in NAA/Cr ratio (7% of controls, p < 0.05) and a remarkable increase in Lip/Cr ratio (40%, p < 0.01) were observed in the brains of Pb-exposed workers as compared to controls. Furthermore, the increased Lip/Cr ratio was significantly associated with BPb (r = 0.46, p < 0.01). Taken together, this study suggests that occupational exposure to Pb may cause subtle structural and functional alteration in human brains. The MRI and MRS brain imaging techniques can be used as the non-invasive means to evaluate Pb-induced neurotoxicity." ], "offsets": [ [ 0, 2250 ] ] } ]

[ { "id": "entity-381-0", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 2236, 2249 ] ], "normalized": [] } ]

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[ { "id": "passage-382", "type": "abstract", "text": [ "Synthesis and biological evaluation of bile acid dimers linked with 1,2,3-triazole and bis-beta-lactam. We report herein the synthesis and biological evaluation of bile acid dimers linked through 1,2,3-triazole and bis-beta-lactam. The dimers were synthesized using 1,3-dipolar cycloaddition reaction of diazido bis-beta-lactams , and terminal alkynes derived from cholic acid/deoxycholic acid in the presence of Cu(i) catalyst (click chemistry). These novel molecules were evaluated in vitro for their antifungal and antibacterial activity. Most of the compounds exhibited significant antifungal as well as antibacterial activity against all the tested fungal and bacterial strains. Moreover, their in vitro cytotoxicities towards HEK-293 and MCF-7 cells were also established." ], "offsets": [ [ 0, 779 ] ] } ]

[ { "id": "entity-382-0", "type": "ADVERSE", "text": [ "cytotoxicities" ], "offsets": [ [ 710, 724 ] ], "normalized": [] } ]

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[ { "id": "passage-383", "type": "abstract", "text": [ "Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. A total of 28 treatment-na?ve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide." ], "offsets": [ [ 0, 909 ] ] } ]

[ { "id": "entity-383-0", "type": "DISEASE", "text": [ "multiple myeloma" ], "offsets": [ [ 129, 145 ] ], "normalized": [] }, { "id": "entity-383-1", "type": "DISEASE", "text": [ "multiple myeloma" ], "offsets": [ [ 208, 224 ] ], "normalized": [] }, { "id": "entity-383-2", "type": "DISEASE", "text": [ "MM" ], "offsets": [ [ 226, 228 ] ], "normalized": [] } ]

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[ { "id": "passage-384", "type": "abstract", "text": [ "Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group Pilot Study. PURPOSE: To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone and in combination with reinduction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL), and to preliminarily assess tumor targeting and efficacy. PATIENTS AND METHODS: Therapy consisted of a single-agent phase (epratuzumab 360 mg/m(2)/dose intravenously twice weekly x four doses), followed by four weekly doses of epratuzumab in combination with standard reinduction chemotherapy. Morphologic and minimal residual disease (MRD) responses were determined at the end of this 6-week period. Serum concentrations of epratuzumab were determined before and 30 minutes after infusions, and CD22 targeting efficiency was determined by quantifying changes in CD22 expression after epratuzumab administration. RESULTS: Fifteen patients (12 fully assessable for toxicity) with first or later CD22-positive ALL marrow relapse enrolled on the feasibility portion of this study from December 2005 to June 2006. Two dose-limiting toxicities occurred: one grade 4 seizure of unclear etiology and one asymptomatic grade 3 ALT elevation. In all but one patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab. Nine patients achieved a complete remission after chemoimmunotherapy, seven of whom were MRD negative. CONCLUSION: Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and acceptably tolerated in children with relapsed CD22-positive ALL. CD22 targeting was efficient, and the majority of patients achieved favorable early responses." ], "offsets": [ [ 0, 1915 ] ] } ]

