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[ { "id": "passage-200", "type": "abstract", "text": [ "Structure-activity relationships of stemphones, potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus. From a further purification study, four new stemphones D to G were isolated along with previously reported stemphones B and C from the culture broth of Aspergillus sp. FKI-2136. Twenty-one derivatives were semisynthetically prepared from stemphones C, E and G. Potentiation of imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA) by all the stemphones including natural and semisynthetic ones was compared to study the structure-activity relationships. Derivatives with a free hydroxy or an O-acyl residue having a C2 to C5 carbon length at C-4 held the potentiating activity, but those with a longer acyl residue lost the activity. The presence of an oxo or a free hydroxy residue at C-10 is important for the potentiating activity because introduction of an alkyl or acyl residue at this position resulted in a loss of activity. Among them, stemphone E exhibited the most potent potentiation of imipenem activity against MRSA and the lowest cytotoxic activity against Jurkat cells." ], "offsets": [ [ 0, 1143 ] ] } ]

[ { "id": "entity-200-0", "type": "ADVERSE", "text": [ "cytotoxic activity" ], "offsets": [ [ 1103, 1121 ] ], "normalized": [] } ]

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[ { "id": "passage-201", "type": "abstract", "text": [ "Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses. The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A45-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p=0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p=0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p=0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p=0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p=0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p=0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N=1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR)=1.25, 95% CI 0.89, 1.74, p=0.19; SS: OR=1.31, 95% CI 0.86, 1.98, p=0.21) or 26-week follow-up (Reference LL; SL: OR=0.93, 95% CI 0.64, 1.33, p=0.68; SS: OR=1.00, 95% CI 0.63, 1.58, p=1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers." ], "offsets": [ [ 0, 1654 ] ] } ]

[ { "id": "entity-201-0", "type": "DISEASE", "text": [ "nicotine dependence" ], "offsets": [ [ 209, 228 ] ], "normalized": [] } ]

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[ { "id": "passage-202", "type": "abstract", "text": [ "Serum lactate dehydrogenase is a novel marker for the evaluation of disease severity in the early stage of toxic epidermal necrolysis. OBJECTIVE: To evaluate serum lactate dehydrogenase (LDH) and its correlation with skin manifestations in patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). METHODS: Serum LDH levels were measured in 33 patients (17 SJS and 16 TEN), from initial hospital admission to remission stage. RESULTS: The mean LDH level was 920.82 +/- 655.50 U/l in TEN and 595.35 +/- 182.03 U/l in SJS (normal range: 218-472). We arbitrarily divided these patients into 2 groups, the first were admitted within 3 days of onset (early stage) and the second after 4 days of onset (late stage). The ratio of early- to late-stage patients was 7:9 in TEN and 7:10 in SJS. The mean LDH level for 7 TEN patients in the early stage was 1,319.14 +/- 843.10 U/l, which was significantly higher than that of the SJS group (686.71 +/- 171.81 U/l; p = 0.024). In the late-stage patients, the mean levels of TEN and SJS patients were 611.0 +/- 160.33 and 531.4 +/- 167.89 U/l, respectively; these differences between TEN and SJS were not significant. CONCLUSION: Serum LDH levels can be used as a marker of disease severity in the early stage of TEN." ], "offsets": [ [ 0, 1280 ] ] } ]

[ { "id": "entity-202-0", "type": "DISEASE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 107, 133 ] ], "normalized": [] }, { "id": "entity-202-1", "type": "DISEASE", "text": [ "Stevens-Johnson syndrome" ], "offsets": [ [ 255, 279 ] ], "normalized": [] }, { "id": "entity-202-2", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 281, 284 ] ], "normalized": [] }, { "id": "entity-202-3", "type": "DISEASE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 290, 316 ] ], "normalized": [] }, { "id": "entity-202-4", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 318, 321 ] ], "normalized": [] }, { "id": "entity-202-5", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 383, 386 ] ], "normalized": [] }, { "id": "entity-202-6", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 394, 397 ] ], "normalized": [] }, { "id": "entity-202-7", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 509, 512 ] ], "normalized": [] }, { "id": "entity-202-8", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 542, 545 ] ], "normalized": [] }, { "id": "entity-202-9", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 790, 793 ] ], "normalized": [] }, { "id": "entity-202-10", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 836, 839 ] ], "normalized": [] }, { "id": "entity-202-11", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "entity-202-12", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 1038, 1041 ] ], "normalized": [] }, { "id": "entity-202-13", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 1046, 1049 ] ], "normalized": [] }, { "id": "entity-202-14", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 1147, 1150 ] ], "normalized": [] }, { "id": "entity-202-15", "type": "DISEASE", "text": [ "SJS" ], "offsets": [ [ 1155, 1158 ] ], "normalized": [] }, { "id": "entity-202-16", "type": "DISEASE", "text": [ "TEN" ], "offsets": [ [ 1276, 1279 ] ], "normalized": [] } ]

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[ { "id": "passage-203", "type": "abstract", "text": [ "A phase I trial of PTK787/ZK222584 in combination with pemetrexed and cisplatin in patients with advanced solid tumors. Angiogenesis is recognized as an important biological process that allows growth of a tumor beyond an initial small size. PTK787/ZK222584, a potent orally active angiogenesis inhibitor capable of inhibiting all known isoforms of Vascular Endothelial Growth Factor (VEGF) receptor, belongs to the class of aminophthalazines. This study investigated a combination of chemotherapy (Cisplatin and Pemetrexed) with PTK787/ZK222584. Eight patients were enrolled but PTK787/ZK222584 dose could not be escalated as planned because of dose limiting toxicities (DLTs) observed on the first dose level. Limited pharmacokinetic profiling of PTK787/ZK222584 revealed no evidence of drug-drug interactions. No responses were seen for this combination. This study was closed secondary to toxicity and lack of efficacy of the designed regimen." ], "offsets": [ [ 0, 948 ] ] } ]

[ { "id": "entity-203-0", "type": "DISEASE", "text": [ "solid tumors" ], "offsets": [ [ 106, 118 ] ], "normalized": [] }, { "id": "entity-203-1", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 207, 212 ] ], "normalized": [] }, { "id": "entity-203-2", "type": "ADVERSE", "text": [ "dose limiting toxicities" ], "offsets": [ [ 647, 671 ] ], "normalized": [] }, { "id": "entity-203-3", "type": "ADVERSE", "text": [ "DLTs" ], "offsets": [ [ 673, 677 ] ], "normalized": [] } ]

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[ { "id": "passage-204", "type": "abstract", "text": [ "Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach. Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60." ], "offsets": [ [ 0, 1364 ] ] } ]

[ { "id": "entity-204-0", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 426, 439 ] ], "normalized": [] } ]

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[ { "id": "passage-205", "type": "abstract", "text": [ "Up-regulation and cytoprotective role of epithelial multidrug resistance-associated protein 1 in inflammatory bowel disease. MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro-inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e.g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e.g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro-apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients." ], "offsets": [ [ 0, 1836 ] ] } ]

[ { "id": "entity-205-0", "type": "DISEASE", "text": [ "inflammatory bowel disease" ], "offsets": [ [ 97, 123 ] ], "normalized": [] }, { "id": "entity-205-1", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 514, 526 ] ], "normalized": [] }, { "id": "entity-205-2", "type": "DISEASE", "text": [ "inflammatory bowel disease" ], "offsets": [ [ 690, 716 ] ], "normalized": [] }, { "id": "entity-205-3", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 718, 721 ] ], "normalized": [] }, { "id": "entity-205-4", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 794, 797 ] ], "normalized": [] }, { "id": "entity-205-5", "type": "DISEASE", "text": [ "Crohn disease" ], "offsets": [ [ 813, 826 ] ], "normalized": [] }, { "id": "entity-205-6", "type": "DISEASE", "text": [ "ulcerative colitis" ], "offsets": [ [ 831, 849 ] ], "normalized": [] }, { "id": "entity-205-7", "type": "DISEASE", "text": [ "inflammation" ], "offsets": [ [ 1615, 1627 ] ], "normalized": [] }, { "id": "entity-205-8", "type": "DISEASE", "text": [ "IBD" ], "offsets": [ [ 1823, 1826 ] ], "normalized": [] } ]

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[ { "id": "passage-206", "type": "abstract", "text": [ "Angiotensin inhibition in renovascular disease: a population-based cohort study. BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce blood pressure in patients with renovascular disease (RVD); yet, randomized cardiovascular prevention trials of these drugs typically exclude individuals with this condition. PATIENTS AND METHODS: We studied the association of renin-angiotensin system inhibition with prognosis in a population-based cohort comprising 3,570 patients with RVD in Ontario, Canada; slightly more than half (n = 1,857, 53%) were prescribed angiotensin inhibitors. The primary outcome was the composite of death, myocardial infarction, or stroke. Secondary outcomes included individual cardiovascular and renal events. RESULTS: Patients receiving angiotensin inhibitors had a significantly lower risk for the primary outcome during follow-up (10.0 vs 13.0 events per 100 patient-years at risk, multivariable adjusted hazard ratio [HR] 0.70, 95% CI 0.59-0.82). In addition, hospitalization for congestive heart failure (HR 0.69, 95% CI 0.53-0.90), chronic dialysis initiation (HR 0.62, 95% CI 0.42-0.92), and mortality (HR 0.56, 95% CI 0.47-0.68) was lower in treated patients. Conversely, patients receiving angiotensin inhibitors were significantly more likely to be hospitalized for acute renal failure during follow-up (HR 1.87, 95% CI 1.05-3.33; 1.2 vs 0.6 events per 100 patient-years at risk). CONCLUSIONS: These data emphasize the high vascular risk of RVD and suggest that angiotensin inhibitors may improve prognosis in this setting at the expense of acute renal toxicity. If the latter are selected in the management of RVD, renal function parameters should be assiduously followed." ], "offsets": [ [ 0, 1758 ] ] } ]

[ { "id": "entity-206-0", "type": "DISEASE", "text": [ "renovascular disease" ], "offsets": [ [ 26, 46 ] ], "normalized": [] }, { "id": "entity-206-1", "type": "DISEASE", "text": [ "renovascular disease" ], "offsets": [ [ 220, 240 ] ], "normalized": [] }, { "id": "entity-206-2", "type": "DISEASE", "text": [ "RVD" ], "offsets": [ [ 242, 245 ] ], "normalized": [] }, { "id": "entity-206-3", "type": "DISEASE", "text": [ "RVD" ], "offsets": [ [ 526, 529 ] ], "normalized": [] }, { "id": "entity-206-4", "type": "ADVERSE", "text": [ "myocardial infarction" ], "offsets": [ [ 679, 700 ] ], "normalized": [] }, { "id": "entity-206-5", "type": "ADVERSE", "text": [ "stroke" ], "offsets": [ [ 705, 711 ] ], "normalized": [] }, { "id": "entity-206-6", "type": "ADVERSE", "text": [ "congestive heart failure" ], "offsets": [ [ 1059, 1083 ] ], "normalized": [] }, { "id": "entity-206-7", "type": "ADVERSE", "text": [ "acute renal failure" ], "offsets": [ [ 1351, 1370 ] ], "normalized": [] }, { "id": "entity-206-8", "type": "ADVERSE", "text": [ "RVD" ], "offsets": [ [ 1526, 1529 ] ], "normalized": [] }, { "id": "entity-206-9", "type": "ADVERSE", "text": [ "acute renal toxicity" ], "offsets": [ [ 1626, 1646 ] ], "normalized": [] }, { "id": "entity-206-10", "type": "DISEASE", "text": [ "RVD" ], "offsets": [ [ 1696, 1699 ] ], "normalized": [] } ]

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[ { "id": "passage-207", "type": "abstract", "text": [ "Inhibition of atopic dermatitis-like skin lesions by topical application of a novel ceramide derivative, K6PC-9p, in NC/Nga mice. Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly begins in childhood. K6PC-9p (N-(Ethyl dihydrogenphosphate)-2-hexyl-3-oxo-decanamide) is a synthetic ceramide derivative of PC-9S (N-Ethanol-2-mirystyl-3-oxo-staramide), which was known to be effective in atopic patients. In this study, we examined the effect of topical application of K6PC-9p on skin inflammation and AD-like skin lesions in mouse models. K6PC-9p dose-dependently inhibited phorbol ester-induced increase in ear thickness in BALB/c mice. Moreover, topical application of K6PC-9p suppressed dust mite extract-induced AD-like skin lesions in NC/Nga mice. Histopathological analysis revealed that both ear swelling and leucocyte infiltration were suppressed by K6PC-9p treatment. K6PC-9p also suppressed IL-4 and TNF-alpha expression in the ears and mast cell infiltration into the ears in NC/Nga mice. Further study demonstrated that K6PC-9p inhibited ConA-induced IL-4 secretion and LPS-induced macrophage activation. Taken together, our results showed that topical application of K6PC-9p exerts beneficial effects in animal model of skin inflammation and AD, suggesting that K6PC-9p might be a promising topical agent for the treatment of inflammatory skin diseases." ], "offsets": [ [ 0, 1391 ] ] } ]

[ { "id": "entity-207-0", "type": "DISEASE", "text": [ "atopic dermatitis-like skin lesions" ], "offsets": [ [ 14, 49 ] ], "normalized": [] }, { "id": "entity-207-1", "type": "DISEASE", "text": [ "Atopic dermatitis" ], "offsets": [ [ 131, 148 ] ], "normalized": [] }, { "id": "entity-207-2", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 150, 152 ] ], "normalized": [] }, { "id": "entity-207-3", "type": "DISEASE", "text": [ "chronic inflammatory skin disease" ], "offsets": [ [ 159, 192 ] ], "normalized": [] }, { "id": "entity-207-4", "type": "DISEASE", "text": [ "skin inflammation" ], "offsets": [ [ 504, 521 ] ], "normalized": [] }, { "id": "entity-207-5", "type": "DISEASE", "text": [ "AD-like skin lesions" ], "offsets": [ [ 526, 546 ] ], "normalized": [] }, { "id": "entity-207-6", "type": "DISEASE", "text": [ "AD-like skin lesions" ], "offsets": [ [ 741, 761 ] ], "normalized": [] }, { "id": "entity-207-7", "type": "DISEASE", "text": [ "ear swelling" ], "offsets": [ [ 824, 836 ] ], "normalized": [] }, { "id": "entity-207-8", "type": "DISEASE", "text": [ "skin inflammation" ], "offsets": [ [ 1258, 1275 ] ], "normalized": [] }, { "id": "entity-207-9", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 1280, 1282 ] ], "normalized": [] }, { "id": "entity-207-10", "type": "DISEASE", "text": [ "inflammatory skin diseases" ], "offsets": [ [ 1364, 1390 ] ], "normalized": [] } ]

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[ { "id": "passage-208", "type": "abstract", "text": [ "Distinct regulatory profiles of interleukins and chemokines in response to cigarette smoke condensate in normal human bronchial epithelial (NHBE) cells. Bronchial epithelium is frequently exposed to air pollutants, and it is hypothesized that these cells elicit inflammatory responses as early elements in pulmonary defense. Our purpose was to evaluate changes in messenger RNA levels of 84 genes representing cytokines and receptors over a repetitive-exposure time course to further define the inflammatory responses associated with mainstream cigarette smoke (MSS) exposure in an in vitro lung model. Normal human bronchial epithelial cells were treated with mainstream cigarette smoke condensate (CSC) prepared from Kentucky 2R4F cigarettes (60 microg total particulate matter/mL media, 0.2% dimethylsulfoxide), and examined by quantitative real-time polymerase chain reaction. Applications of CSC were designed in seven groups to test immediate, early, intermediate, and late responses evaluated at the end of alternating exposure/recovery periods. Three predominant gene expression responses were observed: adaptive (return to baseline), sustained (maintained expression during treatment), and chronic (maintained expression posttreatment). Overall, 25 genes exhibited statistically significant changes: 14 genes exclusively elevated, 10 genes exclusively depressed, and 1, interleukin-8 (IL8), exhibiting both up- and downregulation in the seven groups. The most responsive genes were osteopontin (34-fold upregulation) and CXCL14 (23-fold downregulation). Our observations suggest that specific genes involved in inflammatory pathways respond to CSC in chronic, sustained, or adaptive patterns with the chronic pattern as the predominant behavior." ], "offsets": [ [ 0, 1755 ] ] } ]

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[ { "id": "passage-209", "type": "abstract", "text": [ "Tirapazamine: from bench to clinical trials. Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and chemotherapy is the development of hypoxic cytotoxins such as tirapazamine. The present review covers the history of tirapazamine from preclinical models to clinical trials. The biochemistry as well as the pharmacokinetics of this bioreductive agent are presented. Laboratory data demonstrating the enhanced effect of radiation and cisplatin when combined with tirapazamine are also discussed. There is considerable evidence supporting the potentiation of anti-tumour effect of cisplatin by tirapazamine. Several clinical trials for various tumour sites have been testing the synergistic effect of cisplatin-tirapazamine with and without radiotherapy. These are also reviewed in the present paper. The current literature data on tirapazamine leaves unanswered questions about its action and toxicity. While the current number of phase III trials limits comprehensive conclusions about the administration of this drug, there is a unanimous indication that further clinical studies are warranted." ], "offsets": [ [ 0, 1198 ] ] } ]

[ { "id": "entity-209-0", "type": "DISEASE", "text": [ "Tumour hypoxia" ], "offsets": [ [ 46, 60 ] ], "normalized": [] }, { "id": "entity-209-1", "type": "DISEASE", "text": [ "solid tumours" ], "offsets": [ [ 132, 145 ] ], "normalized": [] }, { "id": "entity-209-2", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 745, 751 ] ], "normalized": [] } ]

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[ { "id": "passage-210", "type": "abstract", "text": [ "Fragrance material review on myrtenol. A toxicologic and dermatologic review of myrtenol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 139 ] ] } ]

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[ { "id": "passage-211", "type": "abstract", "text": [ "Medaka (Oryzias latipes) as a sentinel species for aquatic animals: Medaka cells exhibit a similar genotoxic response as North Atlantic right whale cells. Hexavalent chromium (Cr(VI)) is emerging as a major concern for aquatic environments, particularly marine environments. Medaka (Oryzias latipes) has been used as a model species for human and aquatic health, including the marine environment, though few studies have directly compared toxicological responses in medaka to humans or other aquatic species. We used a medaka fin cell line to compare the genotoxic response of medaka to Cr(VI) to the response observed in North Atlantic right whale cells to see if responses in medaka were similar to those of other aquatic species, particularly aquatic mammals. We used the production of chromosomal aberrations as a measure of genotoxicity. We found that in medaka cells, concentrations of 1, 5 and 10 microM sodium chromate damaged 17, 32 and 43% of metaphases, respectively and these same concentrations 1, 2.5, 5 and 10 microM sodium chromate damaged 14, 24 and 49% of metaphases, respectively, in North Atlantic right whale lung cells and 11, 32 and 41% of metaphases, respectively, in North Atlantic right whale testes cells. These data show that genotoxic responses in medaka are comparable to those seen in North Atlantic right whale cells, consistent with the hypothesis that medaka are a useful model for other aquatic species." ], "offsets": [ [ 0, 1439 ] ] } ]

[ { "id": "entity-211-0", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 830, 842 ] ], "normalized": [] } ]

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[ { "id": "passage-212", "type": "abstract", "text": [ "No occurrence of Pneumocystis jiroveci (carinii) pneumonia in 120 adults undergoing myeloablative unrelated cord blood transplantation. The incidence of pneumonia caused by Pneumocystis carinii (PCP) (organism now renamed Pneumocystis jiroveci) during the early period after cord blood transplantation (CBT) was studied in 120 adults. Initially 89 patients (74%) received oral administration of 2 single-strength trimethoprim-sulfamethoxazole (TMP-SMZ) tablets twice daily from day -21. In 45 of 89 patients (51%), TMP-SMZ administration for a scheduled duration was completed. In the remaining 44 patients (49%), however, TMP-SMZ administration was discontinued prior to day -3 because of toxicity. Among these patients, 42 subsequently received aerosolized pentamidine (AP) on a median of day -13 (range, -20 to -6). Thirty-one patients (26%) received AP without TMP-SMZ administration on a median of day -14 (range, -21 to -9). None of the 120 patients were diagnosed with PCP within 100 days or 2 years after CBT; however, one patient who received AP before CBT but no prophylaxis after CBT developed cerebral toxoplasmosis on day +91. Pre-transplant prophylaxis against PCP did not significantly affect transplantation-related mortality or disease-free survival at 2 years after CBT. The results suggest that PCP during the early period after CBT can be effectively prevented by any pre-transplant prophylactic method." ], "offsets": [ [ 0, 1424 ] ] } ]

[ { "id": "entity-212-0", "type": "DISEASE", "text": [ "Pneumocystis jiroveci (carinii) pneumonia" ], "offsets": [ [ 17, 58 ] ], "normalized": [] }, { "id": "entity-212-1", "type": "DISEASE", "text": [ "pneumonia" ], "offsets": [ [ 154, 163 ] ], "normalized": [] }, { "id": "entity-212-2", "type": "DISEASE", "text": [ "PCP" ], "offsets": [ [ 196, 199 ] ], "normalized": [] }, { "id": "entity-212-3", "type": "DISEASE", "text": [ "PCP" ], "offsets": [ [ 977, 980 ] ], "normalized": [] }, { "id": "entity-212-4", "type": "ADVERSE", "text": [ "cerebral toxoplasmosis" ], "offsets": [ [ 1106, 1128 ] ], "normalized": [] }, { "id": "entity-212-5", "type": "DISEASE", "text": [ "PCP" ], "offsets": [ [ 1176, 1179 ] ], "normalized": [] }, { "id": "entity-212-6", "type": "DISEASE", "text": [ "PCP" ], "offsets": [ [ 1315, 1318 ] ], "normalized": [] } ]

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[ { "id": "passage-213", "type": "abstract", "text": [ "Individualized medicine for renal cell carcinoma: establishment of primary cell line culture from surgical specimens. BACKGROUND: The lack of effective \"in vivo\" and \"in vitro\" models to predict success of pharmacological therapy for patients with renal cell carcinoma, as well as, the variety of cancer cell types demands the development of better experimental models to understand the pathophysiology of the disease and evaluate drug sensitivity in vitro. PURPOSE: To develop primary renal cancer cell culture irrespective of tumor grade and tumor type, harvested from the patient's pathological specimen immediately after the laparoscopic radical nephrectomy to study potential \"in vivo\" pharmacological sensitivity. MATERIALS AND METHODS: A total of 24 patients (17 males and 7 females). Mean age of 63.1+/-3.1 y.o. The mean size of the renal masses was 7.56+/-3.1 cm. Normal and pathological renal tissue was collected immediately after the specimen was extracted and submitted to enzymatic digestion for 16-24 hours. Clear cell carcinoma cells were selected through multiple passages in DMEM medium supplemented with glucose and antibiotics. RESULTS: Establishment of cell line culture from all the patients' specimens irrespective of tumor grade and tumor type was achieved successfully. In addition to the tumor cell line culture, normal parenchyma tissue yielded primary cell lines to allow testing the response of tumor types to various pharmacological therapeutic agents and toxicity of such treatments to healthy tissue. From the initial collection of the specimens obtained after the removal of the kidney to the development of cell lines took occurred in average 32+6 hrs. The cells in culture showed characteristics of epithelial cells; like expression on cytokeratin and were maintained in culture for more than 20 passages. CONCLUSION: The development of renal cancer cell cultures in vitro is labor intense but may yield a more realistic model to tailor pharmacological therapies and predict therapeutic success prior to \"in vivo\" application-a step in the direction of individualized medicine for RCC." ], "offsets": [ [ 0, 2121 ] ] } ]

[ { "id": "entity-213-0", "type": "DISEASE", "text": [ "renal cell carcinoma" ], "offsets": [ [ 28, 48 ] ], "normalized": [] }, { "id": "entity-213-1", "type": "DISEASE", "text": [ "renal cell carcinoma" ], "offsets": [ [ 249, 269 ] ], "normalized": [] }, { "id": "entity-213-2", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 529, 534 ] ], "normalized": [] }, { "id": "entity-213-3", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 545, 550 ] ], "normalized": [] }, { "id": "entity-213-4", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1242, 1247 ] ], "normalized": [] }, { "id": "entity-213-5", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "entity-213-6", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 1425, 1430 ] ], "normalized": [] } ]