[ { "id": "entity-384-0", "type": "DISEASE", "text": [ "acute lymphoblastic leukemia" ], "offsets": [ [ 65, 93 ] ], "normalized": [] }, { "id": "entity-384-1", "type": "DISEASE", "text": [ "acute lymphoblastic leukemia" ], "offsets": [ [ 376, 404 ] ], "normalized": [] }, { "id": "entity-384-2", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "entity-384-3", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1120, 1123 ] ], "normalized": [] }, { "id": "entity-384-4", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 1273, 1280 ] ], "normalized": [] }, { "id": "entity-384-5", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 1816, 1819 ] ], "normalized": [] } ]

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[ { "id": "passage-385", "type": "abstract", "text": [ "Transient gene delivery for functional enrichment of differentiating embryonic stem cells. There is a critical need for new sources of hepatocytes, both clinically to provide support for patients with liver failure and in drug discovery for toxicity, metabolic and pharmacokinetic screening of new drug entities. We have reported previously a variety of methods for differentiating murine embryonic stem (ES) cells into hepatocyte-like cells. One major challenge of our work and others in the field has been the ability to selectively purify and enrich these cells from a heterogeneous population. Traditional approaches for inserting new genes (e.g., stable transfection, knock-in, retroviral transduction) involve permanent alterations in the genome. These approaches can lead to mutations and involve the extra costs and time of developing, validating and maintaining new cell lines. We have developed a transient gene delivery system that uses fluorescent gene reporters for purification of the cells. Following a transient transfection, the cells are purified through a fluorescence-activated cell sorter (FACS), re-plated in secondary culture and subsequent phenotypic analysis is performed. In an effort to test the ability of the reporters to work in a transient environment for our differentiation system, we engineered two non-viral plasmid reporters, the first driven by the mouse albumin enhancer/promoter and the second by the mouse cytochrome P450 7A1 (Cyp7A1) promoter. We optimized the transfection efficiency of delivering these genes into spontaneously differentiated ES cells and sorted independent fractions positive for each reporter 17 days after inducing differentiation. We found that cells sorted based on the Cyp7A1 promoter showed significant enrichment in terms of albumin secretion, urea secretion and cytochrome P450 1A2 detoxification activity as compared to enrichment garnered by the albumin promoter-based cell sort. Development of gene reporter systems that allow us to identify, purify and assess homogeneous populations of cells is important in better understanding stem cell differentiation pathways. And engineering cellular systems without making permanent gene changes will be critical for the generation of clinically acceptable cellular material in the future." ], "offsets": [ [ 0, 2304 ] ] } ]

[ { "id": "entity-385-0", "type": "DISEASE", "text": [ "liver failure" ], "offsets": [ [ 202, 215 ] ], "normalized": [] } ]

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[ { "id": "passage-386", "type": "abstract", "text": [ "Pentachlorophenol decreases ATP levels in human natural killer cells. Pentachlorophenol (PCP) is used as a wood preservative and is found in human blood and urine. PCP causes significant decreases in the tumor-killing (lytic) function of human natural killer (NK) cells, a critical immune defense. The current study examined the association between decreased lytic function and decreased ATP levels, as well as the ability of antioxidants (vitamin E and reduced glutathione) to prevent PCP-induced decreases in either ATP levels or lytic function. Exposure of NK cells to 10 microm PCP decreased ATP levels by 15% at 24 h, and exposure to 5 microm PCP decreased ATP levels by 32% at 48 h. No effects were seen with 0.5 microm at 48 h or with 5 microm at 24 h. However, 10 microm PCP decreased lytic function by 69% at 24 h and 5 microm decreased it by 90% at 48 h. Even 0.5 microm PCP decreased lytic function by 46% at 48 h. None of these effects were prevented by pretreatment with 1 mm vitamin E or reduced glutathione." ], "offsets": [ [ 0, 1023 ] ] } ]

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[ { "id": "passage-387", "type": "abstract", "text": [ "Blood pressure lowering efficacy of renin inhibitors for primary hypertension. BACKGROUND: Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. The renin-angiotensin-aldosterone system is an important target site for five antihypertensive drug classes: beta blockers, renin inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs) and aldosterone inhibitors. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors prevent the formation of both angiotensin I and angiotensin II . Renin inhibitors do not affect kinin metabolism and may produce fewer adverse effects than ACE inhibitors such as dry cough or angioedema. OBJECTIVES: To quantify the dose-related blood pressure lowering efficacy of renin inhibitors versus placebo in the treatment of primary hypertension. SEARCH STRATEGY: We searched the following databases for randomised, double blind, placebo-controlled trials of renin inhibitors: Medline (1966-March 2008), EMBASE (1988-March 2008), Cochrane CENTRAL, and bibliographic citations from retrieved references. No language restrictions were applied. SELECTION CRITERIA: Study design had to meet the following criteria: double-blinded, placebo-controlled; random allocation to a specific dose of renin inhibitor group and parallel placebo group; duration of follow-up of at least three weeks. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using risk of bias tables. Disagreements were resolved by discussion or a third reviewer. Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5. Data for continuous variables were combined using a weighted mean difference method. Dichotomous variables were analysed using relative risk. MAIN RESULTS: Six trials (N=3694) met the inclusion criteria for this review. Aliskiren was the only renin inhibitor studied in these studies. The meta-analysis shows that aliskiren has a dose-related both systolic/diastolic blood pressure lowering effect as compared to placebo: aliskiren 75 mg -2.9/-2.3 mmHg, aliskiren 150 mg -5.5/-3.0 mmHg, aliskiren 300 mg -8.7/-5.0, aliskiren 600 mg -11.4/-6.6 mmHg. Aliskiren 300 mg significantly lowered both SBP and DBP as compared to aliskiren 150 mg (SBP:-2.97 (95% CI -3.99, -1.95) and DBP: -1.66 (95% CI -2.32, -1.0). Aliskiren has no effect on blood pressure variability. No data was available to assess the effect of aliskiren on heart rate and pulse pressure. This review found weak evidence that with short- term use, aliskiren does not increase withdrawals due to adverse effects as compared to placebo. AUTHORS' CONCLUSIONS: Aliskiren has a dose-related blood pressure lowering effect better than placebo. This effect is similar to that determined for ACE inhibitors and ARBs." ], "offsets": [ [ 0, 2899 ] ] } ]

[ { "id": "entity-387-0", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 6, 14 ] ], "normalized": [] }, { "id": "entity-387-1", "type": "DISEASE", "text": [ "primary hypertension" ], "offsets": [ [ 57, 77 ] ], "normalized": [] }, { "id": "entity-387-2", "type": "DISEASE", "text": [ "Hypertension" ], "offsets": [ [ 92, 104 ] ], "normalized": [] }, { "id": "entity-387-3", "type": "DISEASE", "text": [ "dry cough" ], "offsets": [ [ 733, 742 ] ], "normalized": [] }, { "id": "entity-387-4", "type": "DISEASE", "text": [ "angioedema" ], "offsets": [ [ 746, 756 ] ], "normalized": [] }, { "id": "entity-387-5", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 805, 813 ] ], "normalized": [] }, { "id": "entity-387-6", "type": "DISEASE", "text": [ "primary hypertension" ], "offsets": [ [ 887, 907 ] ], "normalized": [] }, { "id": "entity-387-7", "type": "DISEASE", "text": [ "blind" ], "offsets": [ [ 985, 990 ] ], "normalized": [] }, { "id": "entity-387-8", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 2101, 2109 ] ], "normalized": [] }, { "id": "entity-387-9", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 2468, 2476 ] ], "normalized": [] }, { "id": "entity-387-10", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 2570, 2578 ] ], "normalized": [] }, { "id": "entity-387-11", "type": "DISEASE", "text": [ "pressure" ], "offsets": [ [ 2783, 2791 ] ], "normalized": [] } ]