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[ { "id": "passage-214", "type": "abstract", "text": [ "Gemcitabine and cisplatin treatment of advanced-stage non-small-cell lung cancer in patients given cisplatin on day 8. AIMS AND BACKGROUND: Gemcitabine and cisplatin treatment were administered to patients with advanced-stage, non-small-cell lung cancer. During phase II studies, the treatment is performed using a 28-day cycle, with gemcitabine administered on days 1, 8, and 15. Although it is advised that cisplatin not be administered on the first day, gemcitabine and cisplatin treatment is usually performed using a 21-day cycle, with gemcitabine administered on days 1 and 8, and cisplatin is given on the first day in most phase III studies. In contrast with previous phase III studies, cisplatin was administered on day 8 in our study. Dose density, drug toxicity, and efficacy were analyzed. METHODS AND STUDY DESIGN: Chemonaive patients with stage IIIB or stage IV nonsmall-cell lung cancer received gemcitabine (1250 mg/m2) on days 1 and 8 plus cisplatin (75 mg/m2) on day 8 every 3 weeks (1 cycle contained 2 applications). RESULTS: Sixty-seven patients received a total of 293 applications. Dose densities were 92.3% for gemcitabine and 93.9% for cisplatin. The types and rates of grade 3 and grade 4 hematologic toxicities were anemia (6%), granulocytopenia (46%), and thrombocytopenia (6%). Complete remission was seen in 2 patients (3%); partial remission was 40%, stable disease was 39%, and progression of disease, 10%. The median overall survival time was 13 months. The median progression-free survival time was 9.5 months. One-year survival rate was 54% and 2-year survival, 10.4%. CONCLUSIONS: In this 21-day treatment regimen, overall survival was longer than 1 year and the 1-year survival rate was more than 50%. Both the severity and rate of observed thrombocytopenia in the study were very low. Other adverse effects in the current study were comparable to those reported in the literature." ], "offsets": [ [ 0, 1919 ] ] } ]

[ { "id": "entity-214-0", "type": "DISEASE", "text": [ "non-small-cell lung cancer" ], "offsets": [ [ 54, 80 ] ], "normalized": [] }, { "id": "entity-214-1", "type": "DISEASE", "text": [ "non-small-cell lung cancer" ], "offsets": [ [ 228, 254 ] ], "normalized": [] }, { "id": "entity-214-2", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 760, 773 ] ], "normalized": [] }, { "id": "entity-214-3", "type": "DISEASE", "text": [ "nonsmall-cell lung cancer" ], "offsets": [ [ 877, 902 ] ], "normalized": [] }, { "id": "entity-214-4", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 1244, 1250 ] ], "normalized": [] }, { "id": "entity-214-5", "type": "ADVERSE", "text": [ "granulocytopenia" ], "offsets": [ [ 1257, 1273 ] ], "normalized": [] }, { "id": "entity-214-6", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1285, 1301 ] ], "normalized": [] }, { "id": "entity-214-7", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1779, 1795 ] ], "normalized": [] } ]

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[ { "id": "passage-215", "type": "abstract", "text": [ "Prolonged dose-dense epirubicin and cyclophosphamide followed by paclitaxel in breast cancer is feasible. PURPOSE: We conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) x 6 --> paclitaxel (P) x 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil [5-FU]/EC) x 6 with filgrastim --> by weekly paclitaxel alternating with docetaxel x 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility. PATIENTS AND METHODS: Patients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m2) x 6 --> by 2-weekly P (175 mg/m2) x 6 with pegfilgrastim 6 mg on day 2. RESULTS: Between November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled. CONCLUSION: Dose-dense every-2-week EC x 6 --> P x 6 with pegfilgrastim is feasible based on our prospective definition." ], "offsets": [ [ 0, 1567 ] ] } ]

[ { "id": "entity-215-0", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 79, 92 ] ], "normalized": [] }, { "id": "entity-215-1", "type": "DISEASE", "text": [ "pneumonitis" ], "offsets": [ [ 404, 415 ] ], "normalized": [] }, { "id": "entity-215-2", "type": "DISEASE", "text": [ "pericardial/pleural effusion" ], "offsets": [ [ 442, 470 ] ], "normalized": [] }, { "id": "entity-215-3", "type": "DISEASE", "text": [ "pneumonitis" ], "offsets": [ [ 543, 554 ] ], "normalized": [] }, { "id": "entity-215-4", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 685, 698 ] ], "normalized": [] }, { "id": "entity-215-5", "type": "ADVERSE", "text": [ "Febrile neutropenia" ], "offsets": [ [ 1304, 1323 ] ], "normalized": [] } ]

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[ { "id": "passage-216", "type": "abstract", "text": [ "A comparison of two orally bioavailable anti-cancer agents, IRC-110160 and STX140. This study characterises two recently developed anticancer agents in vitro and in vivo, 2-methoxyoestra-1,3,5(10), 16-tetraene-3-carboxamide (IRC-110160) and STX140. MATERIALS AND METHODS: Hormone-dependent (MCF-7), hormone-independent (MDA-MB-231) and P-glycoprotein overexpressing (MCF-7Dox) cells were used for proliferation experiments. For the tumour efficacy studies, female nude mice were inoculated with MDA-MB-231 cells. RESULTS: IRC-110160 is a potent inhibitor of both MCF-7 and MDA-MB-231 cell proliferation. Furthermore, the potency of IRC-110160 was unaffected by the over-expression of the P-glycoprotein drug efflux pump. IRC-110160 and 2-methoxyoestradiol-3,17-O,O-bis-sulfamate (STX140) induced apoptosis in a similar timeframe in the MDA-MB-231 cell line, but only STX140 caused G2/M arrest in these cells. In the MDA-MB-231 xenograft model 300 mg/kg p.o. (daily) of IRC-110160 and 20 mg/kg p.o. STX140 (daily) both completely inhibited tumour growth; however some toxicity was observed with IRC-110160. After 28 days of daily dosing STX140 (20 mg/kg p.o.) had minimal effect on the white blood population of mice with tumours. The masking of STX140 from white blood cells may be due to its interaction with carbonic anhydrase II (CAII) in the red blood cells. In contrast to STX140, IRC-110160 does not inhibit CAII. These studies highlight the activity of two orally bioavailable anti-cancer agents one of which, STX140, may offer a significant clinical advantage over existing drugs as a common dose limiting factor, haemotoxicity, may be minimised." ], "offsets": [ [ 0, 1655 ] ] } ]

[ { "id": "entity-216-0", "type": "DISEASE", "text": [ "tumour" ], "offsets": [ [ 1040, 1046 ] ], "normalized": [] }, { "id": "entity-216-1", "type": "DISEASE", "text": [ "tumours" ], "offsets": [ [ 1222, 1229 ] ], "normalized": [] }, { "id": "entity-216-2", "type": "ADVERSE", "text": [ "haemotoxicity" ], "offsets": [ [ 1623, 1636 ] ], "normalized": [] } ]

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[ { "id": "passage-217", "type": "abstract", "text": [ "Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival." ], "offsets": [ [ 0, 2359 ] ] } ]

[ { "id": "entity-217-0", "type": "DISEASE", "text": [ "melanoma" ], "offsets": [ [ 98, 106 ] ], "normalized": [] }, { "id": "entity-217-1", "type": "DISEASE", "text": [ "melanoma" ], "offsets": [ [ 228, 236 ] ], "normalized": [] }, { "id": "entity-217-2", "type": "DISEASE", "text": [ "melanoma" ], "offsets": [ [ 460, 468 ] ], "normalized": [] }, { "id": "entity-217-3", "type": "ADVERSE", "text": [ "fatigue" ], "offsets": [ [ 2035, 2042 ] ], "normalized": [] }, { "id": "entity-217-4", "type": "ADVERSE", "text": [ "hepatotoxicity" ], "offsets": [ [ 2063, 2077 ] ], "normalized": [] }, { "id": "entity-217-5", "type": "ADVERSE", "text": [ "depression" ], "offsets": [ [ 2093, 2103 ] ], "normalized": [] }, { "id": "entity-217-6", "type": "DISEASE", "text": [ "melanoma" ], "offsets": [ [ 2286, 2294 ] ], "normalized": [] } ]

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[ { "id": "passage-218", "type": "abstract", "text": [ "LDL reduction: how low should we go and is it safe? High-dose statin therapy or combination statin treatment is necessary for most patients to achieve aggressive low-density lipoprotein cholesterol goals. Adding ezetimibe or bile acid sequestrants appears unlikely to increase the risk of myopathy. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be reasonably safe, the safety of combination with high-dose statins has yet to be determined. To enhance patient outcomes, attention must be paid to characteristics that predict muscle and hepatic statin toxicity when considering using high-dose statin or combination statin therapy." ], "offsets": [ [ 0, 672 ] ] } ]

[ { "id": "entity-218-0", "type": "ADVERSE", "text": [ "myopathy" ], "offsets": [ [ 290, 298 ] ], "normalized": [] } ]

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[ { "id": "passage-219", "type": "abstract", "text": [ "Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials. We conducted a systematic review and meta-analysis of randomised and quasi-randomised controlled trials evaluating all clinically relevant pharmacological interventions for the prevention of relapse in people with bipolar disorder. Thirty-four trials were included in the review. Direct comparisons with placebo and with lithium were available for most drugs. In addition, there were direct comparisons of valproate vs. olanzapine, imipramine vs. lithium plus imipramine, olanzapine plus mood stabilisers vs. mood stabilisers and perphenazine plus mood stabilisers vs. mood stabilisers. Methodological quality varied across studies and the strength of evidence was not equal for all treatments or for all comparisons. There is evidence from placebo-controlled trials for the efficacy of lithium, valproate and lamotrigine as maintenance therapy for the prevention of relapse in bipolar disorder. Three drugs have a significant effect in the prevention of manic relapses (lithium, olanzapine and aripiprazole) and three in the prevention of depressive symptoms (valproate, lamotrigine and imipramine). Imipramine is little used in practice, because of concern about adverse effects. The significant effects of olanzapine and aripiprazole were demonstrated in selected responsive bipolar I patients only. Despite widespread use in clinical practice, there is little evidence to support the efficacy of combination therapy." ], "offsets": [ [ 0, 1544 ] ] } ]

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[ { "id": "passage-220", "type": "abstract", "text": [ "Cellular delivery and biological activity of antisense oligonucleotides conjugated to a targeted protein carrier. Targeted delivery can potentially improve the pharmacological effects of antisense and siRNA oligonucleotides. Here, we describe a novel bioconjugation approach to the delivery of splice-shifting antisense oligonucleotides (SSOs). The SSOs are linked to albumin via reversible S-S bonds. The albumin is also conjugated with poly(ethylene glycol) (PEG) chains that terminate in an RGD ligand that selectively binds the alphavbeta3 integrin. As a test system, we utilized human melanoma cells that express the alphavbeta3 integrin and that also contain a luciferase reporter gene that can be induced by delivery of SSOs to the cell nucleus. The RGD-PEG-SSO-albumin conjugates were endocytosed by the cells in an RGD-dependent manner; using confocal fluorescence microscopy, evidence was obtained that the SSOs accumulate in the nucleus. The conjugates were able to robustly induce luciferase expression at concentrations in the 25-200 nM range. At these levels, little short-term or long-term toxicity was observed. Thus, the RGD-PEG-albumin conjugates may provide an effective tool for targeted delivery of oligonucleotides to certain cells and tissues." ], "offsets": [ [ 0, 1267 ] ] } ]

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[ { "id": "passage-221", "type": "abstract", "text": [ "Treatment of patent ductus arteriosus: indomethacin or ibuprofen? Persistent patent ductus arteriosus (PDA) in preterm infants can result in serious hemodynamic changes causing respiratory, gastrointestinal and renal morbidities if not treated within the first week of life. The treatment options available are a conservative approach, pharmacological treatment with cyclo-oxygenase (COX) inhibitors and surgical ligation. The COX inhibitors approved for use in the United States are indomethacin and ibuprofen lysine. Both of these drugs are equally effective in closing the PDA. Subtle differences exist between these two preparations. Indomethacin has a protective effect on the incidence of intraventricular hemorrhage (IVH) but reduces the blood flow to the kidneys and the brain. Ibuprofen is less toxic but has no effect on IVH. Efficacy of pharmacological treatment is influenced by timing of initiation of therapy. Surgical treatment is the only option when pharmacological treatment fails to close the PDA in symptomatic infants. Long-term neurological and respiratory morbidities are associated with surgical ligation. This paper reviews these medical considerations in the treatment options for PDA in premature infants." ], "offsets": [ [ 0, 1233 ] ] } ]

[ { "id": "entity-221-0", "type": "DISEASE", "text": [ "patent ductus arteriosus" ], "offsets": [ [ 13, 37 ] ], "normalized": [] }, { "id": "entity-221-1", "type": "DISEASE", "text": [ "patent ductus arteriosus" ], "offsets": [ [ 78, 102 ] ], "normalized": [] }, { "id": "entity-221-2", "type": "DISEASE", "text": [ "PDA" ], "offsets": [ [ 104, 107 ] ], "normalized": [] }, { "id": "entity-221-3", "type": "DISEASE", "text": [ "PDA" ], "offsets": [ [ 577, 580 ] ], "normalized": [] }, { "id": "entity-221-4", "type": "DISEASE", "text": [ "intraventricular hemorrhage" ], "offsets": [ [ 696, 723 ] ], "normalized": [] }, { "id": "entity-221-5", "type": "DISEASE", "text": [ "IVH" ], "offsets": [ [ 725, 728 ] ], "normalized": [] }, { "id": "entity-221-6", "type": "DISEASE", "text": [ "IVH" ], "offsets": [ [ 832, 835 ] ], "normalized": [] }, { "id": "entity-221-7", "type": "DISEASE", "text": [ "PDA" ], "offsets": [ [ 1013, 1016 ] ], "normalized": [] }, { "id": "entity-221-8", "type": "DISEASE", "text": [ "PDA" ], "offsets": [ [ 1208, 1211 ] ], "normalized": [] } ]

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[ { "id": "passage-222", "type": "abstract", "text": [ "Toward experimental assessment of receptor occupancy: TGN1412 revisited. In March 2006, 6 healthy volunteers experienced serious adverse reactions during a first-in-human clinical trial of the superagonistic anti-CD28 mAb TGN1412. A first investigation excluded contaminations of the drug product or protocol irregularities as the root cause. Later, an expert scientific group convened in the United Kingdom to develop recommendations pertinent to minimizing risks of first-in-human clinical trials. The expert scientific group concluded from in silico calculations that at the initial dose of 0.1 mg/kg, which was adjusted on the basis of the no observed adverse effect level, approximately 86.2% to 90.9% CD28 receptor occupancy was obtained. Here we developed a flow cytometric method that revealed receptor occupancy of approximately 45% to 80% under the above conditions. Thus we present a method to experimentally determine receptor occupancy that can be taken as one parameter to define the minimal anticipated biological effect level as the basis for calculating safer starting doses for first-in-human clinical trials for products in which a potential risk has been identified. Additional measures are being discussed that will help to significantly improve safety of first-in-human clinical trials." ], "offsets": [ [ 0, 1309 ] ] } ]

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[ { "id": "passage-223", "type": "abstract", "text": [ "Blueberry opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activation protein kinase. Alzheimer's Disease (AD) is the most common age-related dementia, with a current prevalence in excess of five million individuals in the United States. The aggregation of amyloid-beta (A beta) into fibrillar amyloid plaques is a key pathological event in the development of the disease. Microglial proinflammatory activation is widely known to cause neuronal and synaptic damage that correlates with cognitive impairment in AD. However, current pharmacological attempts at reducing neuroinflammation mediated via microglial activation have been largely negative in terms of slowing AD progression. Previously, we have shown that microglia express proinflammatory cytokines and a reduced capacity to phagocytose A beta in the context of CD40, A beta peptides and/or lipopolysaccharide (LPS) stimulation, a phenomenon that can be opposed by attenuation of p44/42 mitogen-activated protein kinase (MAPK) signaling. Other groups have found that blueberry (BB) extract both inhibits phosphorylation of this MAPK module and also improves cognitive deficits in AD model mice. Given these considerations and the lack of reduced A beta quantities in behaviorally improved BB-fed mice, we wished to determine whether BB supplementation would alter the microglial proinflammatory activation state in response to A beta. We found that BB significantly enhances microglial clearance of A beta, inhibits aggregation of A beta(1-42), and suppresses microglial activation, all via suppression of the p44/42 MAPK module. Thus, these data may explain the previously observed behavioral recovery in PSAPP mice and suggest a means by which dietary supplementation could mitigate an undesirable microglial response toward fibrillar A beta." ], "offsets": [ [ 0, 1848 ] ] } ]

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[ { "id": "passage-224", "type": "abstract", "text": [ "Concurrent chemoradiation for locally advanced squamous cell carcinoma of the vagina: case series and literature review. BACKGROUND: We reviewed our experience with patients with primary squamous cell carcinoma of the vagina who received concurrent chemoradiation therapy (CCRT). METHODS: We retrospectively analyzed six patients (median age, 60 years) with squamous cell carcinoma of the vagina who underwent CCRT between 2002 and 2005 at the University of the Ryukyus Hospital. Two patients were in International Federation of Obstetricians and Gynecologists (FIGO) stage II, one in stage III, and three in stage IVA. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Tumor size ranged from 3.2 to 7.7 cm. All patients were treated with true pelvic external-beam radiotherapy (EBRT) at 50 Gy. Then two of the six patients underwent intracavitary vaginal brachy-therapy. The remaining four patients received boost EBRT with shrinking fields. Total radiation dose to the vaginal tumor ranged from 60 to 66 Gy. All patients received two or three concomitant cycles of cisplatin during EBRT. RESULTS: All six patients completed their scheduled CCRT, and achieved a clinical complete response. One stage II patient died of disease 24 months after treatment, and the stage III patient had local failure at 12 months. The remaining four patients were free of their disease at 18, 23, 33, and 55 months, respectively. One patient with stage IVA developed a vesicovaginal fistula during CCRT. Nevertheless, CCRT was well tolerated by all six patients, and no grade 3 or 4 late toxicity was observed, as evaluated by the Radiation Therapy Oncology Group (RTOG) scoring system. CONCLUSION: CCRT is effective for primary squamous cell carcinoma of the vagina and should be considered for treatment in patients with high-risk disease having good performance status." ], "offsets": [ [ 0, 1900 ] ] } ]

[ { "id": "entity-224-0", "type": "DISEASE", "text": [ "squamous cell carcinoma of the vagina" ], "offsets": [ [ 47, 84 ] ], "normalized": [] }, { "id": "entity-224-1", "type": "DISEASE", "text": [ "squamous cell carcinoma of the vagina" ], "offsets": [ [ 188, 225 ] ], "normalized": [] }, { "id": "entity-224-2", "type": "DISEASE", "text": [ "squamous cell carcinoma of the vagina" ], "offsets": [ [ 359, 396 ] ], "normalized": [] }, { "id": "entity-224-3", "type": "DISEASE", "text": [ "vaginal tumor" ], "offsets": [ [ 1017, 1030 ] ], "normalized": [] }, { "id": "entity-224-4", "type": "ADVERSE", "text": [ "vesicovaginal fistula" ], "offsets": [ [ 1497, 1518 ] ], "normalized": [] }, { "id": "entity-224-5", "type": "DISEASE", "text": [ "squamous cell carcinoma of the vagina" ], "offsets": [ [ 1757, 1794 ] ], "normalized": [] } ]

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[ { "id": "passage-225", "type": "abstract", "text": [ "Methemoglobin levels during epidural anesthesia for renal transplantation--comparison of prilocaine with bupivacaine. BACKGROUND AND OBJECTIVE: One goal of anesthesia for renal transplantation is to avoid an excess load to be imposed on the newly functioning kidney, by using appropriate agents and dosages in the perioperative management. The purpose of this study was to investigate the effect of prilocaine on serum methemoglobin levels when used as the local anesthetic in epidural anesthesia for renal transplantation, and to compare its effects with that of bupivacaine, which is the standard local anesthetic used. METHODS: 26 adult renal recipients were randomized into 2 equal groups according to the local anesthetic used for epidural anesthesia during the operation. Patients in group P (n = 13) were given prilocaine and those in group B (control, n = 13) received bupivacaine. The methemoglobin measurement intervals were at: baseline before administration of local anesthetic, and then at 2 hours, 5 hours, and 12 hours of local anesthetic administration. RESULTS: Methemoglobin levels in the prilocaine group were above the normal range in all measurements other than baseline. In the bupivacaine group, methemoglobin levels increased only at 5 hours of local anesthetic administration. However, methemoglobin concentrations and hemoglobin levels were comparable between the two groups at all time intervals, and none of the patients demonstrated clinical symptoms. CONCLUSION: The use of prilocaine in epidural anesthesia for renal transplantation surgery resulted in an increase in methemoglobin levels, which did not cause any clinical symptoms and was similar to those of bupivacaine at all time measurements." ], "offsets": [ [ 0, 1729 ] ] } ]

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[ { "id": "passage-226", "type": "abstract", "text": [ "HIV drug resistance tendencies in Latvia. The treatment of HIV infection in Latvia by using highly active antiretroviral therapy (HAART) was started in 1996. The prevalence and tendencies of HIV drug resistance among treated and treatment-naive patients in Latvia in the years 2006-2007 were evaluated in this study. Data of HIV genotyping, performed in 132 HIV-1 infected during years 2006-2007 by TRUGENE HIV-1 genotyping assay (BayerHealthCare-diagnostics) are included in the study. Analysis of data showed that in the group of treatment-naive individuals majority carried wild type virus. Prevalence of resistance-associated mutations (RAMs) in the treatment-naive group according to IAS list was 28%. In most cases it was NRTI mutation A62V that is associated with multinucleoside resistance caused by Q151M, its effect in the absence of Q151M is not known. By many authors A62V is supposed to be a result of polymorphism in RT gene and is excluded from the list of resistance mutations. High prevalence of A62V is typical for HIV-1 subtype A. As majority of treatment-naive cases (89%) in this study were with HIV-1 subtypes A or AE, we excluded A62V mutation and estimated RAMs prevalence in group of treatment-naive HIV-infected individuals as 7%. Minor PI mutations were not included in analyses. In Europe published rates generally very between 5% and 15%. In the group of treatment-experienced HIV infected people 25/75 were with HIV-1 subtype B, the rest part--with non-B subtypes: A/AE (35/75), CRF-01AE (7/75), B/AE (4/75) and others. In treatment-experienced patients RAMs prevalence was estimated as 58.6%. Most frequently RAMs were found for nucleoside reverse transcriptase inhibitors (NRTI) (49.3%) followed by non-nucleoside reverse transcriptase inhibitors (NNRTI) (22.6%) and protease inhibitors (PI) (16%). In the group of NRTI mutations M184V (26/75; 34.6%), A62V (12/75; 16.0%) and T215Y (8/75; 10.6%), in NNRTI mutations K103N (10/75; 13.3%), G190S (6/75; 8.0%), in PI group mutations L90M (6/75; 8.0%) and M461/L (6/75; 8.0%) occurred most frequently. The following drug susceptibility was predicted according to the Trugen expert interpretations: in 33/75 (44%) patients no evidence of resistance, in 21/75 (28%) patients resistance to 1 drug class (NRTI--16/75, NNRTI--4/75, PI--1/75), in 17 patients (22.6%) resistance to 2 drug classes (NRTI+NNRTI--9/75, NRTI+PI--7/75, NNRTI+PI--1/75) and in 3/75 (4%) patients resistance to all 3 classes of drugs (NRTI+NNRTI+PI). We conclude, that prevalence of RAMs in treatment-naive HIV infected persons in Latvia is comparable with prevalence in Europe. The origin of predominated mutation A62V associated with NRTI at present is not clear. In more than half of treated HIV infected patients HIV resistance to at least one HAART class was predicted." ], "offsets": [ [ 0, 2822 ] ] } ]

[ { "id": "entity-226-0", "type": "DISEASE", "text": [ "HIV infection" ], "offsets": [ [ 60, 73 ] ], "normalized": [] } ]

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[ { "id": "passage-227", "type": "abstract", "text": [ "Ibuprofen slow-release foam dressing reduces wound pain in painful exuding wounds: preliminary findings from an international real-life study. BACKGROUND: Wound pain is a serious problem for people with chronic wounds. The aim of this real-life study was to compare the effect of a foam dressing that releases ibuprofen (Biatain Ibu) with local best practice on the treatment of painful exuding wounds. METHODS: A total of 185 patients with painful exuding wounds were randomized to either ibuprofen foam treatment (n = 98) or local best practice (n = 87). The primary endpoint was pain relief over 7 days of treatment, assessed daily using a 5-point verbal rating scale (no relief, slight relief, moderate relief, lots of relief, and complete relief). Secondary endpoints included a total reduction in pain intensity for the whole study period (using an 11-point Numeric Box Scale: 0 = no pain to 10 = worst possible pain) and incidence of adverse events (AEs). RESULTS: More patients in the ibuprofen foam treatment group reported wound pain relief and lower wound pain intensity values after 7 days (p < 0.0001 for both variables). Within the four most common ulcer aetiolgies, patients reported significantly more effective pain relief with ibuprofen foam treatment (venous: p = 0.009, mixed arterial venous: p < 0.0001, arterial: p = 0.0009, and vasculitis: p = 0.009). In all groups, patients from the ibuprofen foam group reported lower pain intensities. The results were significant for patients with venous (p < 0.002) and arterial (p < 0.0001) leg ulcers. Two AEs were reported. CONCLUSIONS: The ibuprofen foam represents an effective and safe alternative to local best practice in the management of painful exuding wounds." ], "offsets": [ [ 0, 1734 ] ] } ]

[ { "id": "entity-227-0", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 45, 55 ] ], "normalized": [] }, { "id": "entity-227-1", "type": "DISEASE", "text": [ "Wound pain" ], "offsets": [ [ 156, 166 ] ], "normalized": [] }, { "id": "entity-227-2", "type": "DISEASE", "text": [ "chronic wounds" ], "offsets": [ [ 204, 218 ] ], "normalized": [] }, { "id": "entity-227-3", "type": "DISEASE", "text": [ "painful exuding wounds" ], "offsets": [ [ 380, 402 ] ], "normalized": [] }, { "id": "entity-227-4", "type": "DISEASE", "text": [ "painful exuding wounds" ], "offsets": [ [ 442, 464 ] ], "normalized": [] }, { "id": "entity-227-5", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "entity-227-6", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 804, 808 ] ], "normalized": [] }, { "id": "entity-227-7", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 891, 895 ] ], "normalized": [] }, { "id": "entity-227-8", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 919, 923 ] ], "normalized": [] }, { "id": "entity-227-9", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 1034, 1044 ] ], "normalized": [] }, { "id": "entity-227-10", "type": "DISEASE", "text": [ "wound pain" ], "offsets": [ [ 1062, 1072 ] ], "normalized": [] }, { "id": "entity-227-11", "type": "DISEASE", "text": [ "ulcer aetiolgies" ], "offsets": [ [ 1164, 1180 ] ], "normalized": [] }, { "id": "entity-227-12", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "entity-227-13", "type": "DISEASE", "text": [ "vasculitis" ], "offsets": [ [ 1352, 1362 ] ], "normalized": [] }, { "id": "entity-227-14", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 1445, 1449 ] ], "normalized": [] }, { "id": "entity-227-15", "type": "DISEASE", "text": [ "leg ulcers" ], "offsets": [ [ 1555, 1565 ] ], "normalized": [] }, { "id": "entity-227-16", "type": "DISEASE", "text": [ "painful exuding wounds" ], "offsets": [ [ 1711, 1733 ] ], "normalized": [] } ]

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[ { "id": "passage-228", "type": "abstract", "text": [ "Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addition, HDACs can also influence transcription-independent events such as mitosis or deoxyribonucleic acid (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clinical trials, showing significant anticancer activity both in hematological and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clinical oncology market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies." ], "offsets": [ [ 0, 1259 ] ] } ]

[ { "id": "entity-228-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 75, 81 ] ], "normalized": [] }, { "id": "entity-228-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 542, 548 ] ], "normalized": [] }, { "id": "entity-228-2", "type": "DISEASE", "text": [ "cutaneous T-cell lymphoma" ], "offsets": [ [ 1183, 1208 ] ], "normalized": [] }, { "id": "entity-228-3", "type": "DISEASE", "text": [ "CTCL" ], "offsets": [ [ 1210, 1214 ] ], "normalized": [] }, { "id": "entity-228-4", "type": "DISEASE", "text": [ "malignancies" ], "offsets": [ [ 1246, 1258 ] ], "normalized": [] } ]

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[ { "id": "passage-229", "type": "abstract", "text": [ "CNS delivery via adsorptive transcytosis. Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity--like the cationization strategy--as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics." ], "offsets": [ [ 0, 1489 ] ] } ]

[ { "id": "entity-229-0", "type": "ADVERSE", "text": [ "immunogenicity" ], "offsets": [ [ 1182, 1196 ] ], "normalized": [] } ]

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[ { "id": "passage-230", "type": "abstract", "text": [ "Simvastatin-induced rhabdomyolysis and acute renal injury. Simvastatin is one of the most commonly prescribed CoA reductase inhibitors. The safety profile of this drug has been widely discussed in the medical and consumer advocacy communities. Like other statins, simvastatin can cause a serious and potentially life-threatening complication: rhabdomyolysis. We describe a case of simvastatin-induced rhabdomyolysis complicated by acute renal failure requiring urgent hemodialysis. The relative safety of simvastatin compared to other HMG-CoA reductase inhibitors and the conditions that can potentiate its toxicity are discussed. The clinical features of rhabdomyolysis, and subsequent acute renal failure, and their treatment modalities are presented." ], "offsets": [ [ 0, 754 ] ] } ]

[ { "id": "entity-230-0", "type": "ADVERSE", "text": [ "rhabdomyolysis" ], "offsets": [ [ 20, 34 ] ], "normalized": [] }, { "id": "entity-230-1", "type": "ADVERSE", "text": [ "acute renal injury" ], "offsets": [ [ 39, 57 ] ], "normalized": [] }, { "id": "entity-230-2", "type": "ADVERSE", "text": [ "rhabdomyolysis" ], "offsets": [ [ 344, 358 ] ], "normalized": [] }, { "id": "entity-230-3", "type": "ADVERSE", "text": [ "rhabdomyolysis" ], "offsets": [ [ 402, 416 ] ], "normalized": [] }, { "id": "entity-230-4", "type": "ADVERSE", "text": [ "acute renal failure" ], "offsets": [ [ 432, 451 ] ], "normalized": [] }, { "id": "entity-230-5", "type": "ADVERSE", "text": [ "rhabdomyolysis" ], "offsets": [ [ 657, 671 ] ], "normalized": [] }, { "id": "entity-230-6", "type": "ADVERSE", "text": [ "acute renal failure" ], "offsets": [ [ 688, 707 ] ], "normalized": [] } ]

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[ { "id": "passage-231", "type": "abstract", "text": [ "The reduction in visceral fat mass in response to growth hormone is more marked in men than in oestrogen-deficient women. CONTEXT: Women with severe growth hormone (GH) deficiency have a less marked response to GH replacement than men. This has mostly been attributed to the attenuating effects of oestrogen replacement therapy. OBJECTIVE: To study gender related differences in the response to GH treatment in men and postmenopausal women. METHODS: Fifteen men and 15 age- and BMI-matched women with abdominal obesity (mean age: 58; range 51-64 years) were treated for one year with similar doses (0.47 vs. 0.51 mg/day) of GH. All women were postmenopausal not receiving oestrogen treatment. Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp and body composition by computed tomography (CT) scans and from total body potassium, K(40). RESULTS: Men and women were comparable at baseline in terms of waist circumference, IGF-1 and lipid levels. After one year of GH treatment, there was a 18% reduction in visceral adipose tissue (VAT) in men and a 5% reduction in women (P=0.0001 men vs. women). Although the magnitude of the difference was small, men increased more in thigh muscle mass (P<0.0001 vs. women). A reduction in thigh intermuscular adipose tissue (IMAT) and diastolic blood pressure was seen only in men (both p<0.05 vs. baseline). A decrease in LDL cholesterol, and an increase in serum insulin, was observed only in women (both p<0.05 vs. baseline). CONCLUSION: Low dose GH treatment reduced VAT more markedly in men as compared with women. As all women were postmenopausal and oestrogen-deficient, this gender difference in responsiveness was not due to an antagonistic effect of oestrogen on peripheral GH action." ], "offsets": [ [ 0, 1756 ] ] } ]

[ { "id": "entity-231-0", "type": "DISEASE", "text": [ "growth hormone (GH) deficiency" ], "offsets": [ [ 150, 180 ] ], "normalized": [] }, { "id": "entity-231-1", "type": "DISEASE", "text": [ "abdominal obesity" ], "offsets": [ [ 502, 519 ] ], "normalized": [] } ]

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[ { "id": "passage-232", "type": "abstract", "text": [ "Fragrance material review on tetrahydromuguol. A toxicologic and dermatologic review of tetrahydromuguol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 155 ] ] } ]

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[ { "id": "passage-233", "type": "abstract", "text": [ "Predictors of subjective and objective quality of life in outpatients with schizophrenia. AIM: In recent years, greater attention has been given to quality of life (QOL) in schizophrenia and several studies reported that negative and depressive symptoms and cognitive dysfunction are related to patient QOL. But because a variety of QOL measures have been used in the previous studies, there seems to be no unanimous predictors for subjective and objective QOL. The purpose of the present study was to elucidate the relationship between clinical variables and subjective and objective QOL in outpatients with schizophrenia, using schizophrenia disease-specific QOL measures. Particular attention was paid to cognitive function as a predictor of QOL. METHODS: Schizophrenia symptoms of the Positive and Negative Syndrome Scale (PANSS) were divided into five factors: positive factor, negative factor, cognitive factor, emotional discomfort, and hostility. The study sample consisted of 84 schizophrenia outpatients. Subjective and objective QOL were assessed with Schizophrenia Quality of Life Scale (SQLS) and the Quality of Life Scale (QLS), respectively. RESULTS: Subjective QOL correlated significantly with emotional discomfort, positive factor, negative factor, extrapyramidal symptoms and cognitive factor, while objective QOL correlated with negative factor, cognitive factor, emotional discomfort, extrapyramidal symptoms, and dose of antipsychotics. Total score and three of four subscales in the QLS correlated significantly with cognitive factor, while cognitive factor had a significant correlation with only one of three scales of SQLS. Stepwise regression showed that subjective QOL was significantly predicted by emotional discomfort and extrapyramidal symptoms, while negative factor was the most important predictor of objective QOL. CONCLUSION: Cognitive dysfunction had a greater influence on objective QOL than subjective QOL. Treating depressive and negative symptoms and extrapyramidal symptoms might contribute to enhanced subjective and objective QOL." ], "offsets": [ [ 0, 2076 ] ] } ]

[ { "id": "entity-233-0", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 75, 88 ] ], "normalized": [] }, { "id": "entity-233-1", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 174, 187 ] ], "normalized": [] }, { "id": "entity-233-2", "type": "DISEASE", "text": [ "depressive symptoms" ], "offsets": [ [ 235, 254 ] ], "normalized": [] }, { "id": "entity-233-3", "type": "DISEASE", "text": [ "cognitive dysfunction" ], "offsets": [ [ 259, 280 ] ], "normalized": [] }, { "id": "entity-233-4", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 610, 623 ] ], "normalized": [] }, { "id": "entity-233-5", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 631, 644 ] ], "normalized": [] }, { "id": "entity-233-6", "type": "DISEASE", "text": [ "Schizophrenia symptoms" ], "offsets": [ [ 760, 782 ] ], "normalized": [] }, { "id": "entity-233-7", "type": "DISEASE", "text": [ "emotional discomfort" ], "offsets": [ [ 919, 939 ] ], "normalized": [] }, { "id": "entity-233-8", "type": "DISEASE", "text": [ "schizophrenia" ], "offsets": [ [ 989, 1002 ] ], "normalized": [] }, { "id": "entity-233-9", "type": "DISEASE", "text": [ "Schizophrenia" ], "offsets": [ [ 1064, 1077 ] ], "normalized": [] }, { "id": "entity-233-10", "type": "DISEASE", "text": [ "emotional discomfort" ], "offsets": [ [ 1212, 1232 ] ], "normalized": [] }, { "id": "entity-233-11", "type": "DISEASE", "text": [ "extrapyramidal symptoms" ], "offsets": [ [ 1268, 1291 ] ], "normalized": [] }, { "id": "entity-233-12", "type": "DISEASE", "text": [ "emotional discomfort" ], "offsets": [ [ 1385, 1405 ] ], "normalized": [] }, { "id": "entity-233-13", "type": "DISEASE", "text": [ "extrapyramidal symptoms" ], "offsets": [ [ 1407, 1430 ] ], "normalized": [] }, { "id": "entity-233-14", "type": "DISEASE", "text": [ "emotional discomfort" ], "offsets": [ [ 1729, 1749 ] ], "normalized": [] }, { "id": "entity-233-15", "type": "DISEASE", "text": [ "extrapyramidal symptoms" ], "offsets": [ [ 1754, 1777 ] ], "normalized": [] }, { "id": "entity-233-16", "type": "DISEASE", "text": [ "Cognitive dysfunction" ], "offsets": [ [ 1864, 1885 ] ], "normalized": [] }, { "id": "entity-233-17", "type": "DISEASE", "text": [ "extrapyramidal symptoms" ], "offsets": [ [ 1994, 2017 ] ], "normalized": [] } ]

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[ { "id": "passage-234", "type": "abstract", "text": [ "Chloroquine psychosis masquerading as PCP: a case report. Chloroquine and its derivatives have been drugs of choice in the prophylaxis and treatment of malaria for over 50 years. These drugs are also frequently used in the treatment of various rheumatologic disorders. Because many Americans now travel abroad and may require chloroquine prophylaxis, as well as the fact that such medications are readily available through Internet-based supply houses, clinicians should be aware of the potential toxicity associated with the use of these agents. We present the case of an adolescent female who presented with acute, chloroquine-induced toxic psychosis resembling that induced by phencyclidine (PCP) in clinical presentation and laboratory findings. In the acute setting, the differentiation between chloroquine toxic psychosis and PCP psychosis may be difficult. Therefore, the syndrome of chloroquine-induced psychosis is reviewed and its differentiation from PCP psychosis highlighted as it relates to important aspects of this case." ], "offsets": [ [ 0, 1037 ] ] } ]

[ { "id": "entity-234-0", "type": "ADVERSE", "text": [ "psychosis" ], "offsets": [ [ 12, 21 ] ], "normalized": [] }, { "id": "entity-234-1", "type": "DISEASE", "text": [ "malaria" ], "offsets": [ [ 153, 160 ] ], "normalized": [] }, { "id": "entity-234-2", "type": "DISEASE", "text": [ "rheumatologic disorders" ], "offsets": [ [ 245, 268 ] ], "normalized": [] }, { "id": "entity-234-3", "type": "ADVERSE", "text": [ "toxic psychosis" ], "offsets": [ [ 638, 653 ] ], "normalized": [] }, { "id": "entity-234-4", "type": "ADVERSE", "text": [ "toxic psychosis" ], "offsets": [ [ 813, 828 ] ], "normalized": [] }, { "id": "entity-234-5", "type": "ADVERSE", "text": [ "PCP psychosis" ], "offsets": [ [ 833, 846 ] ], "normalized": [] }, { "id": "entity-234-6", "type": "ADVERSE", "text": [ "psychosis" ], "offsets": [ [ 912, 921 ] ], "normalized": [] }, { "id": "entity-234-7", "type": "ADVERSE", "text": [ "PCP psychosis" ], "offsets": [ [ 963, 976 ] ], "normalized": [] } ]

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[ { "id": "passage-235", "type": "abstract", "text": [ "Headache: one of the most common and troublesome adverse reactions to drugs. It is difficult to attribute the diagnosis of adverse drug reaction to a condition which is also a common symptom. The decision might be arduous in the case of headache, because this disorder is very frequent in the general population. The drugs that more frequently induce headache belong to a variety of therapeutic classes with different mechanisms of action and different toxicity. In the majority of cases the headache has not a typical feature, it is dose-dependent, and is associated to other symptoms of neurotoxicity. Some drugs cause, instead, a specific headache: this is the case of NO donors, which are also used in experimental studies in order to induce headache. This review describes the classes of drugs which induce headache, analyzes the frequency of headache induction among the drugs of the same class, and discusses the possible mechanisms underlying headache induction. It is to be hoped that a better awareness of this issue would help the physician to consider it in the differential diagnosis of a recent-onset or changed headache and to avoid prescription of drugs known to cause headache to patients already suffering from this disorder." ], "offsets": [ [ 0, 1244 ] ] } ]

[ { "id": "entity-235-0", "type": "ADVERSE", "text": [ "Headache" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "entity-235-1", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 238, 246 ] ], "normalized": [] }, { "id": "entity-235-2", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 352, 360 ] ], "normalized": [] }, { "id": "entity-235-3", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 493, 501 ] ], "normalized": [] }, { "id": "entity-235-4", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 590, 603 ] ], "normalized": [] }, { "id": "entity-235-5", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 643, 651 ] ], "normalized": [] }, { "id": "entity-235-6", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 747, 755 ] ], "normalized": [] }, { "id": "entity-235-7", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 813, 821 ] ], "normalized": [] }, { "id": "entity-235-8", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 849, 857 ] ], "normalized": [] }, { "id": "entity-235-9", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 952, 960 ] ], "normalized": [] }, { "id": "entity-235-10", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 1127, 1135 ] ], "normalized": [] }, { "id": "entity-235-11", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 1186, 1194 ] ], "normalized": [] } ]

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[ { "id": "passage-236", "type": "abstract", "text": [ "Effects of mosapride citrate on patients after vagal nerve, lower esophageal sphincter, and pyloric sphincter-preserving nearly total gastrectomy reconstructed by jejunal J pouch interposition, and postoperative quality of life. BACKGROUND/AIMS: Vagal nerve and pylorus-preserving nearly total gastrectomy reconstructed by interposition of a jejunal J pouch (hereinafter called NTGP) is a function-preserving operation for early gastric cancer. However, some patients after NTGP have suffered from postprandial food stasis in the substitute stomach, and postprandial stasis leads to abdominal symptoms. To clarify the clinical effect of mosapride citrate (hereinafter called MS) for prevention of food stasis in the substitute stomach for patients after NTGP, we studied the clinical effects of MS before and after administration of MS. METHODOLOGY: In a total of 24 patients (18 males, 6 females; aged 44-70 years, average 58.1 years) during 5 years after NTGP for early gastric cancer (D1 lymph node dissection, curability A), the relationship between their postoperative quality of life (QOL) and emptying function of the substitute stomach (hereinafter called EFS) was compared using a radioisotope method before MS therapy and after MS therapy at an oral dose of 15mg/day for 3 months. RESULTS: The interviews showd that after MS therapy, patients had more evident appetite and ate more food with a slight increase in body weight (0.52Kg) compared with patients before MS therapy. Before and after MS therapy, patients had no early dumping symtoms, while patients after MS therapy clearly had fewer symptoms such as reflux esophagitis, nausea, and abdominal pain compared with before MS therapy. After MS therapy, patients also had significantly decreased abdominal fullness compared with before MS therapy (p = 0.0046). Endoscopically, we found reflux esophagitis in 4 patients before MS therapy but in no patients after MS therapy. All patients before MS therapy showed residual contents in the substitute stomach, but only 10 patients after MS therapy showed residual contents in the substitute stomach. There was a significant difference between before and after MS therapy (p = 0.0016). Regarding EFS, the time to 50% residual rate before MS therapy (98.7 +/- 13.0 min) was significantly slower than that after MS therapy (83.2 +/- 13.8 min) (p = 0.0134). After MS therapy (37.0 +/- 4.9%), the residual rates at 120 minutes were significantly decreased compared with patients before MS therapy (44.8 +/- 5.3%) (p = 0.0028). Patients after MS therapy clearly had improved stasis of substitute stomach compared with before MS therapy. CONCLUSIONS: It was considered that MS therapy subsequently improves abdominal fullness due to the postprandial food stasis in the substitute stomach, contributing to the improvement of QOL of patients after NTGP." ], "offsets": [ [ 0, 2857 ] ] } ]

[ { "id": "entity-236-0", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 430, 444 ] ], "normalized": [] }, { "id": "entity-236-1", "type": "DISEASE", "text": [ "abdominal symptoms" ], "offsets": [ [ 584, 602 ] ], "normalized": [] }, { "id": "entity-236-2", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 973, 987 ] ], "normalized": [] }, { "id": "entity-236-3", "type": "ADVERSE", "text": [ "reflux esophagitis" ], "offsets": [ [ 1622, 1640 ] ], "normalized": [] }, { "id": "entity-236-4", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 1642, 1648 ] ], "normalized": [] }, { "id": "entity-236-5", "type": "ADVERSE", "text": [ "abdominal pain" ], "offsets": [ [ 1654, 1668 ] ], "normalized": [] }, { "id": "entity-236-6", "type": "DISEASE", "text": [ "abdominal fullness" ], "offsets": [ [ 1762, 1780 ] ], "normalized": [] }, { "id": "entity-236-7", "type": "DISEASE", "text": [ "reflux esophagitis" ], "offsets": [ [ 1852, 1870 ] ], "normalized": [] }, { "id": "entity-236-8", "type": "DISEASE", "text": [ "abdominal fullness" ], "offsets": [ [ 2713, 2731 ] ], "normalized": [] } ]

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[ { "id": "passage-237", "type": "abstract", "text": [ "Alert: inaccurate lithium assay results. OBJECTIVES: A patient who had experienced bipolar disorder for over 20 years and who had been euthymic for most of that period while highly compliant with lithium, had falsely low lithium levels reported over two periods, 6 years apart, and was actually lithium toxic on the most recent occasion. At that latter time the spuriously low lithium levels reported on the assay risked dispelling any clinical suspicion of lithium toxicity, although toxicity was later confirmed. METHOD: Case report. RESULTS: The latter incident identified a serious problem, whereby it is likely that the particular assay risks generating spuriously low values when high serum levels of lithium are present--a so-called 'hook phenomenon' that has been described for some quantitative immunoassays. CONCLUSIONS: It is in situations of high potential gravity--when lithium toxicity is present--that lithium quantification is most likely to be compromised and low values generated. Also of grave concern is the fact that there are no regulatory processes in place to communicate this problem to lithium prescribers." ], "offsets": [ [ 0, 1133 ] ] } ]

[ { "id": "entity-237-0", "type": "DISEASE", "text": [ "bipolar disorder" ], "offsets": [ [ 84, 100 ] ], "normalized": [] }, { "id": "entity-237-1", "type": "ADVERSE", "text": [ "lithium toxicity" ], "offsets": [ [ 459, 475 ] ], "normalized": [] }, { "id": "entity-237-2", "type": "ADVERSE", "text": [ "lithium toxicity" ], "offsets": [ [ 884, 900 ] ], "normalized": [] } ]

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[ { "id": "passage-238", "type": "abstract", "text": [ "Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Clindamycin phosphate 1.2% together with tretinoin 0.025% as a gel (CTG) is a topical formulation of a fixed and stable combination approved by the FDA for the treatment of acne vulgaris in patients 12 years of age or older. The main indication of CTG is the management of moderate comedonal and mild-to-moderate papulopustular acne, an acne form which is present in more than 50% of acne patients. CTG can also be combined with systemic antiacne therapy, such as systemic isotretinoin, in nodulocystic acne. The product combines the anti-inflammatory and antibacterial properties of clindamycin with the well proven and beneficial comedolytic and anticomedogenic effects of tretinoin (all-trans retinoic acid). The addition of clindamycin to tretinoin enhances the comedolytic efficacy of tretinoin in moderate-to-severe acne of the face. The comedolytic activity of tretinoin and the anti-inflammatory efficacy of clindamycin accelerate resolution of all types of acne lesions without affecting the safety of both compounds. Discontinuation rates due to adverse events related to this formulation were found to be low (</= 1%). Safety of CTG use in pregnancy has not been established. The combination formulation is mainly designed to enhance effectiveness and minimize irritation. The once daily use of CTG, its rapid and dual effect and good tolerability have a positive impact on the duration of disease, patients' compliance and overall costs of therapy." ], "offsets": [ [ 0, 1544 ] ] } ]