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[ { "id": "passage-388", "type": "abstract", "text": [ "Influence of valproic acid on outcome of high-grade gliomas in children. BACKGROUND: Chemotherapy has limited effects in the treatment of high-grade gliomas (HGGs). Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, may sensitize HGGs to radiochemotherapy. As the drug has been given frequently as an antiepileptic drug, a retrospective analysis was conducted to ensure relevant information was not missed before a prospective study was launched. MATERIALS AND METHODS: An analysis of 66 pediatric patients (range, 1-19 years of age) with glioblastoma multiforme (GBM) (n=40) or anaplastic astrocytoma (AA) (n=26) was retrospectively conducted for predictors of survival and response and for effects of VPA on outcome or toxicity. RESULTS: The overall survival (OS) was better for AA (p=0.0114) and complete resection (p<0.00005) and event-free survival (EFS) was better for complete resection (p=0.0049). Nine patients received VPA (for seizure) plus further oncological treatment. The most severe adverse effect was a pulmonary embolism (n=1); no other severe side-effects were noted. The response to nonsurgical treatment after 8 weeks was: complete response (CR): 0, partial response (PR): 3, stable disease (SD): 4, progressive disease (PD): 2. Some of the patients with SD responded later resulting in best response: CR:0, PR:5, SD:2, PD:2. CONCLUSION: Treatment with VPA plus radiochemotherapy is well tolerated with an encouraging response rate." ], "offsets": [ [ 0, 1464 ] ] } ]

[ { "id": "entity-388-0", "type": "DISEASE", "text": [ "gliomas" ], "offsets": [ [ 150, 157 ] ], "normalized": [] }, { "id": "entity-388-1", "type": "DISEASE", "text": [ "HGGs" ], "offsets": [ [ 159, 163 ] ], "normalized": [] }, { "id": "entity-388-2", "type": "DISEASE", "text": [ "glioblastoma multiforme" ], "offsets": [ [ 550, 573 ] ], "normalized": [] }, { "id": "entity-388-3", "type": "DISEASE", "text": [ "GBM" ], "offsets": [ [ 575, 578 ] ], "normalized": [] }, { "id": "entity-388-4", "type": "DISEASE", "text": [ "anaplastic astrocytoma" ], "offsets": [ [ 590, 612 ] ], "normalized": [] }, { "id": "entity-388-5", "type": "DISEASE", "text": [ "AA" ], "offsets": [ [ 614, 616 ] ], "normalized": [] }, { "id": "entity-388-6", "type": "DISEASE", "text": [ "AA" ], "offsets": [ [ 792, 794 ] ], "normalized": [] }, { "id": "entity-388-7", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 949, 956 ] ], "normalized": [] }, { "id": "entity-388-8", "type": "ADVERSE", "text": [ "pulmonary embolism" ], "offsets": [ [ 1031, 1049 ] ], "normalized": [] } ]

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[ { "id": "passage-389", "type": "abstract", "text": [ "Anemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcome. PURPOSE: Sequential treatment (chemotherapy followed by concomitant chemoradiation; CCRT) is increasingly being used for radical treatment of squamous cell cancer of the head and neck (SCCHN), which results in increased myelosuppression. In this study, we review the incidence of anemia and the effect of a policy of hemoglobin (Hb) maintenance by blood transfusion on disease outcomes in these patients. METHODS AND MATERIALS: Retrospective review of the records of patients with SCCHN treated with sequential CCRT formed the basis of this study. The incidence of anemia and statistics on blood transfusion were documented. For the purpose of outcome analyses, patients were divided into four categories by (1) transfusion status, (2) nadir Hb concentration, (3) number of transfusion episodes, and (4) number of units of blood transfused (NOUT). Data on 3-year locoregional control (LRC), relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were analyzed. RESULTS: One hundred and sixty-nine patients were identified. The median follow-up was 23.6 months. The RFS (52% vs. 41%, p = 0.03), DSS (71% vs. 66%, p = 0.02), and OS (58% vs. 42% p = 0.005) were significantly better for patients who did not have a transfusion vs. those who did. The LRC, RFS, DSS, and OS were also significantly better for patients with nadir Hb level >12 vs. <12 g/dL and NOUT 1-4 vs. >4. CONCLUSION: Our study seems to suggest that blood transfusion during radical treatment for SCCHN might be detrimental. Further research should be undertaken into the complex interactions among tumor hypoxia, anemia, and the treatment of anemia before making treatment recommendations." ], "offsets": [ [ 0, 1836 ] ] } ]