[ { "id": "entity-238-0", "type": "DISEASE", "text": [ "acne vulgaris" ], "offsets": [ [ 68, 81 ] ], "normalized": [] }, { "id": "entity-238-1", "type": "DISEASE", "text": [ "acne vulgaris" ], "offsets": [ [ 257, 270 ] ], "normalized": [] }, { "id": "entity-238-2", "type": "DISEASE", "text": [ "papulopustular acne" ], "offsets": [ [ 397, 416 ] ], "normalized": [] }, { "id": "entity-238-3", "type": "DISEASE", "text": [ "acne" ], "offsets": [ [ 421, 425 ] ], "normalized": [] }, { "id": "entity-238-4", "type": "DISEASE", "text": [ "acne" ], "offsets": [ [ 468, 472 ] ], "normalized": [] }, { "id": "entity-238-5", "type": "DISEASE", "text": [ "nodulocystic acne" ], "offsets": [ [ 574, 591 ] ], "normalized": [] }, { "id": "entity-238-6", "type": "DISEASE", "text": [ "acne of the face" ], "offsets": [ [ 906, 922 ] ], "normalized": [] }, { "id": "entity-238-7", "type": "DISEASE", "text": [ "acne lesions" ], "offsets": [ [ 1050, 1062 ] ], "normalized": [] } ]

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[ { "id": "passage-239", "type": "abstract", "text": [ "Maximum effect of triptans in migraine? A comment. The efficacy of triptans in the treatment of migraine was recently contested. How high is then the maximum effect of a triptan? After subcutaneous naratriptan 10 mg a 88% pain-free response was observed. This result was obtained despite the fact that more half of the patients had a migraine duration of > 4 h. These results indicate that subcutaneous naratriptan in a high dose can overcome central sensitization that occurs in migraine attacks." ], "offsets": [ [ 0, 498 ] ] } ]

[ { "id": "entity-239-0", "type": "DISEASE", "text": [ "migraine" ], "offsets": [ [ 30, 38 ] ], "normalized": [] }, { "id": "entity-239-1", "type": "DISEASE", "text": [ "migraine" ], "offsets": [ [ 97, 105 ] ], "normalized": [] }, { "id": "entity-239-2", "type": "DISEASE", "text": [ "migraine" ], "offsets": [ [ 335, 343 ] ], "normalized": [] }, { "id": "entity-239-3", "type": "DISEASE", "text": [ "migraine" ], "offsets": [ [ 481, 489 ] ], "normalized": [] } ]

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[ { "id": "passage-240", "type": "abstract", "text": [ "Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children. BACKGROUND AND PURPOSE: A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. METHODS: The method assigns doses to successive cohorts of patients on the basis of each dose's desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort's dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. RESULTS: Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke." ], "offsets": [ [ 0, 1711 ] ] } ]

[ { "id": "entity-240-0", "type": "DISEASE", "text": [ "ischemic stroke" ], "offsets": [ [ 129, 144 ] ], "normalized": [] }, { "id": "entity-240-1", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 258, 264 ] ], "normalized": [] }, { "id": "entity-240-2", "type": "DISEASE", "text": [ "acute ischemic stroke" ], "offsets": [ [ 1689, 1710 ] ], "normalized": [] } ]

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[ { "id": "passage-241", "type": "abstract", "text": [ "Systemic therapy for unresectable and metastatic transitional cell carcinoma of the urothelium: first-line and beyond. PURPOSE OF REVIEW: The review aims to provide an overview of recent advances and future research direction in the management of patients with advanced transitional cell carcinoma. RECENT FINDINGS: Early data of the randomized phase III study comparing paclitaxel, cisplatin, and gemcitabine with gemcitabine plus cisplatin for advanced urothelial cancer detected no survival difference. A phase II study investigated the safety and efficacy of trastuzumab, carboplatin, gemcitabine, and paclitaxel in human epidermal growth factor receptor-2/neu-positive advanced urothelial carcinoma and reported promising results. Renal-sparing regimens are under active development. A nonrandomized comparison of the 3-week with the 4-week schedule for gemcitabine and cisplatin showed that the 3-week schedule had less hematological toxicity and better dose intensity. Potential molecular markers such as excision repair cross-complementation group 1, emmprin, and survivin for survival and/or platinum resistance in patients with transitional cell carcinoma showed promise. SUMMARY: Recent data do not support change in the current standard of care for advanced transitional cell carcinoma. Clinical testing of emerging anticancer therapies using new agents, new combinations, and new approaches is under active investigation. Rational combination and new strategy in clinical trial design are critical for new drug development for transitional cell carcinoma." ], "offsets": [ [ 0, 1569 ] ] } ]

[ { "id": "entity-241-0", "type": "DISEASE", "text": [ "metastatic transitional cell carcinoma of the urothelium" ], "offsets": [ [ 38, 94 ] ], "normalized": [] }, { "id": "entity-241-1", "type": "DISEASE", "text": [ "transitional cell carcinoma" ], "offsets": [ [ 271, 298 ] ], "normalized": [] }, { "id": "entity-241-2", "type": "DISEASE", "text": [ "urothelial cancer" ], "offsets": [ [ 456, 473 ] ], "normalized": [] }, { "id": "entity-241-3", "type": "DISEASE", "text": [ "urothelial carcinoma" ], "offsets": [ [ 684, 704 ] ], "normalized": [] }, { "id": "entity-241-4", "type": "ADVERSE", "text": [ "hematological toxicity" ], "offsets": [ [ 927, 949 ] ], "normalized": [] }, { "id": "entity-241-5", "type": "DISEASE", "text": [ "transitional cell carcinoma" ], "offsets": [ [ 1139, 1166 ] ], "normalized": [] }, { "id": "entity-241-6", "type": "DISEASE", "text": [ "transitional cell carcinoma" ], "offsets": [ [ 1271, 1298 ] ], "normalized": [] }, { "id": "entity-241-7", "type": "DISEASE", "text": [ "transitional cell carcinoma" ], "offsets": [ [ 1541, 1568 ] ], "normalized": [] } ]

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[ { "id": "passage-242", "type": "abstract", "text": [ "Neuroprotection by Spirulina platensis protean extract and phycocyanin against iron-induced toxicity in SH-SY5Y neuroblastoma cells. We investigated the effect of Spirulina platensis protean extract and the biliprotein phycocyanin isolated from this microalga, on the activities of the antioxidant enzymes SOD, CAT, GPx, and GR, lipid peroxidation inhibitory activity and glutathione levels after the iron induced oxidative stress in SH-SY5Y neuroblastoma cells. Iron is one of the most important agents that produce oxidative stress and decline of neuronal functions. S. platensis protean extract and phycocyanin exert the antioxidant activity by protecting the activity of the cellular antioxidant enzymes total GPx, GPx-Se and GR and by increasing reduced glutathione in cells against oxidative stress induced by iron. These results suggested that S. platensis protean extract is a powerful antioxidant through a mechanism related to antioxidant activity, capable of interfering with radical-mediated cell death. S. platensis may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatments for neurodegenerative disorders as long as iron has been implicated in the neuropathology of several neurodegenerative disorders such as Alzheimer's or Parkinson diseases." ], "offsets": [ [ 0, 1320 ] ] } ]

[ { "id": "entity-242-0", "type": "DISEASE", "text": [ "neurodegenerative disorders" ], "offsets": [ [ 1153, 1180 ] ], "normalized": [] }, { "id": "entity-242-1", "type": "DISEASE", "text": [ "neurodegenerative disorders" ], "offsets": [ [ 1250, 1277 ] ], "normalized": [] }, { "id": "entity-242-2", "type": "DISEASE", "text": [ "Parkinson diseases" ], "offsets": [ [ 1301, 1319 ] ], "normalized": [] } ]

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[ { "id": "passage-243", "type": "abstract", "text": [ "Nutritional supplements with oral amino acid mixtures increases whole-body lean mass and insulin sensitivity in elderly subjects with sarcopenia. Decreases in whole-body lean mass can cause sarcopenia, a disease frequently found in the elderly. This condition is frequently associated with frailty and disability in aging as well as the onset and progression of several geriatric syndromes. Sarcopenia therefore must be managed with multidimensional approaches that include physical training, nutritional support, and metabolic and anabolic treatment. The purpose of our study was to assess the effect of an orally administered special mixture of amino acids (AAs) in elderly subjects with reduced lean body mass and sarcopenia. A randomized, open-label, crossover study was conducted in 41 elderly subjects (age range: 66-84 years) with sarcopenia, assigned to 2 distinct treatments (AAs and placebo). All subjects had normal body weight (body mass index within 19-23). The AA treatment consisted of 70.6 kcal/day (1 kcal = 4.2 kJ) of 8 g of essential AA snacks, given at 10:00 am and 5:00 pm. Lean mass was measured with dual-energy x-ray absorptiometry in leg, arm, and trunk tissues. Significant increases in whole-body lean mass in all areas were seen after 6 months and more consistently after 18 months of oral nutritional supplementation with AAs. Fasting blood glucose, serum insulin, and homeostatic model assessment of insulin resistance (an index of insulin resistance) significantly decreased during AA treatment. Furthermore, a significant reduction in serum tumor necrosis factor-alpha (TNF-alpha) and a significant increase in both insulin-like growth factor-1 (IGF-1) serum concentrations and in the IGF-1/TNF-alpha ratio were also found. No significant adverse effects were observed during AA treatment. These preliminary data indicate that nutritional supplements with the oral AA mixture significantly increased whole-body lean mass in elderly subjects with sarcopenia. The improvement in the amount of whole-body lean mass could be linked to increased insulin sensitivity and anabolic conditions related to IGF-1 availability." ], "offsets": [ [ 0, 2148 ] ] } ]

[ { "id": "entity-243-0", "type": "DISEASE", "text": [ "sarcopenia" ], "offsets": [ [ 134, 144 ] ], "normalized": [] }, { "id": "entity-243-1", "type": "DISEASE", "text": [ "sarcopenia" ], "offsets": [ [ 191, 201 ] ], "normalized": [] }, { "id": "entity-243-2", "type": "DISEASE", "text": [ "frailty" ], "offsets": [ [ 291, 298 ] ], "normalized": [] }, { "id": "entity-243-3", "type": "DISEASE", "text": [ "disability in aging" ], "offsets": [ [ 303, 322 ] ], "normalized": [] }, { "id": "entity-243-4", "type": "DISEASE", "text": [ "geriatric syndromes" ], "offsets": [ [ 371, 390 ] ], "normalized": [] }, { "id": "entity-243-5", "type": "DISEASE", "text": [ "Sarcopenia" ], "offsets": [ [ 392, 402 ] ], "normalized": [] }, { "id": "entity-243-6", "type": "DISEASE", "text": [ "sarcopenia" ], "offsets": [ [ 718, 728 ] ], "normalized": [] }, { "id": "entity-243-7", "type": "DISEASE", "text": [ "sarcopenia" ], "offsets": [ [ 839, 849 ] ], "normalized": [] }, { "id": "entity-243-8", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 1431, 1449 ] ], "normalized": [] }, { "id": "entity-243-9", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 1463, 1481 ] ], "normalized": [] }, { "id": "entity-243-10", "type": "DISEASE", "text": [ "sarcopenia" ], "offsets": [ [ 1979, 1989 ] ], "normalized": [] } ]

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[ { "id": "passage-244", "type": "abstract", "text": [ "Lipid nanoparticles for parenteral delivery of actives. The present review compiles the applications of lipid nanoparticles mainly solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid drug conjugates (LDC) in parenteral delivery of pharmaceutical actives. The attempts to incorporate anticancer agents, imaging agents, antiparasitics, antiarthritics, genes for transfection, agents for liver, cardiovascular and central nervous system targeting have been summarized. The utility of lipid nanoparticles as adjuvant has been discussed separately. A special focus of this review is on toxicity caused by these kinds of lipid nanoparticles with a glance on the fate of lipid nanoparticles after their parenteral delivery in vivo viz the protein adsorption patterns." ], "offsets": [ [ 0, 788 ] ] } ]

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[ { "id": "passage-245", "type": "abstract", "text": [ "Role of physical chemical properties in drug relay into skin compartments. The ability of a drug to reach the interstitial fluid is an important aspect of drug efficacy - as a possible indicator of skin and cell compartment concentration. This overview addresses the relationship of the physical properties of several antibiotics to their ability to enter the interstitial fluid utilizing a cantharidin blister model. By collecting pharmacokinetic data for 12 antibiotics administered orally and 11 intravenously, we compared the fraction of drug that reaches the interstitial fluid (AUC(blister)/AUC(serum)) to partition coefficients. Following data analysis, we found no correlation (p = 0.98 and 0.09, respectively) between hydrophobicity and the ability to reach the interstitium. Both orally and intravenously administered antibiotics display a strong linear correlation (p < 0.001 and p = 0.006, respectively) in the total concentration found in the serum and interstitial fluid indicating that serum concentration may be an important factor in dictating interstitial fluid concentration. This correlation may prove useful in clinical application as a means of determining interstitial fluid concentration by measuring only serum levels." ], "offsets": [ [ 0, 1244 ] ] } ]

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[ { "id": "passage-246", "type": "abstract", "text": [ "Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. PURPOSE: Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis. RESULTS: A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival. CONCLUSION: Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients." ], "offsets": [ [ 0, 2079 ] ] } ]

[ { "id": "entity-246-0", "type": "DISEASE", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 102, 124 ] ], "normalized": [] }, { "id": "entity-246-1", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 154, 160 ] ], "normalized": [] }, { "id": "entity-246-2", "type": "DISEASE", "text": [ "Leukemia" ], "offsets": [ [ 165, 173 ] ], "normalized": [] }, { "id": "entity-246-3", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 204, 210 ] ], "normalized": [] }, { "id": "entity-246-4", "type": "DISEASE", "text": [ "Leukemia" ], "offsets": [ [ 215, 223 ] ], "normalized": [] }, { "id": "entity-246-5", "type": "DISEASE", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 399, 421 ] ], "normalized": [] }, { "id": "entity-246-6", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 423, 426 ] ], "normalized": [] }, { "id": "entity-246-7", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 451, 454 ] ], "normalized": [] }, { "id": "entity-246-8", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1435, 1451 ] ], "normalized": [] }, { "id": "entity-246-9", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1462, 1473 ] ], "normalized": [] }, { "id": "entity-246-10", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 1513, 1519 ] ], "normalized": [] }, { "id": "entity-246-11", "type": "ADVERSE", "text": [ "infection" ], "offsets": [ [ 1527, 1536 ] ], "normalized": [] }, { "id": "entity-246-12", "type": "ADVERSE", "text": [ "malaise" ], "offsets": [ [ 1547, 1554 ] ], "normalized": [] }, { "id": "entity-246-13", "type": "ADVERSE", "text": [ "fatigue" ], "offsets": [ [ 1555, 1562 ] ], "normalized": [] }, { "id": "entity-246-14", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 2066, 2069 ] ], "normalized": [] } ]

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[ { "id": "passage-247", "type": "abstract", "text": [ "Variable response to opioid treatment: any genetic predictors within sight? The aim of this literature review is to summarize and discuss the available evidence for a relationship between polymorphisms in human genes and variability in opioid analgesia and side effects among patients treated for moderate or severe pain. The evidence supporting a role of certain alleles, genotypes or haplotypes in modulation of opioid analgesia is derived from a limited number of studies, a limited number of genes and a limited number of opioids. Although several interesting candidates have emerged as potentially relevant factors, only for one polymorphism, the prevalent 118A>G of the micro-opioid receptor, the accumulated evidence is sufficient to suggest a clinically relevant effect for an opioid used for moderate or severe pain. Still the data are valid only at the group level and cannot be used to predict treatment outcome in individual patients. Only a few of the symptoms often seen as opioid adverse effects in palliative care, such as nausea, vomiting, constipation and sedation, have been associated with genetic variants in various genes, but the results have been based on case reports, healthy volunteers or post-operative patients. So far, there is no clear evidence that genetic markers can be used to predict opioid efficacy or adverse effects in palliative care patients. This reflects the general lack of studies performed in the context of palliative care, the lack of sufficiently scaled studies and the lack of international standards for the assessment of subjective symptoms." ], "offsets": [ [ 0, 1594 ] ] } ]

[ { "id": "entity-247-0", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "entity-247-1", "type": "DISEASE", "text": [ "pain" ], "offsets": [ [ 821, 825 ] ], "normalized": [] }, { "id": "entity-247-2", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 1040, 1046 ] ], "normalized": [] }, { "id": "entity-247-3", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 1048, 1056 ] ], "normalized": [] }, { "id": "entity-247-4", "type": "ADVERSE", "text": [ "constipation" ], "offsets": [ [ 1058, 1070 ] ], "normalized": [] }, { "id": "entity-247-5", "type": "ADVERSE", "text": [ "sedation" ], "offsets": [ [ 1075, 1083 ] ], "normalized": [] } ]

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[ { "id": "passage-248", "type": "abstract", "text": [ "Fragrance material review on geraniol. A toxicologic and dermatologic review of geraniol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 139 ] ] } ]

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[ { "id": "passage-249", "type": "abstract", "text": [ "Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. AIMS: Recent studies have demonstrated the importance of chromatin remodelling via histone acetylation/deacetylation for the control of cardiac gene expression. Specific histone deacetylases (HDACs) can, in fact, play a positive or negative role in determining cardiac myocyte (CM) size. Here, we report on the effect on hypertrophy development of three inhibitors (HDACi) of class I HDACs. METHODS AND RESULTS: The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha1-adrenergic agonist. This initial screening indicated that a truncated derivative of apicidin with class I HDAC specificity, denoted API-D, had the highest efficacy to toxicity ratio, and was thus selected for further analysis in vivo. Administration of this drug significantly decreased myocardial hypertrophy and foetal gene expression after 1 week of pressure overload induced by thoracic aortic constriction (TAC) in mice. After 9 weeks of TAC, when manifest heart failure is encountered, mice treated with API-D presented with significantly improved echocardiographic and haemodynamic parameters of cardiac function when compared with untreated TAC-operated mice. CONCLUSION: The apicidin derivative, API-D, is capable of reducing hypertrophy and, consequently, the transition to heart failure in mice subjected to TAC. Treatment with this substance, therefore, holds promise as an important therapeutic option for heart failure." ], "offsets": [ [ 0, 1628 ] ] } ]

[ { "id": "entity-249-0", "type": "DISEASE", "text": [ "cardiac hypertrophy" ], "offsets": [ [ 79, 98 ] ], "normalized": [] }, { "id": "entity-249-1", "type": "DISEASE", "text": [ "hypertrophy" ], "offsets": [ [ 434, 445 ] ], "normalized": [] }, { "id": "entity-249-2", "type": "DISEASE", "text": [ "hypertrophy" ], "offsets": [ [ 579, 590 ] ], "normalized": [] }, { "id": "entity-249-3", "type": "DISEASE", "text": [ "myocardial hypertrophy" ], "offsets": [ [ 982, 1004 ] ], "normalized": [] }, { "id": "entity-249-4", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 1157, 1170 ] ], "normalized": [] }, { "id": "entity-249-5", "type": "DISEASE", "text": [ "hypertrophy" ], "offsets": [ [ 1430, 1441 ] ], "normalized": [] }, { "id": "entity-249-6", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 1479, 1492 ] ], "normalized": [] }, { "id": "entity-249-7", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 1614, 1627 ] ], "normalized": [] } ]

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[ { "id": "passage-250", "type": "abstract", "text": [ "Peptide-mediated cellular uptake of cryptophane. Cryptophane-A has generated considerable interest based on its high affinity for xenon and potential for creating biosensors for (129)Xe nuclear magnetic resonance (NMR) spectroscopy. Here, we report the cellular delivery of three peptide-functionalized cryptophane biosensors. Cryptophanes were delivered using two cationic cell penetrating peptides into several human cancer and normal cell lines. An RGD peptide targeting alpha(v)beta(3) integrin receptor was shown to increase specificity of cryptophane cell uptake. Labeling the peptides with Cy3 made it possible to monitor cellular delivery using confocal laser scanning microscopy. The peptido-cryptophanes were determined to be relatively nontoxic by MTT assay at the micromolar cryptophane concentrations that are required for (129)Xe NMR biosensing experiments." ], "offsets": [ [ 0, 872 ] ] } ]

[ { "id": "entity-250-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 420, 426 ] ], "normalized": [] } ]

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[ { "id": "passage-251", "type": "abstract", "text": [ "Preparation of BMP-2 containing bovine serum albumin (BSA) nanoparticles stabilized by polymer coating. PURPOSE: The purpose of this study was to investigate the preparation process of bone morphogenetic protein-2 (BMP-2) containing bovine serum albumin (BSA) nanoparticles (NPs), and to assess the bioactivity of BMP-2 encapsulated in such NPs. METHODS: The NPs were prepared by a coacervation method, and the effects of process parameters on NP size and polydispersity were examined. Polymer coated NPs were characterized with respect to amount of adsorbed polymer, particle size and zeta potential. Using bone marrow stromal cells (BMSC), biocompatibility of the NPs was investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) Assay, and bioactivity of the encapsulated BMP-2 was investigated by alkaline phosphatase (ALP) induction and calcification. RESULTS: The size of NPs could be controlled in the 50-400 nm range by process parameters including BSA concentration, non-solvent:solvent ratio and pH value. After coating with cationic polymers, the particle size and zeta potential were significantly increased. MTT assay indicated no toxicity of both the uncoated and coated NPs on BMSC. Based on ALP induction and calcification, full retention of BMP-2 bioactivity was retained in the polymer-coated NPs. CONCLUSIONS: This study described a preparation procedure for BSA NPs with controllable particle size, and such polymer-coated BSA NPs are promising delivery agents for local and systemic administration of BMP-2 in bone regeneration." ], "offsets": [ [ 0, 1580 ] ] } ]

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[ { "id": "passage-252", "type": "abstract", "text": [ "Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible contribution of P-glycoprotein. P-glycoprotein (P-gp) is found to play a very significant role in intestinal and biliary transport of irinotecan and its active metabolite, SN-38. This makes P-gp inhibition a logical strategy for improving irinotecan's oral efficacy and reducing its toxicity. The objective of the present study was to identify the most suitable P-gp inhibitor, amongst various commonly used herbal components via in vitro screening; followed by determination of in vivo effects in rats. Caco-2 cell monolayers were used to investigate the influence of various components (quercetin, hesperitin, piperine, curcumin and naringenin) on the transport of irinotecan. The secretory transport (basolateral-to-apical) was significantly decreased by all components (p<0.05) except piperine. In the apical-to-basolateral transport, quercetin showed the highest absorptive permeability enhancement and P-gp interaction potential making it an appropriate candidate for further in vivo studies in female Wistar rats. Quercetin pre-treatment resulted in increased irinotecan C(max) and area under curve (AUC) with a concomitant decrease in t(max), plasma clearance and volume of distribution (p<0.05). The absolute bioavailability (F) of irinotecan control was 33%, which was increased to 43% (1.3 fold) by quercetin administration. The amounts of irinotecan and SN-38 eliminated in bile in control rats, is reduced to almost half when treated with quercetin. Our studies not only propose a safe approach for bioavailability enhancement and reducing toxicity of irinotecan by P-gp inhibition but in another way also reiterate the significance of elucidating herb-drug interactions for future insights." ], "offsets": [ [ 0, 1835 ] ] } ]

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[ { "id": "passage-253", "type": "abstract", "text": [ "Right-sided vagus nerve stimulation in humans: an effective therapy? Vagus nerve stimulation (VNS) is an additive treatment option for refractory epilepsy. The electrode is placed on the cervical trunk of the left vagus nerve. In patients who are not suitable for left-sided vagus nerve stimulation (L-VNS) right-sided vagus nerve stimulation (R-VNS) may be as effective. In animal models epilepsy is sufficiently suppressed by R-VNS. In a 16 years old boy suffering from medically refractory psychomotoric seizures with secondary generalisation, L-VNS reduced the frequency of generalized seizures. A deep wound infection required the removal of the system eight weeks later. Cicatrisation did not allow preparation of the left vagus nerve, therefore we implanted R-VNS with sufficient seizure suppression. However, compared to L-VNS, the effect occurred months later and cardiac symptoms were induced by stimulation of the right vagus nerve. R-VNS seems to be an effective and alternative therapy in selected patients responding to L-VNS where a left-sided reimplantation is not possible. Placement and adjustment of the device should be performed under ECG control. Further studies are necessary to compare the efficacy of L-VNS and R-VNS." ], "offsets": [ [ 0, 1243 ] ] } ]