[ { "id": "entity-389-0", "type": "ADVERSE", "text": [ "Anemia" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "entity-389-1", "type": "DISEASE", "text": [ "head and neck cancer" ], "offsets": [ [ 71, 91 ] ], "normalized": [] }, { "id": "entity-389-2", "type": "DISEASE", "text": [ "squamous cell cancer of the head and neck" ], "offsets": [ [ 290, 331 ] ], "normalized": [] }, { "id": "entity-389-3", "type": "DISEASE", "text": [ "SCCHN" ], "offsets": [ [ 333, 338 ] ], "normalized": [] }, { "id": "entity-389-4", "type": "ADVERSE", "text": [ "myelosuppression" ], "offsets": [ [ 368, 384 ] ], "normalized": [] }, { "id": "entity-389-5", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 428, 434 ] ], "normalized": [] }, { "id": "entity-389-6", "type": "DISEASE", "text": [ "SCCHN" ], "offsets": [ [ 629, 634 ] ], "normalized": [] }, { "id": "entity-389-7", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 713, 719 ] ], "normalized": [] }, { "id": "entity-389-8", "type": "DISEASE", "text": [ "SCCHN" ], "offsets": [ [ 1643, 1648 ] ], "normalized": [] }, { "id": "entity-389-9", "type": "DISEASE", "text": [ "tumor hypoxia" ], "offsets": [ [ 1745, 1758 ] ], "normalized": [] }, { "id": "entity-389-10", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 1760, 1766 ] ], "normalized": [] }, { "id": "entity-389-11", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 1789, 1795 ] ], "normalized": [] } ]

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[ { "id": "passage-390", "type": "abstract", "text": [ "Intensity-modulated radiotherapy in postoperative treatment of oral cavity cancers. PURPOSE: To present our single-institution experience of intensity-modulated radiotherapy (IMRT) for oral cavity cancer. METHODS AND MATERIALS: Between September 2000 and December 2006, 35 patients with histologically confirmed squamous cell carcinoma of the oral cavity underwent surgery followed by postoperative IMRT. The sites included were buccal mucosa in 8, oral tongue in 11, floor of the mouth in 9, gingiva in 4, hard palate in 2, and retromolar trigone in 1. Most patients had Stage III-IV disease (80%). Ten patients (29%) also received concurrent postoperative chemotherapy with IMRT. The median prescribed radiation dose was 60 Gy. RESULTS: The median follow-up for surviving patients was 28.1 months (range, 11.9-85.1). Treatment failure occurred in 11 cases as follows: local in 4, regional in 2, and distant metastases in 5. Of the 5 patients with distant metastases, 2 presented with dermal metastases. The 2- and 3-year estimates of locoregional progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 84% and 77%, 85% and 85%, 70% and 64%, and 74% and 74%, respectively. Acute Grade 2 or greater dermatitis, mucositis, and esophageal reactions were experienced by 54%, 66%, and 40% of the patients, respectively. Documented late complications included trismus (17%) and osteoradionecrosis (5%). CONCLUSION: IMRT as an adjuvant treatment after surgical resection for oral cavity tumors is feasible and effective, with promising results and acceptable toxicity." ], "offsets": [ [ 0, 1618 ] ] } ]

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[ { "id": "passage-391", "type": "abstract", "text": [ "Selenium nanoparticles fabricated in Undaria pinnatifida polysaccharide solutions induce mitochondria-mediated apoptosis in A375 human melanoma cells. Selenium nanoparticle (Nano-Se) is a novel Se species with novel biological activities and low toxicity. In the present study, we demonstrated a simple method for synthesis of size-controlled Nano-Se by adding Undaria pinnatifida polysaccharides to the redox system of selenite and ascorbic acid. A panel of four human cancer cell lines was shown to be susceptible to Nano-Se, with IC(50) values ranging from 3.0 to 14.1 microM. Treatment of A375 human melanoma cells with the Nano-Se resulted in dose-dependent cell apoptosis as indicated by DNA fragmentation and phosphatidylserine translocation. Further investigation on intracellular mechanisms found that Nano-Se treatment triggered apoptotic cell death in A375 cells with the involvement of oxidative stress and mitochondrial dysfunction. Our results suggest that Nano-Se may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially melanoma cancer." ], "offsets": [ [ 0, 1116 ] ] } ]

[ { "id": "entity-391-0", "type": "DISEASE", "text": [ "melanoma cancer" ], "offsets": [ [ 1100, 1115 ] ], "normalized": [] } ]

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[ { "id": "passage-392", "type": "abstract", "text": [ "Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. BACKGROUND: Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. OBJECTIVE: To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. DESIGN: A 16-week, double-blind, placebo-controlled, parallel-group study. SETTING: Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. PATIENTS: 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. INTERVENTION: Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. MEASUREMENTS: Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). RESULTS: A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]). LIMITATIONS: The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis. CONCLUSION: In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil." ], "offsets": [ [ 0, 3448 ] ] } ]

[ { "id": "entity-392-0", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 86, 117 ] ], "normalized": [] }, { "id": "entity-392-1", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 260, 291 ] ], "normalized": [] }, { "id": "entity-392-2", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 411, 442 ] ], "normalized": [] }, { "id": "entity-392-3", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 643, 674 ] ], "normalized": [] }, { "id": "entity-392-4", "type": "DISEASE", "text": [ "connective tissue disease" ], "offsets": [ [ 717, 742 ] ], "normalized": [] }, { "id": "entity-392-5", "type": "DISEASE", "text": [ "congenital heart disease" ], "offsets": [ [ 757, 781 ] ], "normalized": [] }, { "id": "entity-392-6", "type": "DISEASE", "text": [ "dyspnea" ], "offsets": [ [ 1350, 1357 ] ], "normalized": [] }, { "id": "entity-392-7", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 2408, 2416 ] ], "normalized": [] }, { "id": "entity-392-8", "type": "ADVERSE", "text": [ "dyspepsia" ], "offsets": [ [ 2499, 2508 ] ], "normalized": [] }, { "id": "entity-392-9", "type": "ADVERSE", "text": [ "pain" ], "offsets": [ [ 2589, 2593 ] ], "normalized": [] }, { "id": "entity-392-10", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 2692, 2698 ] ], "normalized": [] }, { "id": "entity-392-11", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 2826, 2857 ] ], "normalized": [] }, { "id": "entity-392-12", "type": "DISEASE", "text": [ "pulmonary arterial hypertension" ], "offsets": [ [ 3128, 3159 ] ], "normalized": [] }, { "id": "entity-392-13", "type": "DISEASE", "text": [ "dyspnea" ], "offsets": [ [ 3350, 3357 ] ], "normalized": [] }, { "id": "entity-392-14", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 3384, 3392 ] ], "normalized": [] }, { "id": "entity-392-15", "type": "ADVERSE", "text": [ "dyspepsia" ], "offsets": [ [ 3397, 3406 ] ], "normalized": [] } ]

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[ { "id": "passage-393", "type": "abstract", "text": [ "Drug insight: aggrecanases as therapeutic targets for osteoarthritis. In healthy cartilage, effective weight-bearing requires a high concentration of intact aggrecan. Degradation and loss of aggrecan are features of osteoarthritis (OA). It is unclear whether ADAMTS-4, ADAMTS-5, or both of these aggrecanases from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzyme family, are responsible for aggrecanolysis in human OA, and at what stage of disease these enzymes are active. Several potential disease-modifying agents for OA include glucosamine and chondroitin sulfate, diacerhein, and pentosan polysulfate; although their mechanisms of action in vivo are unknown, data from in vitro studies and animal models suggest that their efficacy might be partly due to inhibition of proinflammatory pathways that lead to downregulation of ADAMTS enzymes. Some histone deacetylase inhibitors that are successfully used to treat cancer can block ADAMTS-5 expression; however, these inhibitors will only be considered as potential therapies for OA if their toxicity is markedly reduced. ADAMTS inhibitors currently in development are expected to show excellent specificity now that crystal structures for several ADAMTS enzymes are available to guide drug design. ADAMTS-4 and ADAMTS-5 are appropriate targets for OA therapies, but ultimately, inhibitors of these enzymes will form only part of a larger arsenal of therapies." ], "offsets": [ [ 0, 1448 ] ] } ]