[ { "id": "entity-253-0", "type": "DISEASE", "text": [ "refractory epilepsy" ], "offsets": [ [ 136, 155 ] ], "normalized": [] }, { "id": "entity-253-1", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 390, 398 ] ], "normalized": [] }, { "id": "entity-253-2", "type": "DISEASE", "text": [ "refractory psychomotoric seizures" ], "offsets": [ [ 483, 516 ] ], "normalized": [] }, { "id": "entity-253-3", "type": "DISEASE", "text": [ "seizures" ], "offsets": [ [ 591, 599 ] ], "normalized": [] }, { "id": "entity-253-4", "type": "DISEASE", "text": [ "wound infection" ], "offsets": [ [ 608, 623 ] ], "normalized": [] }, { "id": "entity-253-5", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 788, 795 ] ], "normalized": [] }, { "id": "entity-253-6", "type": "DISEASE", "text": [ "cardiac symptoms" ], "offsets": [ [ 874, 890 ] ], "normalized": [] } ]

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[ { "id": "passage-254", "type": "abstract", "text": [ "Safety and pharmacodynamics of lansoprazole in patients with gastroesophageal reflux disease aged <1 year. BACKGROUND: The use of proton pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD) in pediatric patients <1 year of age is increasing. However, few studies with PPIs have been reported in such patients. OBJECTIVES: To assess the effect of once-daily lansoprazole on safety and to characterize the pharmacodynamic profile of lansoprazole in a subset of subjects <1 year of age. The effect of lansoprazole on predefined GERD-associated symptoms was also assessed. METHODS: Two phase I, single- and repeated-dose, randomized, parallel-group, open-label, multicenter studies were performed. Both studies involved either a 7- or 14-day pre-treatment period, with a dose administration period of 5 days, and a follow-up period of 30 days for adverse events collection. A total of six investigative sites were involved: four university hospital/medical centers (three in Poland, one in the US), one large regional medical center (Poland), and one private practice (US). The studies involved 24 neonates (<or=28 days of age) and 24 infants (>28 days but <1 year of age) with GERD-associated symptoms diagnosed by medical history and the clinical judgment of the treating physician. Eligible subjects were randomized to receive either lansoprazole 0.5 or 1.0 mg/kg/day (neonates), or 1.0 or 2.0 mg/kg/day (infants), for 5 days.Safety and pharmacodynamic parameters were the primary outcome measures. Safety and GERD symptoms were assessed in all participants. Intragastric/intraesophageal pH monitoring was performed in a subset of six neonates and six infants at baseline and on dose administration days 1 and 5. RESULTS: Over 5 days of daily dose administration, lansoprazole was well tolerated in neonates and infants. Four neonates and one infant experienced mild to moderate treatment-related adverse events during the dose administration period. One neonate experienced a serious adverse event that was unrelated to treatment. Lansoprazole increased the percentage of time that intragastric pH was above 3, 4, 5, and 6 over the 24-hour post-dose period on days 1 and 5 when compared with baseline. Mean 24-hour integrated gastric acidity decreased from baseline to day 5 in both populations. The daily number of episodes of regurgitation/vomiting was lower than at baseline among neonates after 5 days of lansoprazole treatment; among infants, both the prevalence and the average daily number of episodes of several individual GERD-associated symptoms were lower than at baseline. CONCLUSIONS: After 5 days of open-label administration, lansoprazole was well tolerated and increased intragastric pH in pediatric subjects <1 year of age. A decrease in the frequency of GERD symptoms was also observed." ], "offsets": [ [ 0, 2835 ] ] } ]

[ { "id": "entity-254-0", "type": "DISEASE", "text": [ "gastroesophageal reflux disease" ], "offsets": [ [ 61, 92 ] ], "normalized": [] }, { "id": "entity-254-1", "type": "DISEASE", "text": [ "gastroesophageal reflux disease" ], "offsets": [ [ 182, 213 ] ], "normalized": [] }, { "id": "entity-254-2", "type": "DISEASE", "text": [ "GERD" ], "offsets": [ [ 215, 219 ] ], "normalized": [] }, { "id": "entity-254-3", "type": "DISEASE", "text": [ "GERD-associated symptoms" ], "offsets": [ [ 556, 580 ] ], "normalized": [] }, { "id": "entity-254-4", "type": "DISEASE", "text": [ "GERD symptoms" ], "offsets": [ [ 1540, 1553 ] ], "normalized": [] }, { "id": "entity-254-5", "type": "ADVERSE", "text": [ "regurgitation" ], "offsets": [ [ 2359, 2372 ] ], "normalized": [] }, { "id": "entity-254-6", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 2373, 2381 ] ], "normalized": [] }, { "id": "entity-254-7", "type": "DISEASE", "text": [ "GERD-associated symptoms" ], "offsets": [ [ 2562, 2586 ] ], "normalized": [] }, { "id": "entity-254-8", "type": "DISEASE", "text": [ "GERD symptoms" ], "offsets": [ [ 2803, 2816 ] ], "normalized": [] } ]

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[ { "id": "passage-255", "type": "abstract", "text": [ "Design of potent, non-toxic antimicrobial agents based upon the naturally occurring frog skin peptides, ascaphin-8 and peptide XT-7. The frog skin peptides, ascaphin-8 (GFKDLLKGAAKALVKTVLF.NH(2)) and XT-7 (GLLGPLLKIAAKVGSNLL.NH(2)), show broad-spectrum antimicrobial activity but their therapeutic potential is limited by toxicity against mammalian cells. Circular dichroism spectra demonstrate that the peptides adopt an amphipathic alpha-helical conformation in a membrane-mimetic solvent. This study has investigated the cytolytic properties of analogs containing selected amino acid substitutions that increase cationicity while maintaining amphipathicity. Substitutions at Ala(10), Val(14), and Leu(18) in ascaphin-8 by either L-Lys or D-Lys produced peptides that retained antimicrobial activity against the bacteria Escherichia coli and Staphylococcus aureus and the opportunistic yeast pathogen, Candida albicans but showed appreciably reduced toxicities (>10-fold) against human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. The improved therapeutic index of the L-Lys(18) and D-Lys(18) analogs correlated with a decrease in % helicity and in effective hydrophobicity. Substitution of Gly(4) by L-Lys in XT-7 produced an analog with high potency against micro-organisms (MIC < or = 25 microM) but low cytolytic activity against erythrocytes (LD(50) > 500 microM) and this increase in therapeutic index also correlated with decreased helicity and hydrophobicity. Analogs of XT-7 with increased cationicity, containing multiple substitutions by L-Lys, not only displayed increased antimicrobial potencies, particularly against Candida albicans (MIC < or = 6 microM), but also increased hemolytic activities." ], "offsets": [ [ 0, 1735 ] ] } ]

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[ { "id": "passage-256", "type": "abstract", "text": [ "Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress. Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD." ], "offsets": [ [ 0, 1780 ] ] } ]

[ { "id": "entity-256-0", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 173, 192 ] ], "normalized": [] }, { "id": "entity-256-1", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 194, 196 ] ], "normalized": [] }, { "id": "entity-256-2", "type": "DISEASE", "text": [ "chronic neuronal death" ], "offsets": [ [ 425, 447 ] ], "normalized": [] }, { "id": "entity-256-3", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 501, 507 ] ], "normalized": [] }, { "id": "entity-256-4", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 1145, 1158 ] ], "normalized": [] }, { "id": "entity-256-5", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 1777, 1779 ] ], "normalized": [] } ]

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[ { "id": "passage-257", "type": "abstract", "text": [ "Fragrance material review on 1-ethynylcyclohexyl acetate. A toxicologic and dermatologic review of 1-ethynylcyclohexyl acetate when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 177 ] ] } ]

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[ { "id": "passage-258", "type": "abstract", "text": [ "Protective effect of Pycnogenol in human neuroblastoma SH-SY5Y cells following acrolein-induced cytotoxicity. Oxidative stress is one of the hypotheses involved in the etiology of Alzheimer's disease (AD). Considerable attention has been focused on increasing the intracellular glutathione (GSH) levels in many neurodegenerative diseases, including AD. Pycnogenol (PYC) has antioxidant properties and stabilizes intracellular antioxidant defense systems including glutathione levels. The present study investigated the protective effects of PYC on acrolein-induced oxidative cell toxicity in cultured SH-SY5Y neuroblastoma cells. Decreased cell survival in SH-SY5Y cultures treated with acrolein correlated with oxidative stress, increased NADPH oxidase activity, free radical production, protein oxidation/nitration (protein carbonyl, 3-nitrotyrosine), and lipid peroxidation (4-hydroxy-2-nonenal). Pretreatment with PYC significantly attenuated acrolein-induced cytotoxicity, protein damage, lipid peroxidation, and cell death. A dose-response study suggested that PYC showed protective effects against acrolein toxicity by modulating oxidative stress and increasing GSH. These findings provide support that PYC may provide a promising approach for the treatment of oxidative stress-related neurodegenerative diseases such as AD." ], "offsets": [ [ 0, 1332 ] ] } ]

[ { "id": "entity-258-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 96, 108 ] ], "normalized": [] }, { "id": "entity-258-1", "type": "DISEASE", "text": [ "Alzheimer's disease" ], "offsets": [ [ 181, 200 ] ], "normalized": [] }, { "id": "entity-258-2", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 202, 204 ] ], "normalized": [] }, { "id": "entity-258-3", "type": "DISEASE", "text": [ "neurodegenerative diseases" ], "offsets": [ [ 312, 338 ] ], "normalized": [] }, { "id": "entity-258-4", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 350, 352 ] ], "normalized": [] }, { "id": "entity-258-5", "type": "ADVERSE", "text": [ "oxidative cell toxicity" ], "offsets": [ [ 566, 589 ] ], "normalized": [] }, { "id": "entity-258-6", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 965, 977 ] ], "normalized": [] }, { "id": "entity-258-7", "type": "ADVERSE", "text": [ "acrolein toxicity" ], "offsets": [ [ 1106, 1123 ] ], "normalized": [] }, { "id": "entity-258-8", "type": "DISEASE", "text": [ "neurodegenerative diseases" ], "offsets": [ [ 1294, 1320 ] ], "normalized": [] }, { "id": "entity-258-9", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 1329, 1331 ] ], "normalized": [] } ]

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[ { "id": "passage-259", "type": "abstract", "text": [ "Orally administrated Juzen-taiho-to/TJ-48 ameliorates erythropoietin (rHuEPO)-resistant anemia in patients on hemodialysis. Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis." ], "offsets": [ [ 0, 2163 ] ] } ]

[ { "id": "entity-259-0", "type": "DISEASE", "text": [ "erythropoietin (rHuEPO)-resistant anemia" ], "offsets": [ [ 54, 94 ] ], "normalized": [] }, { "id": "entity-259-1", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 338, 344 ] ], "normalized": [] }, { "id": "entity-259-2", "type": "ADVERSE", "text": [ "iron deficiency" ], "offsets": [ [ 578, 593 ] ], "normalized": [] }, { "id": "entity-259-3", "type": "ADVERSE", "text": [ "infection" ], "offsets": [ [ 595, 604 ] ], "normalized": [] }, { "id": "entity-259-4", "type": "ADVERSE", "text": [ "uremia" ], "offsets": [ [ 606, 612 ] ], "normalized": [] }, { "id": "entity-259-5", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 767, 773 ] ], "normalized": [] }, { "id": "entity-259-6", "type": "DISEASE", "text": [ "anorexia" ], "offsets": [ [ 775, 783 ] ], "normalized": [] }, { "id": "entity-259-7", "type": "DISEASE", "text": [ "fatigue" ], "offsets": [ [ 788, 795 ] ], "normalized": [] }, { "id": "entity-259-8", "type": "DISEASE", "text": [ "erythropoietin-resistant anemia" ], "offsets": [ [ 831, 862 ] ], "normalized": [] }, { "id": "entity-259-9", "type": "DISEASE", "text": [ "erythropoietin-resistant anemia" ], "offsets": [ [ 928, 959 ] ], "normalized": [] }, { "id": "entity-259-10", "type": "DISEASE", "text": [ "renal disease" ], "offsets": [ [ 985, 998 ] ], "normalized": [] }, { "id": "entity-259-11", "type": "DISEASE", "text": [ "erythropoietin-resistant anemia" ], "offsets": [ [ 1029, 1060 ] ], "normalized": [] }, { "id": "entity-259-12", "type": "DISEASE", "text": [ "erythropoietin-resistant anemia" ], "offsets": [ [ 1986, 2017 ] ], "normalized": [] }, { "id": "entity-259-13", "type": "DISEASE", "text": [ "renal disease" ], "offsets": [ [ 2031, 2044 ] ], "normalized": [] } ]

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[ { "id": "passage-260", "type": "abstract", "text": [ "Understanding the genetic causes of inter-patient variability. Clinical relevance with focus on cardiovascular drugs. There is a large inter-patient variability concerning the response to drug therapy and a great interest for determining the causes of this variability. This review takes into discussion some aspects of cardiovascular drugs metabolism and transport, pointing out the effects of genetic variation. Isoenyzmes belonging to the Cytochrome P450 super family have an important role in cardiovascular drug metabolism, namely CYP 1A2; CYP 3A; CYP 2C19; CYP2C9; CYP 2D6, involved in the oxidative phase and also N-acetyltransferase 2, involved in the conjungative phase of the metabolism. P-glycoprotein is implied in cardiovascular drug transport. Polymorphisms of those enzymes and transport protein result in different phenotypes, that is the case of CYP isoenyzmes with abolished, low or increased activity and in the case of N-acetyltransferase 2, slow, intermediate and rapid acetylator phenotypes. There is hope that, in the future, a more individualized treatment of a certain disease, with minimum adverse effects and a maximum therapeutic effect, will be available, by means of genetic testing." ], "offsets": [ [ 0, 1214 ] ] } ]

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[ { "id": "passage-261", "type": "abstract", "text": [ "Utility of published guidelines on the use of nonsteroidal anti-inflammatory drugs in the elderly. Canadian Consensus guidelines regarding appropriate use of nonsteroidal anti-inflammatory drugs (NSAID) were recently published. This study was done to evaluate the application of these guidelines on NSAID practice patterns in frail elderly patients referred to a specialist Geriatric Assessment Clinic. A retrospective chart review was undertaken of referrals who were currently prescribed NSAIDs. Data were captured on age, sex, weight, diagnoses, medications and dosages, indication for NSAID treatment, lying BP (as assessed in the clinic) and recent serum creatinine result. Creatinine clearance was subsequently calculated use the Cockcroft-Gault equation. Complete data were available on 107 patients (68% women, average age 80.6 years). Thirty percent were on a traditional NSAID, the remainder were on a Coxib. Concomitant aspirin was prescribed in 37%. Cytoprotection was being used in 38% and did not increase appreciably in patients with additional risk factors for GI toxicity, i.e., concomitant aspirin usage (35%), and history of GI toxicity (48%). Sixty-seven were taking anti-hypertensive medications, although more than two thirds of these patients were uncontrolled. Newly diagnosed hypertension was present in 19.6%. Calculated creatinine clearance revealed moderate to severe renal impairment in 79% of subjects, although serum creatinine was only elevated in 18%. In total, 70% of subjects were found to have relative or absolute risk factors for NSAID therapy. Given the high prevalence of potential contraindications to anti-inflammatory drug usage in this study, we advocate the dissemination and application of these guidelines in geriatric patients in an attempt to reduce potential morbidity and mortality." ], "offsets": [ [ 0, 1834 ] ] } ]

[ { "id": "entity-261-0", "type": "ADVERSE", "text": [ "GI toxicity" ], "offsets": [ [ 1078, 1089 ] ], "normalized": [] }, { "id": "entity-261-1", "type": "ADVERSE", "text": [ "GI toxicity" ], "offsets": [ [ 1145, 1156 ] ], "normalized": [] }, { "id": "entity-261-2", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 1302, 1314 ] ], "normalized": [] }, { "id": "entity-261-3", "type": "ADVERSE", "text": [ "renal impairment" ], "offsets": [ [ 1397, 1413 ] ], "normalized": [] } ]

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[ { "id": "passage-262", "type": "abstract", "text": [ "The islet beta-cell: fuel responsive and vulnerable. The pancreatic beta-cell senses blood nutrient levels and is modulated by neurohormonal signals so that it secretes insulin according to the need of the organism. Nutrient sensing involves marked metabolic activation, resulting in the production of coupling signals that promote insulin biosynthesis and secretion. The beta-cell's high capacity for nutrient sensing, however, necessitates reduced protection to nutrient toxicity. This potentially explains why in susceptible individuals, chronic fuel surfeit results in beta-cell failure and type 2 diabetes. Here we discuss recent insights into first, the biochemical basis of beta-cell signaling in response to glucose, amino acids and fatty acids, and second, beta-cell nutrient detoxification. We emphasize the emerging role of glycerolipid/fatty acid cycling in these processes." ], "offsets": [ [ 0, 887 ] ] } ]

[ { "id": "entity-262-0", "type": "ADVERSE", "text": [ "nutrient toxicity" ], "offsets": [ [ 465, 482 ] ], "normalized": [] }, { "id": "entity-262-1", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 596, 611 ] ], "normalized": [] } ]

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[ { "id": "passage-263", "type": "abstract", "text": [ "Effect of cement dust exposure on phagocytic function of polymorphonuclear neutrophils in cement mill workers. OBJECTIVES: Exposure to cement dust can cause various occupational health problems due to its increasing incidence and long-term complications. However, the influence of cement dust on phagocytic function of polymorphonuclear neutrophils (PMNs), has not as yet been investigated. Therefore, the aim of the study was to measure the phagocytic activity of PMNs by assessing chemilumiscence (CL) response in cement mill workers and controls. MATERIAL AND METHODS: In this study, 50 volunteer males, aged 25-60 years, apparently healthy and nonsmoking, were randomly selected from among cement mill workers. These workers were further classified into subgroups based on exposure duration of less than 10, 10-20, and more than 20 years. The controls were 50 healthy, nonsmoking, males who matched the study group with respect to age, height, weight, and socioeconomic status. The phagocytic function of PMNs, stimulated with opsonized zymosan, was determined by measuring CL response. RESULTS: The findings show a significant decrease in phagocytic activity of PMNs [PMNs OPZ p < 0.005] in cement mill workers compared to controls. CONCLUSION: It is concluded that exposure to cement dust can impair the phagocytic function of PMNs which is reflected in decreased chemiluminescence response." ], "offsets": [ [ 0, 1398 ] ] } ]

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[ { "id": "passage-264", "type": "abstract", "text": [ "Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Stable isotope-labeled compounds have been synthesized and utilized by scientists from various areas of biomedical research during the last several decades. Compounds labeled with stable isotopes, such as deuterium and carbon-13, have been used effectively by drug metabolism scientists and toxicologists to gain better understanding of drugs' disposition and their potential role in target organ toxicities. The combination of stable isotope-labeling techniques with mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, which allows rapid acquisition and interpretation of data, has promoted greater use of these stable isotope-labeled compounds in absorption, distribution, metabolism, and excretion (ADME) studies. Examples of the use of stable isotope-labeled compounds in elucidating structures of metabolites and delineating complex metabolic pathways are presented in this review. The application of labeled compounds in mechanistic toxicity studies will be discussed by providing an example of how strategic placement of a deuterium atom in a drug molecule mitigated specific-specific renal toxicity. Other examples from the literature demonstrating the application of stable isotope-labeled compounds in understanding metabolism-mediated toxicities are presented. Furthermore, an example of how a stable isotope-labeled compound was utilized to better understand some of the gene changes in toxicogenomic studies is discussed. The interpretation of large sets of data produced from toxicogenomics studies can be a challenge. One approach that could be used to simplify interpretation of the data, especially from studies designed to link gene changes with the formation of reactive metabolites thought to be responsible for toxicities, is through the use of stable isotope-labeled compounds. This is a relatively unexplored territory and needs to be further investigated. The employment of analytical techniques, especially mass spectrometry and NMR, used in conjunction with stable isotope-labeled compounds to establish and understand mechanistic link between reactive metabolite formation, genomic, and proteomic changes and onset of toxicity is proposed. The use of stable isotope-labeled compounds in early human ADME studies as a way of identifying and possibly quantifying all drug-related components present in systemic circulation is suggested." ], "offsets": [ [ 0, 2486 ] ] } ]

[ { "id": "entity-264-0", "type": "ADVERSE", "text": [ "metabolism-mediated toxicity" ], "offsets": [ [ 69, 97 ] ], "normalized": [] }, { "id": "entity-264-1", "type": "ADVERSE", "text": [ "target organ toxicities" ], "offsets": [ [ 492, 515 ] ], "normalized": [] }, { "id": "entity-264-2", "type": "ADVERSE", "text": [ "renal toxicity" ], "offsets": [ [ 1217, 1231 ] ], "normalized": [] }, { "id": "entity-264-3", "type": "ADVERSE", "text": [ "metabolism-mediated toxicities" ], "offsets": [ [ 1351, 1381 ] ], "normalized": [] } ]

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[ { "id": "passage-265", "type": "abstract", "text": [ "Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone. AIMS/HYPOTHESIS: Troglitazone was approved for treatment of type 2 diabetes mellitus, but by 2000 it had been removed from all world markets due to severe drug-induced liver injury. Even today, we still do not know how many patients sustained a long-term liver injury. No system is in place to acquire that knowledge. Regarding toxicity mechanisms, controversy persists as to which ones are class effects of thiazolidinediones (TZDs) and which are unique to troglitazone. This study aims to provide long-term outcome data and new insights on mechanisms of troglitazone-induced liver injury. METHODS: This case series reports the liver injuries sustained by eleven type 2 diabetic patients treated with troglitazone between 1997 and 2000. Exhaustive review of medical records was performed for all patients. Long-term outcomes were available for all the non-fatal cases. A comprehensive literature review was also performed. RESULTS: Long-term liver injury progressing to cirrhosis was identified in seven patients. All eleven cases had liver injury patterns consistent with troglitazone toxicity. Analysis of these cases and of the experimental troglitazone toxicity data points to mitochondrial toxicity as a central factor. The general clinical patterns of mitochondrial hepatotoxic events are reviewed, as are the implications for other members of the TZD family. CONCLUSIONS/INTERPRETATION: This analysis enables the liver injury induced by troglitazone to be better understood. In future cases of delayed drug-induced liver injury that progresses after discontinuation, the possibility of mitochondrial toxicity should be considered. When appropriate, this can then be evaluated experimentally. Such proactive investigation may anticipate clinical risk before a large-scale therapeutic misadventure occurs. Drug-induced liver injury due to mitochondrial hepatotoxins may be less unpredictable than has previously been surmised." ], "offsets": [ [ 0, 2021 ] ] } ]

[ { "id": "entity-265-0", "type": "ADVERSE", "text": [ "hepatotoxicity" ], "offsets": [ [ 38, 52 ] ], "normalized": [] }, { "id": "entity-265-1", "type": "DISEASE", "text": [ "type 2 diabetes mellitus" ], "offsets": [ [ 149, 173 ] ], "normalized": [] }, { "id": "entity-265-2", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 257, 269 ] ], "normalized": [] }, { "id": "entity-265-3", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 344, 356 ] ], "normalized": [] }, { "id": "entity-265-4", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 666, 678 ] ], "normalized": [] }, { "id": "entity-265-5", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 1032, 1044 ] ], "normalized": [] }, { "id": "entity-265-6", "type": "ADVERSE", "text": [ "cirrhosis" ], "offsets": [ [ 1060, 1069 ] ], "normalized": [] }, { "id": "entity-265-7", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 1125, 1137 ] ], "normalized": [] }, { "id": "entity-265-8", "type": "ADVERSE", "text": [ "mitochondrial toxicity" ], "offsets": [ [ 1271, 1293 ] ], "normalized": [] }, { "id": "entity-265-9", "type": "ADVERSE", "text": [ "mitochondrial hepatotoxic events" ], "offsets": [ [ 1348, 1380 ] ], "normalized": [] }, { "id": "entity-265-10", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 1510, 1522 ] ], "normalized": [] }, { "id": "entity-265-11", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 1612, 1624 ] ], "normalized": [] }, { "id": "entity-265-12", "type": "ADVERSE", "text": [ "mitochondrial toxicity" ], "offsets": [ [ 1683, 1705 ] ], "normalized": [] }, { "id": "entity-265-13", "type": "ADVERSE", "text": [ "liver injury" ], "offsets": [ [ 1914, 1926 ] ], "normalized": [] } ]

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[ { "id": "passage-266", "type": "abstract", "text": [ "Catalase ameliorates polychlorinated biphenyl-induced cytotoxicity in nonmalignant human breast epithelial cells. Polychlorinated biphenyls (PCBs) are environmental chemical contaminants believed to adversely affect cellular processes. We investigated the hypothesis that PCB-induced changes in the levels of cellular reactive oxygen species (ROS) induce DNA damage resulting in cytotoxicity. Exponentially growing cultures of human nonmalignant breast epithelial cells (MCF10A) were incubated with PCBs for 3 days and assayed for cell number, ROS levels, DNA damage, and cytotoxicity. Exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) or 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of 4-chlorobiphenyl (PCB3), significantly decreased cell number and MTS reduction and increased the percentage of cells with sub-G1 DNA content. Results from electron paramagnetic resonance (EPR) spectroscopy showed a 4-fold increase in the steady-state levels of ROS, which was suppressed in cells pretreated with catalase. EPR measurements in cells treated with 4-Cl-BQ detected the presence of a semiquinone radical, suggesting that the increased levels of ROS could be due to the redox cycling of 4-Cl-BQ. A dose-dependent increase in micronuclei frequency was observed in PCB-treated cells, consistent with an increase in histone 2AX phosphorylation. Treatment of cells with catalase blunted the PCB-induced increase in micronuclei frequency and H2AX phosphorylation that was consistent with an increase in cell survival. Our results demonstrate a PCB-induced increase in cellular levels of ROS causing DNA damage, resulting in cell killing." ], "offsets": [ [ 0, 1651 ] ] } ]

[ { "id": "entity-266-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 54, 66 ] ], "normalized": [] }, { "id": "entity-266-1", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 380, 392 ] ], "normalized": [] }, { "id": "entity-266-2", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 573, 585 ] ], "normalized": [] } ]

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[ { "id": "passage-267", "type": "abstract", "text": [ "Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. BACKGROUND: Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures. METHODS AND FINDINGS: This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by -1.28% and -1.22% (p = 0.84) (difference of -0.06%; 95% confidence interval [CI] -0.67% to 0.54%) at the lumbar spine and -0.69% and -0.88% (p = 0.51) (difference of 0.19%; 95% CI -0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small. CONCLUSIONS: Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers. Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)." ], "offsets": [ [ 0, 2764 ] ] } ]

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[ { "id": "passage-268", "type": "abstract", "text": [ "Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. PURPOSE: Phosphodiesterase type 5 inhibitors are widely used to treat erectile dysfunction. Preliminary data have suggested phosphodiesterase type 5 inhibitor efficacy in men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. MATERIALS AND METHODS: After a 4-week placebo run-in period 1,058 men with benign prostatic hyperplasia lower urinary tract symptoms were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10 or 20 mg). RESULTS: The International Prostate Symptom Score least squares mean change from baseline to end point was significantly improved for 2.5 (-3.9, p = 0.015), 5 (-4.9, p <0.001), 10 (-5.2, p <0.001) and 20 mg (-5.2, p <0.001) tadalafil compared to placebo (-2.3). International Prostate Symptom Score improvements at 4, 8 and 12 weeks were significant for all tadalafil doses and they demonstrated a dose-response relationship. Tadalafil (2.5 mg) significantly improved the International Prostate Symptom Score obstructive subscore and the International Index of Erectile Function-Erectile Function domain, the latter in sexually active men with a history of erectile dysfunction. Statistically significant improvements were noted for 5, 10 and 20 mg tadalafil compared to placebo, as assessed by the International Prostate Symptom Score irritative and obstructive subscores, International Prostate Symptom Score Quality of Life, Benign Prostatic Hyperplasia Impact Index (nonsignificant for 10 mg), Global Assessment Question and International Index of Erectile Function-Erectile Function domain. No statistically significant effect of treatment compared to placebo was noted for peak flow at any tadalafil dose. Treatment emergent adverse events were infrequent in all tadalafil groups. CONCLUSIONS: Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied 5 mg tadalafil appeared to provide a positive risk-benefit profile." ], "offsets": [ [ 0, 2224 ] ] } ]

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[ { "id": "passage-269", "type": "abstract", "text": [ "A single dose of anti-D immunoglobulin raises platelet count as efficiently as intravenous immunoglobulin in newly diagnosed immune thrombocytopenic purpura in Korean children. OBJECTIVE: The aim of this study is to compare the efficacy and safety of a single dose of anti-D immunoglobulin (anti-D) at 50 mug/kg to intravenous immunoglobulin (IVIG) in Korean children with acute immune thrombocytopenic purpura (ITP). METHODS: We performed this study prospectively by randomly administering 2 consecutive doses of IVIG at a dose of 1.0 g/kg/dor a single dose of anti-D at 50 microg/kg to children upon initial diagnosis of acute ITP. The platelet count and adverse events, including hemoglobin concentration, were then serially evaluated, and the responses were compared. RESULTS: The likelihood of having a platelet count greater than 20x10/mm after 3 days of treatment in the IVIG and anti-D group was 93% and 92%, respectively. In addition, hemoglobin concentration in the anti-D group had declined more than that of the IVIG group (1.49 g/dL vs. 0.80 g/dL, P=0.014) 3 days after treatment. Fever, chills, and headache occurred less frequently in the anti-D group than the IVIG group, however, this difference was not statistically significant (25% vs. 45%, P=0.494). CONCLUSIONS: A single dose of 50 microg/kg of anti-D raised platelet count as efficiently as IVIG in newly diagnosed cases of ITP in Korean children. Although 50 microg/kg of anti-D had a greater effect on the hemoglobin concentration than IVIG, the adverse effects were found to be acceptable, and no serious events were observed." ], "offsets": [ [ 0, 1603 ] ] } ]

[ { "id": "entity-269-0", "type": "DISEASE", "text": [ "immune thrombocytopenic purpura" ], "offsets": [ [ 125, 156 ] ], "normalized": [] }, { "id": "entity-269-1", "type": "DISEASE", "text": [ "acute immune thrombocytopenic purpura" ], "offsets": [ [ 374, 411 ] ], "normalized": [] }, { "id": "entity-269-2", "type": "DISEASE", "text": [ "ITP" ], "offsets": [ [ 413, 416 ] ], "normalized": [] }, { "id": "entity-269-3", "type": "DISEASE", "text": [ "acute ITP" ], "offsets": [ [ 624, 633 ] ], "normalized": [] }, { "id": "entity-269-4", "type": "ADVERSE", "text": [ "Fever" ], "offsets": [ [ 1095, 1100 ] ], "normalized": [] }, { "id": "entity-269-5", "type": "ADVERSE", "text": [ "chills" ], "offsets": [ [ 1102, 1108 ] ], "normalized": [] }, { "id": "entity-269-6", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 1114, 1122 ] ], "normalized": [] }, { "id": "entity-269-7", "type": "DISEASE", "text": [ "ITP" ], "offsets": [ [ 1398, 1401 ] ], "normalized": [] } ]

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[ { "id": "passage-270", "type": "abstract", "text": [ "Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome. OBJECTIVE: Patients with a primary neurodegenerative disorder associated with cognitive impairment are at increased risk for epilepsy. The goal of the present study was to characterize seizure type(s), etiological diagnosis of dementia, electroencephalogram (EEG) and imaging findings, and response to antiepileptic drug (AED) therapy in these individuals. METHODS: A retrospective study was performed identifying patients in the Mayo Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) who were classified as having dementia and epilepsy from 1986 to 2006. Multiple clinical parameters were extracted from patient charts and evaluated to characterize the primary neurodegenerative disorder and seizure outcomes. RESULTS: Sixty-three of the 1738 ADPR and ADRC patients (3.6%) had epilepsy. Twenty-four of the 63 patients were excluded because of insufficient information regarding their epilepsy. The remaining 39 patients were analyzed. Twenty-eight of the 63 patients (72%) experienced complex partial seizures. Head MRI was performed in 35 patients (90%). Fourteen patients (36%) had MRI-identified structural lesions that included remote stroke and prior intracerebral hemorrhage. EEGs were obtained in 29 patients (74%). Fifteen patients (38%) had epileptiform discharges. Overall, it was found that 79% had an excellent response to AED therapy. Approximately one-third of the patients had dose-related side effects from an AED. CONCLUSION: The present study indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled on AED therapy. The long-term effect of seizure activity on the neurodegenerative disorder is unknown." ], "offsets": [ [ 0, 1839 ] ] } ]

[ { "id": "entity-270-0", "type": "DISEASE", "text": [ "seizures" ], "offsets": [ [ 10, 18 ] ], "normalized": [] }, { "id": "entity-270-1", "type": "DISEASE", "text": [ "dementia" ], "offsets": [ [ 36, 44 ] ], "normalized": [] }, { "id": "entity-270-2", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 57, 64 ] ], "normalized": [] }, { "id": "entity-270-3", "type": "DISEASE", "text": [ "neurodegenerative disorder" ], "offsets": [ [ 131, 157 ] ], "normalized": [] }, { "id": "entity-270-4", "type": "DISEASE", "text": [ "cognitive impairment" ], "offsets": [ [ 174, 194 ] ], "normalized": [] }, { "id": "entity-270-5", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 221, 229 ] ], "normalized": [] }, { "id": "entity-270-6", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 281, 288 ] ], "normalized": [] }, { "id": "entity-270-7", "type": "DISEASE", "text": [ "dementia" ], "offsets": [ [ 323, 331 ] ], "normalized": [] }, { "id": "entity-270-8", "type": "DISEASE", "text": [ "Alzheimer Disease" ], "offsets": [ [ 531, 548 ] ], "normalized": [] }, { "id": "entity-270-9", "type": "DISEASE", "text": [ "Alzheimer Disease" ], "offsets": [ [ 577, 594 ] ], "normalized": [] }, { "id": "entity-270-10", "type": "DISEASE", "text": [ "dementia" ], "offsets": [ [ 648, 656 ] ], "normalized": [] }, { "id": "entity-270-11", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 661, 669 ] ], "normalized": [] }, { "id": "entity-270-12", "type": "DISEASE", "text": [ "neurodegenerative disorder" ], "offsets": [ [ 795, 821 ] ], "normalized": [] }, { "id": "entity-270-13", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 826, 833 ] ], "normalized": [] }, { "id": "entity-270-14", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 911, 919 ] ], "normalized": [] }, { "id": "entity-270-15", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 1018, 1026 ] ], "normalized": [] }, { "id": "entity-270-16", "type": "DISEASE", "text": [ "complex partial seizures" ], "offsets": [ [ 1119, 1143 ] ], "normalized": [] }, { "id": "entity-270-17", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 1273, 1279 ] ], "normalized": [] }, { "id": "entity-270-18", "type": "DISEASE", "text": [ "intracerebral hemorrhage" ], "offsets": [ [ 1290, 1314 ] ], "normalized": [] }, { "id": "entity-270-19", "type": "ADVERSE", "text": [ "dose-related side effects" ], "offsets": [ [ 1526, 1551 ] ], "normalized": [] }, { "id": "entity-270-20", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 1651, 1659 ] ], "normalized": [] }, { "id": "entity-270-21", "type": "DISEASE", "text": [ "dementia" ], "offsets": [ [ 1664, 1672 ] ], "normalized": [] }, { "id": "entity-270-22", "type": "DISEASE", "text": [ "complex partial seizures" ], "offsets": [ [ 1678, 1702 ] ], "normalized": [] }, { "id": "entity-270-23", "type": "DISEASE", "text": [ "seizure" ], "offsets": [ [ 1777, 1784 ] ], "normalized": [] }, { "id": "entity-270-24", "type": "DISEASE", "text": [ "neurodegenerative disorder" ], "offsets": [ [ 1801, 1827 ] ], "normalized": [] } ]

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[ { "id": "passage-271", "type": "abstract", "text": [ "A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results. BACKGROUND: Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression. METHODS: Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.). RESULTS: The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49-81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 +/- 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 +/- 2 mg/dL) decreased from 2,086 +/- 390 pg/mL to 1,250 +/- 712 pg/mL (p < 0.002) at target ceruloplasmin (13 +/- 2 mg/dL; p < 0.0001 from baseline). The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non-TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months). CONCLUSIONS: Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy." ], "offsets": [ [ 0, 1987 ] ] } ]

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[ { "id": "passage-272", "type": "abstract", "text": [ "Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma. Docetaxel, usually administered according to maximum tolerated dose (MTD), can inhibit endothelial cell proliferation at low nanomolar concentrations. Docetaxel may exert antiangiogenic effects if dosed so plasma levels are maintained at low nanomolar concentrations over a prolonged time. We evaluated metronomic and MTD-based dosing of docetaxel with and without vandetanib, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, in a head and neck xenograft model. A murine physiologically based pharmacokinetic model was modified to predict docetaxel distribution following i.p. administration to design dosing regimens that target prespecified plasma concentrations, for antiendothelial effects (metronomic), or exposure, to mimic 30 mg/m2 (weekly/MTD) docetaxel in humans. Animals were treated for 28 days with 1 mg/kg/d (DTX1) or 6 mg/kg q4d (DTX6) docetaxel with or without vandetanib (15 mg/kg/d p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe gastrointestinal toxicity. All treatment groups significantly reduced tumor volume, tumor proliferation (Ki-67), and tumor endothelial cell proliferation (Ki-67/von Willebrand factor) compared with control. Addition of vandetanib to docetaxel treatment significantly enhanced tumor growth inhibition over single-agent therapy. A positive correlation of tumor endothelial cell proliferation with tumor growth rates demonstrates vandetanib and docetaxel antiangiogenic effects. Due to the morbidity observed with DTX1 treatment, it is difficult to clearly ascertain if metronomic schedules will be effective for treatment. Docetaxel with vandetanib is effective in treating UMSCC2 xenografts at concentrations relevant to exposures in humans." ], "offsets": [ [ 0, 2002 ] ] } ]

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[ { "id": "passage-273", "type": "abstract", "text": [ "Prospective evaluation of sexual function in patients receiving cryosurgery as a primary radical treatment for localized prostate cancer. OBJECTIVE: To evaluate prospectively the sexual function of patients undergoing cryosurgery as a primary radical treatment for localized prostate cancer, as the development of 17 G cryotherapy probes has improved the delivery of this treatment, but one of the side-effects of cryosurgery is the development of erectile dysfunction (ED). PATIENTS AND METHODS: Between July 2003 and May 2008, 53 patients were treated using an argon-based third-generation cryotherapy system (Oncura, Arlington Heights, IL, USA). Prospective data were collected at 6 weeks, 3 months, then 3-monthly up to 1 year and subsequently 6-monthly. Patients were followed up for up to 54 months, with a median (mean) follow-up 36 (30.5) months. RESULTS: All 53 patients were followed after receiving cryosurgery as primary treatment for prostate cancer; 51 (96.3%) had ED at 6 weeks while two (3.7%) were experiencing partial erections. By 9 months one (2.4%) of 42 patients was fully potent using phosphodiesterase type-5 inhibitors, and six (14.3%) were experiencing partial erections. By 18 months eight (21%) of 39 patients followed up had regained full potency and by 24 months eight (24%) of 33 patients were fully potent and three (9%) experienced partial erections. CONCLUSION: While ED is a significant side-effect of cryotherapy, a considerable proportion of patients who have no ED before treatment (39%) recover full sexual function afterward. Focal nerve-sparing cryosurgery might be the way forward in an attempt to preserve erectile function in men who had no ED before treatment. Erectile aids should be made available for those patients for whom sexual dysfunction compromises the quality of their life and relationships." ], "offsets": [ [ 0, 1849 ] ] } ]

[ { "id": "entity-273-0", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 121, 136 ] ], "normalized": [] }, { "id": "entity-273-1", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 276, 291 ] ], "normalized": [] }, { "id": "entity-273-2", "type": "ADVERSE", "text": [ "erectile dysfunction" ], "offsets": [ [ 449, 469 ] ], "normalized": [] }, { "id": "entity-273-3", "type": "ADVERSE", "text": [ "ED" ], "offsets": [ [ 471, 473 ] ], "normalized": [] }, { "id": "entity-273-4", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 948, 963 ] ], "normalized": [] }, { "id": "entity-273-5", "type": "ADVERSE", "text": [ "ED" ], "offsets": [ [ 1403, 1405 ] ], "normalized": [] }, { "id": "entity-273-6", "type": "ADVERSE", "text": [ "ED" ], "offsets": [ [ 1501, 1503 ] ], "normalized": [] }, { "id": "entity-273-7", "type": "DISEASE", "text": [ "ED" ], "offsets": [ [ 1686, 1688 ] ], "normalized": [] }, { "id": "entity-273-8", "type": "DISEASE", "text": [ "sexual dysfunction" ], "offsets": [ [ 1774, 1792 ] ], "normalized": [] } ]

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[ { "id": "passage-274", "type": "abstract", "text": [ "The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta. Gestational diabetes mellitus is a common medical complication in pregnancy. Recent findings demonstrate that glyburide is effluxed against a concentration gradient from the fetal to the maternal circulation. However, the transport systems involved in the active efflux of glyburide in the human placenta have not yet been identified. The ATP-binding cassette transporter, breast cancer resistance protein (BCRP), is highly expressed in placental syncytiotrophoblast suggesting it may play a role in protecting the fetus from drug toxicity. The objective of the present study was to determine whether BCRP participates in the transport of glyburide across the human placenta. The placental transfer of glyburide in the presence of specific BCRP inhibitor, nicardipine, was investigated using the ex vivo dual perfusion system of isolated human placental lobules. In a closed experiment, glyburide was added (200 ng/mL) to the maternal and fetal circulations and the BCRP inhibitor (20 microM) was added to the maternal circulation. Samples were taken during pre-control, experimental, and post-control periods for measurement of glyburide and markers of tissue viability. Results obtained from perfusions (n=4) in the presence of the BCRP inhibitor show a significant increase in the mean fetal-to-maternal concentration ratio of glyburide determined at 180 min, 0.56+/-0.06, when compared to the mean ratio obtained in the absence of inhibitor, 0.32+/-0.06 (p=0.04). These data indicate that nicardipine partially blocked the transfer of glyburide across the whole placenta through its inhibition of BCRP. This is the first ex vivo evidence that BCRP actively transports glyburide." ], "offsets": [ [ 0, 1792 ] ] } ]

[ { "id": "entity-274-0", "type": "DISEASE", "text": [ "Gestational diabetes mellitus" ], "offsets": [ [ 110, 139 ] ], "normalized": [] }, { "id": "entity-274-1", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 636, 649 ] ], "normalized": [] } ]

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[ { "id": "passage-275", "type": "abstract", "text": [ "Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study. OBJECTIVES: While many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed. STUDY DESIGN: Prenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearman's correlation coefficient. RESULTS: A delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds. DISCUSSION AND CONCLUSION: A relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems." ], "offsets": [ [ 0, 1914 ] ] } ]

[ { "id": "entity-275-0", "type": "DISEASE", "text": [ "malignancies" ], "offsets": [ [ 1878, 1890 ] ], "normalized": [] } ]

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[ { "id": "passage-276", "type": "abstract", "text": [ "The efficacy of Femal in women with premenstrual syndrome: a randomised, double-blind, parallel-group, placebo-controlled, multicentre study. INTRODUCTION: A double-blind, placebo-controlled, randomised, parallel-group, multicentre study was conducted to evaluate the effect of a pollen-based herbal medicinal product, Femal (Sea-Band Ltd, Leicestershire, UK), on premenstrual sleep disturbances (PSD) in women with premenstrual syndrome (PMS). METHODS: Femal, 160 mg twice-daily, was given for four menstrual cycles to 50 women, and placebo to 51 women. PSD were evaluated on a visual analogue scale prior to and after the four cycles. The effect on overall PMS symptoms was assessed with the Steiner premenstrual tension syndrome (PMTS) self-rating questionnaire. The results were analysed statistically based on intention to treat. RESULTS: Femal treatment resulted in a significant reduction in PSD (P<0.05) whereas placebo had no significant effect (P>0.05). In a subgroup analysis of women with irritability as their main PMS symptom cluster, the reduction of PSD was even more pronounced (P<0.001). There was no significant difference in overall degree of PMS symptom reduction between Femal and placebo when all participating women were evaluated (P>0.05). However, in women with irritability as their main PMS symptom cluster, Femal treatment resulted in a significant reduction of the Steiner score (P<0.05). The frequency of adverse events was not significantly different in women on Femal compared to women on placebo (P>0.05). No serious adverse events were recorded. CONCLUSION: Femal treatment reduced PSD to a significant degree, particularly in women with irritability as their main PMS symptom. Femal treatment also reduced overall PMS symptoms in women with irritability (but not dysphoria) as their main PMS symptom. The safety of Femal and its efficacy in PSD and other symptoms in women with irritability as the main symptom cluster makes this herbal medicinal product a promising addition to the therapeutic arsenal for women with PMS." ], "offsets": [ [ 0, 2059 ] ] } ]

[ { "id": "entity-276-0", "type": "DISEASE", "text": [ "premenstrual syndrome" ], "offsets": [ [ 36, 57 ] ], "normalized": [] }, { "id": "entity-276-1", "type": "DISEASE", "text": [ "premenstrual sleep disturbances" ], "offsets": [ [ 365, 396 ] ], "normalized": [] }, { "id": "entity-276-2", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 398, 401 ] ], "normalized": [] }, { "id": "entity-276-3", "type": "DISEASE", "text": [ "premenstrual syndrome" ], "offsets": [ [ 417, 438 ] ], "normalized": [] }, { "id": "entity-276-4", "type": "DISEASE", "text": [ "PMS" ], "offsets": [ [ 440, 443 ] ], "normalized": [] }, { "id": "entity-276-5", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 556, 559 ] ], "normalized": [] }, { "id": "entity-276-6", "type": "DISEASE", "text": [ "PMS symptoms" ], "offsets": [ [ 660, 672 ] ], "normalized": [] }, { "id": "entity-276-7", "type": "DISEASE", "text": [ "premenstrual tension syndrome" ], "offsets": [ [ 703, 732 ] ], "normalized": [] }, { "id": "entity-276-8", "type": "DISEASE", "text": [ "PMTS" ], "offsets": [ [ 734, 738 ] ], "normalized": [] }, { "id": "entity-276-9", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "entity-276-10", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 1002, 1014 ] ], "normalized": [] }, { "id": "entity-276-11", "type": "DISEASE", "text": [ "PMS symptom" ], "offsets": [ [ 1029, 1040 ] ], "normalized": [] }, { "id": "entity-276-12", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 1067, 1070 ] ], "normalized": [] }, { "id": "entity-276-13", "type": "DISEASE", "text": [ "PMS symptom" ], "offsets": [ [ 1164, 1175 ] ], "normalized": [] }, { "id": "entity-276-14", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 1289, 1301 ] ], "normalized": [] }, { "id": "entity-276-15", "type": "DISEASE", "text": [ "PMS symptom" ], "offsets": [ [ 1316, 1327 ] ], "normalized": [] }, { "id": "entity-276-16", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 1618, 1621 ] ], "normalized": [] }, { "id": "entity-276-17", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 1674, 1686 ] ], "normalized": [] }, { "id": "entity-276-18", "type": "DISEASE", "text": [ "PMS symptom" ], "offsets": [ [ 1701, 1712 ] ], "normalized": [] }, { "id": "entity-276-19", "type": "DISEASE", "text": [ "PMS symptoms" ], "offsets": [ [ 1751, 1763 ] ], "normalized": [] }, { "id": "entity-276-20", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 1778, 1790 ] ], "normalized": [] }, { "id": "entity-276-21", "type": "DISEASE", "text": [ "dysphoria" ], "offsets": [ [ 1800, 1809 ] ], "normalized": [] }, { "id": "entity-276-22", "type": "DISEASE", "text": [ "PMS symptom" ], "offsets": [ [ 1825, 1836 ] ], "normalized": [] }, { "id": "entity-276-23", "type": "DISEASE", "text": [ "PSD" ], "offsets": [ [ 1878, 1881 ] ], "normalized": [] }, { "id": "entity-276-24", "type": "DISEASE", "text": [ "irritability" ], "offsets": [ [ 1915, 1927 ] ], "normalized": [] }, { "id": "entity-276-25", "type": "DISEASE", "text": [ "PMS" ], "offsets": [ [ 2055, 2058 ] ], "normalized": [] } ]