[ { "id": "entity-393-0", "type": "DISEASE", "text": [ "osteoarthritis" ], "offsets": [ [ 54, 68 ] ], "normalized": [] }, { "id": "entity-393-1", "type": "DISEASE", "text": [ "osteoarthritis" ], "offsets": [ [ 217, 231 ] ], "normalized": [] }, { "id": "entity-393-2", "type": "DISEASE", "text": [ "OA" ], "offsets": [ [ 233, 235 ] ], "normalized": [] }, { "id": "entity-393-3", "type": "DISEASE", "text": [ "OA" ], "offsets": [ [ 450, 452 ] ], "normalized": [] }, { "id": "entity-393-4", "type": "DISEASE", "text": [ "OA" ], "offsets": [ [ 556, 558 ] ], "normalized": [] }, { "id": "entity-393-5", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 953, 959 ] ], "normalized": [] }, { "id": "entity-393-6", "type": "DISEASE", "text": [ "OA" ], "offsets": [ [ 1068, 1070 ] ], "normalized": [] }, { "id": "entity-393-7", "type": "DISEASE", "text": [ "OA" ], "offsets": [ [ 1337, 1339 ] ], "normalized": [] } ]

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[ { "id": "passage-394", "type": "abstract", "text": [ "Intravenous fat emulsion: a potential novel antidote. Intravenous fat emulsions (IFE) are traditionally used as a component of parenteral nutrition therapy. Recently, IFE was used to resuscitate severe local anesthetic drug toxicity. This review focuses on the potential role of IFE in treatment of toxicity due to local anesthetics and other lipid-soluble drugs. The general properties of IFE, metabolic fate, and associated adverse events are described. Cases of local anesthetic toxicity treated with IFE are presented along with a discussion of the possible antidotal mechanisms. Initial investigations into the antidotal use of IFE for lipophilic central nervous and cardiovascular drug toxicity are also reviewed." ], "offsets": [ [ 0, 720 ] ] } ]

[ { "id": "entity-394-0", "type": "ADVERSE", "text": [ "local anesthetic drug toxicity" ], "offsets": [ [ 203, 233 ] ], "normalized": [] }, { "id": "entity-394-1", "type": "ADVERSE", "text": [ "local anesthetic toxicity" ], "offsets": [ [ 466, 491 ] ], "normalized": [] }, { "id": "entity-394-2", "type": "ADVERSE", "text": [ "cardiovascular drug toxicity" ], "offsets": [ [ 673, 701 ] ], "normalized": [] } ]

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[ { "id": "passage-395", "type": "abstract", "text": [ "Phase I/II study of biweekly paclitaxel and radiation in androgen-ablated locally advanced prostate cancer. PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer. MATERIALS AND METHODS: Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m(2)). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy. RESULTs: Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence. CONCLUSION: Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting." ], "offsets": [ [ 0, 1862 ] ] } ]

[ { "id": "entity-395-0", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 91, 106 ] ], "normalized": [] }, { "id": "entity-395-1", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 250, 265 ] ], "normalized": [] }, { "id": "entity-395-2", "type": "DISEASE", "text": [ "tumors" ], "offsets": [ [ 317, 323 ] ], "normalized": [] }, { "id": "entity-395-3", "type": "DISEASE", "text": [ "tumors" ], "offsets": [ [ 410, 416 ] ], "normalized": [] }, { "id": "entity-395-4", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1136, 1144 ] ], "normalized": [] }, { "id": "entity-395-5", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1359, 1367 ] ], "normalized": [] } ]