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[ { "id": "passage-277", "type": "abstract", "text": [ "Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette syndrome. OBJECTIVES: The primary aim of the study was to evaluate the effectiveness and tolerability of open-label olanzapine on motor and vocal tics in children and adolescents with Tourette syndrome (TS). Secondary aims included assessing the response of TS-associated disruptive behaviors to olanzapine exposure. METHOD: Twelve children and adolescents (mean age 11.3 +/- 2.4 years, range 7-14 years) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) TS were enrolled in a single-site, 6-week, open-label, prospective, flexible-dose design in outpatients receiving monotherapy with olanzapine. Standardized ratings of tic symptoms, disruptive behaviors, and aggression were obtained, along with adverse events and safety data. RESULTS: Over the 6-week trial, olanzapine administration was associated with a significant decrease in total tic severity as measured by the Yale Global Tic Severity Scale (30% reduction by week 6; effect size 0.49). A significant majority of subjects were rated as \"much improved\" or \"very much improved\" on the Clinical Global Impressions-Improvement Scale (GCI-I) by both clinicians (67%; 8/12) and parents (64%; 7/11). Attention-deficit/hyperactivity disorder (ADHD) symptoms showed significant improvements from baseline for both inattention (33% decrease) and hyperactive/impulsivity (50% decrease) scores (effect sizes 0.44 and 0.43, respectively). Aggression was also decreased as assessed by fewer numbers of aggressive episodes on the Overt Aggression Scale (OAS). Little change in anxiety symptoms was noted. The most widely reported side effects were drowsiness/sedation and weight gain; adverse events were generally well tolerated. Mean weight gain of 4.1 +/- 2.0 kg was observed over the 6-week trial, a mean percent change of 8.4 +/- 4.4 (p < 0.001). CONCLUSIONS: Additional studies of the benefits of olanzapine treatment for tic control as well as the commonly associated co-morbid features of TS are indicated, especially if approaches to predict or minimize weight gain can be determined." ], "offsets": [ [ 0, 2170 ] ] } ]

[ { "id": "entity-277-0", "type": "DISEASE", "text": [ "Tourette syndrome" ], "offsets": [ [ 89, 106 ] ], "normalized": [] }, { "id": "entity-277-1", "type": "DISEASE", "text": [ "Tourette syndrome" ], "offsets": [ [ 283, 300 ] ], "normalized": [] }, { "id": "entity-277-2", "type": "DISEASE", "text": [ "TS" ], "offsets": [ [ 302, 304 ] ], "normalized": [] }, { "id": "entity-277-3", "type": "ADVERSE", "text": [ "disruptive behaviors" ], "offsets": [ [ 371, 391 ] ], "normalized": [] }, { "id": "entity-277-4", "type": "DISEASE", "text": [ "Mental Disorders" ], "offsets": [ [ 546, 562 ] ], "normalized": [] }, { "id": "entity-277-5", "type": "DISEASE", "text": [ "TS" ], "offsets": [ [ 585, 587 ] ], "normalized": [] }, { "id": "entity-277-6", "type": "DISEASE", "text": [ "tic symptoms" ], "offsets": [ [ 752, 764 ] ], "normalized": [] }, { "id": "entity-277-7", "type": "DISEASE", "text": [ "disruptive behaviors" ], "offsets": [ [ 766, 786 ] ], "normalized": [] }, { "id": "entity-277-8", "type": "DISEASE", "text": [ "aggression" ], "offsets": [ [ 792, 802 ] ], "normalized": [] }, { "id": "entity-277-9", "type": "DISEASE", "text": [ "tic" ], "offsets": [ [ 971, 974 ] ], "normalized": [] }, { "id": "entity-277-10", "type": "DISEASE", "text": [ "Tic" ], "offsets": [ [ 1015, 1018 ] ], "normalized": [] }, { "id": "entity-277-11", "type": "DISEASE", "text": [ "Attention-deficit/hyperactivity disorder" ], "offsets": [ [ 1285, 1325 ] ], "normalized": [] }, { "id": "entity-277-12", "type": "DISEASE", "text": [ "ADHD" ], "offsets": [ [ 1327, 1331 ] ], "normalized": [] }, { "id": "entity-277-13", "type": "DISEASE", "text": [ "Aggression" ], "offsets": [ [ 1518, 1528 ] ], "normalized": [] }, { "id": "entity-277-14", "type": "DISEASE", "text": [ "Aggression" ], "offsets": [ [ 1613, 1623 ] ], "normalized": [] }, { "id": "entity-277-15", "type": "DISEASE", "text": [ "anxiety" ], "offsets": [ [ 1654, 1661 ] ], "normalized": [] }, { "id": "entity-277-16", "type": "ADVERSE", "text": [ "drowsiness" ], "offsets": [ [ 1725, 1735 ] ], "normalized": [] }, { "id": "entity-277-17", "type": "ADVERSE", "text": [ "sedation" ], "offsets": [ [ 1736, 1744 ] ], "normalized": [] }, { "id": "entity-277-18", "type": "DISEASE", "text": [ "tic" ], "offsets": [ [ 2005, 2008 ] ], "normalized": [] }, { "id": "entity-277-19", "type": "DISEASE", "text": [ "TS" ], "offsets": [ [ 2074, 2076 ] ], "normalized": [] } ]

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[ { "id": "passage-278", "type": "abstract", "text": [ "A novel polyherbal microbicide with inhibitory effect on bacterial, fungal and viral genital pathogens. A polyherbal cream (Basant) has been formulated using diferuloylmethane (curcumin), purified extracts of Emblica officinalis (Amla), purified saponins from Sapindus mukorossi, Aloe vera and rose water along with pharmacopoeially approved excipients and preservatives. Basant inhibits the growth of WHO strains and clinical isolates of Neisseria gonorrhoeae, including those resistant to penicillin, tetracycline, nalidixic acid and ciprofloxacin. It has pronounced inhibitory action against Candida glabrata, Candida albicans and Candida tropicalis isolated from women with vulvovaginal candidiasis, including three isolates resistant to azole drugs and amphotericin B. Basant displayed a high virucidal action against human immunodeficiency virus HIV-1NL4.3 in CEM-GFP reporter T and P4 (Hela-CD4-LTR-betaGal) cell lines with a 50% effective concentration (EC50) of 1:20000 dilution and nearly complete (98-99%) inhibition at 1:1000 dilution. It also prevented the entry of HIV-1(IIIB) virus into P4-CCR5 cells (EC50 approximately 1:2492). Two ingredients, Aloe and Amla, inhibited the transduction of human papillomavirus type 16 (HPV-16) pseudovirus in HeLa cells at concentrations far below those that are cytotoxic and those used in the formulation. Basant was found to be totally safe according to pre-clinical toxicology carried out on rabbit vagina after application for 7 consecutive days or twice daily for 3 weeks. Basant has the potential of regressing vulvovaginal candidiasis and preventing N. gonorrhoeae, HIV and HPV infections." ], "offsets": [ [ 0, 1649 ] ] } ]

[ { "id": "entity-278-0", "type": "DISEASE", "text": [ "vulvovaginal candidiasis" ], "offsets": [ [ 679, 703 ] ], "normalized": [] }, { "id": "entity-278-1", "type": "DISEASE", "text": [ "vulvovaginal candidiasis" ], "offsets": [ [ 1570, 1594 ] ], "normalized": [] }, { "id": "entity-278-2", "type": "DISEASE", "text": [ "HPV infections" ], "offsets": [ [ 1634, 1648 ] ], "normalized": [] } ]

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[ { "id": "passage-279", "type": "abstract", "text": [ "Astaxanthin, canthaxanthin and beta-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. Carotenoids are used for systemic photoprotection in humans. Regarding mechanisms underlying photoprotective effects of carotenoids, here we compared the modulation of UVA-related injury by carotenoids. Human dermal fibroblasts (HDF) were exposed to moderate doses of UVA, which stimulated apoptosis, increased levels of reactive oxygen species and thiobarbituric acid reactive substances, decreased antioxidant enzymes activities, promoted membrane perturbation, and induced the expression of heme oxygenase-1 (HO-1). The carotenoids astaxanthin (AX), canthaxanthin (CX) and beta-carotene (betaC) were delivered to HDF 24 h before exposure to UVA. Astaxanthin exhibited a pronounced photoprotective effect and counteracted all of the above-mentioned UVA-induced alterations to a significant extent. beta-Carotene only partially prevented the UVA-induced decline of catalase and superoxide dismutase activities, but it increased membrane damage and stimulated HO-1 expression. Moreover, betaC dose-dependently induced caspase-3 activity following UVA exposure. In contrast, CX had no effect on oxidative damage, except for HO-1 expression, which was augmented. Uptake of AX by fibroblasts was higher than that of the other two carotenoids. The photostability of the three compounds in fibroblasts was AX > CX >> betaC. The data indicate that the oxo-carotenoid AX has a superior preventive effect towards photo-oxidative changes in cell culture." ], "offsets": [ [ 0, 1594 ] ] } ]

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[ { "id": "passage-280", "type": "abstract", "text": [ "Fragrance Material Review on isopulegol. A toxicologic and dermatologic review of isopulegol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 143 ] ] } ]

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[ { "id": "passage-281", "type": "abstract", "text": [ "The use of ultrasound and micelles in cancer treatment. The high toxicity of potent chemotherapeutic drugs like Doxorubicin (Dox) limits the therapeutic window in which they can be applied. This window can be expanded by controlling the drug delivery in both space and time such that non-targeted tissues are not adversely affected. Recent research has shown that ultrasound (US) can be used to control the release of Dox and other hydrophobic drugs from polymeric micelles in both time and space. It has also been shown using an in vivo rat tumor model that Dox activity can be enhanced by ultrasound in one region, while in an adjacent region there is little or no effect of the drug. In this article, we review the in vivo and in vitro research being conducted in the area of using ultrasound to enhance and target micellar drug delivery to cancerous tissues. Additionally, we summarize our previously published mathematical models that attempt to represent the release and re-encapsulation phenomena of Dox from Pluronic P105 micelles upon the application of ultrasound. The potential benefits of such controlled chemotherapy compels a thorough investigation of the role of ultrasound (US) and the mechanisms by which US accomplishes drug release and/or enhances drug potency. Therefore we will summarize our findings related to the mechanism involved in acoustically activated micellar drug delivery to tumors." ], "offsets": [ [ 0, 1416 ] ] } ]

[ { "id": "entity-281-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 38, 44 ] ], "normalized": [] }, { "id": "entity-281-1", "type": "DISEASE", "text": [ "tumors" ], "offsets": [ [ 1409, 1415 ] ], "normalized": [] } ]

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[ { "id": "passage-282", "type": "abstract", "text": [ "Apaziquone for non-muscle invasive bladder cancer: a critical review. OBJECTIVE: To describe clinical needs in non-muscle invasive bladder cancer (NMIBC) and review the potential of apaziquone in this respect. METHODS: Epidemiology and clinical practice in NMIBC, as well as new drugs and strategies are reviewed. RESULTS: Bladder cancer is a heterogeneous and frequent disease. Clinical risk factors help in determining additional therapy after initial resection. However, current treatments have clear limitations with regard to efficacy and/or toxicity. New drugs and strategies have been tested recently and are in (pre)clinical use. Intravesical apaziquone (EOquin) is a new drug. It has theoretical advantages for intravesical use, has proven safety and is presently under further clinical evaluation. CONCLUSION: Apaziquone is a promising drug for intravesical use in patients with NMIBC." ], "offsets": [ [ 0, 896 ] ] } ]

[ { "id": "entity-282-0", "type": "DISEASE", "text": [ "non-muscle invasive bladder cancer" ], "offsets": [ [ 15, 49 ] ], "normalized": [] }, { "id": "entity-282-1", "type": "DISEASE", "text": [ "non-muscle invasive bladder cancer" ], "offsets": [ [ 112, 146 ] ], "normalized": [] }, { "id": "entity-282-2", "type": "DISEASE", "text": [ "NMIBC" ], "offsets": [ [ 148, 153 ] ], "normalized": [] }, { "id": "entity-282-3", "type": "DISEASE", "text": [ "NMIBC" ], "offsets": [ [ 258, 263 ] ], "normalized": [] }, { "id": "entity-282-4", "type": "DISEASE", "text": [ "Bladder cancer" ], "offsets": [ [ 324, 338 ] ], "normalized": [] }, { "id": "entity-282-5", "type": "DISEASE", "text": [ "NMIBC" ], "offsets": [ [ 890, 895 ] ], "normalized": [] } ]

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[ { "id": "passage-283", "type": "abstract", "text": [ "Limited place for plasma monitoring of new antiepileptic drugs in clinical practice. Therapeutic drug monitoring (TDM) has been recognized as a useful guide in the clinical management of patients with epilepsy, in particular those on therapy with traditional antiepileptic drugs (AEDs). The demonstration of significant drug interactions and the introduction of the concept \"therapeutic range\" have also contributed to the view that monotherapy should be considered the \"gold standard\" in the treatment of epilepsy. Ten new AEDs have been approved and released to the market in the last fifteen years. The most obvious consequence has been an increased number of patients on polytherapy. In general, newer AEDs have better and more predictable pharmacokinetics than older AEDs and usually show lower risk of interactions leading to toxicity as well as large therapeutic indexes. This pragmatic review focuses on practical suggestions about the potential clinical usefulness of TDM of newer AEDs in relation to their mechanism of action and pharmacokinetic characteristics and in response to patient-specific problems. Overall, the usefulness of TDM of newer AEDs seems to be limited and its indiscriminate use is not justified. However, in selected cases or in response to a specific clinical question, a wise use of TDM of some new AEDs could represent a useful tool in the management of epileptic patients. Exceptions are thus represented by special conditions such as renal failure, dialysis, ascertainment of non-compliance, and pregnancy. For some new AEDs, TDM could be selectively and properly used in response to a single patient-specific pharmacokinetic or pharmacodynamic issue." ], "offsets": [ [ 0, 1689 ] ] } ]

[ { "id": "entity-283-0", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 202, 210 ] ], "normalized": [] }, { "id": "entity-283-1", "type": "DISEASE", "text": [ "epilepsy" ], "offsets": [ [ 507, 515 ] ], "normalized": [] }, { "id": "entity-283-2", "type": "DISEASE", "text": [ "renal failure" ], "offsets": [ [ 1472, 1485 ] ], "normalized": [] } ]

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[ { "id": "passage-284", "type": "abstract", "text": [ "The phenomenology of the psychotic break and Huxley's trip: substance use and the onset of psychosis. BACKGROUND: While considerable research attention has been devoted to the causal relationship between substance use and psychosis, the phenomenology of the association between the two has largely been ignored. This is a significant shortcoming, because it blinds researchers to the possibility that there may be elements of the subjective experience of substance use and psychosis that contribute to their apparent relationship in empirical studies. SAMPLING AND METHODS: The current paper examines the phenomenology of the onset of psychosis and the phenomenology of substance intoxication through consideration of two texts: Sass's account of the phenomenology of psychosis onset and Huxley's account of the experience of hallucinogenic intoxication. Sass's account of psychosis onset includes four components: Unreality, Fragmentation, Mere Being, and Apophany. RESULTS: The analysis reveals significant parallels - and also some differences - between this account and the phenomenology of substance intoxication. CONCLUSIONS: We discuss the implications of this for the causal relationship between psychosis and substance use and suggest several ways of understanding the overlapping phenomenologies. This includes the suggestion of a shared factor, perhaps best described as psychotic-like experience, which seems to involve a breakdown of the sign-referent relationship and relationship with the common-sense, practical world. However, in the onset of psychosis, this breakdown is primarily experienced as a sense of alienation from self and world, whereas in the hallucinogenic state a sense of mystical union and revelation seems predominant. Further research may extend this analysis by looking at experiences with other drugs, particularly cannabis, and by examining the phenomenology of psychotic disorder beyond the first episode." ], "offsets": [ [ 0, 1945 ] ] } ]

[ { "id": "entity-284-0", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 91, 100 ] ], "normalized": [] }, { "id": "entity-284-1", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 223, 232 ] ], "normalized": [] }, { "id": "entity-284-2", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 474, 483 ] ], "normalized": [] }, { "id": "entity-284-3", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 636, 645 ] ], "normalized": [] }, { "id": "entity-284-4", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 769, 778 ] ], "normalized": [] }, { "id": "entity-284-5", "type": "ADVERSE", "text": [ "hallucinogenic intoxication" ], "offsets": [ [ 827, 854 ] ], "normalized": [] }, { "id": "entity-284-6", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 874, 883 ] ], "normalized": [] }, { "id": "entity-284-7", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 1205, 1214 ] ], "normalized": [] }, { "id": "entity-284-8", "type": "DISEASE", "text": [ "psychosis" ], "offsets": [ [ 1561, 1570 ] ], "normalized": [] }, { "id": "entity-284-9", "type": "DISEASE", "text": [ "psychotic disorder" ], "offsets": [ [ 1901, 1919 ] ], "normalized": [] } ]

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[ { "id": "passage-285", "type": "abstract", "text": [ "High-dose methylprednisolone in a pregnant woman with Crohn's disease and adrenal suppression in her newborn. BACKGROUND: The synthetic corticosteroid methylprednisolone is used for the treatment of acute exacerbations of Crohn's disease, also in pregnancy. Its use is considered to be less harmful than the effect of active disease on the fetus. Adrenal suppression in a fetus due to administration of methylprednisolone has hitherto been rarely published. OBJECTIVE: To present a case of neonatal adrenal suppression due to the use of high-dose methylprednisolone in late pregnancy of a woman with Crohn's disease. METHODS AND RESULTS: Clinical signs of adrenal suppression were observed in the newborn 3 h after birth. After hydrocortisone supplementation and intensive therapy the baby recovered completely. CONCLUSIONS: Life-threatening adrenal suppression, requiring hydrocortisone supplementation and intensive therapy, was observed and successfully treated in a newborn, whose mother had received high-dose methylprednisolone in late pregnancy." ], "offsets": [ [ 0, 1053 ] ] } ]

[ { "id": "entity-285-0", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 54, 69 ] ], "normalized": [] }, { "id": "entity-285-1", "type": "DISEASE", "text": [ "adrenal suppression" ], "offsets": [ [ 74, 93 ] ], "normalized": [] }, { "id": "entity-285-2", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 223, 238 ] ], "normalized": [] }, { "id": "entity-285-3", "type": "ADVERSE", "text": [ "Adrenal suppression" ], "offsets": [ [ 348, 367 ] ], "normalized": [] }, { "id": "entity-285-4", "type": "ADVERSE", "text": [ "neonatal adrenal suppression" ], "offsets": [ [ 491, 519 ] ], "normalized": [] }, { "id": "entity-285-5", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 601, 616 ] ], "normalized": [] }, { "id": "entity-285-6", "type": "ADVERSE", "text": [ "adrenal suppression" ], "offsets": [ [ 657, 676 ] ], "normalized": [] }, { "id": "entity-285-7", "type": "ADVERSE", "text": [ "adrenal suppression" ], "offsets": [ [ 843, 862 ] ], "normalized": [] } ]

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[ { "id": "passage-286", "type": "abstract", "text": [ "Variability in platelet response to a single daily dose of 150 mg enteric coated aspirin in a high risk population. PURPOSE: Previous studies have reported inadequate anti-platelet effect in 0.4-35% of patients taking aspirin. Such studies have arbitrarily defined the terms \"semi-responders\", \"non-responders\" or \"resistant\" to variable doses of aspirin on the basis of absolute values derived from different ex-vivo platelet aggregation (PA) methods. Our objective was to define response to 150-mg dose of aspirin in terms of normally distributed values using an ex-vivo measure of PA in a population at high risk for vascular events. METHODS: We prospectively studied high risk patients with either established coronary artery disease (CAD) or stroke or transient ischemic attack (TIA) or peripheral vascular disease or with multiple atherothrombotic risk factors like diabetes plus one of the following-- hypertension, increased total cholesterol, cigarette smoking, micro-albuminuria, low-high density lipoprotein (HDL), family history of CAD and receiving single 150 mg dose of aspirin daily. PA was assessed by chronolog lumi-aggregometer (490-2D) using arachidonic acid (AA) reagent. RESULTS: 130 patients were studied. The response of subjects to aspirin followed a normal, bell shaped distribution curve with a mean and standard deviation (S.D.) of 13.1 +/- 4.4%. 3.1% patients had PA values more than 2 S.D. of the mean, hence termed as hypo-responders to aspirin while another 3.1% patients had PA values less than 2 S.D. of the mean, hence termed as hyper-responders to aspirin. CONCLUSION: There is minimal inter-individual variability in the response to aspirin when tested with AA as the reagent. The response to aspirin follows a normal Gaussian distribution. The prevalence of hypo-responders to aspirin in high risk population is only 3.1%. This is the first study to document \"hypo\" and \"hyper-responders\" to single daily dose of 150 mg aspirin. The clinical relevance of these findings remains to be determined." ], "offsets": [ [ 0, 2033 ] ] } ]

[ { "id": "entity-286-0", "type": "DISEASE", "text": [ "coronary artery disease" ], "offsets": [ [ 715, 738 ] ], "normalized": [] }, { "id": "entity-286-1", "type": "DISEASE", "text": [ "CAD" ], "offsets": [ [ 740, 743 ] ], "normalized": [] }, { "id": "entity-286-2", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 748, 754 ] ], "normalized": [] }, { "id": "entity-286-3", "type": "DISEASE", "text": [ "transient ischemic attack" ], "offsets": [ [ 758, 783 ] ], "normalized": [] }, { "id": "entity-286-4", "type": "DISEASE", "text": [ "TIA" ], "offsets": [ [ 785, 788 ] ], "normalized": [] }, { "id": "entity-286-5", "type": "DISEASE", "text": [ "peripheral vascular disease" ], "offsets": [ [ 793, 820 ] ], "normalized": [] }, { "id": "entity-286-6", "type": "DISEASE", "text": [ "diabetes" ], "offsets": [ [ 873, 881 ] ], "normalized": [] }, { "id": "entity-286-7", "type": "DISEASE", "text": [ "hypertension" ], "offsets": [ [ 910, 922 ] ], "normalized": [] }, { "id": "entity-286-8", "type": "DISEASE", "text": [ "CAD" ], "offsets": [ [ 1045, 1048 ] ], "normalized": [] } ]

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[ { "id": "passage-287", "type": "abstract", "text": [ "Allopregnanolone impairs episodic memory in healthy women. OBJECTIVE: Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the gamma-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women. MATERIALS AND METHODS: Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed. RESULTS: The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task. CONCLUSION: Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability." ], "offsets": [ [ 0, 1601 ] ] } ]

[ { "id": "entity-287-0", "type": "ADVERSE", "text": [ "diminished learning" ], "offsets": [ [ 301, 320 ] ], "normalized": [] }, { "id": "entity-287-1", "type": "ADVERSE", "text": [ "memory impairment" ], "offsets": [ [ 325, 342 ] ], "normalized": [] } ]

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[ { "id": "passage-288", "type": "abstract", "text": [ "Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction: evolution of the docetaxel, cisplatin, and 5-fluorouracil regimen. Advanced gastroesophageal cancer patients are often treated with systemic combination chemotherapy. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fluorouracil (CF) provided benefits with regard to overall survival, response rate, time-to-disease progression, clinical benefit, and health-related quality of life. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profile of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies. The objective of the current review was to identify trials that investigated modifications to the original DCF regimen to improve its toxicity profile and summarize response rate and toxicities. An attempt was also made to summarize ongoing modifications of the DCF regimen. MEDLINE, major meeting proceedings, and the government clinical trials website were searched until 2007. The modified DCF regimens appear to improve the toxicity profile when compared with the original DCF regimen. The docetaxel-based triplet combinations appear to have a higher response rate than the doublet combinations. Many institutions and cooperative groups continue to study docetaxel-based modifications of the DCF regimen to treat patients with gastroesophageal carcinoma. However, although modified DCF reduces the frequency of severe toxicities previously reported with DCF, considerably more advances are needed to improve the safety, survival, and convenience of patients with advanced gastroesophageal cancer." ], "offsets": [ [ 0, 1808 ] ] } ]

[ { "id": "entity-288-0", "type": "DISEASE", "text": [ "cancer of the gastric and gastroesophageal junction" ], "offsets": [ [ 51, 102 ] ], "normalized": [] }, { "id": "entity-288-1", "type": "DISEASE", "text": [ "gastroesophageal cancer" ], "offsets": [ [ 181, 204 ] ], "normalized": [] }, { "id": "entity-288-2", "type": "DISEASE", "text": [ "gastroesophageal carcinoma" ], "offsets": [ [ 1539, 1565 ] ], "normalized": [] }, { "id": "entity-288-3", "type": "DISEASE", "text": [ "gastroesophageal cancer" ], "offsets": [ [ 1784, 1807 ] ], "normalized": [] } ]

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[ { "id": "passage-289", "type": "abstract", "text": [ "Multicenter clinical study on the efficacy and safety of inhalable insulin aerosol in the treatment of type 2 diabetes. BACKGROUND: A new inhalable insulin aerosol (Inh-Ins) was developed in China. The aim of this multicenter clinical study was to evaluate the efficacy and safety of this new Inh-Ins as a treatment of type 2 diabetes. Regular porcine insulin (RI) was used as a control. METHODS: This study is a prospective, randomized, open-label, parallel-group multicenter clinical trial in which 253 qualified patients with type 2 diabetes received the insulin Glargine daily at bedtime plus either a pre-meal Inh-Ins or a pre-meal subcutaneous RI for 12 weeks. HbA1c, fasting plasma glucose (FPG), the 1-hour-postprandial blood glucose (1hPBG) and the 2-hour-postprandial blood glucose (2hPBG) were measured. Events were monitored for adverse effects. RESULTS: After 12 weeks, the HbA1c decreased significantly from baseline in both treatment groups, with no significant difference between the two regimens. In the Inh-Ins group, FPG, both 1hPBG and 2hPBG significantly declined from baseline after the 8th- and 12th-weeks of treatment. The reduced values of FPG or 1hPBG between the two groups showed a more significant hypoglycemic effect with the Inh-Ins than the RI. After 12 weeks, the pulmonary carbon monoxide diffusing capacity (DLco) was significantly lower in Inh-Ins group than in the RI. The main side effects of Inh-Ins were coughing, excessive sputum, and hypoglycemia. CONCLUSIONS: Inh-Ins was effective in decreasing HbA1c like the RI. It was better in lowering the FPG and the 1hPBG than the RI. Its main side effects were coughing, excessive sputum, and hypoglycemia. Also, Inh-Ins slightly impaired DLco." ], "offsets": [ [ 0, 1730 ] ] } ]

[ { "id": "entity-289-0", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 103, 118 ] ], "normalized": [] }, { "id": "entity-289-1", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 320, 335 ] ], "normalized": [] }, { "id": "entity-289-2", "type": "DISEASE", "text": [ "type 2 diabetes" ], "offsets": [ [ 530, 545 ] ], "normalized": [] }, { "id": "entity-289-3", "type": "ADVERSE", "text": [ "coughing" ], "offsets": [ [ 1445, 1453 ] ], "normalized": [] }, { "id": "entity-289-4", "type": "ADVERSE", "text": [ "excessive sputum" ], "offsets": [ [ 1455, 1471 ] ], "normalized": [] }, { "id": "entity-289-5", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 1477, 1489 ] ], "normalized": [] }, { "id": "entity-289-6", "type": "ADVERSE", "text": [ "coughing" ], "offsets": [ [ 1647, 1655 ] ], "normalized": [] }, { "id": "entity-289-7", "type": "ADVERSE", "text": [ "excessive sputum" ], "offsets": [ [ 1657, 1673 ] ], "normalized": [] }, { "id": "entity-289-8", "type": "ADVERSE", "text": [ "hypoglycemia" ], "offsets": [ [ 1679, 1691 ] ], "normalized": [] } ]

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[ { "id": "passage-290", "type": "abstract", "text": [ "Inhibition of cell-cycle progression in human colorectal carcinoma Lovo cells by andrographolide. In recent years, attention has been focused on the anti-cancer properties of pure components, an important role in the prevention of disease. Andrographolide (Andro), the major constituent of Andrographis paniculata (Burm. F.) Nees plant, is implicated towards its pharmacological activity. To investigate the mechanism basis for the anti-tumor properties of Andro, Andro was used to examine its effect on cell-cycle progression in human colorectal carcinoma Lovo cells. The data from cell growth experiment showed that Andro exhibited the anti-proliferation effect on Lovo cells in a time- and dose-dependent manner. This event was accompanied the arrest of the cells at the G1-S phase by Andro at the tested concentrations of 0-30 microM. Cellular uptake of Andro and Andro was confirmed by capillary electrophoresis analysis and the intracellular accumulation of Andro (0.61+/-0.07 microM/mg protein) was observed when treatment of Lovo cells with Andro for 12h. In addition, an accumulation of the cells in G1 phase (15% increase for 10 microM of Andro) was observed as well as by the association with a marked decrease in the protein expression of Cyclin A, Cyclin D1, Cdk2 and Cdk4. Andro also inducted the content of Cdk inhibitor p21 and p16, and the phosphorylation of p53. Further immunoprecipitation studies found that, in response to the treatment, the formation of Cyclin D1/Cdk4 and Cyclin A/Cdk2 complexes had declined, preventing the phosphorylation of Rb and the subsequent dissociation of Rb/E2F complex. These results suggested Andro can inhibit Lovo cell growth by G1-S phase arrest, and was exerted by inducing the expression of p53, p21 and p16 that, in turn, repressed the activity of Cyclin D1/Cdk4 and/or Cyclin A/Cdk2, as well as Rb phosphorylation." ], "offsets": [ [ 0, 1874 ] ] } ]

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[ { "id": "passage-291", "type": "abstract", "text": [ "INN-toxin, a highly lethal peptide from the venom of Indian cobra (Naja naja) venom-Isolation, characterization and pharmacological actions. A novel toxic polypeptide, INN-toxin, is purified from the venom of Naja naja using combination of gel-permeation and ion-exchange chromatography. It has a molecular mass of 6951.6Da as determined by MALDI-TOF/MS and the N-terminal sequence of LKXNKLVPLF. It showed both neurotoxic as well as cytotoxic activities. INN-toxin is lethal to mice with a LD(50) of 1.2mg/kg body weight. IgY raised in chicks against basic peptide pool neutralized the toxicity of INN-toxin. INN-toxin did not inhibit cholinesterase activity. It is toxic to Ehrlich ascites tumor (EAT) cells, but it is not toxic to leukocyte culture. The toxin appears to be specific in its mode of action. Interaction of N-bromosuccinamide (NBS) with the peptide resulted in the modification of tryptophan residues and loss of lethal toxicity of INN-toxin." ], "offsets": [ [ 0, 960 ] ] } ]

[ { "id": "entity-291-0", "type": "ADVERSE", "text": [ "cytotoxic activities" ], "offsets": [ [ 435, 455 ] ], "normalized": [] } ]

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[ { "id": "passage-292", "type": "abstract", "text": [ "Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma. PURPOSE: Anthracycline-based chemotherapy, which improves survival for patients with non-Hodgkin's lymphoma, is often withheld from elderly patients because of its cardiotoxicity. We studied the cardiac effects of doxorubicin in a population-based sample of older patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Among patients age > or = 65 years diagnosed with DLBCL from 1991 to 2002 in the Surveillance, Epidemiology, and End Results-Medicare database, we developed logistic regression models of the associations of doxorubicin with demographic, clinical, and cardiac variables. We then developed Cox proportional hazards models of the association between doxorubicin and subsequent congestive heart failure (CHF), taking predictors of CHF into account. RESULTS: Of 9,438 patients with DLBCL, 3,164 (42%) received doxorubicin-based chemotherapy. Any doxorubicin use was associated with a 29% increase in risk of CHF (95% CI, 1.02 to 1.62); CHF risk increased with number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension; hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio = 1.8; P < .01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in doxorubicin-treated patients versus 79% in patients not treated with doxorubicin. CONCLUSION: Among patients receiving chemotherapy for DLBCL, those with prior heart disease were less likely than others to be treated with doxorubicin, and those who received doxorubicin were more likely than others to develop CHF. Various cardiac risk factors increased CHF risk, but only hypertension was synergistic with doxorubicin. Doxorubicin has dramatically improved survival of DLBCL patients; nonetheless, some subgroups may benefit from efforts to reduce doxorubicin-related CHF risk." ], "offsets": [ [ 0, 1979 ] ] } ]

[ { "id": "entity-292-0", "type": "ADVERSE", "text": [ "cardiac toxicity" ], "offsets": [ [ 39, 55 ] ], "normalized": [] }, { "id": "entity-292-1", "type": "DISEASE", "text": [ "B-cell non-Hodgkin's lymphoma" ], "offsets": [ [ 89, 118 ] ], "normalized": [] }, { "id": "entity-292-2", "type": "DISEASE", "text": [ "non-Hodgkin's lymphoma" ], "offsets": [ [ 206, 228 ] ], "normalized": [] }, { "id": "entity-292-3", "type": "ADVERSE", "text": [ "cardiotoxicity" ], "offsets": [ [ 285, 299 ] ], "normalized": [] }, { "id": "entity-292-4", "type": "DISEASE", "text": [ "diffuse large B-cell lymphoma" ], "offsets": [ [ 399, 428 ] ], "normalized": [] }, { "id": "entity-292-5", "type": "DISEASE", "text": [ "DLBCL" ], "offsets": [ [ 430, 435 ] ], "normalized": [] }, { "id": "entity-292-6", "type": "DISEASE", "text": [ "DLBCL" ], "offsets": [ [ 510, 515 ] ], "normalized": [] }, { "id": "entity-292-7", "type": "ADVERSE", "text": [ "congestive heart failure" ], "offsets": [ [ 834, 858 ] ], "normalized": [] }, { "id": "entity-292-8", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 860, 863 ] ], "normalized": [] }, { "id": "entity-292-9", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 887, 890 ] ], "normalized": [] }, { "id": "entity-292-10", "type": "DISEASE", "text": [ "DLBCL" ], "offsets": [ [ 937, 942 ] ], "normalized": [] }, { "id": "entity-292-11", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1063, 1066 ] ], "normalized": [] }, { "id": "entity-292-12", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1091, 1094 ] ], "normalized": [] }, { "id": "entity-292-13", "type": "ADVERSE", "text": [ "prior heart disease" ], "offsets": [ [ 1161, 1180 ] ], "normalized": [] }, { "id": "entity-292-14", "type": "ADVERSE", "text": [ "diabetes" ], "offsets": [ [ 1197, 1205 ] ], "normalized": [] }, { "id": "entity-292-15", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [] }, { "id": "entity-292-16", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 1225, 1237 ] ], "normalized": [] }, { "id": "entity-292-17", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1287, 1290 ] ], "normalized": [] }, { "id": "entity-292-18", "type": "DISEASE", "text": [ "DLBCL" ], "offsets": [ [ 1537, 1542 ] ], "normalized": [] }, { "id": "entity-292-19", "type": "ADVERSE", "text": [ "prior heart disease" ], "offsets": [ [ 1555, 1574 ] ], "normalized": [] }, { "id": "entity-292-20", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1711, 1714 ] ], "normalized": [] }, { "id": "entity-292-21", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1755, 1758 ] ], "normalized": [] }, { "id": "entity-292-22", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 1774, 1786 ] ], "normalized": [] }, { "id": "entity-292-23", "type": "DISEASE", "text": [ "DLBCL" ], "offsets": [ [ 1871, 1876 ] ], "normalized": [] }, { "id": "entity-292-24", "type": "ADVERSE", "text": [ "CHF" ], "offsets": [ [ 1970, 1973 ] ], "normalized": [] } ]

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[ { "id": "passage-293", "type": "abstract", "text": [ "Safety of drug eluting stents: current concerns and controversies. Coronary artery stenting is currently the most frequently performed percutaneous coronary intervention for the treatment of coronary artery disease. Recently, drug- eluting stents, loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs, have revolutionized the management of coronary artery disease by markedly reducing in-stent restenosis. Despite the excellent short- and mid-term results of randomized controlled trials observed with drug-eluting stents, there remain a number of unresolved issues and valid concerns about long-term safety and efficacy of this revolutionary technology. Important safety issues such as thrombosis, late stent malapposition, aneurysm formation, edge effect, late inflammation due to choice of polymer used to bind the drug, the release of toxins, and potential interactions with brachytherapy and drugs have not been completely addressed. This review article evaluates current available scientific evidence on the various safety issues related to the use of drug-eluting stents." ], "offsets": [ [ 0, 1113 ] ] } ]

[ { "id": "entity-293-0", "type": "DISEASE", "text": [ "coronary artery disease" ], "offsets": [ [ 192, 215 ] ], "normalized": [] }, { "id": "entity-293-1", "type": "DISEASE", "text": [ "coronary artery disease" ], "offsets": [ [ 375, 398 ] ], "normalized": [] }, { "id": "entity-293-2", "type": "ADVERSE", "text": [ "thrombosis" ], "offsets": [ [ 722, 732 ] ], "normalized": [] }, { "id": "entity-293-3", "type": "ADVERSE", "text": [ "stent malapposition" ], "offsets": [ [ 739, 758 ] ], "normalized": [] }, { "id": "entity-293-4", "type": "ADVERSE", "text": [ "aneurysm" ], "offsets": [ [ 760, 768 ] ], "normalized": [] }, { "id": "entity-293-5", "type": "ADVERSE", "text": [ "edge effect" ], "offsets": [ [ 780, 791 ] ], "normalized": [] }, { "id": "entity-293-6", "type": "ADVERSE", "text": [ "inflammation" ], "offsets": [ [ 798, 810 ] ], "normalized": [] } ]

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[ { "id": "passage-294", "type": "abstract", "text": [ "Pharmacogenetics of analgesics: toward the individualization of prescription. The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics." ], "offsets": [ [ 0, 1545 ] ] } ]

[ { "id": "entity-294-0", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 627, 640 ] ], "normalized": [] } ]

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[ { "id": "passage-295", "type": "abstract", "text": [ "Chronopharmacology and antimicrobial therapeutics. Chronobiology studies the phenomenon of rhythmicity in living organisms. Circadian rhythms are genetically determined and are regulated by external synchronizers (i.e. light/day cycle). Several biological processes involved in the pharmacokinetics and pharmacodynamics of drugs are subject to circadian variations. Chronopharmacology studies how biological rhythms impact on drug pharmacokinetic (chronokinetics), pharmacodynamics (chronoesthesy) and toxicity and determines whether time of day administration modifies drug's pharmacological characteristics. Chronotherapy applies chronopharmacological studies to clinical treatments, determining the best biological time for its dosing, i.e. when beneficial effects are maximal and incidence and/or intensity of related side-effects and toxicity are minimal. Significant variations in the pharmacokinetics and toxicity of antibiotics (aminoglycosides, beta-lactams and fluoroquinolones) related to administration time are well known. The aims of this review are to discuss, briefly, the currently accepted model of the circadian system that substantiates endogenous rhythmicity and to provide an update on the knowledge of circadian rhythms applied to drugs used as medicines, with a special mention to the possible impact on antimicrobial treatments. It is concluded that the dosing time of an antimicrobial agent might be clinically relevant in some treatments, thus, clinicians should be aware that the dosing time might affect the clinical response of a drug." ], "offsets": [ [ 0, 1566 ] ] } ]

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[ { "id": "passage-296", "type": "abstract", "text": [ "Effect of darbepoetin alfa administered once monthly on maintaining hemoglobin levels in older patients with chronic kidney disease. BACKGROUND: The anemia of chronic kidney disease (CKD) is associated with increased hospitalizations, increased cardiovascular morbidity and mortality, and diminished quality of life in the elderly. Darbepoetin alfa is an erythropoiesis-stimulating agent that has been shown to be effective in treating anemia in patients with CKD (but not on dialysis) when administered using extended-dosing regimens. OBJECTIVE: The purpose of this post hoc analysis was to examine the efficacy and safety profile of once-monthly (QM) darbepoetin alfa in study patients stratified according to age (ie, <65, 65-74, and > or =75 years). METHODS: Patients with CKD but not on dialysis, receiving darbepoetin alfa every other week (Q2W), and with stable hemoglobin (Hb) levels between 11 and 13 g/dL, inclusive, were enrolled in this 33-week, multicenter, open-label, single-arm study. The study was carried out at 36 US centers and consisted of a 24-week QM darbepoetin alfa dose-titration period followed by an 8-week evaluation period. Hb levels were measured Q2W. Study results were stratified according to patient age (<65, 65-74, and > or =75 years). RESULTS: A total of 152 patients (79 women, 73 men) were enrolled; 55 patients (36%) were <65 years of age, 46 (30%) were 65 to 74 years of age, and 51 (34%) were > or =75 years of age. In patients who received > or =1 dose of darbepoetin alfa, Hb levels > or =11 g/dL were maintained in 76%, 80%, and 71% of patients aged <65, 65 to 74, and > or =75 years, respectively. For patients who completed the study, the proportions who maintained Hb levels > or =11 g/dL were 83%, 88%, and 85%, respectively, for the 3 age groups. The safety profile of QM darbepoetin alfa in this study was consistent with that expected in patients with CKD not receiving dialysis. CONCLUSIONS: Darbepoetin alfa administered QM maintained Hb levels > or =11 g/dL in patients with CKD (not on dialysis) aged <65, 65 to 74, and > or =75 years. This treatment regimen may help optimize anemia management for older community-dwelling and long-term care patients." ], "offsets": [ [ 0, 2209 ] ] } ]

[ { "id": "entity-296-0", "type": "DISEASE", "text": [ "chronic kidney disease" ], "offsets": [ [ 109, 131 ] ], "normalized": [] }, { "id": "entity-296-1", "type": "DISEASE", "text": [ "anemia of chronic kidney disease" ], "offsets": [ [ 150, 182 ] ], "normalized": [] }, { "id": "entity-296-2", "type": "DISEASE", "text": [ "CKD" ], "offsets": [ [ 184, 187 ] ], "normalized": [] }, { "id": "entity-296-3", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 437, 443 ] ], "normalized": [] }, { "id": "entity-296-4", "type": "DISEASE", "text": [ "CKD" ], "offsets": [ [ 461, 464 ] ], "normalized": [] }, { "id": "entity-296-5", "type": "DISEASE", "text": [ "CKD" ], "offsets": [ [ 778, 781 ] ], "normalized": [] }, { "id": "entity-296-6", "type": "DISEASE", "text": [ "CKD" ], "offsets": [ [ 1905, 1908 ] ], "normalized": [] }, { "id": "entity-296-7", "type": "DISEASE", "text": [ "CKD" ], "offsets": [ [ 2031, 2034 ] ], "normalized": [] }, { "id": "entity-296-8", "type": "DISEASE", "text": [ "anemia" ], "offsets": [ [ 2134, 2140 ] ], "normalized": [] } ]

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[ { "id": "passage-297", "type": "abstract", "text": [ "Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and beta-adrenergic receptor signaling pathways. Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) and beta-adrenergic receptors. Treatment of cells with alpha-bungarotoxin (alpha-BTX, alpha7nAChR antagonist) or propranolol (beta-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE(2) and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE(2) induction can only be suppressed by propranolol, but not alpha-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis." ], "offsets": [ [ 0, 1986 ] ] } ]

[ { "id": "entity-297-0", "type": "ADVERSE", "text": [ "cancer" ], "offsets": [ [ 486, 492 ] ], "normalized": [] }, { "id": "entity-297-1", "type": "ADVERSE", "text": [ "gastric tumor" ], "offsets": [ [ 1830, 1843 ] ], "normalized": [] }, { "id": "entity-297-2", "type": "ADVERSE", "text": [ "gastric carcinogenesis" ], "offsets": [ [ 1963, 1985 ] ], "normalized": [] } ]

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[ { "id": "passage-298", "type": "abstract", "text": [ "Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Pept2 knockout mice are an important tool to evaluate the evolving role and relevance of this proton-coupled oligopeptide transporter beyond drug disposition, where the transporter also modulates the pharmacodynamic and toxicodynamic effects of drug substrates. Our in vivo studies with glycylsarcosine in Pept2 knockout mice have established \"proof of concept\" that PEPT2 can have a significant effect on dipeptide disposition. Subsequent studies with the aminocephalosporin antibiotic cefadroxil have shown relevance to pharmacology and infectious disease. Finally, studies with the endogenous peptidomimetic 5-aminolevulinic acid have demonstrated relevance to toxicology in the framework of porphyria- and lead-induced neurotoxicity. These studies have consistently demonstrated the dual action of PEPT2 with respect to its apical localization in choroid plexus epithelium and kidney in: 1) effluxing substrates from CSF into choroid plexus, thereby affecting regional pharmacokinetics in brain; and 2) reabsorbing substrates from renal tubular fluid into proximal tubules, thereby affecting systemic pharmacokinetics and exposure. Moreover, these studies have shown that the regional effect of PEPT2 in limiting substrate concentrations in the CSF is more dramatic than its effect in increasing systemic exposure. In the case of 5-aminolevulinic acid, such regional modulation of drug disposition translates directly into significant changes in neurotoxicity." ], "offsets": [ [ 0, 1538 ] ] } ]

[ { "id": "entity-298-0", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 797, 810 ] ], "normalized": [] }, { "id": "entity-298-1", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 1524, 1537 ] ], "normalized": [] } ]

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[ { "id": "passage-299", "type": "abstract", "text": [ "Protective effects of asiatic acid on rotenone- or H2O2-induced injury in SH-SY5Y cells. Parkinson's disease (PD) is a progressive neurodegenerative disorder with a prevalence of 1-2% in people over the age of 50. Mitochondrial dysfunction occurred in PD patients showing a 15-30% loss of activity in complex I. Asiatic acid (AA), a triterpenoid, is an antioxidant and used for depression treatment, but the effect of AA against PD-like damage has never been reported. In the present study, we investigated the protective effects of AA against H(2)O(2) or rotenone-induced cellular injury and mitochondrial dysfunction in SH-SY5Y cells. Mitochondrial membrane potential (MMP) and the expression of voltage-dependent anion channel (VDAC) were detected with or without AA pretreatment following cellular injury to address the possible mechanisms of AA neuroprotection. The results showed that pre-treatment of AA (0.01-100 nM) protected cells against the toxicity induced by rotenone or H(2)O(2). In addition, MMP dissipation occurred following the exposure of rotenone, which could be prevented by AA treatment. More interestingly, pre-administration of AA inhibited the elevation of VDAC mRNA and protein levels induced by rotenone(100 nM) or H(2)O(2) (300 microM).These data indicate that AA could protect neuronal cells against mitochondrial dysfunctional injury and suggest that AA might be developed as an agent for PD prevention or therapy." ], "offsets": [ [ 0, 1446 ] ] } ]

[ { "id": "entity-299-0", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 90, 109 ] ], "normalized": [] }, { "id": "entity-299-1", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 111, 113 ] ], "normalized": [] }, { "id": "entity-299-2", "type": "DISEASE", "text": [ "progressive neurodegenerative disorder" ], "offsets": [ [ 120, 158 ] ], "normalized": [] }, { "id": "entity-299-3", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 253, 255 ] ], "normalized": [] }, { "id": "entity-299-4", "type": "DISEASE", "text": [ "depression" ], "offsets": [ [ 379, 389 ] ], "normalized": [] }, { "id": "entity-299-5", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 430, 432 ] ], "normalized": [] }, { "id": "entity-299-6", "type": "ADVERSE", "text": [ "cellular injury" ], "offsets": [ [ 574, 589 ] ], "normalized": [] }, { "id": "entity-299-7", "type": "ADVERSE", "text": [ "cellular injury" ], "offsets": [ [ 794, 809 ] ], "normalized": [] } ]

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