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[ { "id": "passage-396", "type": "abstract", "text": [ "Prolactin and dopamine: what is the connection? A review article. Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a 'short-loop feedback mechanism'. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood-brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia." ], "offsets": [ [ 0, 1639 ] ] } ]

[ { "id": "entity-396-0", "type": "ADVERSE", "text": [ "sustained hyperprolactinaemia" ], "offsets": [ [ 958, 987 ] ], "normalized": [] }, { "id": "entity-396-1", "type": "ADVERSE", "text": [ "sustained hyperprolactinaemia" ], "offsets": [ [ 1609, 1638 ] ], "normalized": [] } ]

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[ { "id": "passage-397", "type": "abstract", "text": [ "Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Dietary flavonoids have many health-promoting actions, including anticancer activity via proteasome inhibition. Bor-tezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients." ], "offsets": [ [ 0, 1509 ] ] } ]

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[ { "id": "passage-398", "type": "abstract", "text": [ "Paternal exposure and counselling: experience of a Teratology Information Service. We describe paternal exposure and counselling in a selected population calling to an Italian Teratology Information Service (TIS). The majority of callers asked for paternal drug exposure (76%, drugs except chemotherapy) and treatment for cancer (17%, chemotherapy and/or radiotherapy). Others asked for exposure to diagnostic radiations (4%), recreational drugs (2%) and occupational chemicals (1%). Among paternal drugs neurological compounds, immunosuppressive drugs and antiviral agents were the main reasons for calling. In humans, there are no evidences of birth defects after paternal exposures, but to minimize any possible risk, counselling in men exposed to radio and chemotherapy should recommend delaying conception for at least 3 months after the end of the therapy. Male patients treated with drugs, whose teratogenic potential has been well assessed or suspected for maternal exposure, should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy." ], "offsets": [ [ 0, 1183 ] ] } ]

[ { "id": "entity-398-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 323, 329 ] ], "normalized": [] }, { "id": "entity-398-1", "type": "ADVERSE", "text": [ "birth defects" ], "offsets": [ [ 647, 660 ] ], "normalized": [] } ]

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[ { "id": "passage-399", "type": "abstract", "text": [ "Iatrogenic intravenous medication errors reported to the PIC Erfurt. BACKGROUND: We investigated the iatrogenic intravenous medication errors (IIME) reported to the Poisons Information Center (PIC) Erfurt. METHODS: All IIME over a ten year period were analyzed retrospectively and categorized into error types, age groups, drugs involved, and estimated risk of toxicity. RESULTS: From 1997 to 2006 the PIC Erfurt registered 132 cases of IIME. They increased from 7 in 1997 to 31 in 2006. Children accounted for 31.1% of the patients affected and adults for 68.9%. The drug classes (ATC classification) involved most frequently were antipsychotics (9.8%) and antihistamines for systemic use (7.5%). The main types of IIME were overdose (53.1%) and incorrect route of administration (29.7%). The estimated risk of toxicity was: 14.4% none, 71.2% risk of toxicity, and 14.4% unpredictable risk. Medical treatment was recommended in 82%. The outcome of 104 of the 132 (78.8%) courses was unknown. In the 28 cases followed to a known outcome, 9 (32%) were asymptomatic and 19 (68%) symptomatic with minor (9 cases), moderate (1 case), and severe features (6 cases) but mostly complete recovery. Two IIME resulted in hypoxia-induced brain damage and one in death despite of resuscitation. CONCLUSION: Approximately 0.1% of all calls registered by the PIC Erfurt from 1997 to 2006 concerned IIME. Thirty-two percent of IIME followed to a known outcome resulted in severe symptoms. These data show that IIME can be harmful." ], "offsets": [ [ 0, 1516 ] ] } ]

[ { "id": "entity-399-0", "type": "ADVERSE", "text": [ "brain damage" ], "offsets": [ [ 1228, 1240 ] ], "normalized": [] } ]

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